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Disseminated Intravascular Coagulation and Coagulation Disorders Carl-Erik Dempfle

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Disseminated intravascular coagulation 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 fibrin-related marker Disseminated intravascular coagulation is defined as a typical ISTH International Society for Thrombosis and Hemostasis disease 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 coagulopathy, sepsis-induced purpura 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 purpura fulminans 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 tissue factor production in monocytes and related markers (FRMs), prolonged prothrombin time, macrophages, inducing microvascular thrombosis and low platelet count, and low fibrinogen level. Additional consumption of platelets and coagulation factors. Current indicators of DIC are low levels of coagulation inhibitors scoring systems do not distinguish between patients with such as antithrombin or protein C, and other indicators of asymptomatic disseminated intravascular coagulation, coagulation activation, such as thrombin–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 factor V Leiden mutation 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 Medicine, University Hospital of Mannheim, Mannheim, Germany Correspondence to Prof. Dr med. Carl-Erik Dempfle, Department of Medicine, Consumption coagulopathy is an acquired bleeding 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 fibrinogen Low protein C 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 anticoagulant 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 heparin 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 factor V Leiden mutation and patients with finding was made in the KYBERSEPT study (Kybernin DIC. Protein C replacement has been proposed for in sepsis
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