sign in sign up
<<
Home , Drotrecogin alfa, Factor V Leiden, Microvascular occlusion, Prothrombin G20210A, Thrombophilia

Disseminated intravascular and coagulation disorders Carl-Erik Dempfle

Purpose of review Abbreviations An update on recent developments in diagnosis and treatment aPTT activated partial thromboplastin time of disseminated intravascular coagulation. DAA drotrecogin a (activated) DIC disseminated intravascular coagulation Recent findings FRM -related marker Disseminated intravascular coagulation is defined as a typical ISTH International Society for and Hemostasis condition with laboratory findings indicating massive # coagulation activation and reduction in procoagulant capacity. 2004 Lippincott Williams & Wilkins 0952-7907 Clinical syndromes associated with the condition are consumption , -induced fulminans, and viral hemorrhagic fevers. Consumption coagulopathy is Introduction observed in patients with sepsis, aortic aneurysms, acute The diagnosis of disseminated intravascular coagulation promyelocytic leukemia, and other disseminated malignancies. (DIC) is based on the combination of a disease condition Sepsis-induced is characterized by with laboratory findings indicating massive coagulation microvascular occlusion causing hemorrhagic necrosis of the activation and reduction in procoagulant capacity (Table skin and organ failure. Viral hemorrhagic fevers result in 1). Current scoring systems include elevated fibrin- massively increased production in monocytes and related markers (FRMs), prolonged , macrophages, inducing microvascular thrombosis and low count, and low fibrinogen level. Additional consumption of and coagulation factors. Current indicators of DIC are low levels of coagulation inhibitors scoring systems do not distinguish between patients with such as or C, and other indicators of asymptomatic disseminated intravascular coagulation, coagulation activation, such as –antithrombin consumption coagulopathy and thrombotic syndromes. Patients complexes and prothrombin fragment F1.2. Most with sepsis may be identified by activated partial thromboplastin investigators use D-dimer antigen or fibrin degradation time waveform analysis performed as part of routine coagulation product assays as FRMs, but assays for soluble fibrin may testing. Drotrecogin a (activated) reduces mortality in patients also be employed [1 .]. with severe sepsis with and without disseminated intravascular coagulation and has been used in patients with sepsis-induced Two scoring systems have been suggested for the purpura fulminans. Tifacogin does not reduce mortality in severe diagnosis of overt DIC: the system of the Japanese sepsis associated with impaired coagulation. Patients with Ministry of Health and Welfare [2], and the system of heterozygous Leiden and severe sepsis show- the International Society for Thrombosis and Hemo- ed a lower 28-day mortality than patients without this mutation, stasis (ISTH) [3]. Wada et al. [4] compared the results of supporting the assumption that an enhanced level of coagulation the scoring systems in a group of 1284 Japanese patients activation may be beneficial in patients with severe sepsis. with DIC and found an agreement of 67.4% for the Summary diagnosis of overt DIC. Wada et al.[5..] identified one Whereas antithrombin and tifacogin failed to improve clinical problem with the scores: both scoring systems use low outcome in severe sepsis, drotrecogin a (activated) increased fibrinogen levels as an indicator of DIC, although high the chances of survival of patients with severe sepsis with and rather than low fibrinogen levels are associated with poor without disseminated intravascular coagulation. clinical outcome. Despite this limitation, the diagnosis of Keywords overt DIC has a prognostic value in patients with sepsis disseminated intravascular coagulation, sepsis, drotrecogin a and other clinical conditions. According to the study of (activated), tifacogin, acute promyelocytic leukemia, aortic Gogos et al. [6] the diagnosis of overt DIC in patients aneurysm with sepsis is associated with a mortality of 62%, whereas the mortality of patients with sepsis without overt DIC is Curr Opin Anaesthesiol 17:125–129. # 2004 Lippincott Williams & Wilkins. 28%. Department of , University Hospital of Mannheim, Mannheim, Germany Correspondence to Prof. Dr med. Carl-Erik Dempfle, Department of Medicine, Consumption coagulopathy is an acquired University Hospital of Mannheim, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany disorder observed in patients with sepsis as well as in a Tel. +49 621 383 4002; e-mail: [email protected] variety of other diagnoses, ascribed to the consumption of Current Opinion in Anaesthesiology 2004, 17:125–129 procoagulant factors and platelets in the course of coagulation activation. The coagulation process may be

