Disseminated Intravascular CHAPTER 29 Velu Nair

Introduction The syndrome can be considered to involve a 2 Disseminated intravascular coagulation (DIC) is phase phenomenon: a hypercoagulable phase that an acquired hypercoagulable state, induced by the leads into a hypocoagulable phase manifesting in progressive generation of in circulation. It . Most physicians encounter patients in the is a pathophysiologic term describing a continuum hypocoagulable state with bleeding manifestations in of events that occur in the coagulation pathway as critical illnesses. The thrombotic complications are a complication of many different serious and life- more frequently seen in patients with malignancies threatening disease states. The International Society who run a chronic course. In acute promyelocytic on and Hemostasis has suggested the patient usually presents with bleeding the following definition for DIC: “An acquired tendency secondary to DIC triggered by the syndrome, characterized by the intravascular granules released from the promyelocytes. activation of coagulation with loss of localization DIC is initiated by the activation of the arising from different causes. It can originate clotting cascade, mainly the tissue factor (TF) from and cause damage to the microvasculature, pathway. Diagnosis of DIC can be difficult, which if sufficiently severe, can produce organ depending upon the phase in which a diagnosis is dysfunction.1 DIC occurs in acute and chronic attempted, since many laboratory parameters can forms. In its acute (overt) form it is a hemorrhagic be normal in the hypercoagulable phase except disorder, characterized by multiple ecchymoses, for a falling count. The diagnosis of the mucosal bleeding and consumption of hypocoagulable phase is easier, as the patient and clotting factors. Chronic (nonovert) DIC, manifests clinical bleeding with abnormalities in on the other hand, is more subtle and involves global coagulation parameters. venous thromboembolism (VTE) accompanied by DIC is seen in association with a number of well- evidence of activation of the coagulation system defined clinical situations, including sepsis, major and is associated with conditions like malignancies trauma, and abruptio placenta with laboratory and intrauterine death of fetus. With chronic DIC, evidence of the following1 coagulation factors may be normal, increased, or moderately decreased, as may the platelet • Activation of procoagulant pathway counts.2 • Activation of fibrinolytic pathway Disseminated Intravascular Coagulation 231

• Inhibitor (natural ) The mortality rates in different diseases complicated consumption by DIC is as under: • Evidence of end-organ damage or failure • Septic abortion with shock due to clostridial Though numerous laboratory tests are available infection associated with severe DIC has a to monitor DIC, most patients are managed mortality rate of 50%. successfully using only routine screening tests, • In major trauma, the presence of DIC platelet counts and assays for and approximately doubles the mortality rate. D-dimer. Treatment of DIC should focus on • Idiopathic fulminans associated with reversing the underlying disorder initiating the DIC has a mortality rate of 18%. . Supportive care with appropriate Sex: Incidence is equal in males and females. blood components is paramount to minimise the mortality and morbidity. By and large, the outcome Age: No age predilection is known. of DIC is dictated by the severity of the underlying disorders leading to DIC and how successfully Pathogenesis they can be managed. Novel treatments are being The pathogenetic pathways of DIC have been largely investigated for treating DIC, many of which target clarified by recent studies in animal models and humans. the excessive TF activity that characterizes DIC. DIC occurs when monocytes and endothelial cells are activated by toxic substances elaborated in the course Frequency of certain diseases. These cells generate TF, which • DIC may occur in 30-50% of patients with sepsis in turn activates the coagulation cascade generating with equal frequency in gram negative and thrombin. Thrombin leads to systemic formation positive bacterial infections. In patients with of fibrin.3 Simultaneously, there is consumption of severe trauma who have a systemic inflammatory naturally occurring anticoagulants and a delayed response syndrome, DIC can occur in 50-70% removal of fibrin due to impairment in the fibrinolytic patients, particularly in patients with neuro- pathways. Several pro-inflammatory cytokines play a trauma. In obstetrical patients with abruptro pivotal role in the causation of systemic inflammatory placentae, septic abortions and amniotic fluid response. The principal cytokines involved appears to