(12) Patent Application Publication (10) Pub. No.: US 2011/0268732 A1 Johanss0n (43) Pub

US 20110268732A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0268732 A1 Johanss0n (43) Pub. Date: Nov. 3, 2011

(54) METHODS OF IDENTIFYING CRITICALLY A6IP II/00 (2006.01) ILL PATIENTSAT INCREASED RISK OF A6IPI3/2 (2006.01) DEVELOPMENT OF ORGAN FAILURE AND A6IP 7/00 (2006.01) COMPOUNDS FOR THE TREATMENT A6IP 2L/00 (2006.01) HEREOF A6IPI/00 (2006.01) A6IP 9/04 (2006.01) (75) Inventor: Pair Johansson, Dosjebro (SE) A6IPL/8 (2006.01) A6IPL/I6 (2006.01) (73) Assignee: Thrombologic ApS. Copenhagen A6IP 9/00 (2006.01) (DK) A6IP 9/02 (2006.01) A6II 3/343 (2006.01)

(22) PCT Filed: Dec. 30, 2009 (52) U.S. Cl...... 424/133.1: 514/469 (86). PCT No.: PCT/DK09/50357 S371 (c)(1), (57) ABSTRACT (2), (4) Date: Jun. 30, 2011 The present invention relates to compounds for treatment that Related U.S. Application Data protects the endothelium, prevent pathologic thrombus for mation in the microcirculation and preserve platelet number (60) Provisional application No. 61/161,487, filed on Mar. and function and thus may be related to minimizing or pre 19, 2009. venting development of organ failure, including multiple organ failure (MOF), and, hence, death in critically ill patients (30) Foreign Application Priority Data by administration of agent(s) limiting the platelets ability to aggregate and form clots and/or by agents modulating/pre Dec. 30, 2008 (DK) ...... PA 2008 O1844 serving endothelial integrity and/or by agent(s) increasing the rate of thrombus lysis, and Another aspect of the invention Publication Classification related to by a cell-based whole blood viscoelastical haemo (51) Int. Cl. static assay identifying critically ill patients at increased risk A 6LX 39/395 (2006.01) of development of organ failure, including multiple organ A6IP 9/00 (2006.01) failure (MOF) and death.

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Patent Application Publication Nov. 3, 2011 Sheet 3 of 4 US 2011/0268732 A1

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METHODS OF DENTIFYING CRITICALLY sion of vessels and cell death, exemplified by acute myocar ILL PATIENTSAT INCREASED RISK OF dial infarction De Meyer et al. 2009). DEVELOPMENT OF ORGAN FAILURE AND 0006. In Intensive Care Unit (ICU) patients and especially COMPOUNDS FOR THE TREATMENT in sepsis, pathologic thrombus formation attributed to inflam HEREOF mation induced endothelial dysfunction and platelet activa tion is likely to be one of the main causes of morbidity and mortality. Thus, almost half of all patients with sepsis, major 0001 All patent and non-patent references cited in the trauma or other critical illness present with or develop throm application, or in the present application, are also hereby bocytopenia. In critically ill patients, thrombocytopenia upon incorporated by reference in their entirety. arrival to the intensive care unit (ICU), is common and is associated with increased mortality Moreau et al. 2009. FIELD OF THE INVENTION longer ICU stays, a higher incidence of bleeding events, greater transfusion requirements and regardless of the cause, 0002 The present invention relates to a novel use of com thrombocytopenia or declining platelet count is an indepen pounds that protect the endothelium, prevent pathologic dent predictor of multi organ failure (MOF) Nguyen and thrombus formation in the microcirculation and/or preserve Carcillo 2006 and ICU mortality Levi and Lowenberg platelet number and function in the circulation and thus may 2008. The pathogenesis of low or declining platelet count in be related to minimizing or preventing development of organ critically ill patients is multifactorial and involve e.g., bleed failure, including multiple organ failure (MOF), and, hence, ing, sepsis, thrombotic microangiopathy including dissemi death in critically ill patients by administration of agent(s) nated intravascular coagulation (DIC) and immune or drug limiting the platelets ability to aggregate and form clots and/ induced thrombocytopenia Nguyen and Carcillo 2006; Levi or by agents modulating/preserving endothelial integrity and/ and Lowenberg 2008. or by agent(s) increasing the rate of thrombus lysis, and 0007 Thrombocytopenia and a decline in platelet count methods of by a cell-based whole blood viscoelastical hae may reflect the same pathophysiologic disturbances seen in mostatic assay identifying critically ill patients at increased sepsis, disseminated intravascular coagulation (DIC), Vita risk of development of organ failure, including multiple organ min deficiencies, macrophage activation, drug-induced tox failure (MOF) and death. icity, liver disease, haematologic disorders, massive transfu sions, immune mediated thrombocytopenia and unidentified BACKGROUND OF THE INVENTION factors ref Moreau et al.2007. The increased mortality in critically patients with thrombocytopenia is complex and 0003 Platelets are anucleate fragments of megakaryocyte relates also in part to development of progressive organ fail cytoplasm. They are pivotal for haemostatic plug formation, ure accompanied by a decline in platelet count, thrombocy both by forming the initial thrombus at the site of vascular topenia associated multi organ failure (TAMOF). TAMOF is lesion and by providing template for coagulation protein a thrombotic microangiopathic syndrome that can be defined assembly with Subsequent thrombin generation resulting in by a spectrum of pathology that includes disseminated intra conversion of fibrinogen to fibrin which interacts with the vascular coagulation (DIC) and secondary thrombotic activated platelets through the GPIb/IIIa receptor forming microangiopathy (TMA) Nguyen and Carcillo 2006. the haemostatic clot Roberts et al. 2006 and by maintaining 0008. A common feature for TAMOF is the progressive vascular wall integrity Nachman and Rafi 2008 decline in platelet count related to systemic profound coagu 0004 Under physiologic conditions, platelet aggregation lation activation, down-regulation of both fibrinolysis and and haemostasis is prevented by the vascular endothelium. natural anticoagulants resulting in platelet consumption and The endothelium provides a physical barrier and secretes microvascular thrombus formation where the platelets play platelet inhibitory products, such as prostacycline (PGI2) and an integral role Nguyen and Carcillo. 2006. A non-exhaus nitric oxide (NO). These compounds regulate the adhesive tive list of conditions associated with TAMOF is presented in ness of platelets and the activation state of the platelet recep Table 1. tor GPIIb/IIIa in a paracrine way and also maintain the endot helium in a quiescent state through autocrine mechanisms TABLE 1 Zardi et al 2005. 0005 With endothelial activation or injury (trauma, criti Conditions associated with organ cal illness like sepsis, atherosclerosis), platelets adhere to the failure, including MOF and TAMOF endothelium or subendothelium, respectively. This adhesion Cancer activates platelets, causes a shape change and a release reac Transplantation (Solid organs, haematopoietic stem cells) tion where ADP is released (which is a potent platelet ago Cardiovascular Surgery cardiopulmonary bypass extracorporeal membrane oxygenation (ECMO) nist). The platelet membrane integrin receptor, GPIb/IIIa, Vascular Surgery becomes activated. Fibrinogen binds to this receptor, effec Autoimmune disease tively cross-linking platelets to form a platelet plug. During Systemic infection Vasculitis platelet activation, thromboxane A2 is formed from hydroly Exposure to toxins sis of phospholipids (especially phosphatidylcholine) in the Cyclosporine Atherapy platelet membrane. This is an important platelet agonist, FK506 therapy recruiting other platelets and activating them, thus promoting Chemotherapy further platelet aggregation. Thrombus formation is a prob Radiation Ticlopidine treatment lem in many clinical situations, mainly cardiovascular dis Hemolytic Uremic Syndrome variant syndromes. eases where platelets are also involved in atherothrombotic Trauma (e.g. polytrauma, neurotrauma, fat embolism) disease where they support development of thrombus forma tion on atherosclerotic plaques eventually resulting in occlu US 2011/0268732 A1 Nov. 3, 2011

0009. Non-exhaustive list of conditions associated with venous thrombosis (DVT), but this benefit did not extend to TAMOF-DIC is presented in Table 2. enhanced protection against pulmonary embolism (PE). Additionally, LMWH and UFH had similar bleeding out TABLE 2 comes and hence VTE prophylaxis with heparins is standard therapy in critically ill medical and Surgical patients, also in Clinical conditions that may be associated the ICU. It is recommended that, on admission to the ICU, all with disseminated intravascular coagulation patients are assessed for their risk of VTE, and that most Sepsis severe infection (any microorganism) receive thromboprophylaxis (Grade 1A) Kanaan et al. 2007, Malignancy Geerts et al. 2008. Myeloproliferative/lymphoproliferative malignancies 0022. Ad 2. Thrombin Inhibitors Solid tumors 0023 Direct thrombin inhibitors (DTIs) act as anticoagul Metastasis lants (delaying blood clotting) by directly inhibiting the Trauma (e.g. bluntipenetrating trauma, polytrauma, neurotrauma, fat embolism, burn trauma) enzyme thrombin. There are two types of DTIs, dependent on Obstetrical calamities their interaction with the thrombin molecule. Bivalent DTIs (hirudin and analogs) bind both to the active site and exosite Amniotic fluid embolism Abruptio placentae 1, while univalent DTIs bind only to the active site. Bivalent: Organ destruction (e.g. Severe pancreatitis) Hirudin, Bivalirudin, Lepirudin, Desirudin; Univalent: Arga Severe toxic or immunologic reactions troban, Melagatran, Dabigratan 0024 Ad 3. Antithrombin Snakebites Recreational drugs 0025 A Cochrane analysis included 20 randomized trials Transfusion reactions with a total of 3458 participants; 13 of these trials had high Transplant rejection (graft vs. host disease, host vs. graft disease) risk of bias. When combining all trials, AT III did not statis Vascular abnormalities tically significantly reduce overall mortality compared with Kasabach-Merritt syndrome the control group (RR 0.96, 95% CI 0.89 to 1.03; no hetero Large vascular aneuysms geneity between trials). A total of 32 Subgroup and sensitivity Severe hepatic failure analyses were carried out. Analyses based on risk of bias, Embolism different populations, and the role of adjuvant heparin gave insignificant differences. AT III reduced the multiorgan fail Thromboembolism Cholesterol embolism ure score among Survivors in an analysis involving very few Fat embolism patients. AT III increased bleeding events (RR 1.52, 95% CI Air embolism 1.30 to 1.78). ATIII therapy of critically ill patients is not Septic embolism Tissue embolism recommended Afshari et al. 2008. Foreign body embolism 0026. Ad 4. TFPI Amniotic fluid embolism 0027 Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis was evaluated in a randomized controlled trial (OPTIMIST) encompassing 0010 Standard treatment in the intensive care unit of criti 1754 patients. All cause mortality in the TFPI treated group cally ill patients with or without thrombocytopenia focuses was 34.2% vs. 33.9% in placebo treated patients, p=0.88. O Tifacogin administration was associated with an increase in 0011 1. Identification and specific treatment of the under risk of bleeding, irrespective of baseline INR and there is lying disorder causing the patients condition, and currently no indication for TFPI treatment of patients with 0012. 2. Support of vital organs in case of failure exempli severe sepsis Abraham et al. 2003. fied by ventilatory Support, haemodialysis, vasopressor treat 0028. Ad 5. Activated Protein C ment, parenteral nutrition, fluid Support, corticosteroids, tight (0029. The PROWESS study in patients with severe sepsis glycemic control, administration of blood products and oth was prematurely stopped at the second interim analysis ers generally referred to as intensive care management Bick because of a significant reduction in mortality in the APC R. 1996, Bick R. 1998). treated patients Bernard et al 2001. A total number of 1728 0013 Furthermore, the treatment may include attenuation patients were included and randomized in this study, of which of the procoagulant condition by Systemic administration of 1690 were eligible for analysis. Of these patients, 840 were agents which decrease enzymatic coagulation activation Such randomized to receive recombinant human APC at a dose of aS 24 mg/kg/h for 96 h, and 850 patients received placebo. 0014) 1. Heparins (low molecular weight heparin Mortality was 24.7% in the APC group as compared with (LMWH), unfractioned heparin (UFH)) 30.8% in the placebo group (relative risk reduction 19.4 per 00.15 2. Thrombin inhibitors centages, 95% confidence interval 6.6-30.5). The series of 0016 3. Antithrombin negative trials in specific populations of patients with severe 0017. 4. Tissue factor pathway inhibitor (TFPI) sepsis performed after the PROWESS study has added to the 0018, 5. Activated Protein C scepticism regarding the use of APC Marti-Carvajal et al. 0019 have been evaluated and especially in critically ill 2007). Furthermore, on the basis of the ADDRESS study, patients with severe sepsis which carries a high mortality treatment with APC seems not to be indicated in patients with (>50%). sepsis and a relatively low disease severity Levi M2008. No 0020 Ad 1. Heparins consensus regarding the use of APC in patients with severe 0021 Meta-analysis suggests that venous thromboembo sepsis exists today. lism (VTE) prophylaxis with an LMWH (including fonda 0030 Despite all these initiatives, many patients do not parinux) or UFH is effective in reducing the rate of deep achieve homeostasis, continue to bleed, become immunode US 2011/0268732 A1 Nov. 3, 2011

ficient, loose endothelial wall integrity (the endothelial wall endothelial activation, dysfunction and integrity loss and becomes activated), and/or develop MOF and/or TAMOF and immunodeficiency through compromised platelet function die. Thus, there remains a need for a method of treatment for on a per cell basis and through a general reduction in platelets critically ill patients; a method which may include treatment mass, all contributing to pathologies, exemplified by organ and/or prevention of development of organ failure Such as failure, in ICU patients. MOF and/or TAMOF, and/or arrest bleeding, and/or prevent 0042. As stated above, the inventors propose that thromb immunodeficiency, and/or preserving endothelial integrity in ocytopenia perse results in immunodeficiency through loss of critically/acutely ill patients and furthermore, there is a need platelet-mediated immune functions. Due to significant for a composition that may be used in this method. redundancy, the thrombocytopenia associated immunodefi ciency (TAID) may be aggravated when other limbs of the BRIEF DESCRIPTION OF DRAWINGS immune system are compromised, as in critically ill patients. 0031 FIG. 1: Recording haemostatic activity using TEG TAID in critical illness may thus in part explain the negative assay. predictive value of low or declining platelet count and the 0032 FIG. 2: MultiPlate continuously records platelet administration of the compounds, combinations of same and aggregation. The increase of impedance by the attachment of pharmaceutical compositions described herein may also be platelets onto the Multiplate sensors is transformed to arbi beneficial to this novel aspect of thrombocytopenia. trary aggregation units (AU) and plotted against time. 0043 Under physiologic conditions, platelet aggregation and haemostasis is prevented by the vascular endothelium. 0033 FIG. 3: Comparison of baseline TEG values with The endothelium provides a physical barrier and secretes samples obtained after 60- and 120 min of flolan infusion. platelet inhibitory products, such as prostacyclin (PGI2) and 0034 FIG. 4: Comparison of baseline Multiplate values nitric oxide (NO). These compounds regulate the adhesive with samples obtained after 60- and 120 min of flolan infu ness of platelets and the activation state of the platelet recep S1O. tor GPIIb/IIIa in a paracrine way and also maintain the endot helium in a quiescent state through autocrine mechanisms BRIEF DESCRIPTION OF THE INVENTION Zardi et al 2005. Without being bound by theory it is sug 0035) Surprisingly, the present inventors have found that gested that preservation of normal circulating platelet count the administration of a combination of a platelet inhibitor and may protect against bleeding alone through these paracrine at least one other compound, the at least one other compound mechanisms, despite concomitant direct inhibition of platelet being selected amongst a compound capable of modulating/ aggregation and clot formation Goerge et al. 2008. preserving the endothelial integrity, a compound capable of 0044) The present invention relates in a first aspect to augmenting the fibrinolytic activity, or a TAFIa inhibitor is pharmaceutical compositions comprising one or more of any beneficial in the treatment and/or prevention of organ failure, of the compounds mentioned herein below, such as one com wherein organ failure is defined as altered organ function in pound, such as at least two compounds, such as at least three an acutely ill patient. The patient may require medical inter compounds. When using more than one compound, the com vention to achieve homeostasis; and organ failure includes as pounds may be selected from the same group of compounds, used herein MOF and TAMOF, in at least one organ, such as or more preferably the at least two compounds may be in at least two, three, four or five organs. selected from different groups of compounds. Accordingly, in 0036 Furthermore, a combination of compounds that tar one embodiment one compound is a platelet inhibitor and the get both the platelets and endothelium to obtain a synergistic at least one other compound is a compound capable of modu effect of the compounds as compared to only targeting either lating/preserving the endothelial integrity, a compound the platelets or the endothelium is an aspect of the present capable of augmenting the fibrinolytic activity, or a TAFIa invention. Also, it is an aspect that by combining the treat inhibitor. In another embodiment, one compound is a com ments, a lower level/dosage of the compound(s) to be admin pound capable of modulating/preserving the endothelial istered may be required with the advantage of reduced risk of integrity and the at least one other compound is a compound possible adverse events. capable of augmenting the fibrinolytic activity, or a TAFIa 0037. The theory behind the current invention is that inhibitor. In a third embodiment one compound is a com thrombocytopenia and/or declining platelet count in critical pound capable of augmenting the fibrinolytic activity and the illness: at least one other compound is a TAFIa inhibitor. 0038 1. Is a consequence of enhanced platelet activa 0045 Preferably the one or more compounds area platelet tion, aggregation and thrombus formation in the inhibitor and a compound capable of modulating/preserving microvasculature and hence a strong marker of the endothelial integrity, more preferably an antithrombotic increased risk of microthrombi-ischemia-induced organ compound even more preferably a GPIb/IIIa inhibitor and failure and/or PGI2. 0039 2. Induces endothelial dysfunction through lack 0046. Another aspect of the invention relates to the use of of and/or dysregulated paracrine effects of platelets a pharmaceutical composition as described herein for treat released mediators on endothelial integrity and/or acti ment and/or prevention organ failure wherein organ failure is Vation state and/or defined as altered organ function in an acutely ill patient 0040. 3. Results in immunodeficiency through an inte requiring medical intervention to achieve homeostasis; organ grated effect of platelets on cells of the innate and adpa failure includes as used herein MOF and TAMOF, in at least tive immune system and hence on the inflammatory one organ, Such as in at least two, three, four or five organs. response. 0047 Still another aspect of the invention relates to the use 0041. The thrombocytopenia observed in many ICU of the pharmaceutical composition as described herein for patients is thus a marker and/or driver of profound dysregu prevention or treatment of organ failure wherein organ failure lation attributed to exaggerated microthrombi formation, is defined as altered organ function in an acutely ill patient US 2011/0268732 A1 Nov. 3, 2011