DOI: 10.1097/01.aco.0000124544.64032.5e 125 126 Intensive care

Table 1. Definitions of procoagulant conditions observed in sepsis it has been shown that patients with DIC frequently Consumption display an abnormality of the optical tracing of the Overt DIC coagulopathy Purpura fulminans clotting process during measurement of activated partial Clinical condition Laboratory criteria of Bacterial or viral thromboplastin time (aPTT). According to recent results which may be overt DIC infection which may this clotting waveform abnormality is related to the associated with Bleeding be associated with presence of sepsis rather than to DIC. DIC development of High FRM purpura fulminans Prothrombin time (meningococcal or Tifacogin prolongation/ pneumococcal Tifacogin is a recombinant tissue factor pathway increased INR infections, Decreased platelet hemophilus, others) inhibitor and was developed as a potential treatment count High FRM for sepsis. A phase II trial of the drug in 210 patients Decreased Low with severe sepsis showed a 20% reduction in 28-day all- level Microvascular thrombosis cause mortality. The effect was most prominent in (skin, organs) patients with an International normalized ratio (INR) in Tissue necrosis prothrombin time (PT) greater than 1.2 [13]. The Bleeding elevated INR may be interpreted as a sign of DIC, disseminated intravascular coagulation; FRM, fibrin-related marker. disseminated intravascular coagulation activation, lead- ing to reduced levels of factor VII and possibly factors II, V, X, and fibrinogen. Based on these data, a phase III trial, the OPTIMIST trial (Optimized phase 3 Tifacogin localized such as in vascular malformations or aneurysms, in multicenter international sepsis trial), was performed, or nonlocalized as in sepsis or disseminated malignant including 1754 patients with severe sepsis and an INR of disease. Purpura fulminans is found in the context of at least 1.2 [14 ..]. Patients were randomly assigned to an meningococcal [7], pneumococcal [8], and other bacterial intravenous infusion of 0.025 mg/kg per hour of tifacogin or viral infections [9–11]. Fibrin deposits can be detected or placebo for 96 h. The overall mortality at 28 days was in the microvasculature of the skin and various organs 34.2% for the tifacogin-treated group and 33.9% for the [12]. Patients with consumption coagulopathy and placebo group (P = 0.88). Interestingly, the mortality was purpura fulminans comprise a subgroup of patients with 29.1% for the tifacogin-treated group and 38.9% for the overt DIC. The current version of the ISTH DIC score placebo group at the first interim analysis after inclusion does not differentiate between patients with asympto- of 722 patients (P = 0.006), but this effect was not matic DIC and patients with consumption coagulopathy sustained during the further course of the study. Despite or purpura fulminans. The Japanese Ministry of Health the effect on coagulation activation (reduced levels of and Welfare DIC score includes bleeding as one thrombin–antithrombin complexes and other markers of parameter, but evidence of microvascular thrombosis or coagulation activation in plasma from patients treated tissue necrosis is not considered. with tifacogin), treatment with tifacogin did not result in increased survival in patients with severe sepsis. It is Treatment with drugs has been proposed possible that tifacogin is effective in subgroups of for various conditions associated with DIC, especially patients with DIC not identified by current classifica- severe sepsis. Three anticoagulant drugs have been tions, such as patients with sepsis-induced purpura tested in large multicenter, randomized, placebo-con- fulminans or viral hemorrhagic fevers, but further clinical trolled phase III trials: plasma-derived antithrombin, studies are needed. recombinant activated protein C (drotrecogin a (acti- vated) or DAA), and recombinant tissue pathway factor In the group of patients treated with tifacogin, mortality inhibitor (tifacogin). The results for antithrombin and