embolism, DIC occurs in more than 50% be interleukin -6, interleukin -1β and tumor necrosis patients. Cancer patients with metastatic tumors factor-α which are active in both polytrauma and 4 have DIC in approximately 10-15% patients and sepsis. it occurs in 15% cases with acute leukemia with Thrombin is generated predominantly by the highest frequency in APML.1 extrinsic pathway (involving tissue factor and • Incidence of DIC varies with the energy with activated factor VII) the inhibition of which totally which the diagnosis is pursued. High index suppressed endotoxin induced thrombin generation of clinical suspicion is warranted in a clinical in animal models. However, interference with the setting for DIC. The incidence is 1:1000 intrinsic pathway did not in anyway affect activation 4 admissions in a general hospital. Most of these of coagulation. data is from the West and there is a need to There is a decrease in the levels of all major generate epidemiological data from India. physiological anti-coagulants like anti-thrombin III, protein C and tissue factor pathway inhibitor Morbidity / Mortality (TFPI). Anti-thrombin III which is the most potent Morbidity and mortality depend on both, the thrombin inhibitor, is markedly reduced due to underlying disease and the severity of coagulopathy. consumption, impaired synthesis and degradation 232 Update 2008  Vol. 18

Table 1 : Conditions underlying DIC syndrome cutaneous bleeds should always raise the possibility Infections of DIC in the ICU setting. Look for symptoms Acute DIC: Bacteria and their toxins, fungi, viruses, and signs of thrombosis in large vessels, such as rickettsiae Chronic DIC: Chronic infection. e.g., tuberculosis, DVT, and of microvascular thrombosis, such as abscesses, osteomyelitis renal failure. Bleeding from at least 3 unrelated Obstetrical complications sites is particularly suggestive of DIC. Patient can Acute DIC: Abruptio placentae, abortions (especially therapeutic and septic abortions), amniotic fluid present with varied symptoms due to affection of embolism, hemorrhagic shock any organ in the body. The common presentation Chronic DIC: Dead fetus syndrome include. Trauma Acute DIC: Polytrauma; neurotrauma • Skin ecchymosis, bleeding from I/V sites, Venoms endotracheal tubes and urinary catheters Acute DIC: bites and rarely spider bites • Gingival bleeding, epistaxis Malignancy Acute DIC: Acute promyelocytic leukemia, acute • Cough, dyspnea myelomonocytic or monocytic leukemia, disseminated prostatic carcinoma • Confusion, disorientation Chronic DIC: Gastrointestinal, lung and breast • Fever malignancy Vascular disease Acute and Chronic DIC Acute DIC: Brain infarction or hemorrhage Chronic DIC: Aortic aneurysm, giant hemangioma Acute DIC is the most commonly seen form in clinical Noninfectious inflammatory diseases practice and presents with bleeding manifestations Inflammatory bowel disease: Crohn’s disease and similar from various sites. It is a hematological emergency disorders and is rapidly progressive because of explosive Others generation of thrombin. (PT) Acute DIC: Heparin-induced with thrombosis (HITT); in newborns and activated partial time (APTT) (homozygous ); transfusion of ABO are prolonged along with hypofibrinogenemia and incompatible red cells. thrombocytopenia. FDP and D-Dimer levels are by elastase released from activated neutrophils. increased. The decrease in total protein-C levels is caused Chronic DIC is less explosive as there is time by consumption and impaired synthesis. The fibrinolytic system is suppressed at the time of for compensatory responses to take place. Usually maximal activation of coagulation. This inhibition presents with features of hyper-coagulable state is caused by a sustained increase in the levels of with or without VTE. Platelet levels are low plasminogen activator inhibitor type -1 (PAI-1). along with raised levels of FDP and D-Dimer. PT Though secondary fibrionolysis occurs in response and APTT may be normal or mildly prolonged. to fibrin formation, its activity is too low to APTT may be shortened in the hyper-coagulable counteract systemic deposition of fibrin. phase. Clinical Features Conditions Associated with DIC In addition to the symptoms related to the The conditions that regularly give rise to the underlying disease, ascertain history of blood loss DIC syndrome are outlined in Table 1. A high such as gastrointestinal bleeding and hypovolemia. index of clinical suspicion in a given setting helps Fresh bleeding from the percutaneous intravenous anticipate onset of DIC with timely intervention catheter sites in an ICU patient with muco- by the physician. Disseminated Intravascular Coagulation 233 Differential Diagnosis 3. Fibrinogenolysis A number of clinical disorders