requiring medical intervention to achieve homeostasis; organ tion in an acutely ill patient requiring medical intervention to failure includes as used herein MOF and TAMOF, in at least achieve homeostasis; organ failure includes as used herein one organ, Such as in at least two, three, four or five organs MOF and TAMOF, in at least one organ, such as in at least wherein the organs are selected from the group consisting of two, three, four or five organs. cardiovascular, respiratory, renal, haematological, neurologi 0054. In a particular embodiment the organ failure is due cal, gastrointestinal and hepatic organs. to sepsis or due to malignant diseases such as Solid tumours, 0048. Another aspect of the invention relates to a compo haematological malignancies and metastatic tumours or the sition comprising one or more compounds selected from the systemic inflammatory response syndrome and compensa group consisting of platelet inhibitors, compounds capable of tory anti-inflammatory response syndrome, accompanying modulating/preserving the endothelial integrity, compounds trauma. capable of augmenting the fibrinolytic activity, or TAFIa 0055. In a further particular embodiment the organ or inhibitors for use in treatment and prevention of organ failure organs, which are Subject to failure are selected from the wherein organ failure is defined as altered organ function in group consisting of cardiovascular, respiratory, renal, haema an acutely ill patient requiring medical intervention to tological, neurological, gastrointestinal and hepatic organs, achieve homeostasis; organ failure includes as used herein Such as heart, liver, lungs, gut, kidneys, spleen, and brain. MOF and TAMOF, in at least one organ, such as in at least 0056. In a still further aspect the invention relates to a one two, three, four or five organs. or more compounds capable of modulating/preserving endot 0049. Another aspect of the invention relates to a compo helial integrity for prevention or treatment of organ failure sition comprising a platelet inhibitor and a compound capable wherein organ failure is defined as altered organ function in of modulating/preserving endothelial integrity for use in the an acutely ill patient requiring medical intervention to treatment and prevention of organ failure wherein organ fail achieve homeostasis; organ failure includes as used herein ure is defined as altered organ function in an acutely ill patient MOF and TAMOF, in at least one organ, such as in at least requiring medical intervention to achieve homeostasis; organ two, three, four or five organs. failure includes as used herein MOF and TAMOF, in at least 0057. A further aspect of the invention relates to a method one organ, Such as in at least two, three, four or five organs. of treating or preventing organ failure, including multi organ 0050. Another aspect of the invention relates to a compo failure, defined as altered organ function in an acutely ill sition comprising one or more compounds selected from the patient requiring medical intervention to achieve homeosta group consisting of platelet inhibitors, compounds capable of sis; organ failure includes as used herein MOF and TAMOF modulating/preserving the endothelial integrity, compounds comprising administering one or more compounds selected capable of augmenting the fibrinolytic activity, or TAFIa from the group consisting of platelet inhibitors, compounds inhibitors for use in treatment and prevention of organ failure capable of modulating/preserving the endothelial integrity, wherein organ failure is defined as altered organ function in compounds capable of augmenting the fibrinolytic activity, or an acutely ill patient requiring medical intervention to TAFIa inhibitors. achieve homeostasis; organ failure includes as used herein 0.058 Another aspect of the invention relates to the use of MOF and TAMOF, in at least one organ, such as in at least one or more compounds selected from the group consisting of two, three, four or five organs. platelet inhibitors, compounds capable of modulating/pre 0051 Yet another aspect of the invention relates to a com serving the endothelial integrity, compounds capable of aug position comprising a platelet inhibitor and a compound menting the fibrinolytic activity, or TAFIa inhibitors in the capable of modulating/preserving endothelial integrity for manufacture of a medicament for the treatment or prevention use in the treatment and prevention of organ failure wherein of organ failure, including multi organ failure, defined as organ failure is defined as altered organ function in an acutely altered organ function in an acutely ill patient requiring medi ill patient requiring medical intervention to achieve homeo cal intervention to achieve homeostasis; organ failure stasis; organ failure includes as used herein MOF and includes as used herein MOF and TAMOF. TAMOF, in at least one organ, Such as in at least two, three, four or five organs. 0059 Another aspect of the invention relates to a pharma 0052 Another aspect of the invention relates to a com ceutical composition for treating or preventing organ failure, pound as described herein or a composition as described including multi organ failure, defined as altered organ func herein for prevention or treatment of organ failure, wherein tion in an acutely ill patient requiring medical intervention to organ failure is defined as altered organ function in an acutely achieve homeostasis; organ failure includes as used herein ill patient requiring medical intervention to achieve homeo MOF and TAMOF comprising one or more compounds stasis; organ failure includes as used herein MOF and selected from the group consisting of plateletinhibitors, com TAMOF, in at least one organ, Such as in at least two, three, pounds capable of modulating/preserving the endothelial four or five organs, wherein the organ failure is due to sys integrity, compounds capable of augmenting the fibrinolytic temic inflammation or due to severe infections or due to activity, or TAFIa inhibitors as an active ingredient. sepsis or due to Systemic inflammatory response syndrome 0060. In another particular embodiment the organ failure (SIRS) and/or compensatory anti-inflammatory response is due to reperfusion injury following ischemia. syndrome CARS or due to coagulopathy or due to trauma 0061. In another aspect the invention relates to a com and/or burns or due to malignant diseases such as haemato pound capable of augmenting the fibrinolytic activity in logical malignancies, Solid tumours and metastatic tumours whole blood for prevention or treatment of organ failure, or due to ischemia or due to cardiovascular thromboembolic wherein organ failure is defined as microthrombosis in at least diseases or due to intoxication. one organ, Such as in at least two, three, four or five organs. 0053. In a further aspect the invention relates to one or 0062. In yet another aspect the invention relates to a more platelet inhibitors for prevention or treatment of organ thrombinactivatable fibrinolysis inhibitor (TAFI) an inhibitor failure wherein organ failure is defined as altered organ func for prevention or treatment of organ failure, wherein organ US 2011/0268732 A1 Nov. 3, 2011

failure is defined as microthrombosis in at least one organ, the administration of platelet inhibitors) will prohibit or Such as in at least two, three, four or five organs. reduce development of thrombus formation in the microvas 0063 A further aspect relates to the use of a combination culature and therefore reduce endothelial activation, will of compounds and/or compositions as herein described for increase, preserve and/or reduce the fall in the circulating treatment of critically ill patients by the preservation of plate platelet count and therefore improve endothelial integrity let count, whereby the patient suffers less risk of becoming and/or limit and/or avoid thrombocytopenia associated immunodeficient. 0064. Thus the use of the pharmaceutical composition as immunodeficiency and hence, limit and/or prevent develop herein disclosed for the preservation of platelet number and/ ment of organ failure including MOF. or function in a critically ill patient requiring medical inter 0075. Furthermore, interventions aiming at modulating/ vention to achieve homeostasis is also an aspect of the present preserving endothelial integrity (keeping the endothelium in invention. a quiescent inactivated anti-coagulant state, eg. by the admin 0065. Another aspect of the present invention relates to the istration of endothelial modulators) will reduce endothelial use of the compounds and/or compositions as herein activation and improve endothelial integrity and therefore described for immunostimulating purposes, the immuno prohibit and/or reduce development of thrombus formation in stimulation being direct and/or indirect. the microvasculature which will increase and/or preserve cir 0066. Yet another aspect of the invention relates to a culating platelet count and avoid thrombocytopenia associ method of diagnosing, monitoring or determining the likeli ated immunodeficiency and hence, limit and/or prevent hood ofa organ failure including multi organ failure (MOF) in development of organ failure including MOF. a critical ill human being, wherein said method is capable of identifying critical ill human beings who have a significantly 0076 Also, interventions aiming at increasing the fibrin increased risk of developing organ failure, including MOF. olysis (eg. the administration of pro-fibrinolytics) will reduce said method comprising the steps of clot stability through enhanced fibrinolysis and thereby 0067 i) determining at least one of the viscoelastical reduce or prohibit development of thrombus formation in the values R. Angle and MA by thromboelastography microvasculature and therefore, through the abovementioned (TEG) or equivalent parameters identified by throm effects on endothelial cells and immune function, limit and/or boelastometry in a whole blood sample from the human prevent development of organ failure including MOF. being critically ill, such as in a citrated whole blood 0077. In addition, interventions aiming at reducing the sample, Such as in a citrated whole blood sample acti activity of TAFIa (eg. the administration of TAFIa-inhibitors) vated by kaolin, such as in a citrated whole blood sample will reduce clot stability through enhanced fibrinolysis and activated by tissue factor, such as in a native whole blood thereby reduce or prohibit development of thrombus forma sample, such as a native whole blood sample activated tion in the microvasculature and therefore, through the above by kaolin, such as in a citrated whole blood sample mentioned effects on endothelial cells and immune function, activated by tissue factor limit and/or prevent development of organ failure, including 0068 ii) comparing said value with a predetermined MOF. cutoff value, said cutoff value being an equivalent to a 0078 Finally, interventions aiming at reducing/inhibiting cutoff value determined by TEG in a citrated whole the platelets ability to participate in the clot building process blood sample activated by kaolin wherein said cutoff (platelet inhibitors) and/or modulating/preserving endothe value is lial integrity (endothelial modulators) and/or increasing the 0069 a) R higher than 8.0 minutes, such as higher fibrinolytic activity (pro-fibrinolytics) and/or reducing the than 8.5 minutes, or lower than 4.0 minutes, such as activity of TAFIa (TAFIa-inhibitors) in any combination will lower than 3.0 minutes, reduce clot stability and thereby reduce or prohibit develop (0070 b) Angle lower than 55°, such as lower than ment of thrombus formation in the microvasculature and 52°, or higher than 78°, such as higher than 80°, and therefore, through the above mentioned effects on endothelial (0071 c)MA lowerthan 51 mm, such as lower than 50 cells and immune function, limit and/or prevent development mm, or higher than 69 mm, Such as higher than 72 mm of organ failure including MOF. wherein an R-value higher or lower than the cutoff value 0079 Accordingly, the present invention relates to com and/or an Angle-value higher or lower than the cutoff value pounds for a new treatment modality for critically ill patients, and/or a MA higher or lower than the cutoff value is indicative in particular patients having acquired or at increased risk of of a significantly increased risk of developing organ failure as development of organ failure, including MOF. Such as compared to a human being wherein neither R, Angle-value TAMOF or any condition associated with systemic inflam or MA is higher or lower than the cutoff value. mation. 0072 The method allows for the identification of critically 0080 Given the above mentioned association between ill patients with a significantly increased risk of development critical illness with imminent or manifest organ failure and organ failure, including MOF, and 30-day mortality earlier platelet activation and/or loss, endothelial activation and/or than conventional coagulation analyses exemplified by acti dysregulation and immunodeficiency and/or dysregulation, vated partial thromboplastin time (APTT), prothrombin time interventions that simultaneously (PT), platelet count and D-dimer. 0081 1. Modulate and/or preserve endothelial integrity 0073. Additional aspects of the present invention and par by keeping the endothelium in a quiescent inactivated ticular embodiments will be apparent from the description anti-coagulant state (endothelial modulators, described below, as well from the appended claims. herein below); and DETAILED DESCRIPTION OF THE INVENTION 0082 2. Reduce and/or inhibit the platelets ability to 0074 Interventions aiming at reducing/inhibiting the participate in the clot building process (platelet inhibi platelets ability to participate in the clot building process (eg. tors, described herein below); or US 2011/0268732 A1 Nov. 3, 2011

I0083. 3. Enhance fibrinolysis and thereby dissolve patients presenting either with a hypocoagulable TEG, already formed microthrombi or prevent formation of defined as a cut-off value wherein (when using Kaolin acti microthrombi in the microcirculation (pro-fibrinolyt vated citrated whole blood) a Rhigher than 8 minutes, such as ics); or 8.5 minutes or higher, and/or MA lower than 51 mm, such as I0084. 4. Inhibit thrombin-activatable fibrinolysis lower than 50 mm and/or Angle lower than 55°, such as lower inhibitor (TAFI)a and thereby enhance fibrinolysis than 52 or a hypercoagulable TEG defined as R lower than (TAFIa-inhibitors) 4.0 minutes, such as lowerthan 3.0 minutes, angle higher than should be used to prevent and/or cure imminent and/or mani 80°, and MA higher than 69 mm, such as higher than 72 mm. fest organ failure and/or serve to induce/preserve homeostasis 0090. Definitions in critically ill patients. These patients may have any condi 0091. The term “antiaggregatory” is intended to mean a tion associated with systemic inflammation (conditions Suit lower than normal ability of the platelets to interact in the clot able for the invention, described herein below). building process secondary to administration of compounds 0085. A further aspect relates to preserving/upholding the and/or variants that inhibit the platelets ability to aggregate platelet count and/or platelet function in a Subject/patient. Kawasaki et al 2007, Fries et al. 2006, Velik-Salchner et al. The patient may be a critically ill patient. Such a patient may 2007, Bassus et al. 2006, Tomokiyo et al. 2003. be in the need of medical intervention to achieve homeostasis. 0092. The term “antithrombotic” is also intended to mean By preserving the platelet count, the competency of the plate a lower than normal ability of the platelets to interact in the lets as immunocompetent cells is preserved and the immuno clot building process secondary to administration of com deficiency typically observed in patients and especially in pounds and/or variants that inhibit and/or decreases the plate critically ill patients is hereby avoided. By upholding or pre lets ability to aggregate and inhibit the platelets ability to form serving the platelet count is understood an action that aims at clots (thrombus formation). maintaining the platelet count within normal levels ie. a level 0093. The terms “antiaggregatory” and “antithrombotic' above a level defined as thrombocytopenic and below a level is used interchangeably and refers to the effect of compound indicative of thrombocytosis. Thus the level may be a level (s) that reduces the platelets ability to interact in the clot Such as in a healthy individual wherein a normal platelet building process and hence form thrombi. count ranges from 150,000 and 450,000 per mm (or microli 0094. The term “modulating/preserving endothelial integ tre) (150-450x109/L). These limits, however, are deter rity' is intended to mean pharmacological treatment aiming mined by the 2.5th lower and upper percentile, and a deviation at maintaining the endothelium in a quiescent inactivated does not necessary imply any form of disease nor alleviate the anti-coagulant state. Thus a “compound capable of modulat need for treatment as herein proposed. Administering the ing/preserving endothelial integrity is intended to mean any herein disclosed compounds or combinations/compositions compound that may assist in maintaining/inducing the endot comprising the same will have the effect of preserving the helium in a quiescent inactivated anti-coagulant state. platelet count in an individual in need hereof. As follows here (0095. The term “fibrinolytic activity” or fibrinolysis is from, the individual will thus be receiving an immunostimu intended to mean process wherein a fibrin clot, the product of lating treatment. The immunostimulating treatment will be by coagulation, is broken down. indirect immunostimulation as it regards the number/function 0096. The term “augmenting fibrinolytic activity” is of the platelets. intended to mean pharmacological treatment aiming at aug I0086. It is thus an object of the present invention that the menting the break down of fibrin clots. herein disclosed compounds, combinations hereof and com (0097. The term “hypocoagulability” used herein will positions comprising these compounds are for use in the reflect a slower initiation phase (increased R), and/or reduced treatment of immunodeficiency and/or thrombocytopenia thrombin burst (decreased Angle) and/or reduced clot and/or critical illness and/or for use as (indirect) immuno strength (reduced MA) as evaluated by TEG as compared to stimulating compounds/compositions. These compounds and the normal reference. compositions are to the preservation of platelet counts within (0098. The term “hypercoagulability” used herein will normal levels in Subjects in need there of. Such subjects reflect an increased coagulation activity in the initiation phase include Subjects Suffering from immunodeficiency and/or in (decreased R), and/or increased thrombin burst (increased need of immunostimulation and/or subjects Suffering from Angle) and/or increased clot strength (increased MA) as critical illness. evaluated by TEG as compared to the normal reference. 0087. It follows that the compound and compositions of (0099. The term “homeostasis” refers to the body’s ability the present invention may be used for immunotherapy, espe to regulate physiologically its inner environment to ensure its cially activating immunotherapy which is defined as treat stability. An inability to maintain homeostasis may lead to ment of a condition or a disease by inducing and/or enhancing death or a disease. an immune response. 0100. The term “Organ Failure' is altered organ function 0088. Therefore an object of the present invention relates in an acutely ill patient requiring medical intervention to to the use of the pharmaceutical compositions herein dis achieve homeostasis; organ failure includes as used herein closed for the preservation of platelet number and/or func Multi Organ Failure “MOF and Thrombocytopenia Associ tion. The recipient of the treatment may be a critically ill ated Multi Organ Failure “TAMOF. patient requiring medical intervention to achieve homeosta 0101. The term “MOF' (Multi Organ Failure) is altered S1S. organ function in an acutely ill patient requiring medical 0089. In a further aspect the present invention relates to a intervention to achieve homeostasis: MOF includes as used method of diagnosing critically ill patients at increased risk of herein TAMOF. MOF is also known as Multiple organ dys development of organ failure, including MOF. Such as function syndrome (MODS). TAMOF, employing a viscoelastical citrated whole blood 0102) The term “TAMOF' (Thrombocytopenia Associ assay, such as TEG analysis, upon arrival to the ICU, for those ated Multi Organ Failure) used herein will reflect any condi US 2011/0268732 A1 Nov. 3, 2011 tion affecting critically ill patients related to development of induced hypotension (<90 mmHg or a reduction of 240 multiorgan failure secondary to a pathological consumption mmHg from baseline) and diffuse intravascular coagulation, of platelets resulting in thrombus formation in the microcir among other things. culation either due to thrombotic microangiopathic disease or 0110. Examples of end-organ dysfunction include the fol secondary to disseminated intravascular coagulation or any lowing: other condition associated with a decline in platelet count 0.111 Lungs and/or function. 0112 acute lung injury (ALI) (PaC)/FiO<300) or (0103) The term “TAID” (thrombocytopenia associated acute respiratory distress syndrome (ARDS) (PaO/ immunodeficiency) used herein refers to a defective immu FiO<200) nologic competence and/or dysregulated inflammatory 0113 Brain response resulting in increased risk of acquiring an infection, 0114 encephalopathy dissemination of an established infection and/or excessive 0115 symptoms: dysregulated inflammation with accompanying increased 0116 agitation morbidity and mortality. 0117 confusion 0104. The term “critically ill, herein also acutely ill, is 0118 coma meant to include any condition rendering the patient in need 0119) etiologies: for intensive care therapy. Intensive care therapy may include 0120 ischemia but is not limited to induction of homeostasis, ventilation (eg. I0121 hemorrhage mechanical ventilation), haemodialysis, Vasopressor Support, 0.122 microthrombi fluid support, parenteral nutrition, administration of red blood (0123 microabscesses cell concentrates, fresh frozen plasma, platelet concentrates, 0.124 multifocal necrotizing leukoencephal whole blood, systemic antibiotic and/or antiviral and/or anti opathy fungal and/or antiprotozoic therapy, granulocyte infusion, T 012.5 Liver cell infusion, stem cell infusion, anticoagulant therapy 0.126 disruption of protein synthetic function: mani including but not limited to administration of activated pro fests acutely as progressive coagulopathy due to tein C and/or antithrombin and/or TFPI and/or heparins, inability to synthesize clotting factors including low molecular weight heparins, and/or thrombin I0127 disruption of metabolic functions: manifests as inhibitors, administration of corticosteroids, tight glycemic cessation of bilirubin metabolism, resulting in control. elevated unconjugated serumbilirubin levels (indirect 0105. A “subject' includes humans and other mammals, bilirubin) and thus the methods are applicable to both human therapy 0128 Kidney and Veterinary applications, in particular to human therapy. I0129 oliguria and anuria The term “mammal’ includes humans, non-human primates 0.130 electrolyte abnormalities (e.g. baboons, orangutans, monkeys), mice, pigs, cows, goats, 0131 volume overload cats, dogs, rabbits, rats, guinea pigs, hamsters, horse, mon (0132 Heart keys, sheep or other non-human mammal. 0.133 systolic and diastolic heart failure, likely due to 0106 “Treatment’, as used in this application, is intended cytokines that depress myocyte function to include both prevention of an expected development or 0.134 cellular damage, manifest as a troponin leak treatment of an established organ failure, including MOF. (although not necessarily ischemic in nature) Four classes of compounds are envisaged as beneficial for this 0.135 “SIRS' or systemic inflammatory response syn purpose: drome as used herein is intended to mean systemic inflam 0107 “Reperfusion injury” as used herein refers to dam mation in response to an insult without confirmed infectious age to tissue caused when blood Supply returns to the tissue process. When an infection is suspected or proven (by culture, after a period of ischemia. The absence of oxygen and nutri stain, or polymerase chain reaction (PCR)), together with ents from blood creates a condition in which the restoration of SIRS, this is per definition sepsis. Specific evidence for infec circulation results in inflammation and oxidative damage tion includes WBCs in normally sterile fluid (such as urine or through the induction of oxidative stress rather than restora cerebrospinal fluid (CSF), evidence of a perforated viscus tion of normal function. (free air on abdominal X-ray or CT scan, signs of acute peri 0108. The term "systemic inflammation' is altered organ tonitis), abnormal chest X-ray (CXR) consistent with pneu function in an acutely ill patient due to the nonspecific con monia (with focal opacification), or petechiae, purpura, or served response of the body (vasculature, immune system, purpura fulminans tissues) to infections, non-infectious antigens, trauma, burn, 0.136 “Trauma' as used herein is intended to mean any organ/tissue destruction/degeneration/damage, ischemia, body wound or shock produced by Sudden physical injury, as haemorrhage, intoxication, and/or malignancy. from accident, injury, or impact. 0109) “Sepsis as used herein is intended to refer to whole body inflammatory state (called a systemic inflammatory Embodiments response syndrome or SIRS) and the presence of a known or 0.137 As described herein above, a main aspect of the Suspected infection. Severe sepsis occurs when sepsis leads to invention relates to compounds for treatment that protects the organ dysfunction, low blood pressure (hypotension), or endothelium, prevent pathologic thrombus formation in the insufficient blood flow (hypoperfusion) to one or more organs microcirculation and preserve platelet number and function (causing, for example, lactic acidosis, decreased urine pro and thus may be related to minimizing or preventing devel duction, or altered mental status). Sepsis can lead to septic opment of organ failure, including multiple organ failure shock, multiple organ dysfunction syndrome/multiple organ (MOF), and, hence, death in critically ill patients by admin failure, and death. Organ dysfunction results from sepsis istration of compound(s) limiting the platelets ability to US 2011/0268732 A1 Nov. 3, 2011 aggregate and form clots and/or by agents modulating/pre cyclic petides, peptidomimetics inhibiting this receptor serving endothelial integrity and/or by agent(s) increasing the and the like, and mixtures hereof and other compounds. rate of thrombus lysis, and pharmaceutical compositions 0152. In a particular embodiment the compound comprising one or more of any of the compounds mentioned. inhibiting the platelet GPIb/IIIa receptor is adminis 0138 Said compounds are preferably antithrombotic tered together with a prostacyclin or a prostacyclin compounds and are more preferably selected from one or analog, see below. more of the groups described herein below. 0153. 2. Compounds inhibiting the platelet ADP recep 0139 Antithrombotic compounds tor (P2Y12) such as: AR-C69931 MX, Ticlopidine, Clo 0140) 1. Platelet inhibitors pidogrel, Prasugrel, AZD6140, cangrelor, ticagrelor and 0141 2. Agents modulating/preserving endothelial other compounds inhibiting this receptor. integrity 0154) In a particular embodiment the compound 0142. 3. Pro-fibrinolytic compounds inhibiting the platelet ADP receptor (P2Y12) is 0.143 4. Inhibitors against TAFIa administered together with a prostacyclin or a prosta 0144 Antithrombotic compounds belonging to the four cyclin analog, see below. different groups are disclosed below. It is envisaged that more 0155 3. Compounds inhibiting the platelet P2Y recep than one compound from each of the four classes may be tor such as: MRS2500, MRS2298, MRS2496, A2P5P, administered to a person in need thereof for the prevention or A3P5P, ATP, 2-MeSATP, and 2-CIATP. treatment of organ failure, including MOF, in particular 0156. In a particular embodiment the compound TAMOF in critically ill patients and patients with systemic inhibiting the platelet receptor (P2Y 1) is adminis inflammation. In a particular embodiment at least two com tered together with a prostacyclin or a prostacyclin pounds from at least two of the different classes listed above analog, see below. or one compound from one of the different classes listed 0157 4. Compounds inhibiting the platelet COX1 and/ above are administered to a person in need thereof for the or COX2 pathways such as prevention or treatment of critical illness, systemic inflam 0158 a. COX inhibitors which have the ability to mation, organ failure, including MOF, in particular TAMOF. inhibit as well COX1 as COX2, such as 0145. In the following, names of compounds of relevance 0159) i. Salicylates selected from the group con for the present invention are listed. Trade names covering any sisting of Acetylsalicylic acid (Aspirin), Amox of the herein mentioned compounds are also of relevance for iprin, Benorylate/Benorilate, Choline magnesium the present invention. salicylate. Diflunisal, Ethenzamide, Faislamine, 0146 Platelet Inhibitors Methyl salicylate, Magnesium salicylate, Salicyl 0147 Platelet inhibitors are compounds that interfere with Salicylate and Salicylamide: platelet activation (including adhesion, secretion), aggrega 0160 ii. Arylalkanoic acids selected from the tion and ultimate platelet-fibrin clot formation. Consequently, group consisting of Diclofenac, Aceclofenac, platelet activation including secretion of alpha, dense, lyso Acemethacin, Alclofenac, Bromfenac, Etodolac, Somal and other granules are reduced or inhibited. Also, expo Indomethacin, Nabumetone, Oxametacin, Proglu Sure of negatively charged phosphatidylserine on the platelet metacin, Sulindac and Tolimetin: surface is reduced or inhibited. Furthermore, activation of the 0161 iii. 2-Arylpropionic acids (profens) selected GPIb/IIIa receptor, being the final common pathway for from the group consisting of Ibuprofen, Almino activation by the thromboxane receptor, ADP receptor and profen, Benoxaprofen, Carprofen, Dexibuprofen, PAR receptors is prevented or limited. In addition, exposure Dexketoprofen, Fenbufen, Fenoprofen, Flunox several platelet receptors and/or molecules are reduced or aprofen, Flurbiprofen, Ibuproxam, Indoprofen, inhibited. Ketoprofen, Ketorolac, Loxoprofen, Naproxen, 0148 Any agent that reversibly or irreversibly reduces and Oxaprozin, Pirprofen, Suprofen and Tiaprofenic more preferably inhibits platelet activation/aggregation by acid; blocking sites on the platelet Surface or capable of intracel 0162 iv. N-Arylanthranilic acids (fenamic acids) lular inhibition can be used as the platelet inhibitor in the Selected from the group consisting of Mefenamic present invention. acid, Flufenamic acid, Meclofenamic acid and 0149 Platelet inhibitors according to present invention Tolfenamic acid; may include any agent that is intended to be used as an 0163 V. Pyrazolidine derivatives selected from the antithrombotic or antiaggregatory agent. Any agent that group consisting of PhenylbutaZone, Ampyrone, reversibly or irreversibly reduces and more preferably inhib AZapropaZone, ClofeZone, KebuZone, Metami its platelet activation/aggregation by blocking sites on the Zole, Mofebutazone, Oxyphenbutazone, platelet surface or capable of intracellular inhibition of path Phenazone and Sulfinpyrazone: ways that mediates platelet activation can be used as the 0164 vi. Oxicams selected from the group consist platelet inhibitor in the present invention. ing of PiroXicam, Droxicam, Lornoxicam, Meloxi 0150. A non-exhaustive list of examples of platelet inhibi cam and Tenoxicam, tors for the prevention or treatment of organ failure including (0165 b. COX inhibitors which are specific for inhi MOF and TAMOF in critically ill patients and/or patients bition of COX2 such as Celecoxib, Etoricoxib, with Systemic inflammation encompass the following: Lumiracoxib, Parecoxib, Rofecoxib, Valdecoxib, 0151. 1. Compounds inhibiting the platelet GPIb/IIIa Nimesulide, Licofelone and Omega-3 fatty acids. receptor such as: abciximab, eptifibatide, tirofiban, 0166 In a particular embodiment the compound orbofiban, xemilofiban, lamifiban, XJ757, DUP728, inhibiting COX is administered together with a pros XR299, linear or novel cyclic RGD peptide anlogs, tacyclin or a prostacyclin analog, see below US 2011/0268732 A1 Nov. 3, 2011