was similar whether patients received concomitant low- DAA were published in 2001, the results of the tifacogin dose or not (34.6% versus 34.0%). In the placebo trial in 2003. For DAA, subgroup analyses published in group, patients who received low-dose heparin had a 2003 have revealed interesting information concerning much lower mortality (29.8% versus 42.7%). A similar patients with mutation and patients with finding was made in the KYBERSEPT study (Kybernin DIC. Protein C replacement has been proposed for in sepsis trial) of plasma-derived antithrombin concen- treatment of patients with sepsis-induced purpura trate in severe sepsis. Patients receiving placebo and fulminans, but in view of the impaired protein C low-dose heparin had the lowest mortality (36.6% versus activation in sepsis, treatment with activated protein C 43.6% for patients without heparin) [15]. In patients might be more effective. Massive release of tissue factor treated with high-dose antithrombin concentrate, mor- has been shown to cause DIC in primate models of viral tality was 37.6% for patients not treated with heparin, hemorrhagic fevers. This may be the basis for develop- and 39.4% for patients treated with heparin. In both the ment of therapeutic strategies in these . Finally, KYBERSEPT and the OPTIMIST study patients were Disseminated intravascular coagulation Dempfle 127 not randomized to receive heparin. In the OPTIMIST with homozygous factor V Leiden mutation, patients study, patients who received prophylactic heparin were with combination defects such as factor V Leiden found to be less severely ill than the corresponding mutation plus hereditary protein C or patients who did not receive heparin. Without appro- deficiency, or patients with heterozygous factor V priate randomized studies of heparin in patients with Leiden mutation and earlier venous thromboembolism. severe sepsis and other conditions associated with DIC, The effect of another common marker, it cannot be decided if patients should or should not the prothrombin G20210A mutation [27], which is receive heparin. Earlier studies have shown a high rate of also associated with increased in-vivo thrombin forma- venous thromboembolism in intensive care patients [16– tion [28], also needs to be determined. 18]. This may contribute to the adverse outcome of patients receiving neither heparin nor other anticoagu- Sepsis-induced purpura fulminans lant drugs. Infectious purpura fulminans is a syndrome of micro- vascular thrombosis with hemorrhagic infarction of the Drotrecogin a (activated) skin, extremity loss and multiple organ failure [29]. It In contrast to antithrombin and tifacogin, treatment with mainly occurs in patients with Neisseria meningitides, recombinant human activated protein C (DAA) reduced Streptococcus pneumoniae,orHaemophilus influenzae infec- mortality in patients with severe sepsis [19]. The reason tion, although additional hereditary or acquired factors may be the combination of profibrinolytic and anti- such as elevated levels of inhi- inflammatory effects of DAA in addition to the anti- bitor-1 may be necessary to initiate the syndrome coagulant effect. [30,31]. Sepsis-related purpura fulminans has been observed in patients double heterozygous for factor V Overt DIC, according to the laboratory criteria of the Leiden mutation and protein S deficiency [32], and DIC subcommittee of the ISTH [3], was present in 22% mutation and protein S deficiency of patients with severe sepsis included in the PRO- [33]. Typically, patients with sepsis-induced purpura WESS (Protein C worldwide evaluation in severe sepsis) fulminans have very low plasma levels of protein C. study [20 .]. The 28-day mortality was 30.5% in patients Protein C replacement with protein C concentrate has with overt DIC treated with DAA and 43.0% in patients therefore been recommended for treatment of such with overt DIC given placebo. A small number of patients. Only a dose of 150 IU/kg body weight or more patients with heterozygous factor V Leiden mutation given every 6 h resulted in significantly increased levels had been included in the study, although earlier deep of activated protein C in patients with purpura fulmi- or known APC (activated protein C) nans, whereas lower doses failed to cause an increase in resistance were exclusion criteria. Interestingly the activated protein C levels [34 ..]