can result in acquired This condition presents with bleeding diathesis bleeding diathesis and hemostatic laboratory and is caused by severe liver disease, puerperium, abnormalities and needs to be distinguished from post CABG and in disseminated neoplasm. DIC. Some of these common conditions are as It is characterized by hypo-fibrinogenemia, under. prolonged PT & APTT with elevated FDP. 1. Liver Disease and DIC However, the platelet counts and D-Dimer levels are normal. Management involves treatment Patients with advanced liver disease are prone of the underlying cause, use of anti-fibrinolytic to a number of hemostatic and thrombotic (tranexamic acid) agents and supportive care derangements. The various factors responsible with cryoprecipitate to replenish fibrinogen for these are altered hepatic synthesis of levels. coagulation factors, fibrinolytic proteins and natural inhibitors. Besides this the patients 4. Disorders of Hemostasis have impaired renal clearance of these At times, acquired disorders of coagulation may activated proteins. Portal hypertension leads mimic a picture of DIC but the clinical profile to splenomegaly with enhanced platelet and laboratory parameters (correctible factor sequestration and thrombocytopenia. The deficiency) differentiate hemostasis related tests reflecting thrombin generation such disorders from DIC. as Protamine paracoagulation assay, the K deficiency is seen after prolonged prothrombin fragment 1.2, thrombin- antibiotic therapy, malnutrition and liver antithrombin (TAT) complex levels and disease. It can present with the bleeding D-dimer levels may help exclude liver disease. diathesis with abnormal coagulation profile. Factor VIII levels will be normal in liver However, D-Dimer levels will be normal. disease without DIC. 5. Thrombocytopenia 2. Thrombotic Micro-angiopathies (TMA) It can result from bone marrow failure These should be suspected when patient has a syndromes, immune destruction or systemic classical picture of TMA e.g, microangiopathic illnesses. Laboratory results can easily hemolytic (MAHA), neurological differentiate between these. It is important to manifestations, fever, thrombocytopenia differentiate thrombocytopenia, secondary to and renal dysfunction or at least three out of bone marrow involvement from that due to DIC. these (MAHA, neurological symptoms and In thrombocytopenia due to DIC, glycocalicin thrombocytopenia). It resolves rapidly after (released from degraded GP1b/IX complex) child birth and usually does not recur. levels are raised. Platelet activating factor, HELLP(hemolysis with elevated liver enzymes released from neutrophils and endothelial cells and low platelets) syndrome is a TMA seen in acute inflammatory diseases, is raised and in 20% patients with pregnancy and severe correlates inversely with platelet counts. pre-eclampsia. More common in multiparous women and 70% cases occur before 27 weeks Laboratory Studies of gestation. This is a multisystem disorder No single laboratory test is diagnostic of DIC. characterized by MAHA, hepatic dysfunction, A clinical setting, wherein, DIC is known to raised LDH levels and thrombocytopenia. In occur along with a combination of screening its severe form DIC can also occur. and confirmatory tests helps in arriving at a 234 Medicine Update 2008  Vol. 18 diagnosis of DIC. It involves tests for thrombin formation of fibrin monomer, which is cross-linked and plasmin generation and screening tests for by F XIIIa.6 hemostatic function that delineate the severity The D-Dimer Test of coagulation factor consumption. Although abnormalities in the screening assays such as the D-dimer is very sensitive test for the diagnosis of DIC PT, a PTT or platelet count may provide important and has a high negative predictive value of > 90% corroborative evidence of hemostatic component (normal value 0.2 to 0.5 µg/ml; cutoff values varies 7 consumption, the diagnosis of DIC should not be with the type of assay kit) . It detects plasmin-cleaved, made without at least one positive test indicative insoluble, cross-linked fibrin. A positive test confirms of excessive of thrombin generation (Table 2). The the formation of both thrombin and plasmin, making it two most readily available tests that document the a powerful diagnostic test for DIC. Thrombin cleaves excess activity of thrombin are immunoassays for fibrinogen to liberate fibrinopeptides A and B, leaving D-dimers and protamine Para coagulation assay for fibrin monomer. Thrombin also activates factor XIII fibrin monomer.5 to induce soluble fibrin monomer to interact end- to-end and side-to-side, causing it to become cross- Laboratory diagnosis consists of 2 stages: (1) linked, making the soluble protein insoluble.5 When Screening assays and (2) Confirmatory assays. plasmin forms, it cleaves insoluble, cross-linked, The Screening Tests fibrin monomer that is held together by its D domains The common screening tests used to diagnose DIC liberating a dimer of the D domain, which is measured are by the antibody directed to this region. D-dimers may be falsely elevated in patients who have undergone • Prothrombin time (PT), recent surgery, trauma, renal, liver and cardiac failure.6 • Activated partial thromboplastin time (a Therefore, patients with D-dimer level < 0.5 µg/ml PTT), should not be diagnosed as having DIC unless there • Platelet count, is other corroborative evidence. • Fibrinogen level. The Fibrin Degradation Products (FDPs) If 2 of these tests are abnormal, diagnosis is FDPs are a measure of plasmin-cleaved fibrinogen or possible; if 3 tests are abnormal, diagnosis is fibrin. Fibrin/fibrinogen degradation products (FDP’s) probable if all tests are abnormal, diagnosis is do not distinguish between the plasmin degradation most likely. The scoring system for DIC mentioned by-product of either fibrin or fibrinogen. FDPs have a earlier is useful in arriving at a diagnosis of DIC.2 sensitivity of 85% and specificity of only 50% (normal value < 10 µg/ml). It is increased in DIC, primary Occasionally the snakebite of rattle snake fibrinolysis, hepatic & renal failure and post surgery. A (Crotalus horridus) will lyse fibrinogen and aggregate combination of FDP and D-dimer has 100% specificity platelets but will not cause DIC because there is no and sensitivity. increased thrombin or plasmin formation. In these patients, if one measures all coagulation factors, Other tests available but not routinely done are, they are within normal range. The thrombin time can be prolonged because Confirmatory Tests of fibrinogen consumption. These provide objective evidence of simultaneous Detecting thrombin (TAT) complexes in plasma thrombin and plasmin generation and are listed in suggests prior thrombin formation. Table 2. D-dimers are the proteolytic by-products Plasma levels of factors V and VIII can be of plasmin degradation of cross-linked fibrin low in patients with acute and severe DIC. Normal polymers. The formation of D-dimers requires prior or elevated levels do not exclude the diagnosis. Disseminated Intravascular Coagulation 235

Table 2 : Lab tests in DIC Table 3 : Scoring system for overt Disseminated 2 Screening assays for factor and platelet consumption Intravascular Coagulation (DIC) • Platelet count 1. Risk assessment: Does the patient have an underlying disorder known to be associated with overt DIC? • Prothrombin time (PT) If yes: Proceed. • Activated partial thromboplastin time (APTT) If no: Do not use this algorithm. • Thrombin time (TT) 2. Order global coagulation tests (platelet count, prothrombin • Quantitative fibrinogen assay time, fibrinogen, fibrin related marker) Laboratory markers of thrombin generation 3. Score global coagulation test results. • D-dimers • Platelet count • Protamine paracoagulation assay for fibrin monomer (> 100 = 0; < 100 = 1; < 50 = 2) • Ethanol gel assay for fibrin monomers • Elevated fibrin related marker (e.g. D-Dimers; fibrin • Fibrinopeptide A degradation products) • Prothrombin fragment 1.2 (no increase = 0; moderate increase = 2; strong • Thrombin-antithrombin complex increase = 3) Ancillary tests • Prolonged prothrombin time • FDP’S (< 3 sec = 0; > 3 but < 6 sec = 1; > 6 sec = 2) • Euglobin test • Fibrinogen level • Antithrombin levels (>1.0 g/l = 0; < 1.0 g/l = 1) • Antiplasmin levels 5. Calculate score • level If ≥ 5: compatible with overt DIC: repeat score daily If < 5: suggestive (not affirmative) for non-overt DIC: Schistocytes can be observed on a peripheral repeat next 1-2 days. smear, although only in a minority of patients. In the presence of established DIC the A useful scoring system to help diagnose DIC cornerstone remains identification and aggressive has been formulated by the International Society of management of the underlying cause accompanied Thrombosis and Hemostasis (Table 3). The scoring by timely, appropriate supportive care. There system is applied only if the patient has a clinical may be difficulty in determining the extent of setting for DIC. This has to be done dynamically consumption of clotting factors and fibrinolysis in on a daily basis. each case. Frequent monitoring of blood counts There are a large number of tests available to and coagulation parameters helps in optimising be done in DIC. However, in routine practice supportive care. Monitoring of circulatory volume in most cases diagnosis of DIC can be made by status, gas exchange and electrolyte balance is also demonstrating thrombocytopenia and schistocytes. of paramount importance. (in a minority) along with