0.167 5. Compounds inhibiting thromboxane-synthase 0183 13. A compound of haemoglobin conjugated with (TX-synthase) Such as flavonoids and thromboxane polyethylene glycol, a compound that besides its platelet receptor (TP)-antagonists, such as SQ29548, Bay u inhibitory function also improves oxygenation of the 3405, or BM 13.177. microvasculature, such as but not exclusively MP40X 0.168. In a particular embodiment the compound (Hemospan, polyethylene glycol-hemoglobin com inhibiting thromboxane-synthase (TX-synthase) and/ plexes) or thromboxane receptor (TP)-antagonists is admin 0184. In a particular embodiment the hemoglobin istered together with a prostacyclin or a prostacyclin conjugated to PEG is administered together with a analog, see below. prostacyclin or a prostacyclin analog, see below. 0169. 6. Compounds inhibiting adenosine uptake in the 0185. 14. Antibodies and/or inhibitors of C-type lectin platelets such as dipyramidol, Persantin, Asasantin, like receptor 2 (CLEC-2) May et al 2009 AggrenoX and other compounds with a similar mode of 0186. In a particular embodiment the antibodies/in action. hibitors of CLEC-2 is administered together with a 0170 In a particular embodiment the compound prostacyclin or a prostacyclin analog, see below. inhibiting adenosine uptake in the platelets is admin 0187. 15. High-energy glycolitic metabolites like fruc istered together with a prostacyclin or a prostacyclin tose-1,6-bisphosphate (FBP) de Oliveira et all analog, see below. 0188 In a particular embodiment the FBP is admin 0171 7. Compounds inhibiting the platelet GPIb recep istered together with a prostacyclin or a prostacyclin tor, such as mABIb-23, mAB 6B4, R9alpha557 peptide, analog, see below. aurintricarboxylic acid (ATA), crotalin, agkistin, pep 0189 In a preferred embodiment the platelet inhibitor has tide (Trp-Ile-Arg-Arg-Pro-Phe-Phe-Pro-Phe) from a halftime of less than 3 hours (such as eptifibatide), prefer alpha B-crystallin. ably less than 2.5 hours (such as tirofiban), more preferably 0172. In a particular embodiment the compound less than 1 hour (such as abciximab). In a preferred embodi inhibiting the platelet GPIb receptor is administered ment a compound inhibiting the platelet GPIb/IIIa receptor together with a prostacyclin or a prostacyclin analog, is administered. Eptifibatide is an example of a most preferred see below. compound. (0173 8. Compounds inhibiting the platelet GPVI 0190. In another preferred embodiment the platelet inhibi receptor, such as EXP3179, triplatin-1 and -2, JAQ1, tor has a halftime of less than 12 hours (such as Ticlopidine), mAB 1OB12, mAB 1C3, mAb 12G1. preferably less than 8 hours (such as Clopidogrel), more 0.174. In a particular embodiment the compound preferably about 3-5 min (such as cangrelor). Another pref inhibiting the platelet GPVI receptor is administered erence is in the reversibility of the ADP receptor inhibition: together with a prostacyclin or a prostacyclin analog, Ticagrelor is an example of a compound that blocks the recep see below. tor in a reversible manner and Ticagrelor is for this reason 0.175 9. Compounds inhibiting the PAR receptors such preferable. Thus in an equally preferred embodiment a com as thrombin inhibitors, heterocycle-based peptide-mi pound inhibiting the platelet ADP receptor (P2Y 12) is admin imetic antagonists of PAR-1, RWJ-56110 and RWJ istered. 58259, SCH 79797, SCH203099, and PAR4 antagonists 0191 In regards to the half lives/halftimes of the herein such as trans-cinnamoyl-YPGKF-amide (tc-Y NH mentioned compounds: the halftime depends on the admin (2)) and palmitoyl-SGRRYGHALR-amide (P4pal10), istration form and/or the dosage. In general, intravenous PAR-2 antagonist ENMD-1068, PAR2 monoclonal anti administration is preferred. body SAM-11. 0.192 Agents Modulating/Preserving Endothelial Integ 0176). In a particular embodiment the compound rity inhibiting the PAR receptors is administered together 0193 The endothelium maintains under physiological with a prostacyclin or a prostacyclin analog, see conditions a normal vascular function by regulating the bal below. ance between vasodilator and vasoconstrictor mediators and (0177 10. Phosphodiesterase inhibitor PDE3 such as by regulating the expression of adhesion receptors. Endothe Cilostazol with therapeutic focus on increasing cAMP. lial modulators encompass any agent that affects the endot An increase in cAMP results in an increase in protein helium to either maintain or develop into a non-activated kinase A (PKA), which is directly related with an inhi quiescent state, which optimally preserves and ensures vas bition in platelet aggregation. cular integrity. In a state with vascular integrity, the endothe 0178. In a particular embodiment the Phosphodi lium exerts anti-inflammatory and anti-thrombotic properties esterase inhibitor is administered together with a down-regulating and counteracting platelet activation prostacyclin or a prostacyclin analog, see below. through the generation of PGI2 (prostaglandin I2, prostacy (0179 11. Nitroaspirin (NCX4016) an aspirin that can clin) and through the production of ADPase, the latter cata release NO. lyzing the degradation of ADP. Endothelial cells can also 0180. In a particular embodiment nitroaspirin is prevent the activation of the coagulation cascade by express administered together with a prostacyclin or a prosta ing Surface molecules with anticoagulant properties Such as cyclin analog, see below heparan Sulfate, dermatan Sulfate, tissue factor pathway 0181 12. A compound of albumin conjugated with inhibitor (TFPI), protein S (PS) and thrombomodulin (TM). polyethylene glycol (PEG). Endothelial cells express plasminogen, tissue-type plasmino 0182. In a particular embodiment the albumin conju gen activator (tPA), urokinase-type plasminogen activator gated with PEG inhibitor is administered together (uPA), urokinase-type plasminogen activator receptor with a prostacyclin or a prostacyclin analog, see (uPAR) as well as membrane-associated plasminogen activa below. tor binding sites, thus favouring the generation of plasmin, US 2011/0268732 A1 Nov. 3, 2011 10 and they express endothelial protein C receptor (EPCR), thine oxidase, PETN, Heparan sulfates (PI-88), heparan which enhances the anticoagulant activity. sulfate mimetics, Activators of oxidized/heme-free sGC 0194 The endothelial modulators may be selected from (BAY 58-2667), and Anti-PECAM/SOD. any of the classes of compounds (1-11) described below: 0202 7. Honokiol, a biphenyl neolignan isolated from 0.195 1. Compounds such as PGI2, PGX, prostacyclin Hou pu, the cortex of Magnolia officinalis. (Epoprostenol) or variants thereof. Such as beraprost 0203 8. Compounds that directly modulate endothelial Sodium, epoprostenol sodium, iloprost, iloprost in com barrier function through modulating effects on sphin bination with bosentan, iloprost in combination with gosine-1-phosphate (S1P)-receptors (eg.: FTY720, sildenafil citrate, treprostinil, pegylated treprostinil, tre AA-R, AAL-S, KRP-203, AUY954, CYM-5442, prostinil diethanolamine and treprostinil Sodium. Fur SEW2871, W146, W140, VPC44116, VPC23019, JTE ther compounds are 2-4-(5,6-diphenylpyrazin-2-yl) 013) Marsolais et al 2009. (isopropyl)aminobutoxy-N-(methylsulfonyl) 0204 9. Antibodies and/or other molecules against/an acetamide, {4-(5,6-diphenylpyrazin-2-yl)(isopropyl) tagonizing histones that through their inhibition dimin aminobutoxyacetic acid, 8-1,4,5-triphenyl-1H ishes histone-mediated endothelial damage and/or imidazol-2-yl-oxyoctanoic acid, isocarbacyclin, microthrombi formation and/or fibrin deposition Xu et cicaprost, 4-2-(1,1-Diphenylethylsulfanyl)-ethyl-3, all 2009. 4-dihydro-2H-benzo 1.4 oxazin-8-yloxy-acetic acid 0205 10. Compounds enhancing the natural anticoagul N-Methyl-d-glucamine, 7,8-dihydro-5-(2-(1-phenyl-1- lant pathways and hence protecting the endothelium pyrid-3-yl-methiminoxy)-ethyl)-a-naphthyloxyacetic such as but not exclusively: Protein C pathway (Acti acid, (5-(2-diphenylmethyl aminocarboxy)-ethyl)-a- vated protein C (APC, Drotrecogin alfa), protein C, naphthyloxyaceticacid, 2-3-2-(4,5-diphenyl-2-ox compounds that either mimics and/or protects from deg azolyl)ethylphenoxyacetic acid, 3-4-(4,5-diphenyl radation and/or enhances soluble thrombomodulin and/ 2-oxazolyl)-5-oxazolylphenoxyacetic acid, bosentan, or EPCR and/or protein S), Antithrombin III (ATIII) (or 17alpha, 20-dimethyl-DELTA6,6a-6a-carba PGI1, ATIII like compounds and/or compounds that enhance and 15-deoxy-16alpha-hydroxy-16 beta).20-dim ATIII function) and tissue factor pathway inhibitor ethyl-DELTA6,6a-6a-carba PGI1, pentoxifylline(1- (TFPI) (or TFPI compounds and/or compounds that {5-oxohexyl)-3,7-dimethylxanthine). enhance TFPI function). 0196. Trade names for prostacyclins include, but are 0206 11. Compounds that maintain and/or promote not limited to: flolan, remodulin, and Ventavis. Gfy function and/or signalling following endothelial 0.197 2. A combination of prostacyclin or a prostacyclin PAR activation to ensure reannealing of adherens junc analogue and endothelin receptor antagonist may tions opened following inflammatory PAR mediated improve the safety profile of prostacyclin therapy by activation of Ga Knezevic et al 2009 reducing potential side effects of prostacyclin Such as 0207 Various other potential target sites to modulate the jaw pain, headache and hypotension. endothelial function, activation state and integrity are given in 0198 3. Compounds with modulating/preserving Table 3, below. endothelial effects such as nitric oxide (also Endothe lium Derived Relaxing Factor) produced by healthy TABLE 3 endothelial cells induce vasodilatation and favours an anti-adhesive and anti-inflammatory phenotype of the Potential endothelial modulating target sites endothelium through a rise in cytosolic coMP Cines et Targets Compound all 1998: Zardi et al 2005. 1. Inhibition of Rho-kinase Fasudil (0199 4. CD39 and CD73 are vascular membrane Y-27632 bound ecto-nucleotidases expressed at the luminal Sur 2. Inhibition of PARP PJ-34 face of healthy endothelial cells. They hydrolyze extra INO 1001 cellular plasma ATP and ADP and thereby inhibit 3-Aminobenzamide 3. Inhibition of PTPase Bis(malotalo) oxovanadium nucleotide mediated platelet activation Atkinson et al 4. Activation of Akt Demethylasterriquinone 2006; Colgan et al 2006. In addition to platelet inhibi 5. Activation of PKA 8-Br-cAMP tion, soluble CD39 and CD73 agonists inhibit endothe 6. Inhibition of caveolin Daidzein lial cell apoptosis and activation Goepfert et al 2000 7. estrogen-receptor (ER) agonist 17-beta-Estradiol 8. Activation of and prevent hypoxia induced vascular leakage Thomp PPAR alpha Fibrates son et al 2004. PPARgamma Thiazolidinediones 0200 5. Compounds involved in redox control of endot PPAR delta GW Of242 9. Inhibition of CETP Torcetrapib helial functions such as: L-Arginine and tetrahydrobiop CET-1 vaccine terin, Antioxidants (AScorbate, Glutathione, C.-toco 10. Activation of lipoprotein lipase NO-1886 pherol, ubiquinol-10, Probucol), Iron chelators, and 11. Activation of S1P FTY720 Polyphenols. 12. Activation of transketolase Benfotiamine 13. Inhibition of GGT GGTI-298 0201 6. Clinical drugs involved in redox control of 14. Inhibition of epoxide hydrolase 1-Cyclohexyl-3-dodecylurea endothelial functions such as: HMG-CoA reductase N,N'-Dicyclohexylurea inhibitors (Fluvastatin, Lovastatin, Pravastatin, Simvas N,N'-Adamantanyl-N'-dodecanoic tatin), Angiotensin-receptor antagonists and ACE le:8 15. Activation of ACE 2 AVE O991 inhibitors (Captopril, Zofenopril, Enalapril, Ramipril, 16. Inhibition of JAK AG-490 Quinapril, Perindopril, Lisinopril, Benazepril, Fosino WHI-P154 pril, Casokinins, lactokinins), Peroxisome proliferator activated receptors (PPARs), NADPH oxidase, Xan US 2011/0268732 A1 Nov. 3, 2011