. A dose of 600 IU/kg mortality of patients with heterozygous factor V Leiden body weight per day increased plasma protein C levels to mutation was considerably lower (12.1% in patients 2–3 IU/ml and activated protein C levels to three- to treated with DAA, 15.6% in patients given placebo) than fourfold of baseline [34 ..]. No effect of protein C mortality of patients without the factor V Leiden concentrate infusion on mortality was found in the phase mutation (24.1% in patients treated with DAA, 31.0% II dose-finding study [34 ..]. Plasma exchange may be an in patients given placebo) [21 ..]. The higher level of alternative source of protein C and other plasma coagulation activation in patients with heterozygous components deficient in purpura fulminans [35]. factor V Leiden mutation appears to be beneficial in sepsis, supporting the assumption that ‘latent coagula- Protein C activation is impaired in patients with severe tion’ or nonovert DIC is part of the defense system sepsis [36,37]. Endothelial thrombomodulin and protein against sepsis. Fibrin binds active thrombin, thereby C receptor are reduced, and plasma levels of soluble modulating in-vivo thrombin activity [22 ..]. Fibrin is thrombomodulin shed from the endothelium are necessary for effective activation of plasminogen by increased in patients with sepsis [37]. Lignell et al. tissue plasminogen activator [23]. Thrombin modulates [38] found a prolonged half-life of protein C in a various cellular reactions by activation of protease- patient with meningococcal septic , indicating low activated receptors and activates protein C. Activated utilization of the proenzyme. It therefore seems logical protein C activates protease-activated receptor-1 [24 ..] to use activated protein C in patients with sepsis- and modulates inflammatory processes [25 .]. Inhibition induced purpura fulminans. The median level of of coagulation by treatment with coagulation inhibitors activated protein C in patients with severe sepsis such as heparin, or antithrombin impairs protein treated with DAA is 44.9 ng/ml, in contrast to levels C activation [26 .]. Therefore, a certain level of coagula- lower than 1 ng/ml typically found in patients with tion activation may be beneficial in patients with sepsis severe sepsis not treated with DAA [39 .]. Case reports or other assaults to the vascular system. There are no have been published on the use of DAA in meningo- published data on sepsis-related mortality of patients coccal sepsis [40,41]. 128 Intensive care

Hemorrhagic fevers Conclusion A specific type of DIC is observed in viral hemorrhagic For clinical use as well as clinical studies, the clinical fevers. Wills et al. [42 .] performed a prospective study in manifestations of DIC need to be considered. Asympto- 167 Vietnamese children with dengue hemorrhagic fever matic patients without bleeding or microvascular throm- and found low levels of fibrinogen, protein C, protein S, bosis fulfilling the laboratory criteria of overt DIC should and antithrombin. Levels of plasminogen activator be distinguished from symptomatic patients with acute inhibitor-1 correlated with bleeding severity, indicating hemorrhage or patients with microvascular thrombosis. A a link between microvascular occlusion and clinical certain level of coagulation activation is required for symptoms, similar to bacterial sepsis-induced purpura effective activation of plasminogen, the protein C fulminans. Geisbert et al. [43 ..] published results of system, and various cellular responses, and may be primate studies of Ebola hemorrhagic fever showing that beneficial in patients with sepsis, as shown by the fact tissue factor expression and release from Ebola virus- that patients with APC resistance caused by hetero- infected monocytes and macrophages is the key factor zygous factor V Leiden mutation display a considerably for the initiation of DIC and intravascular fibrin lower mortality in severe sepsis. Only DAA has shown an deposition. In parallel to coagulation activation, plasma effect on overall mortality of patients with severe sepsis levels of activated protein C drop, indicating dysfunc- and this effect is present in patients with and without tional protein C activation despite elevated levels of DIC. The aPTT waveform analysis may be helpful in thrombin. Hemorrhage in Ebola virus infection is not clinical routine for the early identification of patients with caused by virus-induced cytolysis of endothelial cells or sepsis, which may benefit from treatment with DAA. other mechanisms related to an infection of endothelial cells [44 .]. Treatment with DAA may also be helpful in patients with Ebola and other hemorrhagic fevers, but no References and recommended reading clinical trials or case reports have been published to date. Papers of particular interest, published within the annual period of review, have been highlighted as: Drugs directly affecting tissue factor-induced coagula- . of special interest tion activation such as tifacogin could also be effective. .. of outstanding interest