prolongation of PT, a Prompt treatment of the underlying cause of DIC PTT and TT. Fibrinogen levels will be low. viz., optimal antibiotics in sepsis syndrome, uterine Management of DIC evacuation for abruptio placentae, restoration of hemodynamic stability for , When there is no bleeding or VTE with only antisnake venom for snake bite is considered the laboratory evidence of DIC, it is best to observe most important part of management. these patients without any replacement therapy and aggressively treat the underlying disease. No efforts Antibiotics should be spared to identify the underlying disease Antibiotics are started after taking blood cultures at the earliest. and is always administered intravenously. Careful 236 Medicine Update 2008  Vol. 18 planning using the hospital infection committee very few situations. Heparin potentiates the guidelines to decide on the type of antibiotics used naturally occurring plasma protease inhibitor, to treat the nosocomial infections will be an effective antithrombin, to inhibit thrombin, factor Xa, strategy. Outcomes are worse if the micro-organism and other coagulation enzymes. In patients with is insensitive to the initial antibiotic regimens. adequate levels of antithrombin, the addition of Component Support heparin may increase the inhibitory activity of this protease.8 Since heparin is a potent , Blood component support where indicated it can itself, accelerate bleeding. Heparin probably especially replacement of platelets and clotting is best reserved for patients who have self-limited factors minimises bleeding episodes. There is evidence of digital ischemia and acral cyanosis no truth in the old notion that blood component and in chronic DIC with VTE. Heparin therapy therapy adds “fuel to fire” theory. is also useful in patients with purpura fulminans Platelet Transfusion from protein C or S deficiency, a retained dead fetus and migratory thrombophlebitis. Its use in Platelets should be maintained around 20-30,000 / acute DIC is, controversial. cumm in a bleeding patient. In case there is major bleed or if there is an organ dysfunction a higher Indications level may be required. One unit of random donor Chronic DIC of malignancy platelet raises the count by approximately 5000 Clinical thrombosis: dermal necrosis, purpura - 8000/cumm assuming normal splenic pooling. fulminans, acral ischemia, VTE Single donor platelet harvested by apheresis raises the platelet count by 20-40,000/ cumm. As far as Retained dead fetus with hypofibrinogenemia feasible platelet should be of same blood group. AML-M3 prior to conventional chemotherapy Presence of fever, active bleeding and use of drugs In acute DIC when there is persistent bleeding like amphotericin will lower platelet counts. and there is no rise in platelets or clotting factors Cryoprecipitate despite adequate replacement therapy, implying Cryoprecipitate is rich in fibrinogen, factor VIII ongoing consumptive coagulopathy, a trial of low and vWF and is infused to maintain fibrinogen level dose of Heparin (300-500 U / hour) may be tried > 100 mg/dL. The fibrinogen content of each unit along with appropriate replacement therapy varies from 100-250 mg depending upon processing Reduce the dose of heparin from that used for techniques. Thus 1- 2 units/ 10 Kg can be given. anticoagulation therapy for the management of Fresh Frozen Plasma (FFP) DVT. Usually, heparin therapy is initiated without any loading dose as a constant infusion adjusting FFP provides all clotting factors and helps to dose every 4 hours by 100-200 U/h. The decision correct PT/ APTT. It should be given in a dose to make an adjustment in the dose depends on the of 10-15 ml/ kg every 8 to 12 hourly. Ideally PT/ changes in the monitored parameters e.g. a rise APTT should be repeated 6 hourly at the onset of or fall in platelet count, fibrinogen level, FDP therapy, but tests done once a day in the morning and D-dimer levels. A rise in platelet counts and as a routine may be sufficient. Transfusion can be fibrinogen level is a sensitive marker indicating stopped once lab parameters are corrected and improvement in DIC status. clinical status improves. However, it is important to appreciate that Heparin heparin is less likely to improve outcome in the Use of heparin is a theoretically attractive presence of ongoing DIC and can exacerbate proposition but it is practically used in bleeding in these patients. Disseminated Intravascular Coagulation 237 LMWH is as effective in DIC as un-fractionated and heparin. Such a situation arises due to heparin providing reproducible anticoagulation circulating FDP’s. with less frequent dosing. The incidence of heparin induced thrombocytopenia is much lower with use Complications of LMWH. Organ infarction and limb