0208 Prostacyclin, a metabolite of arachidonic acid, is a capable of modulating/preserving the endothelial integrity, naturally occurring prostaglandin with potent vasodilatory compounds capable of augmenting the fibrinolytic activity, or activity and inhibitory activity of platelet aggregation, TAFIa inhibitors. released by healthy endothelial cells. Prostacyclin performs 0218. Thus the invention relates to any combination of any its function through a paracrine signalling cascade that of the classes of compounds mentioned above (platelet inhibi involves G protein-coupled receptors on nearby platelets and tors, endothelial modulators, pro-fibrinolytics, TAFIa-inhibi endothelial cells. In the clinical setting, Epoprostenol (pros tors). Such as one compound, such as at least two compounds, tacyclin analogue) has 2 major pharmacological actions: (1) Such as at least three compounds. When using more than one direct vasodilation of pulmonary and systemic arterial vascu compound the compounds may be selected from the same lar beds, and (2) inhibition of platelet aggregation. Epopros class of compounds, or more preferably the at least two com tenol is indicated for the long-term intravenous treatment of pounds may be selected from different classes of compounds. primary pulmonary hypertension and pulmonary hyperten 0219. Accordingly, in one embodiment one compound is sion associated with the Scleroderma spectrum of disease in selected from a compound capable of modulating/preserving NYHA Class III and Class IV patients who do not respond the endothelium (endothelial modulator) and the at least one adequately to conventional therapy. The antiaggregatory other compound is selected from a compound capable of effect of prostacyclin analogs on platelets is mediated by the inhibiting the platelets (platelet inhibitor), a compound Gas protein-coupled receptor (prostacyclin receptor, IP) that capable of increasing fibrinolysis either directly (pro-fibrin is activated upon prostacyclin analog binding. This activation olytics) or indirectly (TAFIa-inhibitors). signals adenylyl cyclase to produce cAMP, which in turn 0220. In another embodiment one compound is selected activates Protein Kinase A to decrease free intracellular cal from a compound capable of inhibiting the platelets (platelet cium concentrations. The rise in cAMP directly inhibits plate inhibitor) and the at least one other compound is selected let activation (secretion and aggregation) and counteracts from a compound capable of modulating/preserving the increases in cytosolic calcium resulting from platelet activa endothelium or increasing fibrinolysis directly (pro-fibrin tion by agonists such as thrombin, ADP, TXA2. PAF, collagen olytics) or indirectly (TAFIa-inhibitors). and 5-HT (Biharietal, 1988; Schereen etal, 1997: Xing etal 0221. In a third embodiment one compound is selected 2008. from a compound capable of directly enhancing fibrinolysis 0209. The modulating/preserving effect on endothelial (pro-fibrinolytics) and the at least one other compound is a integrity is mediated by binding of prostacyclin analog to TAFIa-inhibitor. endothelial prostacyclin receptors with ultimate rise in cyto 0222. Accordingly, combination treatment may include solic cAMP and Protein Kinase A activation. This leads to administration of any combination of one or more anti-throm Smooth muscle relaxation and vasodilatation with improved botic compounds, such as one or more of the following: microvascular perfusion and “cytoprotection' through stabi platelet inhibitors including but not limited to GPIb/IIIa lization of lysozomal and cell membranes with reduced inhibitors, ADP receptor inhibitors, P2Y1 inhibitors, COX1 inflammation. It also favours an anti-coagulant, anti-adhe and COX2 inhibitors, TX-synthase inhibitors, adenosine sive, anti-apoptotic and anti-inflammatory phenotype of the uptake inhibitors, GPIb inhibitors, GPVI inhibitors, PAR endothelium, less likely to support coagulation, leukocyte receptor inhibitors, phosphodiesterase inhibitors, nitroaspi adhesion/migration and inflammation Zardietal 2005; Zardi rin, albumin conjugated with polyethylene glycol, MP4OX, et al 2007. anti-CLEC-2 antibodies, FBP or similar compounds and/or 0210. In a preferred embodiment the compound capable of endothelial modulators including but not limited to PGI/ modulating/preserving the endothelial integrity has a half prostacyclin analogues and variants hereof, prostacyclin/ time of less than 4 hours (such as Treprostinil), preferably less prostacyclin analogue combined with endothelin receptor than 1 hours (such as Beraprost (35-40 min)), more preferably antagonists, NO, CD39, CD73, compounds involved in redox less than /2 hour (such as Iloprost (20-30 min)), preferably control, clinical drugs involved in redox control (HMG-CoA less than 5 min (such as Epoprostenol (0.5-3 min)) reductase inhibitors), Honokiol, compounds modulating 0211 Pro-Fibrinolytics S1P-receptors, antibodies and/or other molecules against/an 0212. Also denoted compounds capable of augmenting tagonizing histones, compounds enhancing/modulating the the fibrinolytic activity in whole blood. This group includes natural anticoagulant pathways Such as the protein C pathway compounds such as (t-PA, u-PA) or (rt-PA, ru-PA) such as: including but not limited to APC, PC, PS, STM, she PCR), Actilyse, Metalyse, Rapilysin, Streptase, Urokinase and ATIII pathway (ATIII), TFPI pathway (TFPI), G|By stimula other compounds containing t-PA and/or rt-PA, uPA, r-uPA. tors and/or any pro-fibrinolytics such as t-PA, u-PA, rt-PA, 0213 TAFIa Inhibitors ru-PA (Actilyse, Metalyse, Rapilysin, Streptase, Urokinase 0214. Also denoted compounds that inhibit thrombin-ac and other compounds containing t-PA and/or rt-PA, uPA, tivatable fibrinolysis inhibitor (TAFIa). Compounds included r-uPA and any TAFIa-inhibitors including but not limited to in this class are for example CPU-I, AZD9684, MERGETPA, CPU-I, AZD9684, MERGETPA, Compound 21 (UK-396, Compound 21 (UK-396,082) and other compounds with a 082) and other compounds with a similar effect. 0223 Thus, in preferred embodiments platelet inhibitor is similar effect. selected from the group consisting of abciximab, eptifibatide, 0215 Combinations tirofiban, orbofiban, xemilofiban, lamifiban, XJ757, DUP728 0216 Administration of combinations of the compounds and XR299 and the compound capable of modulating/pre discussed herein is also envisaged by the present invention as serving the endothelial integrity is selected from the group discussed above. consisting of PGI2, PGX, nitrogen oxide, CD39, CD73 and 0217. The invention relates to a pharmaceutical composi prostacyclin or variants thereof. Such as beraprost sodium, tion comprising one or more one or more compounds selected epoprostenol sodium, iloprost, iloprost in combination with from the group consisting of platelet inhibitors, compounds bosentan, iloprost in combination with sildenafil citrate, tre US 2011/0268732 A1 Nov. 3, 2011

prostinil, pegylated treprostinil, treprostinil diethanolamine (35-40 min)), more preferably less than /2 hour (such as and treprostinil sodium, 2-4-(5,6-diphenylpyrazin-2-yl) Iloprost (20-30 min)), preferably less than 5 min (such as (isopropyl)aminobutoxy-N-(methylsulfonyl)acetamide, Epoprostenol (0.5-3 min)) {4-(5,6-diphenylpyrazin-2-yl)(isopropyl)aminol 0227 Furthermore, the treatment may include administra butoxyacetic acid, 8-1,4,5-triphenyl-1H-imidazol-2-yl tion of one or more of the antithrombotic compounds men oxyoctanoic acid, isocarbacyclin, cicaprost, 4-2-(1,1- tioned above in combination with therapies including but not Diphenylethylsulfanyl)-ethyl-3,4-dihydro-2H-benzo 1.4 limited to plasma exchange or plasma infusion, and/or anti oxazin-8-yloxy-acetic acid N-Methyl-d-glucamine, 7.8- coagulation with heparins (such as UFH, LMWH), and/or dihydro-5-(2-(1-phenyl-1-pyrid-3-yl-methiminoxy)-ethyl)- antithrombin and/or activated protein C and/or TFPI and/or a-naphthyloxyacetic acid, (5-(2-diphenylmethyl coumadins and/or direct or indirect thrombin inhibitors and/ aminocarboxy)-ethyl)-a-naphthyloxyaceticacid, 2-3-2-(4. or direct or indirect factor Xa inhibitors. 0228. In particular a combination of platelet inhibitors and 5-diphenyl-2-oxazolylethylphenoxyacetic acid, 3-4-(4. compound capable of modulating/preserving endothelial 5-diphenyl-2-oxazolyl)-5-oxazolylphenoxyacetic acid, integrity is envisaged by the present invention, such as a bosentan, 17alpha 20-dimethyl-DELTA6,6a-6a-carba combination of a GPIb/IIIa platelet inhibitor and a prostacy PGI1, 15-deoxy-16alpha-hydroxy-16 beta).20-dimethyl clin, optionally further combined with other compounds. A DELTA6,6a-6a-carba PGI1 and pentoxifylline(1-(5-oxo preferred combination is GPIb/IIIa platelet inhibitor and a hexyl)-3,7-dimethylxanthine). prostacyclin further combined with endothelin receptor 0224. In another equally preferred embodiment the plate antagonists. let inhibitor is selected from the group consisting of AR 0229. Furthermore, the term “treatment “also includes C69931 MX, Ticlopidine, Clopidogrel, Prasugrel, AZD6140 administration of a fibrinolysis activator, Such as tissue plas and cangrelor, ticagrelor and the compound capable of modu minogen activator (tPA), urokinase plasminogen activator lating/preserving the endothelial integrity is selected from the (uPA) or variants hereofalone or in any combination of thera group consisting of PGI2, PGX, nitrogen oxide, CD39, CD73 pies including but not limited to antithrombotics and/or and prostacyclin or variants thereof. Such as beraprost endothelial modulators (such as prostacyclin, NO) and/or Sodium, epoprostenol sodium, iloprost, iloprost in combina plasma exchange, plasma infusion, and/or anticoagulation tion with bosentan, iloprost in combination with sildenafil with heparins (such as UFH, LMWH), and/or antithrombin citrate, treprostinil, pegylated treprostinil, treprostinil dietha and/or activated protein C and/or TFPI and/or coumadins nolamine and treprostinil sodium, 2-4-(5,6-diphe and/or direct or indirect thrombin inhibitors and/or direct or nylpyrazin-2-yl)(isopropyl)aminobutoxy-N-(methylsulfo indirect factor Xa inhibitors). nyl)acetamide, {4-(5,6-diphenylpyrazin-2-yl)(isopropyl) 0230. The compounds to be applied in the method of the present invention may be administered with at least one other aminobutoxyacetic acid, 8-1,4,5-triphenyl-1H-imidazol compound. The compounds may be administered simulta 2-yl-oxyoctanoic acid, isocarbacyclin, cicaprost, 4-2-(1,1- neously, either as separate formulations or combined in a unit Diphenylethylsulfanyl)-ethyl-3,4-dihydro-2H-benzo 1.4 dosage form, or administered sequentially. oxazin-8-yloxy-acetic acid N-Methyl-d-glucamine, 7.8- 0231. Dosages dihydro-5-(2-(1-phenyl-1-pyrid-3-yl-methiminoxy)-ethyl)- 0232. As used herein, "dose' shall mean any concentra a-naphthyloxyacetic acid, (5-(2-diphenylmethyl tion of the agents administered to the patient resulting in aminocarboxy)-ethyl)-a-naphthyloxyaceticacid, 2-3-2-(4. inhibition of the aggregating/clot forming properties of the 5-diphenyl-2-oxazolyl)ethylphenoxyacetic acid, 3-4-(4. platelets and/or maintaining the endothelium in a quiescent 5-diphenyl-2-oxazolyl)-5-oxazolylphenoxyacetic acid, state and/or a reduced resistance of the thrombus to fibrinoly bosentan, 17alpha 20-dimethyl-DELTA6,6a-6a-carba sis and/or preserving the platelet count and/or function. A PGI1, 15-deoxy-16alpha-hydroxy-16 beta).20 dose sufficient to produce the desired effect in relation to the dimethyl4DELTA6,6a-6a-carba PGI1 and pentoxifylline(1- conditions for which it is administered shall be described as {5-oxohexyl)-3,7-dimethylxanthine). the “effective dose’ or “effective amount. 0225. In other preferred embodiments the platelet inhibi 0233. As will be understood by the person skilled in the tor is capable of inhibiting the GPIb/IIIa receptor and has a art, amounts effective for this purpose will depend on the halftime of less than 3 hours (such as eptifibatide), preferably number and functionality of circulating platelets and endot less than 2.5 hours (such as tirofiban), more preferably less helial cells in the patient and the number of receptors on the than 1 hour (such as abciximab) and the compound capable of respective platelets and endothelial cells. modulating/preserving the endothelial integrity a halftime of 0234. The dosage requirements will vary with the particu less than has a halftime of less than 4 hours (such as Trepro lar drug composition employed, the route of administration stinil), preferably less than 1 hours (such as Beraprost (35-40 and the particular subject being treated. Ideally, a patient to be min)), more preferably less than /2 hour (such as Iloprost treated by the present method will receive a pharmaceutically (20-30 min)), preferably less than 5 min (such as Epopros effective amount of the compound in the maximum tolerated tenol (0.5-3 min)). dose, generally no higher than that required before drug resis 0226. In other preferred embodiments the platelet inhibi tance develops. tor is capable of inhibiting platelet ADP receptor P2Y12 and 0235 Administration of the compounds and/or composi has a halftime of 12 hours (such as Ticlopidine), preferably tions of the present invention are to be given to a subject less than 8 hours (such as Clopidogrel), more preferably resulting in a systemic concentration of the compounds. about 3-5 min (Such as cangrelor) and the compound capable Methods of administration include enteral, such as oral, Sub of modulating/preserving the endothelial integrity a halftime lingual, gastric or rectal and/or parenterally, that is by intra of less than has a half time of less than 4 hours (such as venous, intraarterial, intramuscular, Subcutaneous, intrana Treprostinil), preferably less than 1 hours (such as Beraprost sal, intrapulmonary, intrarectal, intravaginal or US 2011/0268732 A1 Nov. 3, 2011

intraperitoneal administration. The Subcutaneous and intra mined quantity of a compound, alone or in combination with venous forms of parenteral administration are generally pre other agents, calculated in an amount Sufficient to produce the ferred. Appropriate dosage forms for Such administration desired effect in association with a pharmaceutically accept may be prepared by conventional techniques. The compounds able diluent, carrier, or vehicle. The specifications for the unit may also be administered by inhalation that is by intranasal dosage forms of the present invention depend on the particu and oral inhalation administration. Appropriate dosage forms lar compound or compounds employed and the effect to be for Such administration, Such as an aerosol formulation or a achieved, as well as the pharmacodynamics associated with metered dose inhaler, may be prepared by conventional tech niques. each compound in the host 0236. The compounds according to the invention may be 0243 It is an object of the present invention that the com administered with at least one other compound. The com pounds and/or compositions herein disclosed are adminis pounds may be administered simultaneously, either as sepa tered systemically. It is also an object of the present invention rate formulations or combined in a unit dosage form, or that the compounds are administered parenterally, preferably administered sequentially. intravenously and/or intrarterially. 0237 Normally the dose should be capable of preventing 0244 Pharmaceutical Compositions of the Invention and or lessening the severity or spread of the condition or indica its Use tion being treated. The exact dose will depend on the circum 0245. The present invention also relates to a pharmaceu stances, such as the condition being treated, the administra tical composition comprising any combination of any of the tion schedule, whether the compounds are administered alone compounds mentioned above (platelet inhibitors, endothelial or in conjunction with another therapeutic agent, the plasma modulators, pro-fibrinolytics, TAFIa-inhibitors), such as one half-life of the compounds and the general health of the compound, Such as at least two compounds, such as at least Subject. three compounds and one or more pharmaceutically accept 0238. The compounds disclosed herein are generally well able carriers or excipients. Such pharmaceutically acceptable known to a person skilled in the art and the appropriate carrier or excipient as well as Suitable pharmaceutical formu dosages for their use are disclosed in pharmacopeias, phar lation methods are well known in the art (see for example maceutical handbooks, and patient information leaflets. Thus Remington's Pharmaceutical Sciences, 18th ed., Mack Pub the compounds of the present invention may be administered lishing Company, Easton, Pa. (1990). In a preferred embodi in the dosages recommended by the manufacturers or as are ment the platelet inhibiting/endothelial protecting variants known to be efficient to those skilled in the art, i.e. medical are prepared in a parenteral composition. Such methods for practitioners. preparing parenterally administrable compositions will also 0239. As will be understood by the person skilled in the be known or apparent to those skilled in the art and are art, amounts effective for this purpose will depend on the described in more detail in, for example, Remington's Phar severity of the disease or injury as well as the weight and maceutical Sciences, 18th ed., Mack Publishing Company, general state of the subject. The dose is preferably given by Easton, Pa. (1990). As used herein, the term “pharmaceutical the parenteral administration route, notably the intravenous, acceptable” means carriers or excipients that does not cause intraarterial, intramuscular and/or the Subcutaneous, Sublin any untoward effects in Subjects to whom it is administered. gual, trans-mucosal, intrapulmonal and intra-alveolar route. 0246 The compositions for parenteral administration 0240. The dosages given in the following is contemplated comprise the plateletantiaggregatory agents of the invention to be in the same order of magnitude irrespective of the in combination with, preferably dissolved in, a pharmaceuti parenteral administration route. cally acceptable carrier, preferably an aqueous carrier. A vari 0241. For all methods of use disclosed herein for the com ety of aqueous carriers may be used. Such as water, buffered pounds, the daily parenteral dosage regimen about 0.001 to water, saline e.g. such as 0.7%, 0.8%, 0.9% or 1%, glycine about 80 mg/kg of total body weight. The daily oral dosage such as 0.2%, 0.3%, 0.4% or 0.5% and the like. Normally, it regimen will preferably be from about 0.01 to about 80 mg/kg is aimed that the composition has an osmotic pressure corre of total body weight. The daily topical dosage regimen will sponding to a 0.9% w/w sodium chloride solution in water. preferably be from 0.1 mg to 150 mg, administered one to Moreover, as known by a person skilled in the art, dependent four, preferably two or three times daily. The daily inhalation on the specific administration route, pH may be adjusted dosage regimen will preferably be from about 0.01 mg/kg to within suitable ranges centred around pH 7.4. The composi about 1 mg/kg per day. It will also be recognized by one of tions may be sterilised by conventional, well-known sterili skill in the art that the optimal quantity and spacing of indi sation techniques. The resulting aqueous Solutions may be vidual dosages of a compound or a pharmaceutically accept packaged for use or filtered under aseptic conditions and able salt thereof will be determined by the nature and extent of lyophilised, the lyophilised preparation being combined with the condition being treated, the form, route and site of admin a sterile aqueous Solution prior to administration. istration, and the particular patient being treated, and that 0247 The compositions may contain pharmaceutically Such optimums can be determined by conventional tech acceptable auxiliary Substances as required to approximate niques. It will also be appreciated by one of skill in the art that physiological conditions, such as pH adjusting and buffering the optimal course of treatment, i.e., the number of doses of a agents, stabilizing agents, preservatives, non-ionic Surfac compound or a pharmaceutically acceptable salt thereof tants or detergents, antioxidants, tonicity adjusting agents and given per day for a defined number of days, can be ascertained the like, for example, Sodium acetate, sodium lactate, sodium by those skilled in the art using conventional course of treat chloride, potassium chloride, calcium chloride, etc. ment determination tests. 0248. The main routes of drug delivery, in the treatment 0242. The term “unit dosage form as used herein refers to method are intravenous, oral, and topical, as will be described physically discrete units Suitable as unitary dosages for below. Other drug-administration methods, such as Subcuta human and animal Subjects, each unit containing a predeter neous injection or via inhalation, which are effective to US 2011/0268732 A1 Nov. 3, 2011

deliver the drug to a target site or to introduce the drug into the bloodstream, are also contemplated. TABLE 5 0249 Compounds of the invention may be administered parenterally, that is by intravenous, intramuscular, Subcuta Non-exclusive list of conditions and/or diseases associated neous intranasal, intrarectal, intravaginal or intraperitoneal with systemic inflammation, according to medical speciality administration. Appropriate dosage forms for Such adminis and/or anatomical localization, Suitable for prophylaxis tration may be prepared by conventional techniques. The and/or treatment by compounds of the invention. compounds may also be administered by inhalation that is by Conditions and/or diseases intranasal and oral inhalation administration. Appropriate associated with systemic Medical speciality and/or dosage forms for Such administration, Such as an aerosol inflammation anatomical localization formulation or a metered dose inhaler, may be prepared by The following SIRS, compensatory anti-inflammatory conventional techniques. manifestations response syndrome (CARS), shock, organ 0250. The compounds are preferably administered intra whatever their cause failure, MOF, DIC, coagulopathy Microthrombi?emboli? occlusion venously and/or intraalveolar and it may be administered by (imminent, Suspected, manifest) in one continuous or pulsatile infusion or as a bolus. or more organs 0251. The compounds to be applied in the method of the Severe infections caused by Sepsis, severe sepsis, Septic shock, organ any microorganism including failure, MOF, DIC present invention may be administered with at least one other Necrotisizing fasciitis compound. The compounds may be administered simulta Surgery, trauma and/or SIRS, compensatory anti-inflammatory neously, either as separate formulations or combined in a unit burns including response syndrome, Shock, tissue dosage form, or administered sequentially. It is thus also hypoperfusion, base deficit, lactate acidosis, MOF, DIC, coagulopathy contemplated that one compound may be administered intra (hypercoagulability, hypocoagulability, venously for example in combination with another compound hyperfibrinolysis) that is administered orally. Malignant diseases and Solid tumours, haematological 0252 Clinical Indications chemotherapeutic? malignancies, metastatic tumours 0253) As described herein above the present invention immunosuppressive Chemotherapy (Alkylating agents (LO1A) treatinent examplified by Cisplatin, carboplatin and relates to treatment and/or prevention of organ failure, oxaloplatin: Anti-metabolites (LO1B) wherein organ failure is defined as altered organ function in a masquerade as purine (azathioprine, critically ill patient requiring medical intervention to achieve mercaptopurine)) or pyrimidine: Plant alkaloids and terpenoids (LO1C) as homeostasis. Organ failure includes as used herein MOF and examplified by Vincristine, Vinblastine, TAMOF, in at least one organ, such as in at least two, three, Vinorelbine, Vindesine, Podophyllotoxin. four or five organs. Taxanes (LO1CD), Taxol, Docetaxel. 0254 Furthermore, the compounds and/or pharmaceuti Topoisomerase inhibitors (LO1CB and L01XX) topotecan, irinotecan, amsacrine, cal compositions described herein are also Suitable for pro etoposide, etoposide phosphate, phylaxis, reduction and/or treatment of any conditions and/or teniposide. Antitumour antibiotics (L01D) diseases associated with systemic inflammation (low-grade dactinomycin, doxorubicin, epirubicin, as well as high-grade) and/or enhanced platelet and/or endot bleomycin. helial activation and/or dysregulation are Suitable for prophy Monoclonal antibodies such as trastuzumab, cetuximab, rituximab, laxis and/or treatment with compounds of the invention. Bevacizumab Irradiation and/or irradiation therapy TABLE 4 (Conventional external beam radiotherapy, Virtual simulation, 3-dimensional Non-exclusive list of conditions associated with systemic conformal radiotherapy, and intensity inflammation, according to pathology, Suitable for prophylaxis modulated radiotherapy, Radioisotope and/or treatment by compounds of the invention. Therapy (RIT)) Transplantation and their Solid organs (heart, lungs, liver, kidneys, Condition Pathology complications pancreas, intestines or any combination hereof), allogenic or autologous Infections Any microorganism (bacteria (intra-, haematopoietic stem cells, bone marrow, extracellular, myco-), virus, fungi, T-cells, B-cells parasites, prions) Graft versus host disease (acute, chronic), Non-infectious antigens Organistem cell transplantation, blood graft rejection (host vs. graft) transfusion, biological drugs Extracorporeal circulation, Cardiopulmonary bypass, ECMO, Trauma Blunt, penetrating trauma, polytrauma, vascular prosthesis and/or ventricular assist devices, non-biologic neurotrauma, minor, major apheresis treatment valvular prosthesis, vascular prosthesis Burns freeze burns (biological, non-biological) in any Organtissue Pancreatitis location in the human organism destruction degeneration damage Irradiation Plasmapheresis, leukapheresis, dialysis, Ischemia Atherosclerosis, thrombi, emboli renal replacement therapy (cholesterol, fat, air, septic, tissue, Toxins Spider, Snake, Scorpion, jellyfish, wasp, foreign body, amniotic fluid), trauma, bee, poison dart frog, honeybee, vascular occlusion, vasculitis, Cyanotoxins, Pitvipers, such as aneurysms, severe anemia rattlesnakes Haemorrhage Neurological diseases Degenerative diseases (Parkinson's Intoxication Alcohol, recreational drugs, iatrogenic disease, Alzheimer's disease), Stroke, (chemotherapy, overdose, interaction, Neurotrauma (brain, spinal cord), Seizure adverse event), Snakefinsect bites disorders (epilepsy), Malignancies Malignancy Myeloproliferative/lymphoproliferative (brain spinal cord tumors), Infections malignancies, Solid tumors (meningitis, encephalitis) metastasis Cardiovascular diseases Angina, Atherosclerosis, Cardiomyopathy, Congestive heart failure, Coronary artery US 2011/0268732 A1 Nov. 3, 2011 15