1 Nakahara K, Kazahaya Y, Shintani Y, et al. Measurement of soluble fibrin Abnormal activated partial thromboplastin . monomer–fibrinogen complex in plasmas derived from patients with various time waveform analysis underlying clinical situations. Thromb Haemost 2003; 89:832–836. Description of a new soluble fibrin assay currently under clinical investigation for Downey et al. [45,46] described an abnormality of the DIC and other clinical conditions. optical transmission waveform obtained during measure- 2 Wada H, Wakita Y, Nakase T, et al. Outcome of disseminated intravascular ment of the aPTT on a specific photometric hemostasis coagulation in relation to the score when treatment was begun. Mie DIC autoanalyzer, the MDA-180. This abnormality is related Study Group. Thromb Haemost 1995; 74:848–852. 3 Taylor FB Jr, Toh CH, Hoots WK, et al. Towards definition, clinical and to calcium-dependent formation of complexes between laboratory criteria, and a scoring system for disseminated intravascular very low density lipoprotein and C-reactive protein coagulation. Thromb Haemost 2001; 86:1327–1330. .. [47 ,48], and has been shown to be predictive for DIC 4 Wada H, Gabazza EC, Asakura H, et al. Comparison of diagnostic criteria for disseminated intravascular coagulation (DIC): diagnostic criteria of the [45,46]. The majority of patients with DIC in these International Society of Thrombosis and Hemostasis and of the Japanese studies were intensive care patients diagnosed with Ministry of Health and Welfare for overt DIC. Am J Hematol 2003; 74:17–22. . sepsis. Toh et al. [49 ] examined 1187 consecutive 5 Wada H, Mori Y, Okabayashi K, et al. High plasma fibrinogen level is .. patients admitted to an and found an associated with poor clinical outcome in DIC patients. Am J Hematol 2003; 72:1–7. abnormal aPTT waveform in 29.1%. The mortality of Report showing that high rather than low plasma fibrinogen levels are indicators of patients with abnormal aPTT waveform was 44%, adverse outcome in sepsis and other clinical conditions associated with DIC. compared with 26% in patients without the aPTT 6 Gogos CA, Lekkou A, Papageorgiou O, et al. Clinical prognostic markers in patients with severe sepsis: a prospective analysis of 139 consecutive cases. waveform abnormality. Most patients with the aPTT J Infect 2003; 47:300–306. waveform abnormality suffered from sepsis. The results 7 Haslund R. Waterhouse Friderichsen syndrome: endotoxin shock treated of Toh et al. were confirmed by an investigation of with massive doses of cortisol. J Oslo City Hosp 1973; 23:49–64. Fernandes and Giles [50] showing a 3-month mortality of 8 Auburtin M, Porcher R, Bruneel F, et al. Pneumococcal meningitis in the intensive care unit: prognostic factors of clinical outcome in a series of 80 42.6% in patients with an abnormal aPTT waveform. cases. Am J Respir Crit Care Med 2002; 165:713–717. Overt DIC according to the criteria of the ISTH was 9 Lineaweaver W, Franzini D, Dragonetti D, et al. Haemophilus influenzae present in only 10% of patients with abnormal aPTT meningitis and Waterhouse-Friderichsen syndrome in an adult. South Med J waveform, but sepsis was diagnosed in 54%. Although 1986; 79:1034–1036. 10 Canpolat C, Bakir M. A case of purpura fulminans secondary to transient most patients with abnormal aPTT waveform have as a complication of chickenpox infection. Turk J Pediatr clinical conditions that may be associated with DIC, 2002; 44:148–151. the abnormal aPTT waveform appears to be an indicator 11 Karakousis PC, Page KR, Varello MA, et al. Waterhouse-Friderichsen syndrome after infection with group A streptococcus. Mayo Clin Proc 2001; of sepsis rather than coagulation activation. The 76:1167–1170. abnormal aPTT waveform is an indicator for high 12 Fox B. Disseminated intravascular coagulation and the Waterhouse- mortality in intensive care unit patients. Friderichsen syndrome. Arch Dis Child 1971; 46:680–685. Disseminated intravascular coagulation Dempfle 129