ischemia may occur. Hence in nutshell heparin has very limited role in Renal, adrenal, and respiratory failure followed the management of DIC. Its use should be guided by multi-organ dysfunction may occur. More often by institutional protocols. death occurs due to infection or even uncontrolled bleeding. Synthetic Inhibitors of Thrombin Prognosis In heparin induced thrombocytopenia (HIT) and when heparin is ineffective in the presence of The prognosis depends on the underlying disorder. antithrombin deficiency, these agents can be used If the condition is self-limiting then the prognosis as they directly inhibit thrombin. Antithrombin is is good. Aggressive approach towards antibiotic not required for their action. It includes agents such therapy is paramount as a delay in instituting as recombinant hirudin, desirudin, bivalirudin, appropriate antibiotics will have a negative impact argatroban, melagatran/ ximelagatran and on the outcome. The requirement for optimal blood dabigatran. The last two are oral agents. These component support can not be over emphasised. A drugs have a potential disadvantage as they do not team approach with good co-ordination between the have an antidote. hematologist, critical care team, laboratory services and the blood bank is most helpful. Prognosis is Anti-Thrombin Concentrates poor if there is: Anti-thrombin concentrates neutralize thrombin, generated during DIC and potentially ameliorate • Failure to recognize the underlying etiology. thrombosis.9,10 This effect is more understandable in • Failure to understand that a good outcome presence of hepatic insufficiency. However, there is dependent on the nature of the underlying is no improvement in mortality. etiology, than on the DIC itself as illustrated by Activated Protein-C Concentrates the following examples. Activated protein C has been used in DIC associated • A patient with acute DIC that is associated with gram negative septicemia.11 But its use in other with metastatic gastric carcinoma is likely situations is less well established. Further studies to be fatal, regardless of treatment. are needed to determine its utility in DIC. • Alternatively, a patient with acute DIC Fibrinolysis Inhibitors associated with abruptio placenta needs quick recognition and obstetric treatment; These act by blocking secondary fibrinolysis that the DIC resolves on treating the obstetrical accompanies DIC. The commonly used ones are catastrophe. tranexamic acid and aminocaproic acid. Under most circumstances these should not be used. They Conclusion are useful in certain situations like: 12 An awareness of the clinical setting in which • When intense primary fibrinogenolysis can be DIC can occur and the diagnostic features that demonstrated in association with disease states warn of its presence will help the physician to like acute promyelocytic leukemia. diagnose and treat DIC appropriately. Failure to • When patient is bleeding profusely, not do so can lead to development of complications responding to therapy even after components of DIC which can be devastating. The focus 238 Medicine Update 2008  Vol. 18

should be on treating the underlying cause of 4. Franchini M, Lippi G, Manzato F. Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated DIC accompanied by optimal supportive care intravascular coagulation. Thrombosis Journal 2006, 4:4 for thromboembolic and bleeding complications. 5. Creasey et al. Tissue factor pathway inhibitor reduces The prognosis depends on underlying cause and mortality from E coli septic shock.J Clin Invest 2002; 91: the stage of the disease. The role of newer agents 2880-86. remains to be defined. 6. Levi et al. The cytokine mediated imbalance between coagulant and anti coagulant mechanisms in sepsis. Eur J Clin Invest 1997; 27: 3-9. References 7. Horan JT. Seminar Thromb Hemost 2001; 27: 657-66 1. Furlong MA, Furlong BR. Disseminated Intravascular 8. Bick RL et al. Disseminated intravascular coagulopathy, Coagulation. Jan 2007. http://www.emedicine.com/emerg/ Semin Thromb Hemost 2000; 22:69-88. topic150.htm 9. Fourrier et al. Double blind placebo-controlled trial of 2. Toh CH, Hoots WK. The scoring system of the Scientific and antithrombin III in septic shock.Chest 2001; 104:882-88. Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis 10. Eisele et al. Antithrombin in severe sepsis.Intensive Care Med and Hemostasis: a 5-year overview. Journal of Thrombosis and 1999; 24; 663-72. Hemostasis 2006; 5: 604–606 11. Taylor et al. Protein C in sepsis, J Cli Invest 2003; 79:918- 3. Messmore HL Jr, Wehrmacher WH. Disseminated 925. Intravascular Coagulation.: a primer for primary care 12. Levi et al. Disseminated intracoagulation: 1999, Thromb physician. Postgrad Med 2002; 1139(3) (page number) Hemost.