TABLE 5-continued TABLE 5-continued

Non-exclusive list of conditions and/or diseases associated Non-exclusive list of conditions and/or diseases associated with systemic inflammation, according to medical speciality with systemic inflammation, according to medical speciality and/or anatomical localization, Suitable for prophylaxis and/or anatomical localization, Suitable for prophylaxis and/or treatment by compounds of the invention. and/or treatment by compounds of the invention. Conditions and/or diseases Conditions and/or diseases associated with systemic Medical speciality and/or associated with systemic Medical speciality and/or inflammation anatomical localization inflammation anatomical localization disease, Carotid artery disease, Orthopedic diseases Trauma, Surgery, Fractures, Malignancies Endocarditis, Heart attack (coronary of bone, cartilage and soft tissues thrombosis, myocardial infarction), including Multiple Myeloma, Arthritis Hypertension, (Osteoarthritis, Rheumatoid arthritis), Hypercholesterolemia hyperlipidemia, Cerebral Palsy, Osteonecrosis, Gout, Peripheral artery disease, Stroke infections, Myasthenia, Osteoporosis, Respiratory diseases Asthma, Bronchitis, Emphysema, Chronic Pagets disease, Spondylitis obstructive pulmonary disease, Infections Haematological diseases Malignant (Leukaemia, Myelodysplastic (exemplified by influenza, pneumonia and syndrome) tuberculosis), Malignancies (Lung cancer), Non-malignant (Thrombotic Sarcoidosis, Pleurisy hrombocytopenic purpura, haemolytic Gastrointestinal diseases Inflammatory bowel diseases (Colitis uraemic syndrome, aplastic anaemia, ulcerosa, Mb Crohn's disease) Hemophagocytic Lymphohistiocytosis) Hepatic diseases Alcoholic liver disease, Infectious diseases caused infections caused by any microorganism in Cholangiocarcinoma, Hepatitis, Hepatic by any microorganism he cardiovascular, respiratory, renal, encephalopathy, Hepatic failure, Liver exemplified by bacteria haematological, neurological, abscess, Malignantibenign liver tumours, (intra-, extracellular, myco-), gastrointestinal, hepatic and Liver cirrhosis, Liver coagulopathy, virus, fungi, parasites, musculoskeletal organs, such as heart, Glycogen storage diseases, Portal prions) vessels, microvasculature, lungs, kidney, hypertension, Primary biliary cirrhosis, bone marrow, brain, gut, pancreas, liver, Primary sclerosing cholangitis bones, joints and muscles Renal diseases Acuteichronic kidney failure, Acute Endocarditis, Meningitis, Encephalitis, nephritic syndrome, Atheroembolic renal Diarrhea, Hepatitis, Urinary Tract disease, Chronic nephritis, Nephrotic infections, Intra-Abdominal Infections, syndrome, End-stage renal disease, Pneumonia, Pharyngitis, Joint Infections, Goodpasture syndrome, Interstitia Skin and SoftTissue infections nephritis, Kidney Allergic diseases Anaphylaxis, asthma, eosinophil cancer damage infection injury stones, esophagitis, food allergy, urticaria, insect Lupus nephritis, Glomerulonephritis, sting allergy, rhinitis, sinusitis, Membranous nephropathy, immunodeficiency, mastocytosis Nephroblastoma, Nephrocalcinosis, Immunologic/rheumatologic Systemic autoimmune diseases Nephrogenic diabetes insipidus, diseases (Rheumatoid arthritis (juvenile and/or Nephropathy - IgA, Polycystic kidney adult form), systemic lupus erythro disease, Reflux nephropathy, Renal matosis, Sclerodermia, antiphospholipid papillary necrosis, Renal tubular acidosis antibody syndrome, polymyositis, mixed Endocrine diseases Adrenal disorders (Adrenal insufficiency, connective tissue disease), Sjögrens Addison's disease, Mineralocorticoid syndrome, Fibromyalgia), Sarcoidosis, deficiency, Conn's syndrome, Cushings Vasculitis (Behcet's Disease, Buerger's syndrome, Pheochromocytoma, Disease, Central Nervous System Adrenocortical carcinoma) Vasculitis, Churg-Strauss Syndrome, Glucose homeostasis disorders (Diabetes Cryoglobulinemia, Giant Cell Arteritis, mellitus, Hypoglycemia, Idiopathic Henoch-Schönlein Purpura, Microscopic hypoglycemia, Insulinoma) Polyangiitis, Polyarteritis Nodosa, Metabolic bone disease Polymyalgia Rheumatica, Rheumatoid Pituitary gland disorders (Diabetes Vasculitis, Takayasu's Arteritis, insipidus, Hypopituitarism (or Wegener's Granulomatosis) Panhypopituitarism), Inherited disorders Pituitary tumors, Hyperprolactinemia, Any identified and/or Acromegaly, gigantism, Cushing's disease Suspected genetic defects Parathyroid gland disorders accompanied with disease (Primary/Secondary Tertiary hyperparathyroidism, Hypoparathyroidism, 0255 Accordingly, in one embodiment the present inven Pseudohypoparathyroidism) tion relates to a method of treating a critically ill patient, Menstrual function or fertility disorders wherein said patient is at increased risk of acquiring organ (Polycystic ovary syndrome) failure as defined above by administering one or more com Thyroid disorders (Goiter, pounds as discussed above belonging to one or more of the Hyperthyroidism and Graves classes: Basedow disease, Hypothyroidism, Thyroiditis, Thyroid cancer, Tumours 0256 1. Platelet inhibitors of the endocrine glands, Multiple 0257 2. Agents modulating/preserving endothelial endocrine neoplasia, Autoimmune integrity polyendocrine syndromes) 0258. 3. Pro-fibrinolytic compounds Gynaecologic obstetric Obstetric complications (Preeclampsia, 0259 4. Inhibitors against TAFIa diseases eclampsia, HELLP syndrome, amniotic 0260 Optionally combined with further compounds. fluid embolism, abruptio placentae) 0261 The increased risk of organ failure may be judged by the clinical appearance of the patient and/or standard labora US 2011/0268732 A1 Nov. 3, 2011

tory tests. Furthermore, the critically ill patient may addition 0269. Identification of Critically Ill Patients Using TEG ally be evaluated by TEG/ROTEM as described herein below 0270. Another aspect of the present invention relates to the as being at risk of acquiring organ failure as discussed above. identification of critically ill patients using TEG. In particular if the critically ill patient is diagnosed as being 0271 Identification of critically ill patients with the high hypocoagulable or hypercoagulable, such as when evaluated est risk of multiorgan failure (MOF) and treatment of these by TEG/ROTEM, the patient is considered at increased risk of with interventions that protects the endothelium, prevent acquiring organ failure. pathologic thrombus formation in the microcirculation and preserve platelet number and function may protect these criti 0262 The patient may be critically ill due to a variety of cally ill patients against development of MOF, bleeding and diseases and conditions, and a non-exhaustive list of clinical immunodeficiency. Importantly, the notion that the preven conditions associated with Systemic inflammation and hence tion of thrombocytopenia and/or preservation of circulating increased risk of organ failure is presented above in Tables 4 platelet number and function may be a tool to avoid MOF and and 5. immunodeficiency is a shift in the paradigm and based on the 0263. In one embodiment, the invention thus relates to emerging role of platelets in the host defence and the inflam administration of a compound inhibiting any of the platelet matory response where they contribute directly to clear infec receptors and/or intracellular pathways mediating platelet tions and cooperate with and coordinate the function of clas activation, alone or in combination with endothelial modula sical immune cells. tors and/or pro-fibrinolytics and/or TAFIa-inhibitors, as out 0272. The introduction of the cell based model of haemo lined above for the treatment or prophylaxis of systemic Stasis has emphasized the pivotal role of platelets and the inflammation and/or organ failure in patients with any of the kinetics of thrombin generation for clot development and disorders described in tables 4 and 5. stability. Together with the finding that the results of the TEG analysis correlate with the individuals ability to generate 0264. In yet another embodiment, the invention thus thrombin an increased interest in this whole blood analysis relates to administration of a compound modulating the vas has revived Ganter et al. 2008. The TEG method is cular endothelium through any of the endothelial receptors described below. and/or intracellular pathways mediating endothelial activa 0273 Viscoelastical Citrated Whole Blood Haemostasis tion, alone or in combination with platelet inhibitors and/or Assay: Thrombelastoqraphy (TEG) or Thrombelastometry pro-fibrinolytics and/or TAFIa-inhibitors, as outlined above (ROTEM) for the treatment or prophylaxis of systemic inflammation (0274 The TEG in vitro assay is suitable for determining and/or organ failure in patients with any of the disorders important parameters in the clotting activity and clotstrength. described in tables 4 and 5. The TEG system's approach to monitoring patient haemosta 0265. In another embodiment, the invention thus relates to sis is based on the premise that the end result of the haemo administration of a compound enhancing and/or modulating static process is the clot. The clot's physical properties deter fibrinolysis through any of the pathways described above, mine whether the patient will have normal hemostasis, or will alone or in combination with TAFIa-inhibitors, as outlined be at increased risk for haemorrhage or thrombosis Salooja above for the treatment or prophylaxis of systemic inflamma et al. 2001. tion and/or organ failure in patients with any of the disorders 0275. The TEG analyzer uses a small whole blood sample described in tables 4 and 5. in a rotating cup and a pin Suspended in the blood by a torsion 0266 Thus, one aspect of the invention relates to a phar wire, which is monitored for motion. To speed up the clot maceutical composition comprising one or more of a platelet formation, a standardized amount of an activator of coagula inhibitor, an endothelial modulator, pro-fibrinolytics and tion (e.g. Kaolin, tissue factor) may be added to the cup just TAFIa-inhibitors either administered alone or in combination before the pin is placed in the cup. The torque of the rotating of two or three or four compounds for prevention and/or cup is transmitted to the immersed pin only after fibrin and/or treatment of imminent, Suspected or manifest organ failure, fibrin-platelet bonding has linked the cup and pin together. wherein organ failure is defined as clinical and/or paraclinical The strength and rate of these bonds affect the magnitude of Suspected organ dysfunction and/or as altered organ function the pin motion such that strong clots move the pin directly in in an acutely ill patient requiring medical intervention to phase with cup motion. Thus, the TEG technology documents achieve homeostasis; organ failure includes as used herein the interaction of platelets with the protein coagulation cas MOF and TAMOF in at least one organ, such as in at least two, cade from the time of placing the blood in the analyzer until three, four, five or six organs. initial fibrin formation, clot rate strengthening and fibrin 0267 In a particular embodiment the organ failure is due platelet bonding via GPIb/IIIa, through eventual clot lysis. to systemic inflammation or due to severeinfections or due to The TEGR parameter reflects the initiation phase, reaction sepsis or due to SIRS and/or CARS or due to coagulopathy or time, from start of coagulation until the first fibrin band is due to trauma and/or burns or due to malignant diseases Such formed; the Angle (a) represents the increase in clot strength, as haematological malignancies, Solid tumours and meta clot kinetics, correlating with the thrombin generation. The static tumours or due to ischemia or due to cardiovascular maximal amplitude (MA) parameter reflects maximal clot thromboembolic diseases or due to intoxication. strength i.e. the maximal elastic modus of the clot. Ly30 0268. In a further particular embodiment the organ or demonstrate the proportion of the clot that is dissolved 30 min organs, which are Subject to failure are selected from the after MA is reached, reflecting fibrinolysis. group consisting of cardiovascular, respiratory, renal, haema 0276. The clot strength and stability and changes herein tological, neurological, gastrointestinal and hepatic organs may be measured as increases in relative clot strength by the and musculoskeletal. Such as heart, vessels, microvascula TEG (Thrombelastography) measurable parameter MA and ture, lungs, kidney, bone marrow, brain, gut, pancreas, liver, clot stability by the TEG derivable parameter Lysis AUC. The bones, joints and muscles. maximal amplitude (MA) parameter reflects maximal clot US 2011/0268732 A1 Nov. 3, 2011

strength i.e. the maximal elastic modus of the clot. The area hypocoagulability reflects patients with an increased con under the lysis curve, i.e. area under the curve from MA is Sumption of platelets that participates in microthrombus for obtained (Lysis AUC) reflects degree offibrinolysis. Both clot mation in vital organs, as illustrated by a higher maximal strength and stability may be measured, or one parameter SOFA score than patients presenting with a normal TEG upon only may be followed during a procedure Such as either the ICU admission. clot stability or the clot strength. It is an object of the present 0279. The hypercoagulability reflects an increased activa invention that the clotstrength measured by the MA increases tion of the haemostatic system rendering the platelets hyper relative to the MA prior to administration of a pro-haemo reactive, and thus prone to thrombus development. static agonist by 105%, such as by 110%, such as by 115%, 0280) Identification of Patients at Increased Risk of Devel such as by 120%, such as by 125%, such as by 130%, such as opment of Organ Failure, Including MOF, by a Viscoelastical by 135%, such as by 140%, such as by 145%, such as by Citrated Whole Blood Haemostatic Assay 150%, such as by 155%, such as by 160%, such as by 165%, 0281. In one embodiment, the invention thus relates to a such as by 170%, such as by 175%, such as by 180%, such as method of identifying critically ill patients at increased risk of by 185%, such as by 190%, such as by 195%, such as by development of organ failure including MOF and TAMOF by 200% or more. Likewise it is an object of the present inven analyzing a citrated whole blood sample, Such as in a citrated tion that the clot stability increases Lysis AUC. This param whole blood sample activated by kaolin, Such as in a citrated eter may with a TEG analysis be measured e.g. after addition whole blood sample activated by tissue factor, Such as in a of tissue plasminogen activator (tPA), and thus it is an object native whole blood sample, such as a native whole blood of the present invention that the clot stability measured by the sample activated by kaolin, such as in a citrated whole blood Lysis AUC increases relative to the Lysis AUC prior to admin sample activated by tissue factor from the patient by a cell istration of a sympathicomimetic agonist by 105%, Such as by based viscoelastical assay upon arrival at the ICU. 110%, such as by 115%, such as by 120%, such as by 125%, 0282. In one embodiment, the invention thus relates to a such as by 130%, such as by 135%, such as by 140%, such as method of identifying critically ill patients at increased risk of by 145%, such as by 150%, such as by 155%, such as by development of TAMOF by analyzing a citrated whole blood 160%, such as by 165%, such as by 170%, such as by 175%, sample from the patient by the thrombelastography (TEG) such as by 180%, such as by 185%, such as by 190%, such as system. by 195%, such as by 200% or more. 0283. In one embodiment, the invention thus relates to a 0277. The TEG system has been recognized as a uniquely method of identifying critically ill patients at increased risk of useful tool and has been used extensively in the management development of TAMOF by analyzing a citrated whole blood of haemostasis during major Surgical interventions such as sample from the patient by the thrombelastometry (ROTEM) liver transplantations Kang et al 1985 and cardiovascular systems. procedures as well as obstetrics, trauma, neuroSurgery, man 0284. In one embodiment, the invention thus relates to a agement of deep vein thrombosis, and the monitoring and method of identifying hypocoagulable critically ill patients at differentiation among platelet GPIb/IIIa antagonists Di risk of development of TAMOF by analyzing a whole blood Benedetto 2003. TEG-guided transfusion therapy aiming at sample from the patient by the thrombelastography (TEG) normalising clot strength (MA) has resulted in a reduction in and/or thrombelastometry (ROTEM) system. the use of blood products, a reduction in the rate of re-explo 0285. In one embodiment, the invention thus relates to a ration, prediction of bleeding in cardiac Surgery. It has also method of identifying hypercoagulable critically ill patients been employed in the monitoring of heart assist devices. The at risk of development of TAMOF by analyzing a citrated clinical utility of the TEG comes from that this analysis whole blood sample from the patient by the thrombelastog identifies and quantifies the patient's ability to generate raphy (TEG) and/or the thrombelastometry (ROTEM) sys thrombin and the resulting physical properties of the clot as tem. well as identifying enhanced fibrinolysis Rivard etal. 2005. 0286. Items 0278. The data in Example 1 demonstrate that TEG iden 0287. In one embodiment, the invention thus relates to a tifies patients at increased risk of organ failure, including composition comprising one or more platelet inhibitors and MOF, and mortality earlier than conventional coagulation one or more compounds capable of augmenting the fibrin analysis, which are included in different prognostic scores olytic activity. such as the ISTH DIC score. The clinical importance of the TEG result is further illustrated by that patients presenting 0288. In one embodiment, the invention thus relates to a with a hypocoagulable TEG at ICU admission also had sig composition comprising one or more platelet inhibitors and nificantly increased APACHE II score and developed higher one or more TAFIa inhibitors. maximum SOFA score and increased creatinine as compared 0289. In one embodiment, the invention thus relates to a to patients with a normal TEG upon arrival. Since TEG, but composition comprising one or more compounds capable of not platelet count differed upon arrival, TEG is able to reflect modulating/preserving the endothelial integrity and one or changes of pathophysiological significance in the haemo more compounds capable of augmenting the fibrinolytic static system earlier and more specifically than routine labo activity. ratory parameters. TEG was performed in citrated whole 0290. In one embodiment, the invention thus relates to a blood and looks beyond the first trace amount of fibrin composition comprising one or more compounds capable of formed. This technique describes the quality and speed of the modulating/preserving the endothelial integrity and one or entire coagulation and clot formation process. In contrast, more TAFIa inhibitors. commonly used routine laboratory tests are performed in 0291. In one embodiment, the invention thus relates to a centrifuged plasma fractions and therefore overlook impor composition wherein the platelet inhibitor capable of inhib tant interactions between the protein coagulation cascade, on iting the platelet GPIb/IIIa receptor is administered together the one hand, and platelets and fibrin, on the other hand. The with an inhibitor of thromboxane synthase. US 2011/0268732 A1 Nov. 3, 2011