13 Abraham E, Reinhart K, Svoboda P, et al. Assessment of the safety of 33 al-Ismail S, Collins P, Najib R, et al. Postinfection purpura fulminans in a recombinant tissue factor pathway inhibitor in patients with severe sepsis: a patient heterozygous for prothrombin G20210A and acquired protein S multicenter, randomized, placebo-controlled, single-blind, dose escalation resistance. Pediatr Hematol Oncol 1999; 16:561–564. study. Crit Care Med 2001; 29:2081–2089. 34 de Kleijn ED, de Groot R, Hack CE, et al. Activation of protein C following 14 Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin .. infusion of protein C concentrate in children with severe meningococcal .. (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized sepsis and purpura fulminans: a randomized, double-blinded, placebo- controlled trial. JAMA 2003; 290:238–247. controlled, dose-finding study. Crit Care Med 2003; 31:1839–1847. Original publication of the OPTIMIST Phase III trial of tifacogin in severe sepsis Good pharmacokinetic and pharmacodynamic study of protein C concentrate in showing no effect on 28-day mortality. patients with meningococcal purpura fulminans. 15 Warren BL, Eid A, Singer P, et al. Caring for the critically ill patient: high-dose 35 Hodgson A, Ryan T, Moriarty J, et al. Plasma exchange as a source of protein antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; C for acute onset protein C pathway failure. Br J Haematol 2002; 116:905– 286:1869–1878. 908. 16 Marik PE, Andrews L, Maini B. The incidence of deep venous thrombosis in 36 Yan SB, Dhainaut JF. Activated protein C versus protein C in severe sepsis. ICU patients. Chest 1997; 111:661–664. Crit Care Med 2001; 29:S69–S74. 17 Hirsch DR, Ingenito EP, Goldhaber SZ. Prevalence of deep venous thrombosis among patients in medical intensive care. JAMA 1995; 37 Faust SN, Levin M, Harrison OB, et al. Dysfunction of endothelial protein C 274:335–337. activation in severe meningococcal sepsis. N Engl J Med 2001; 345:408– 416. 18 Fraisse F, Holzapfel L, Couland JM, et al. Nadroparin in the prevention of deep thrombosis in acute decompensated COPD. The Association of 38 Lignell A, Siegbahn A, Stridsberg M, et al. Low utilisation of unactivated Non-University Affiliated Intensive Care Specialist of France. Am J protein C in a patient with meningococcal and disseminated Respir Crit Care Med 2000; 161:1109–1114. intravascular coagulation. Acta Anaesthesiol Scand 2003; 47:897–900. 19 Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant 39 Macias WL, Dhainaut JF, Yan SC, et al. Pharmacokinetic-pharmacodynamic human activated protein C for severe sepsis. N Engl J Med 2001; 344:699– . analysis of drotrecogin alfa (activated) in patients with severe sepsis. Clin 709. Pharmacol Ther 2002; 72:391–402. Additional data from the PROWESS study on DAA. 20 Ely EW, Laterre PF, Angus DC, et al. Drotrecogin alfa (activated) . administration across clinically important subgroups of patients with severe 40 Weisel G, Joyce D, Gudmundsdottir A, Shasby DM. Human recombinant sepsis. Crit Care Med 2003; 31:12–19. activated protein C in meningococcal sepsis. Chest 2002; 121:292–295. Evaluation of the PROWESS study data concerning DIC and other parameters. 41 Bachli EB, Vavricka SR, Walter RB, et al. Drotrecogin alfa (activated) for the 21 Kerlin BA, Yan SB, Isermann BH, et al. Survival advantage associated with .. treatment of meningococcal purpura fulminans. Intensive Care Med 2003; heterozygous factor V Leiden mutation in patients with severe sepsis and in 29:337. mouse endotoxemia. 2003; 102:3085–3092. Evaluation of the PROWESS study data showing a survival advantage of patients 42 Wills BA, Oragui EE, Stephens AC, et al. Coagulation abnormalities in with heterozygous factor V Leiden mutation in severe sepsis. . dengue hemorrhagic fever: serial investigations in 167 Vietnamese children 22 Mosesson MW. Antithrombin I: inhibition of thrombin generation in plasma by with Dengue shock syndrome. Clin Infect Dis 2002; 35:277–285. .. fibrin formation. Thromb Haemost 2003; 89:9–12. Good clinical characterization the clinical picture of dengue hemorrhagic fever. Very informative paper on ‘antithrombin I’, the inhibition of thrombin by adsorption 43 Geisbert TW, Young HA, Jahrling PB, et al. Mechanisms underlying to fibrin. .. coagulation abnormalities in Ebola hemorrhagic fever: overexpression of 23 Yakovlev S, Makogonenko E, Kurochkina N, et al. Conversion of fibrinogen to tissue factor in primate monocytes/macrophages is a key event. J Infect Dis fibrin: mechanism of exposure of tPA- and plasminogen-binding sites. 