0292. In one embodiment, the invention thus relates to a Benazepril, Fosinopril, Casokinins, lactokinins), Peroxisome composition, wherein the platelet inhibitor is capable of proliferator-activated receptors (PPARs), NADPH oxidase, inhibiting the platelet COX1 and/or COX2 pathways such as Xanthine oxidase, PETN, Heparan sulfates (PI-88), heparan salicylates, arylalkanoic acids, 2-Arylpropionic acids, sulfate mimetics, Activators of oxidized/heme-free sGC N-Arylanthranilic acids, pyrazolidine derivatives and oxi (BAY 58-2667), Anti-PECAM/SOD. CaS. 0305. In one embodiment, the invention thus relates to a 0293. In one embodiment, the invention thus relates to a composition wherein the compound capable of modulating/ composition wherein the platelet inhibitor is capable of inhib preserving the endothelial integrity is Honokiol. iting Thromboxane-synthase. Such as Flavonoids, such as 0306. In one embodiment, the invention thus relates to a Apigenin, and TP-antagonists such as SQ29548, Bayu 3405, composition wherein the compound capable of modulating/ BM 13177. preserving the endothelial integrity is a compound that 0294. In one embodiment, the invention thus relates to a directly modulates endothelial barrier function through composition wherein the platelet inhibitor is capable of inhib modulating effects on sphingosine-1-phosphate (S1P)-recep iting adenosine uptake in the platelets such as dipyramidol tOrS. Such as Persantin, Asasantin, AggrenoX. 0307. In one embodiment, the invention thus relates to a 0295. In one embodiment, the invention thus relates to a composition wherein the compound capable of modulating/ composition wherein the platelet inhibitor is capable of inhib preserving the endothelial integrity is selected from the group iting the platelet GPIb receptor, such as maB Ib-23, maB consisting of TY720, AA-R, AAL-S, KRP-203, AUY954, 6B4, R9alpha557 peptide, aurintricarboxylic acid (ATA). CYM-5442, SEW2871, W146, W140, VPC44116, crotalin, agkistin, peptide (Trp-Ile-Arg-Arg-Pro-Phe-Phe VPC23019, JTE-013). Pro-Phe) from alpha B-crystallin 0308. In one embodiment, the invention thus relates to a 0296. In one embodiment, the invention thus relates to a composition wherein the compound capable of modulating/ composition wherein the platelet inhibitor is capable of inhib preserving the endothelial integrity is an antibody and/or iting the platelet GPVI receptor, such as EXP3179, triplatin-1 another molecule against/antagonizing histones through their and -2, JAQ1, mAB 10B12, mAB 1C3, mAb 12G1. inhibition histone-mediated endothelial damage and/or 0297. In one embodiment, the invention thus relates to a microthrombi formation and/or fibrin deposition. composition wherein the platelet inhibitor is capable of inhib 0309. In one embodiment, the invention thus relates to a iting the platelet PAR receptors, such as thrombin inhibitors, composition wherein the compound capable of modulating/ heterocycle-based peptide-mimetic antagonists of PAR-1, preserving the endothelial integrity is a compound enhancing RWJ-56110 and RWJ-58259, SCH 79797 SCH 203099 and the natural anticoagulant pathways and hence protecting the PAR4 antagonists such as trans-cinnamoyl-YPGKF-amide endothelium such as but not exclusively: Protein C pathway (tc-Y NH(2)) and palmitoyl-SGRRYGHALR-amide (Activated protein C (APC, Drotrecogin alfa), protein C, (P4pal10), PAR-2 antagonist ENMD-1068, PAR2 mono compounds that either mimics and/or protects from degrada clonal antibody SAM-11. tion and/or enhances soluble thrombomodulin and/or EPCR 0298. In one embodiment, the invention thus relates to a and/or protein S), Antithrombin III (ATIII) (or ATIII like composition wherein the platelet inhibitor is Phosphodi compounds and/or compounds that enhance ATIII function) esterase inhibitor PDE3 such as Cilostazol. and tissue factor pathway inhibitor (TFPI) (or TFPI com 0299. In one embodiment, the invention thus relates to a pounds and/or compounds that enhance TFPI function). composition wherein the platelet inhibitor is Nitroaspirin 0310. In one embodiment, the invention thus relates to a (NCX4016). composition wherein the compound capable of modulating/ 0300. In one embodiment, the invention thus relates to a preserving the endothelial integrity is a compound that main composition wherein the platelet inhibitor is a Polyethylene tain and/or promote GBY function and/or signalling following Glycol-Conjugated Albumin. endothelial PAR activation to ensure reannealing of adherens 0301 In one embodiment, the invention thus relates to a junctions opened following inflammatory PAR mediated acti composition wherein the compound capable of modulating/ vation of Go. preserving the endothelial integrity is selected from the group 0311. In one embodiment, the invention thus relates to a consisting of CD39 and CD73. composition wherein the compound capable of augmenting 0302. In one embodiment, the invention thus relates to a the fibrinolytic activity is selected from the group consisting composition wherein the compound capable of modulating/ of tissue plasminogen activators such as: Alteplase, Tenect preserving the endothelial integrity is a compound involved in eplase, Reteplase, Streptokinase disse er ikke terapeutisk redox control of endothelial functions. interessente men med for at dkke omradet of 0303. In one embodiment, the invention thus relates to a 0312. In one embodiment, the invention thus relates to a composition wherein the compound capable of modulating/ TAF1a inhibitor for prevention or treatment of organ failure, preserving the endothelial integrity is selected from the group including multi organ failure, defined as microthrombosis in consisting of L-Arginine and tetrahydrobiopterin, Antioxi at least one organ, Such as in at least two organs. dants (AScorbate, Glutathione, C.-tocopherol, ubiquinol-10, 0313. In one embodiment of the invention the TAF1a Probucol), Iron chelators, Polyphenols inhibitor is selected from the group consisting of CPU-1, 0304. In one embodiment, the invention thus relates to a AZD9684, MERGETPA, Compound 21 (UK-396,082). composition wherein the compound capable of modulating/ 0314. In one embodiment of the invention the compound preserving the endothelial integrity is selected from the group capable of inhibiting the platelet GPIb/IIIa receptor is consisting of HMG-CoA reductase inhibitors (Fluvastatin, administered together with an inhibitor of thromboxane syn Lovastatin, Pravastatin, Simvastatin), Angiotensin-receptor thase. antagonists and ACE inhibitors (Captopril, Zofenopril, 0315. In one embodiment of the invention the platelet Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, inhibitor is capable of inhibiting the platelet COX1 and/or US 2011/0268732 A1 Nov. 3, 2011

COX2 pathways such as Salicylates, arylalkanoic acids, gous haematopoietic stem cells, bone marrow, T-cells, B-cells 2-Arylpropionic acids, N-Arylanthranilic acids, pyrazolidine are referred to. Furthermore treatment of a complication of derivatives and oxicams. 55-60 allogenic transplantation, graft versus host disease and/or 0316. In one embodiment of the invention the platelet graft rejection (host vs. graft) is included herein. inhibitor is capable of inhibiting Thromboxane-synthase, 0328. In one embodiment, the invention thus relates to a Such as Flavonoids, Such as Apigenin, and TP-antagonists compound for the treatment or prophylaxis of TAMOF in such as SQ2.9548, Bay u 3405, BM 13.177. patients secondary to extracorporeal circulation Such as but 0317. In one embodiment of the invention the platelet not limited to patients undergoing cardiopulmonary bypass, inhibitor is capable of inhibiting adenosine uptake in the on ECMO treatment, receiving ventricular assist devices, platelets such as dipyramidol Such as Persantin, Asasantin, receiving non-biologic valvular prosthesis. AggrenoX. 0329. In one embodiment, the invention thus relates to a 0318. In one embodiment of the invention the platelet compound for the treatment or prophylaxis of TAMOF in inhibitor is capable of inhibiting the platelet GPIb receptor, patients with vascular prosthesis in any location in the human such as mAB Ib-23, maB 6B4, R9alpha557 peptide, aurin organism. tricarboxylic acid (ATA), crotalin, agkistin, peptide (Trp-Ile 0330. In one embodiment, the invention thus relates to a Arg-Arg-Pro-Phe-Phe-Pro-Phe) from alpha B-crystallin compound for the treatment or prophylaxis of TAMOF in 0319. In one embodiment of the invention the platelet patients with autoimmune diseases such as but not limited to inhibitor is capable of inhibiting the platelet GPVI receptor, rheumatoid arthritis (juvenile and/or adult form), systemic such as EXP3179, triplatin-1 and -2, JAQ1, mAB 10B12, lupus erythromatosis, Sclerodermia, antiphospholipid anti mAB 1C3, mAb 12G1. body syndrome. 0320 In one embodiment of the invention the platelet 0331. In one embodiment, the invention thus relates to a inhibitor is capable of inhibiting the platelet PAR receptors, compound for the treatment or prophylaxis of TAMOF in such as thrombin inhibitors, heterocycle-based peptide-mi patients with colitis ulcerosa or Mb Crhohn's disease. imetic antagonists of PAR-1, RWJ-56110 and RWJ-58259, SCH 79797 SCH203099 and PAR4 antagonists such as trans 0332. In one embodiment, the invention thus relates to a cinnamoyl-YPGKF-amide (tc-Y-NH(2)) and palmitoyl compound for the treatment or prophylaxis of TAMOF in SGRRYGHALR-amide (P4pal10), PAR-2 antagonist patients with necrotisizing fasceitis. ENMD-1068, PAR2 monoclonal antibody SAM-11. 0333. In one embodiment, the invention thus relates to a 0321. In one embodiment, the invention thus relates to a compound for the treatment or prophylaxis of TAMOF in compound capable of augmenting the fibrinolytic activity in patients with burn trauma. whole blood for prevention or treatment of organ failure, 0334. In one embodiment, the invention thus relates to a wherein organ failure is defined as altered organ function in compound for the treatment or prophylaxis of TAMOF in an acutely ill patient requiring medical intervention to patients exposed to irradiation. achieve homeostasis; organ failure includes as used herein 0335. In one embodiment, the invention thus relates to a MOF and TAMOF, in at least one organ, such as in at least compound for the treatment or prophylaxis of TAMOF in two, three, four or five organs. patients with obstetric complications such as but not limited 0322. In one embodiment of the invention the compound to preeclampsia, HELLP syndrome. capable of augmenting the fibrinolytic activity in whole blood 0336. In one embodiment the organ failure is due to rep is selected from the group consisting of tissue plasminogen erfusion injury following ischemia. activators such as: Alteplase, Tenecteplase, Reteplase, Strep 0337. In one embodiment, the invention thus relates to a tokinase compound for the treatment or prophylaxis of TAMOF in 0323. In one embodiment, the invention thus relates to a patients with systemic inflammatory response syndrome. TAF1a inhibitor for prevention or treatment of organ failure, 0338. In one embodiment, the invention thus relates to a including multi organ failure, wherein organ failure is defined compound for the treatment or prophylaxis of TAMOF in as altered organ function in an acutely ill patient requiring patients with acute vascular occlusions such as but not limited medical intervention to achieve homeostasis; organ failure to mesenteric thrombosis. includes as used herein MOF and TAMOF, in at least one organ, such as in at least two, three, four or five organs. 0339. In one embodiment, the invention thus relates to a 0324. In one embodiment of the invention the TAF1a compound for the treatment or prophylaxis of TAMOF in inhibitor is selected from the group consisting of CPU-1, patients with haemolytic-uraemic syndrome. AZD9684, MERGETPA, Compound 21 (UK-396,082). 0340. In one embodiment, the invention thus relates to a 0325 In one embodiment, the invention thus relates to a compound for the treatment or prophylaxis of TAMOF in compound for the treatment or prophylaxis of TAMOF in patients with systemic infections (any agent) Such as but not patients with malignant diseases such as, but not limited to, limited to bacteria, mycoplasma, mycobacteria, ricketsiae, Solid tumours, haematological malignancies, metastatic viral, fungal, protozoal infections. tumours, 0341. In one embodiment, the invention thus relates to a 0326 In one embodiment, the invention thus relates to a compound for the treatment or prophylaxis of TAMOF after compound for the treatment or prophylaxis of TAMOF in Surgery or trauma. patients undergoing transplantation. With transplantation 0342. In one embodiment, the invention thus relates to a means Solid organs such as heart, lungs, liver, kidneys, pan compound for the treatment or prophylaxis of TAMOF in creas, intestines or any combination hereof. patients with vasculitis such as, but not limited to Behcet’s 0327. In one embodiment, the invention thus relates to a Disease, Buerger's Disease, Central Nervous System Vascu compound for the treatment or prophylaxis of TAMOF in litis, Churg-Strauss Syndrome, Cryoglobulinemia, Giant Cell patients undergoing transplantation of allogenic or autolo Arteritis, Henoch-Schönlein Purpura, Microscopic Poly US 2011/0268732 A1 Nov. 3, 2011 20 angiitis, Polyarteritis Nodosa, Polymyalgia Rheumatica, exemplified by bacteria (intra-, extracellular, myco-), virus, Rheumatoid Vasculitis, Takayasu's Arteritis, Wegener's fungi, parasites, prions) including infections caused by any Granulomatosis. microorganism in the cardiovascular, respiratory, renal, hae 0343. In one embodiment, the invention thus relates to a matological, neurological, gastrointestinal, hepatic and mus compound for the treatment or prophylaxis of TAMOF in culoskeletal organs, such as heart, vessels, microvasculature, patients with toxins, such as, but not limited to spider, Snake, lungs, kidney, bone marrow, brain, gut, pancreas, liver, bones, Scorpion, jellyfish, wasp, bee, poison dart frog, honeybee, joints and muscles Endocarditis, Meningitis, Encephalitis, Cyanotoxins, Pit vipers, such as rattlesnakes. diarrhea, Hepatitis, Urinary Tract Infections, Intra-Abdomi 0344. In one embodiment, the invention thus relates to a nal Infections, Pneumonia, Pharyngitis, Joint Infections, Skin method for the treatment or prophylaxis of TAMOF in and Soft Tissue infections. patients treated with chemotherapy such as but not limited to 0350. In one embodiment, the invention thus relates to a alkylating agents (L01A) exemplified by Cisplatin, carbopl compound for the treatment of or prophylaxis of organ failure atin and oxaloplatin; Anti-metabolites (L01B) masquerade as due to ischemia due to stherosclerosis, thrombi, emboli (cho purine (azathioprine, mercaptopurine)) or pyrimidine— lesterol, fat, air, septic, tissue, foreign body, amniotic fluid), which become the building blocks of DNA; Plant alkaloids trauma, Vascular occlusion, vasculitis, aneurysms, severe and terpenoids (L01C) as exemplified by Vincristine, Vin anemia and/or microthrombi/emboli? occlusion (imminent, blastine, Vinorelbine, Vindesine, Podophyllotoxin. Taxanes Suspected, manifest) in one or more organs or severe infec (LO1CD) Taxol. Docetaxel. Topoisomerase inhibitors tions caused by any microorganism including sepsis, severe (LO1CB and L01XX) topotecan., irinotecan, amsacrine, eto sepsis, septic shock, organ failure, MOF. DIC, necrotisizing poside, etoposide phosphate, teniposide. Antitumour antibi fasciitis. otics (L01D) dactinomycin, doxorubicin, epirubicin, bleo 0351. In one embodiment, the invention thus relates to a mycin. Monoclonal antibodies such as trastuzumab, compound for the treatment of or prophylaxis of organ failure cetuximab, rituximab, Bevacizumab. due to Surgery, trauma and/or burns including SIRS, compen 0345. In one embodiment, the invention thus relates to a satory anti-inflammatory response syndrome, Shock, tissue method for the treatment or prophylaxis of TAMOF in hypoperfusion, base deficit, lactate acidosis, MOF. DIC, patients treated with irradiation therapy Such as but not lim coagulopathy (hypercoagulability, hypocoagulability, hyper ited to conventional external beam radiotherapy, Virtual fibrinolysis). simulation, 3-dimensional conformal radiotherapy, and 0352. In one embodiment, the invention thus relates to a intensity-modulated radiotherapy, Radioisotope Therapy compound for the treatment of or prophylaxis of organ failure (RIT). due to malignant diseases and chemotherapeutic/immuno 0346. In one embodiment, the invention thus relates to Suppressive treatment, Solid tumours, haematological malig compound, herein defined as a pharmaceutical composition nancies, metastatic tumours. comprising one or more of a platelet inhibitor, an endothelial 0353. In one embodiment, the invention thus relates to a modulator, pro-fibrinolytics and TAFIa-inhibitors either compound for the treatment of or prophylaxis of organ failure administered alone or in combination of two or three or four due to chemotherapy (Alkylating agents (L01A) exemplified compounds for prevention and/or treatment of imminent, Sus by Cisplatin, carboplatin and oxaloplatin; Anti-metabolites pected or manifest organ failure, wherein organ failure is (L01B) masquerade as purine (azathioprine, mercaptopu defined as clinical and/or paraclinical Suspected organ dys rine)) or pyrimidine: Plant alkaloids and terpenoids (LO1C) as function and/or as altered organ function in an acutely ill exemplified by Vincristine, Vinblastine, Vinorelbine, Vin patient requiring medical invention to achieve homeostasis; desine, Podophyllotoxin. Taxanes (LO1CD) Taxol. Doc organ failure includes as used herein MOF and TAMOF in at etaxel. Topoisomerase inhibitors (LO1CB and L01XX) topo least one organ, Such as in at least two, three, four, five or six tecan, irinotecan, amsacrine, etoposide, etoposide phosphate, Organs. teniposide. Antitumour antibiotics (L01D) dactinomycin, 0347 In one embodiment, the invention thus relates to a doxorubicin, epirubicin, bleomycin. compound for the treatment of or prophylaxis of organ failure 0354. In one embodiment, the invention thus relates to a due to systemic inflammation or due to severe infections or compound for the treatment of or prophylaxis of organ failure due to sepsis or due to SIRS and/or CARS or due to coagul due to monoclonal antibodies such as trastuzumab, cetux opathy or due to trauma (Blunt, penetrating trauma, poly imab, rituximab, Bevacizumab. trauma, neurotrauma, minor, major) and/or burns/freezing 0355. In one embodiment, the invention thus relates to a burns or due to malignant diseases Such as haematological compound for the treatment of or prophylaxis of organ failure malignancies, Solid tumours and metastatic tumours or due to due to irradiation and/or irradiation therapy (Conventional ischemia/haemorrhage or due to cardiovascular thromboem external beam radiotherapy, Virtual simulation, 3-dimen bolic diseases or due to intoxication. sional conformal radiotherapy, and intensity-modulated 0348. In one embodiment, the invention thus relates to a radiotherapy, Radioisotope Therapy (RIT)) compound for the treatment of or prophylaxis of organs, 0356. In one embodiment, the invention thus relates to a which are subject to failure are selected from the group con compound for the treatment of or prophylaxis of organ failure sisting of cardiovascular, respiratory, renal, haematological, due to transplantation (heart, lungs, liver, kidneys, pancreas, neurological, gastrointestinal and hepatic organs and muscu intestines or any combination hereof), allogenic or autolo loskeletal. Such as heart, vessels, microvasculature, lungs, gous haematopoietic stem cells, bone marrow, T-cells, B-cells kidney, bone marrow, brain, gut, pancreas, liver, bones, joints and their complications such as graft versus host disease and muscles. (acute, chronic), graft rejection (host vs. graft). 0349. In one embodiment, the invention thus relates to a 0357. In one embodiment, the invention thus relates to a compound for the treatment of or prophylaxis of organ failure compound for the treatment of or prophylaxis of organ failure due to Infectious diseases caused by any microorganism due to extracorporeal circulation, plasmapheresis, leukapher US 2011/0268732 A1 Nov. 3, 2011 esis, dialysis, renal replacement therapy, vascular prosthesis langiocarcinoma, Hepatitis, Hepatic encephalopathy, and/orapheresis treatment, cardiopulmonary bypass, ECMO. Hepatic failure, Liver abscess, Malignant/benign liver Ventricular assist devices. tumours, Liver cirrhosis, Liver coagulopathy, Glycogen Stor 0358. In one embodiment, the invention thus relates to a age diseases, Portal hypertension, Primary biliary cirrhosis, compound for the treatment of or prophylaxis of organ failure Primary Sclerosing cholangitis. due to non-biologic valvular prosthesis, vascular prosthesis 0367. In one embodiment, the invention thus relates to a (biological, non-biological) in any location in the human compound for the treatment of or prophylaxis of organ failure organism. due to Endocrine diseases like Adrenal disorders (Adrenal 0359. In one embodiment, the invention thus relates to a insufficiency. Addison's disease, Mineralocorticoid defi compound for the treatment of or prophylaxis of organ failure ciency, Conn's syndrome, Cushing's syndrome, Pheochro due to intoxication with alcohol, recreational drugs, iatro mocytoma, Adrenocortical carcinoma), Glucose homeostasis genic (chemotherapy, overdose, interaction, adverse event), disorders (Diabetes mellitus, Hypoglycemia, Idiopathic Snake/insect bites (spider, Snake, Scorpion, jellyfish, wasp, hypoglycemia, Insulinoma), Metabolic bone disease, Pitu bee, poison dart frog, honeybee), cyanotoxins, Pit vipers, itary gland disorders (Diabetes insipidus, Hypopituitarism Such as rattlesnakes. (or Panhypopituitarism), Pituitary tumors, Hyperprolactine 0360. In one embodiment, the invention thus relates to a mia, Acromegaly, gigantism, Cushing's disease, Parathyroid compound for the treatment of or prophylaxis of organ failure gland disorders (Primary/Secondary/Tertiary hyperparathy due to cardiovascular diseases like but not exclusively roidism, Hypoparathyroidism, Pseudohypoparathyroidism), Angina, Atherosclerosis, Cardiomyopathy, Congestive heart Menstrual function or fertility disorders (Polycystic ovary failure, Coronary artery disease, Carotid artery disease, syndrome), Thyroid disorders (Goiter, Hyperthyroidism and Endocarditis, Heart attack (coronary thrombosis, myocardial Graves-Basedow disease, Hypothyroidism, Thyroiditis, Thy infarction), Hypertension, Hypercholesterolemia/hyperlipi roid cancer, Tumours of the endocrine glands, Multiple endo demia, Peripheral artery disease, Stroke, reperfusion injury crine neoplasia, Autoimmune polyendocrine syndromes). following ischemia. 0368. In one embodiment, the invention thus relates to a 0361. In one embodiment, the invention thus relates to a compound for the treatment of or prophylaxis of organ failure compound for the treatment of or prophylaxis of organ failure due to gastrointestinal diseases such as Inflammatory bowel due to systemic autoimmune diseases (Rheumatoid arthritis diseases (Colitis ulcerosa, Mb Crohn's disease). (juvenile and/or adult form), systemic lupus erythromatosis, 0369. In one embodiment, the invention thus relates to a sclerodermia, antiphospholipid antibody syndrome, poly compound for the treatment of or prophylaxis of organ failure myositis, mixed connective tissue disease), Sjögrens Syn due to Gynaecologic/obstetric diseases such as Obstetric drome, Fibromyalgia), Sarcoidosis. complications (Preeclampsia, eclampsia, HELLP syndrome, 0362. In one embodiment, the invention thus relates to a amniotic fluid embolism, abruptio placentae). compound for the treatment of or prophylaxis of organ failure 0370. In one embodiment, the invention thus relates to a due to vasculitis (Behcet's Disease, Buerger's Disease, Cen compound for the treatment of or prophylaxis of organ failure tral Nervous System Vasculitis, Churg-Strauss Syndrome, due to Neurological diseases such as Degenerative diseases Cryoglobulinemia, Giant Cell Arteritis, Henoch-Schönlein (Parkinson's disease, Alzheimer's disease), Stroke, Neu Purpura, Microscopic Polyangiitis, Polyarteritis Nodosa, rotrauma (brain, spinal cord), Seizure disorders (epilepsy), Polymyalgia Rheumatica, Rheumatoid Vasculitis, Takaya Malignancies (brain/spinal cord tumors), Infections (menin su's Arteritis, Wegener's Granulomatosis). gitis, encephalitis). 0363. In one embodiment, the invention thus relates to a 0371. In one embodiment, the invention thus relates to a compound for the treatment of or prophylaxis of organ failure compound for the treatment of or prophylaxis of organ failure due to allergic diseases including Anaphylaxis, asthma, eosi due to Haematological diseases such as Malignant (Leu nophil esophagitis, food allergy, urticaria, insect sting allergy, kaemia, Myelodysplastic syndrome) and/or Non-malignant rhinitis, sinusitis, immunodeficiency, mastocytosis. (Thrombotic thrombocytopenic purpura, haemolytic 0364. In one embodiment, the invention thus relates to a uraemic syndrome, aplastic anaemia, Hemophagocytic Lym compound for the treatment of or prophylaxis of organ failure phohistiocytosis). due to respiratory diseases including Asthma, Bronchitis, 0372. In one embodiment, the invention thus relates to a Emphysema, Chronic obstructive pulmonary disease, Infec compound for the treatment of or prophylaxis of organ failure tions (exemplified by influenza, pneumonia and tuberculo due to Orthopedic diseases Such as Trauma, Surgery, Frac sis), Malignancies (Lung cancer), Sarcoidosis, Pleurisy. tures, Malignancies of bone, cartilage and soft tissues includ 0365. In one embodiment, the invention thus relates to a ing Multiple Myeloma, Arthritis (Osteoarthritis, Rheumatoid compound for the treatment of or prophylaxis of organ failure arthritis), Cerebral Palsy, Osteonecrosis, Gout, Infections, due to Renal diseases such as Acute/chronic kidney failure, Myasthenia, Osteoporosis, Pagets disease, Spondylitis. Acute nephritic syndrome, Atheroembolic renal disease, Chronic nephritis, Nephrotic syndrome, End-stage renal dis DETAILED DESCRIPTION OF DRAWINGS ease, Goodpasture syndrome, Interstitial nephritis, Kidney cancer/damage/infection/injury/stones, Lupus nephritis, 0373 FIG. 1: Recording haemostatic activity using Glomerulonephritis, Membranous nephropathy, Nephroblas Thrombelastography (TEG): TEG records the viscoelastic toma, Nephrocalcinosis, Nephrogenic diabetes insipidus, changes during coagulation by analysis of whole blood Nephropathy-IgA, Polycystic kidney disease, Reflux nephr placed in a rotating cup. A pin is Suspended in the blood from opathy, Renal papillary necrosis, Renal tubular acidosis. a torsion wire, and its resistance to motion is recorded. Four 0366. In one embodiment, the invention thus relates to a parameters are routinely reported: R (reaction time) denotes compound for the treatment of or prophylaxis of organ failure the latency from the time at which the blood is placed in the due to Hepatic diseases such as Alcoholic liver disease, Cho cup until the clot begins to form; the angle (Angle) represents US 2011/0268732 A1 Nov. 3, 2011 22 the progressive increase in clot strength; the maximum ampli 0381. These data demonstrate that TEG identifies patients tude (MA) reflects the maximal clotstrength; and lysis (Ly30) at increased risk of organ failure, including MOF, and mor reflects clot lysis. tality earlier than conventional coagulation analysis, which 0374 FIG. 2: Multiplate whole blood aggregometry is a are included in different prognostic scores such as the ISTH platelet function test, (Multiplate R, Dynabyte Medical, DIC score. The clinical importance of the TEG result is fur Munich, Germany). This test is based on multiple electrode ther illustrated by that patients presenting with a hypocoagul platelet aggregometry (MEA), which measures platelet lable TEG at ICU admission also had significantly increased aggregation in whole blood (WB) after stimulation with APACHE II score and developed higher maximum SOFA selective platelet agonists Such as trombinactivated peptide score and increased creatinine as compared to patients with a (TRAP), ADP, ASPI and COLlagen. The increase of imped normal TEG upon arrival. Since TEG, but not platelet count ance by the attachment of platelets onto the Multiplate sen differed upon arrival, TEG is able to reflect changes of patho sors is transformed to arbitrary aggregation units (AU) and physiological significance in the haemostatic system earlier plotted against time. Multiplate thereby allows analyzing the and more specifically than routine laboratory parameters. effect of antithrombotic drugs like aspirin, clopidogrel and TEG was performed in citrated whole blood and looks prostacycline on platelet aggregation. beyond the first trace amount offibrin formed. This technique 0375 FIG. 3: Comparison of baseline TEG values with describes the quality and speed of the entire coagulation and samples obtained after 60- and 120 min of flolan infusion. clot formation process. In contrast, commonly used routine 0376 FIG. 4: Comparison of baseline Multiplate values laboratory tests are performed in centrifuged plasma fractions with samples obtained after 60- and 120 min of flolan infu and therefore overlook important interactions between the S1O. protein coagulation cascade, on the one hand, and platelets and fibrin, on the other hand. The hypocoagulability reflects EXAMPLES patients with an increased consumption of platelets that par ticipates in microthrombus formation in vital organs, as illus Example 1 trated by a higher maximal SOFA score than patients present 0377. It has now surprisingly been found that in critically ing with a normal TEG upon ICU admission. ill patients the TEG result upon arrival to the ICU predicts 30 0382. The hypercoagulability reflects an increased activa and 90-day mortality. In 88 medical ICU patients, none of the tion of the haemostatic system rendering the platelets hyper conventional laboratory analysis including APTT. PT, INR, reactive and thus prone to thrombus development. platelet count, D dimer, CRP or haemoglobin differed at admission between 30-day survivors (n=51) and non-survi Example 2 vors (n=37). The TEG at admission, however, differed sig nificantly between Survivors and non-survivors, respectively 0383 Ninety-four critically ill patients admitted to the in all three aspects of the haemostatic process R 6.4 (+2.7) vs. intensive care unit (ICU) underwent haemofiltration with or 8.07 (+3.0), p=0.002; Angle 61.0 (+13.1) vs. 51.7 (+18.0), without concomitant Flolan (prostacyclin) treatment. Flolan p=0.01; MA 57.3 (+13.0) vs. 49.4 (+17.8), p=0.02. was administered in a low dose of 4-6 ng/kg/min in the filters 0378 Thus, a prolonged R was associated with a 3.7 (95% to prevent these from clotting and consequently there was Cl 1.3-10.0) increased odds ratio (unadjusted) for 30-day only a minor spill over of Flolan to the systemic circulation. mortality, a decreased Angle with a 3.8 (95% 1.6-9.5) The patients were retrospectively reviewed. increased odds ratio (unadjusted) for mortality, and a decreased MA with a 2.8 (95% CI 1.2-6.8) increased odds TABLE 6 ratio (unadjusted) for 30-day mortality. Multivariate logistic regression with use of the significant associated variables Flolan group Non-FIolan group (age and APACHE II) was repeated twice for the 88 medical (n = 24) (n = 70) patients identifying R8 minutes as an independent risk fac APACHE II score (mean) 26 28 Platelet count (difference before +14 -17 tor for mortality (adjusted OR3.8; 95% CI 1.3-11.3) after vs. after haemofiltration) adjustment forage>65 years (adjusted OR 1.9; 95% CI 0.7-5) 90 day Survival (%) 67 47 and APACHE ID25 (adjusted OR 4.1; 95% CI 1.6-10.7). Hosmer and Lemeshow Goodness-of-Fit test, p=0.85. APACHE II: AcutePhysiology and Chronic Health Evaluation II, ICU: Intensive Care Unit 0379 Also MA-50 mm, was an independent risk factor for mortality (adjusted OR3.0; 95% CI 1.1-8.0) after adjust 0384 The two groups (Flolan vs. non-flolan) were com ment forage>65 years (adjusted OR2.5: 95% CI 0.9-7.2) and parable in regards to APACHE II at admission. However, APACHE IID25 (adjusted OR3.5; 95% CI 1.3-9.0). Hosmer patients in the flolan group were more severely ill as evaluated and Lemeshow Goodness-of-Fittest, p=0.68. Consequently a by a lower platelet count at start of hemofiltration, a higher hypocoagulable TEG result upon arrival in these patients may frequency of severe thrombocytopenia, a higher frequency of represent a therapeutic target. DIC diagnoses, a higher maximum SOFA score and a higher 0380 Furthermore, patients presenting with hypercoagul SOFA score at hemofiltration initiation as compared to the lability defined as a R-4 min and/or Angle>78° and/or patients receiving non-flolan. The finding of increased total MA>69 mm had a higher survival rate than patients being transfusion requirements and specifically of FFP during hypocoagulable (74% vs. 54%) but a lower survival rate than hemofiltration in the flolan group vs. the non-flolan group patients presenting with a normal TEG result upon ICU might thus be attributed to the higher disease severity and admission (74% vs. 87%), emphasizing that perturbations in associated coagulopathy and not to an increased risk of bleed coagulability, in either the hypo or hyper direction, have a ing due to the use of flolan as anticoagulant. Importantly, negative predictive value for clinical outcome in these criti when comparing mortality between groups, we found that the cally ill patients. flolan group tended to have decreased mortality at 30 days US 2011/0268732 A1 Nov. 3, 2011