2003; 188:1618–1629. Biochemistry 2000; 39:15730–15741. Very important animal study on Ebola hemorrhagic fever giving data on the mechanism of coagulation activation and DIC in this rare but frequently lethal 24 Riewald M, Petrovan RJ, Donner A, et al. Activation of endothelial cell disease. .. protease activated receptor 1 by the protein C pathway. Science 2002; 296:1880–1882. 44 Geisbert TW, Young HA, Jahrling PB, et al. Pathogenesis of Ebola Important paper for explaining the antiinflammatory activity of activated protein C, . hemorrhagic fever in primate models: evidence that hemorrhage is not a showing direct activation of protease-activated receptor 1. direct effect of virus-induced cytolysis of endothelial cells. Am J Pathol 2003; 163:2371–2382. 25 Joyce DE, Grinnell BW. Recombinant human activated protein C attenuates Study showing that the pathomechanism of Ebola hemorrhagic fever is probably . the inflammatory response in endothelium and monocytes by modulating not related to endothelial dysfunction or ‘endothelitis’. nuclear factor-kappaB. Crit Care Med 2002; 30:S288–S293. Paper on the antiinflammatory mechanisms induced by treatment with DAA. 45 Downey C, Kazmi R, Toh CH. Novel and diagnostically applicable information 26 Linder R, Frebelius S, Jansson K, Swedenborg J. Inhibition of endothelial cell- from optical waveform analysis of blood coagulation in disseminated . mediated generation of activated protein C by direct and antithrombin- intravascular coagulation. Br J Haematol 1997; 98:68–73. dependent thrombin inhibitors. Blood Coagul 2003; 14:139–146. 46 Downey C, Kazmi R, Toh CH. Early identification and prognostic implications In-vitro study showing that coagulation inhibition by antithrombin, heparin, low in disseminated intravascular coagulation through transmittance waveform molecular weight heparin and thrombin inhibitors interferes with protein C analysis. Thromb Haemost 1998; 80:65–69. activation. 47 Toh CH, Samis J, Downey C, et al. Biphasic transmittance waveform in the 27 Franco RF, Trip MD, ten Cate H, et al. The 20210 G?A mutation in the 3’- .. APTT coagulation assay is due to the formation of a Ca(++)-dependent untranslated region of the prothrombin gene and the risk for arterial complex of C-reactive protein with very-low-density lipoprotein and is a novel thrombotic disease. Br J Haematol 1999; 104:50–54. marker of impending disseminated intravascular coagulation. Blood 2002; 28 Eikelboom JW, Ivey L, Ivey J, Baker RI. Familial thrombophilia and the 100:2522–2529. prothrombin 20210A mutation: association with increased thrombin genera- Elucidation of the aPTT waveform slope-1 phenomenon in intensive care unit tion and unusual thrombosis. Blood Coagul Fibrinolysis 1999; 10:1–5. patients. 29 Childers BJ, Cobanov B. Acute infectious purpura fulminans: a 15-year 48 Nesheim M, Samis J, Walker J, et al. Lipoprotein-complexed C-reactive retrospective review of 28 consecutive cases. Am Surg 2003; 69:86–90. protein and the biphasic transmittance waveform in critically ill patients. Blood 30 Westendorp RG, Hottenga JJ, Slagboom PE. Variation in plasminogen- Rev 2002; 16 (Suppl 1):S15–S22. activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet 49 Toh CH, Ticknor LO, Downey C, et al. Early identification of sepsis and 1999; 354:561–563. . mortality risks through simple, rapid clot-waveform analysis: implications of 31 Hermans PW, Hibberd ML, Booy R, et al. 4G/5G promoter polymorphism in lipoprotein-complexed C reactive protein formation. Intensive Care Med the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal 2003; 29:55–61. disease. Meningococcal Research Group. Lancet 1999; 354:556–560. Clinical data on the predictive value of aPTT waveform analysis, showing that the waveform abnormality is in most cases related to sepsis. 32 Inbal A, Kenet G, Zivelin A, et al. Purpura fulminans induced by disseminated intravascular coagulation following infection in 2 unrelated children with 50 Fernandes B, Giles A. An abnormal activated partial thromboplastin time double heterozygosity for factor V Leiden and . Thromb clotting waveform is associated with high mortality and a procoagulant state. Haemost 1997; 77:1086–1089. Lab Hematol 2003; 9:138–142.