(21% vs. 39%, p=0.12), 90 days (34% vs. 53%, p=0.10) and catheters were placed (1 for endotoxin infusion and 1 for each 365 days (38% vs. 57%, p=0.09). of the 2 study drugs or saline (Placebo)). 0385 Flolan does not negatively influence the haemostatic 0397 Group 1 (n-6): Endotoxin--drugs competence as evaluated by transfusion requirements in criti 0398 Endotoxin (LPS (Sigma-Aldrich, Cat. No. 2762) cally ill patients undergoing haemofiltration and thereby from e. coli strain 026:B6IV injection (5 mg/kg bolus) questions the assumption that prostacycline is a powerful 0399 IV infusion for 8 hours with a combination of two antithrombotic agent. test drugs 0386 Furthermore, the significant decrease in mortality (0400 GPIb/IIIa inhibitor-abciximab=RheoPro 1 mg/kg observed in haemofiltrated patients receiving flolan in the bolus and 0.250 mikrogram/kg/min filters indicate that the minor systemic spill-over affects the 04.01 PGI flolan 20 ng/kg/min endothelium, limiting the pro-coagulant effects of systemic 0402 Group 2 (n-6): Endotoxin-placebo inflammation and coagulation activation preventing (0403 Endotoxin (LPS (Sigma-Aldrich, Cat. No. 2762) microvascular occlusion and organ failure. from e. coli strain 026:B6) IV injection (5 mg/kg bolus) 0404 IV infusion for 8 hours with saline (placebo) Example 3 04.05 The animals were sacrificed after 8 hours treatment/ 0387 Six healthy volunteers were administered flolan placebo after receiving a heparin infusion to avoid post-mor (prostacyclin) intravenously at a dose of 4 ng/kg/min for 2 h. tem intravascular fibrin deposition. Blood samples for whole blood viscoelastical assay (Throm 0406 Analyses before and after treatment/placebo: belastography TEG) and whole blood platelet aggregation 0407 Platelet count, hemoglobin, blood pressure, heart (Multiplate) was obtained before infusion of Flolan, after 60 rate min infusion of Flolan and after 120 min infusion of Flolan. 0408 Post-mortem histopathology analyses of bleeding 0388 With regard to the TEG assay this was performed as and thrombosis: recommended by the manufacturer and 340 ulare mixed with 04.09 CNS, heart, lungs, liver, kidneys and intestine 20 ul CaCl 0.2M (final concentration 11.1 mM in the cup)and 0410. Results kaolin at 37° C. after which the haemostatic activity is 0411 Rats receiving the study drugs demonstrated a recorded as depicted in FIG. 1. diminished decline in platelet count after 8 hours of endot 0389 Whole blood impedance aggregometry analyzed by oxin infusion than the placebo group (-39.4% vs. -63.9%), a the Multiple Platelet function Analyzer (MultiPlate R ana diminished increase in heart rate (+4.8% vs. +27.6%) and a lyzer). Analysis employing various platelet agonists: ASPIt diminished drop in blood pressure (+0.7% vs. -20.3%). No est (activation by arachidonic acid), COLtest (activation by differences between groups was found with regard to haemo collagen through the collagen receptor), TRAPtest (activa globin indicating that the rats treated with the study drug did tion by TRAP-6 stimulates the thrombin receptor on the plate not bleed Post mortem histopathology demonstrated no evi let surface and ADPtest (activation by ADP stimulates plate dence of increased bleeding in vital organs in the group let activation by the ADP receptors). receiving the study drugs as compared to the placebo group. 0390 MultiPlate continuously records platelet aggrega 0412 Conclusions tion. The increase of impedance by the attachment of platelets 0413 Infusion of a combination of RheoPro onto the Multiplate sensors is transformed to arbitrary aggre (abciximab-a GPIb/IIIa inhibitor) and Flolan (prostacy gation units (AU) and plotted against time as depicted in FIG. clin) to rats with endotoxaemia resulted in improved mainte 2. nance of platelet count and reduced clinical deterioration, as 0391 Results: evaluated by reduced increase in heart rate and reduced 0392. No significant difference was observed when com decline in blood pressure, as compared to rats that received paring baseline TEG values with samples obtained after 60 placebo. RheoPro is a potent reversible GPIb/IIIa platelet and 120 min of flolan infusion for any of the parameters inhibitor preventing formation of platelet aggregates in the investigated (R, Angle, MA) in any of the 6 volunteers stud microcirculation. In addition, flolan, a prostacyclin analogue, ied, see FIG. 3. maintains endothelial integrity and prevents development of a 0393 Similarly, no significant difference was observed procoagulant phenotype limiting the interaction between when comparing baseline Multiplate values with Samples platelets and endothelial cells. obtained after 60- and 120 minofflolan infusion for any of the 0414. Also, infusion of a combination of RheoPro at a agonists investigated (ASPI, COL, ADP, TRAP) in any of the dose twice the recommended dose for humans and Flolan, at 6 volunteers studied, see FIG. 4. a dose 10 times the maximal recommended dose in humans 0394 Conclusions: will not result in an increased bleeding tendency as evaluated 0395. Infusion of Flolan at the doses recommended for by hemoglobin and histopathological examination of vital clinical use did not negatively affect whole blood haemostatic organs including CNS, heart, lungs, liver, kidneys and intes competence as evaluated by TEG. Furthermore, with regard tine. to whole blood platelet aggregation, employing various plate let agonists is not affected negatively by flolan infusion indi TABLE 7 cating that such administration not compromise haemostasis. Prostacyclin and Example 4 GPIIB, IIa inhibitor Saline l 6 6 0396 To test the effect of IV infused GPIIb/IIIa inhibitor Bodyweight 9. 295 301 and PGI2 on bleeding and thrombosis, a rat endotoxemia HGB % change 0-7 hours -23.6% -23.1% model was established employing 12 Sprague Dawley rats, PLT % change 0-7 hours -39% -70% males, 250-300 g. The rats were anaesthesized and three IV US 2011/0268732 A1 Nov. 3, 2011 24

0445 Rivard et al., 2005, Journal of Thrombosis and Hae TABLE 7-continued mostasis, 4: 411-416 0446 Roberts et al. 2006 Semin Thromb Hemost. 2006 Prostacyclin and April: 32 Suppl 1:32-8 GPIB, IIa inhibitor Saline 0447 Salooja et al., Blood Coagul Fibrinolysis. 2001 July; HR % change 0-7 hours 4.8% 27.6% 12(5):327-37. Review. Erratum in: Blood Coagul Fibrinoly BP % change 0-7 hours O.7% -20.3% sis 2002 January; 13(1):75. 0448 Schereen et al., Intensive Care Med (1997) 23: 146 158 REFERENCES 0449 Thompson et al., J. Exp. Med. Volume 200, Number 11, Dec. 6, 2004 1395-1405 0415. Abraham et al., JAMA. 2003 Jul.9; 290(2):238-47. 0450 Tomokiyo et al., Vox Sang. 2003 November: 85(4): 0416 Afshari et al., Cochrane Database Syst Rev. 2008 290-9. Jul.16; (3):CD005370. 0451 Velik-Salchner et al., J Thromb Haemost. 2007 0417. Atkinson et al., Blood Cells, Molecules, and Dis May: 5(5):1019-25. eases 36 (2006) 217-222 0452 Xu et al., Nat Med. 2009 November, 15(11): 1318 0418 Bassus et al., Platelets. 2006 September; 17(6):378 21. 84. 0453 Zardi et al., International Immunopharmacology 5 0419 Bernard et al., Crit Care Med. 2001 November; (2005) 437-459 29(11):2051-9. 0454 Zardi et al., Prostaglandins & other Lipid Mediators 0420 Bick R., Semin Thromb Hemost. 1996:22(1):69-88. 83 (2007) 1-24 0421 Bick R., Semin Thromb Hemost. 1998:24(1):3-18. 0455 Irish Critical Care Trials Group 2008 0422 Bihari et al., Intensive Care Med. 1988:15(1):2-7 0456 American College of Chest Physicians/Society of 0423 Cines et al., 1998, Blood 91:3527-3561. Critical Care Medicine Consensus Conference (Bone et al. 0424 Colgan et al., Purinergic Signalling (2006) 2: 351 1992) 36O. 1. A pharmaceutical composition comprising one or more 0425 De Meyer et al., Cardiovasc Hematol Disord Drug compounds selected from the group consisting of platelet Targets. 2009 March; 9(1):9-20 inhibitors, compounds capable of modulating/preserving the 0426 DiBenedetto et al., Minerva Anestesiol. 2003 June; endothelial integrity, compounds capable of augmenting the 69(6):501-9,509-15. fibrinolytic activity, or TAFIa inhibitors. 0427 Fries et al., Anesth Analg. 2006 February; 102(2): 2. The pharmaceutical composition of claim 1 comprising 347-51. one or more platelet inhibitors and one or more compounds 0428 Ganter et al., Anesth Analg. 2008 May; capable of modulating/preserving the endothelial integrity. 106(5):1366-75. 3. The pharmaceutical composition of any of claims 1 and 0429 Geerts et al., Chest. 2008 June; 133(6 Suppl):3815 2, wherein the platelet inhibitor is capable of inhibiting the 4535. GPIb/IIIa receptor and the compound capable of modulat 0430 Goepfert et al., 2000, Molecular Medicine 6(7): ing/preserving the endothelial integrity is PGI2 or variants 591-603. thereof. 0431 Goerge et al. 2008, Blood. 2008 May 15: 111(10): 4. The pharmaceutical composition any of claims 1 and 2. 4958-64. wherein the platelet inhibitor is capable of inhibiting the 0432 Kanaan et al., Clin Ther. 2007 November, 29(11): GPIb/IIIa receptor. 2395-405. 5. The pharmaceutical composition of any of claims 1, 2 0433 Kang et al., Anesth Analg. 1985 September: 64(9): and 3, wherein the platelet inhibitor is selected from the group 888-96. consisting of abciximab, eptifibatide, tirofiban, orbofiban, 0434 Kawasaki et al., Stroke. 2000 March; 31(3):591-5. Xemilofiban, lamifiban, XJ757, DUP728 and XR299. 0435 Knezevic et al., Exp Med. 2009 Nov. 23; 206(12): 6. The pharmaceutical composition of any of claims 1, 2, 3 2761-77 and 4, wherein the platelet inhibitor has a halftime of less than 0436 Levi M., Curr Opin Hematol. 2008 September; 3 hours (such as eptifibatide), preferably less than 2.5 hours 15(5):481-6. (such as tirofiban), more preferably less than 1 hour. 0437. Levi and Lowenberg, Semin Thromb Hemost 2008: 7. The pharmaceutical composition of claim 1, wherein the 34(5):417-424. platelet inhibitor is capable of inhibiting platelet ADP recep 0438 Marsolais et al., Nat Rev Drug Discov. 2009 April; tor P2Y12. 8(4):297-307. 8. The pharmaceutical composition of claim 7, wherein the 0439 Marti-Carvajal et al., Cochrane Database Syst Rev. platelet inhibitor is selected from the group consisting of 2007 Jul. 18; (3):CD004388. AR-C69931 MX, Ticlopidine, Clopidogrel, Prasugrel, 0440 Review. Update in: Cochrane Database Syst Rev. AZD6140 and cangrelor, ticagrelor. 2008: (1):CD004388. 9. The pharmaceutical composition of any of claims 1 7 0441 Moreau et al., Chest 2007: 131(6):1735-1741. and 8, wherein the platelet inhibitor has a halftime of less than 0442 Nachman and Rafii, N EnglJMed, 2008; 359:1261 12 hours (such as Ticlopidine), preferably less than 8 hours 70. (such as Clopidogrel), more preferably about 3-5 min (such as 0443 Nguyen and Carcillo, 2006, Critical Care 2006, cangrelor. 10:235. 10. The pharmaceutical composition of claim 1, wherein 0444 de Oliveira et al., J. Thromb Thrombolysis. 2009 the platelet inhibitor is capable of inhibiting platelet receptor Aug. 25 P2Y 1. US 2011/0268732 A1 Nov. 3, 2011

11. The pharmaceutical composition of claim 10, wherein hour (such as lloprost (20-30 min), preferably less than 5 min the platelet inhibitor is selected from the group consisting of (such as Epoprostenol (0.5-3 min)). MRS2500, MRS2298, MRS2496, A2P5P, A3P5P, ATP, 20. The pharmaceutical composition of any of claims 1, 2 2-MeSATP, and 2-CIATP. and 3, wherein the platelet inhibitor is capable of inhibiting 12. The pharmaceutical composition of claim 1, wherein platelet ADP receptor P2Y12 and has a halftime of 12 hours the platelet inhibitor is a haemoglobin conjugated with poly (such as Ticlopidine), preferably less than 8 hours (such as ethylene glycol, a compound that besides its platelet inhibi Clopidogrel), more preferably about 3-5 min (such as cangre tory function also improves oxygenation of the microvascu lor and the compound capable of modulating/preserving the lature, such as but not exclusively MP4OX (Hemospan, endothelial integrity a halftime of less than has a halftime of polyethylene glycol-hemoglobin complexes) less than 4 hours (such as Treprostinil), preferably less than 1 13. The pharmaceutical composition of claim 1, wherein hours (such as Beraprost (35-40 min)), more preferably less the platelet inhibitor is a antibody and/or inhibitors of C-type than /2 hour (such as Iloprost (20-30 min)), preferably less lectin-like receptor 2 (CLEC-2). than 5 min (such as Epoprostenol (0.5-3 min)). 14. The pharmaceutical composition of claim 1, wherein 21. The pharmaceutical composition of any of claims 1, 2, the platelet inhibitor is a high-energy glycolitic metabolites 3 and 19, wherein the platelet inhibitor is selected from the like fructose-1,6-bisphosphate (FBP). group consisting of abciximab, eptifibatide, tirofiban, orbo 15. The pharmaceutical composition of claims 1, 2 and 3. fiban, xemilofiban, lamifiban, XJ757, DUP728 and XR299 wherein the compound capable of modulating/preserving the and the compound capable of modulating/preserving the endothelial integrity is selected from the group consisting of endothelial integrity is selected from the group consisting of PGI2, PGX, nitrogen oxide, and prostacyclin or variants PGI2, PGX, nitrogen oxide, CD39, CD73 and prostacyclinor thereof. variants thereof. Such as beraprost sodium, epoprostenol 16. The pharmaceutical composition of claims 3 and 15, Sodium, iloprost, iloprost in combination with bosentan, illo wherein the prostacyclin variant is selected from the group prost in combination with sildenafil citrate, treprostinil, pegy consisting of beraprost sodium, epoprostenol Sodium, ilo lated treprostinil, treprostinil diethanolamine and treprostinil prost, iloprost in combination with bosentan, iloprost in com sodium, 2-4-(5,6-diphenylpyrazin-2-yl)(isopropyl)amino bination with sildenafil citrate, treprostinil, pegylated trepro butoxy-N-(methylsulfonyl)acetamide, {4-(5,6-diphe stinil, treprostinil diethanolamine and treprostinil Sodium, nylpyrazin-2-yl)(isopropyl)aminobutoxyacetic acid, 8-1, 2-4-(5,6-diphenylpyrazin-2-yl)(isopropyl)aminobutoxy}- 4,5-triphenyl-1H-imidazol-2-yl-oxyoctanoic acid, N-(methylsulfonyl)acetamide, {4-(5,6-diphenylpyrazin-2- isocarbacyclin, cicaprost, 4-2-(1,1-Diphenylethylsulfanyl)- yl)(isopropyl)aminobutoxyacetic acid, 8-1,4,5-triphenyl ethyl-3,4-dihydro-2H-benzo 1.4oxazin-8-yloxy-acetic 1H-imidazol-2-yl-oxyoctanoic acid, isocarbacyclin, acid N-Methyl-d-glucamine, 7,8-dihydro-5-(2-(1-phenyl-1- cicaprost, 4-2-(1,1-Diphenylethylsulfanylyethyl-3,4-di pyrid-3-yl-methiminoxy)-ethyl)-a-naphthyloxyacetic acid, hydro-2H-benzo 1.4oxazin-8-yloxy-acetic acid N-Methyl (5-(2-diphenylmethyl aminocarboxy)-ethyl)-a-naphthyloxy d-glucamine, 7,8-dihydro-5-(2-(1-phenyl-1-pyrid-3-yl-me aceticacid, 2-3-2-(4,5-diphenyl-2-oxazolyl)ethylphe thiminoxy)-ethyl)-a-naphthyloxyacetic acid, (5-(2- noxyacetic acid, 3-4-(4.5-diphenyl-2-oxazolyl)-5-ox diphenylmethyl aminocarboxy)-ethyl)-a- azolylphenoxyacetic acid, bosentan, 17alpha, naphthyloxyaceticacid, 2-3-2-(4,5-diphenyl-2-oxazolyl) 20-dimethyl-DELTA6,6a-6a-carba PGI1, 15-deoxy-16al ethylphenoxyacetic acid, 3-4-(4.5-diphenyl-2-oxazolyl)- pha-hydroxy-16 beta).20-dimethyl4DELTA6,6a-6a-carba 5-oxazolylphenoxyacetic acid, bosentan, 17alpha. PGI1 and pentoxifylline (1-(5-oxohexyl)-3,7-dimethylxan 20-dimethyl-DELTA6,6a-6a-carba PGI1, 15-deoxy-16al thine). pha-hydroxy-16 beta).20-dimethyl4DELTA6,6a-6a-carba 22. The pharmaceutical composition of any of claims 1, 2, PGI1 and pentoxifylline (1-(5-oxohexyl)-3,7-dimethylxan 18 and 20, wherein the platelet inhibitor is selected from the thine). group consisting of AR-C69931 MX, Ticlopidine, Clopi 17. The pharmaceutical composition of any of claims 3, 15 dogrel, Prasugrel, AZD6140 and cangrelor, ticagrelor and the and 16, wherein the compound capable of modulating/pre compound capable of modulating/preserving the endothelial serving the endothelial integrity has a halftime of less than 4 integrity is selected from the group consisting of PGI2, PGX, hours (such as Treprostinil), preferably less than 1 hours nitrogen oxide, CD39, CD73 and prostacyclin or variants (such as Beraprost (35-40 min)), more preferably less than thereof. Such as beraprost sodium, epoprostenol sodium, illo 1/2 hour (such as lloprost (20-30 min)), preferably less than 5 prost, iloprost in combination with bosentan, iloprost in com min (such as Epoprostenol (0.5-3 min)). bination with sildenafil citrate, treprostinil, pegylated trepro 18. The pharmaceutical composition of any of claims 1 and stinil, treprostinil diethanolamine and treprostinil Sodium, 2, wherein the platelet inhibitor is capable of inhibiting plate 2-4-(5,6-diphenylpyrazin-2-yl)(isopropyl)aminobutoxy}- let ADP receptor P2Y12 and the compound capable of modu N-(methylsulfonyl)acetamide, {4-(5,6-diphenylpyrazin-2- lating/preserving the endothelial integrity is PGI2 or variants yl)(isopropyl)aminobutoxyacetic acid, 8-1,4,5-triphenyl thereof. 1H-imidazol-2-yl-oxyoctanoic acid, isocarbacyclin, 19. The pharmaceutical composition of any of claims 1, 2 cicaprost, 4-2-(1,1-Diphenylethylsulfanyl)-ethyl-3,4-di and 3, wherein the platelet inhibitor is capable of inhibiting hydro-2H-benzo 1.4oxazin-8-yloxy-acetic acid N-Methyl the GPIb/IIIa receptor and has a halftime of less than 3 hours d-glucamine, 7,8-dihydro-5-(2-(1-phenyl-1-pyrid-3-yl-me (such as eptifibatide), preferably less than 2.5 hours (such as thiminoxy)-ethyl)-a-naphthyloxyacetic acid, (5-(2- tirofiban), more preferably less than 1 hour, and the com diphenylmethyl aminocarboxy)-ethyl)-a- pound capable of modulating/preserving the endothelial naphthyloxyaceticacid, 2-3-2-(4,5-diphenyl-2-oxazolyl) integrity a halftime of less than has a halftime of less than 4 ethylphenoxyacetic acid, 3-4-(4.5-diphenyl-2-oxazolyl)- hours (such as Treprostinil), preferably less than 1 hours 5-oxazolylphenoxyacetic acid, bosentan, 17alpha. (such as Beraprost (35-40 min)), more preferably less than /2 20-dimethyl-DELTA6,6a-6a-carba PGI1, 15-deoxy-16al US 2011/0268732 A1 Nov. 3, 2011 26 pha-hydroxy-16 beta).20-dimethyl4DELTA6,6a-6a-carba 34. The platelet inhibitor according to claim 33 selected PGI1 and pentoxifylline (1-(5-oxohexyl)-3,7-dimethylxan from the group consisting of Ticlopidine, Clopidogrel, Pra thine). Sugrel, AZD6140 and cangrelor and ticagrelor. 23. Use of the pharmaceutical composition according to 35. A compound capable of modulating/preserving endot any of claims 1 to 22, for treatment and prevention of organ helial integrity for prevention or treatment of organ failure, failure, wherein organ failure is defined as altered organ func wherein organ failure is defined as altered organ function in tion in an acutely ill patient requiring medical intervention to an acutely ill patient requiring medical intervention to achieve homeostasis; organ failure includes as used herein MOF and TAMOF, in at least one organ, such as in at least achieve homeostasis; organ failure includes as used herein two, three, four or five organs. MOF and TAMOF, in at least one organ, such as in at least 24. The use according to claim 23 wherein the organ failure two, three, four or five organs. is due to systemic inflammation or due to severeinfections or 36. The compound according to claim 35 selected from the due to sepsis or due to SIRS and/or CARS or due to coagul group consisting of PGI2, PGX, nitrogen oxide, CD39, CD73 opathy or due to trauma and/or burns or due to malignant and prostacyclin or variants thereof. diseases such as haematological malignancies, solid tumours 37. The compound according to any of claims 35 and 36, and metastatic tumours or due to ischemia or due to cardio wherein the prostacyclin variant is selected from the group vascular thromboembolic diseases or due to intoxication consisting of beraprost sodium, epoprostenol sodium, ilo 25. The use according to claim 23 wherein the organ or prost, iloprost in combination with bosentan, iloprost in com organs, which are Subject to failure are selected from the bination with sildenafil citrate, treprostinil, pegylated trepro group consisting of cardiovascular, respiratory, renal, haema stinil, treprostinil diethanolamine and treprostinil Sodium. tological, neurological, gastrointestinal and hepatic organs Further compounds are 2-4-(5,6-diphenylpyrazin-2-yl) and musculoskeletal. Such as heart, vessels, microvascula ture, lungs, kidney, bone marrow, brain, gut, pancreas, spleen, (isopropyl)aminobutoxy-N-(methylsulfonyl)-acetamide, liver, bones, joints and muscles. {4-(5,6-diphenylpyrazin-2-yl)(isopropyl)amino 26. Use of the pharmaceutical composition according to butoxyacetic acid, 8-1,4,5-triphenyl-1H-imidazol-2-yl any of claims 1 to 22 for the preservation of platelet number oxyoctanoic acid, isocarbacyclin, cicaprost, 4-2-(1,1- and/or function in a critically ill patient requiring medical Diphenylethylsulfanyl)-ethyl-3,4-dihydro-2H-benzo 1.4 intervention to achieve homeostasis. oxazin-8-yloxy-acetic acid N-Methyl-d-glucamine, 7.8- 27. A composition comprising one or more compounds dihydro-5-(2-(1-phenyl-1-pyrid-3-yl-methiminoxy)-ethyl)- selected from the group consisting of platelet inhibitors, com a-naphthyloxyacetic acid, (5-(2-diphenylmethyl pounds capable of modulating/preserving the endothelial aminocarboxy)-ethyl)-a-naphthyloxyaceticacid, 2-3-2-(4. integrity, compounds capable of augmenting the fibrinolytic 5-diphenyl-2-oxazolyl)ethylphenoxyacetic acid, 3-4-(4. activity, or TAFIa inhibitors for use in treatment and preven 5-diphenyl-2-oxazolyl)-5-oxazolylphenoxyacetic acid, tion of organ failure wherein organ failure is defined as altered bosentan, 17alpha 20-dimethyl-DELTA6,6a-6a-carba organ function in an acutely ill patient requiring medical PGI1, and 15-deoxy-16alpha-hydroxy-16 beta).20-dim intervention to achieve homeostasis; organ failure includes as ethyl-DELTA6,6a-6a-carba PGI1, pentoxifylline (1-5- used herein MOF and TAMOF, in at least one organ, such as oxohexyl)-3,7-dimethylxanthine). in at least two, three, four or five organs. 38. A compound according to any of claims 29 to 37, or a 28. A composition comprising a platelet inhibitor and a composition according to any of claims 1 to 22 for prevention compound capable of modulating/preserving endothelial or treatment of organ failure, wherein organ failure is defined integrity for use in the treatment and prevention of organ as altered organ function in an acutely ill patient requiring failure wherein organ failure is defined as altered organ func medical intervention to achieve homeostasis; organ failure tion in an acutely ill patient requiring medical intervention to includes as used herein MOF and TAMOF, in at least one achieve homeostasis; organ failure includes as used herein organ, Such as in at least two, three, four or five organs. MOF and TAMOF, in at least one organ, such as in at least wherein the organ failure is due to systemic inflammation or two, three, four or five organs. due to severe infections or due to sepsis or due to systemic 29. A platelet inhibitor for prevention or treatment of organ inflammatory response syndrome (SIRS) and/or compensa failure, wherein organ failure is defined as altered organ func tory anti-inflammatory response syndrome CARS or due to tion in a critically ill patient requiring medical intervention to coagulopathy or due to trauma and/or burns or due to malig achieve homeostasis; organ failure includes as used herein nant diseases such as haematological malignancies, Solid MOF and TAMOF, in at least one organ, such as in at least tumours and metastatic tumours or due to ischemia or due to two, three, four or five organs. cardiovascular thromboembolic diseases or due to intoxica 30. The platelet inhibitor according to claim 29, which is tion. capable of inhibiting the GPIIb/IIIa receptor. 39. A compound according to any of claims 29 to 38 for 31. The platelet inhibitor according to any of claims 29 and prevention or treatment of organ failure, including multi 30 selected from the group consisting of abciximab, eptifi organ failure, defined as microthrombosis in at least one batide, tirofiban, orbofiban, xemilofiban, lamifiban, XJ757, organ, wherein prevention or treatment of the organ failure is DUP728 and XR299. in patients with malignant diseases such as Solid tumours, 32. The platelet inhibitor of any of claim 30 or 31 which has haematological malignancies and metastatic tumours or the a halftime of less than 3 hours (such as eptifibatide), prefer systemic inflammatory response syndrome and compensa ably less than 2.5 hours (such as tirofiban), more preferably tory anti-inflammatory response syndrome accompanying less than 1 hour (Such as abciximab). trauma. 33. The platelet inhibitor of claim 29, which is capable of 40. A compound according to any of claims 29 to 38 for inhibiting platelet ADP receptor P2Y. prevention or treatment of organ failure, including multi US 2011/0268732 A1 Nov. 3, 2011 27 organ failure, defined as altered organ function in an acutely i) determining at least one of the Viscoelastical data points ill patient requiring medical intervention to achieve homeo R. Angle and MA by thromboelastography (TEG) or Stasis; thromboelastometry in a whole blood sample from the organ failure includes as used herein MOF and TAMOF, human being critically ill. Such as in a citrated whole wherein the organs are selected from the group consist blood sample, Such as in a citrated whole blood sample activated by kaolin, ing of cardiovascular, respiratory, renal, haematological, ii) comparing said concentration with a predetermined cut neurological, gastrointestinal and hepatic organs and off value, said cutoff value being an equivalent to a musculoskeletal. Such as heart, vessels, microvascula cutoff value determined by TEG in a citrated whole ture, lungs, kidney, bone marrow, brain, gut, pancreas, blood sample activated by kaolin wherein said cutoff spleen, liver, bones, joints and muscles. value is 41. A method of treating or preventing organ failure, a) R higher than 8.0 minutes, such as higher than 8.5 including multi organ failure, defined as altered organ func minutes, or lower than 4.0 minutes, such as lower than tion in an acutely ill patient requiring medical intervention to 3.0 minutes, achieve homeostasis; organ failure includes as used herein b) Angle lower than 55°, such as lower than 52°, or MOF and TAMOF comprising administering one or more higher than 78°, such as higher than 80°, and compounds selected from the group consisting of platelet c) MA lower than 51 mm, such as lower than 50 mm, or inhibitors, compounds capable of modulating/preserving the higher than 69 mm, Such as higher than 72 mm endothelial integrity, compounds capable of augmenting the wherein an R-value higher or lower than the cutoff value fibrinolytic activity, or TAFIa inhibitors. and/or an Angle-value higher or lower than the cutoff value 42. Use of one or more compounds selected from the group and/or a MA higher or lower than the cutoff value is indicative consisting of platelet inhibitors, compounds capable of of a significantly increased risk of developing organ failure modulating/preserving the endothelial integrity, compounds including MOF as compared to a human being wherein nei capable of augmenting the fibrinolytic activity, or TAFIa ther R, Angle-value or MA is higher or lower than the cutoff inhibitors in the manufacture of a medicament for the treat value. ment or prevention of organ failure, including multi organ 45. The method according to claim 1 and wherein the failure, defined as altered organ function in an acutely ill whole blood sample from the critical ill human has i) an R-value above the cutoff value of 8 min and an patient requiring medical intervention to achieve homeosta Angle-value lower than the cutoff value of 55°; or S1S, ii) an R-value above the cutoff value of 8 minutes and an organ failure includes as used herein MOF and TAMOF. MA-value lower than the cutoff value of 50 mm; or 43. A pharmaceutical composition for treating or prevent iii) an Angle-value lower than the cutoff value of 55° and an ing organ failure, including multi organ failure, defined as MA-value lower than the cutoff value of 50 mm; or altered organ function in an acutely ill patient requiring medi iv) an R-value above the cutoff value of 8 minutes and an cal intervention to achieve homeostasis; organ failure Angle-value lower than the cutoff value of 55° and an includes as used herein MOF and TAMOF comprising one or MA-value lower than the cutoff value of 50 mm more compounds selected from the group consisting of plate V) an R-value below the value of 4 min and an Angle-value let inhibitors, compounds capable of modulating/preserving higher than the value of 78°, or the endothelial integrity, compounds capable of augmenting vi) an R-value below the value of 4 minutes and an MA the fibrinolytic activity, or TAFIainhibitors as an active ingre value higher than the value of 69 mm; or dient. vii) an Angle-value higher than the value of 78° and an 44. A method of diagnosing, monitoring or determining the MA-value higher than the value of 69 mm; or likelihood of a organ failure including multi organ failure viii) an R-value below the value of 4 minutes and an Angle (MOF) in a critical ill human being, wherein said method is value higher than the value of 78° and an MA-value capable of identifying critical ill human beings who have a higher than the value of 69 mm. significantly increased risk of developing organ failure, including MOF, said method comprising the steps of c c c c c