Increased activated protein C to protein C ratio in sepsis and cirrhosis
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Drotrecogin alfa
The protein C pathway, which plays an important role in maintaining normal hemostasis and is a critical link between the inflammatory and procoagulant host responses to infection, is involved in modulating the coagulation and inflammation associated with severe sepsis. Recombinant human activated protein C (APC), or drotrecogin alfa (activated), shares the intrinsic pharmacologic activity of endogenous APC. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, drotrecogin alfa (activated) decreased absolute mortality by 6% and relative risk of mortality by 19% compared with placebo. Drotrecogin alfa (activated) is an important advancement in the treatment of adult patients with severe sepsis.
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Severe sepsis is a common cause of mortality in critically ill patients. Drotrecogin alfa (activated), synonymous with recombinant human activated protein C (rhAPC), is a new therapeutic tool with anticoagulant, anti-inflammatory and profibrinolytic properties with proven effect in reducing mortality in severe sepsis.As part of a multi-centre study, the patients received an infusion of rhAPC, 24 microg/kg/h for 96 hours according to an open-labeled phase IIIb study protocol.Out of a total of 28 patients, 6 (21%) died before day 28. One of the deaths was classified as possibly related to rhAPC. In three patients rhAPC was transiently stopped because of surgery or postoperative bleeding. Use of the compound rarely interfered with commonly used diagnostic and therapeutic procedures.Treatment with rhAPC is easily carried out in an intensive care unit. Patients with severe sepsis and two or more failing vital organs should be considered for treatment with rhAPC.
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The paper presents provisional data on the use of antithrombin III concentrate in the therapy of disseminated intravascular coagulation. Correction of insufficient antithrombin III activity in the complex therapy of thrombinemia and multiple organ dysfunctions is pathogenetically substantiated.
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A study was conducted to test the hypotheses that antithrombin III (antithrombin) improves disseminated intravascular coagulation (DIC) when applied to DIC patients diagnosed by sensitive criteria and that the administration of high-dose antithrombin is a beneficial treatment for DIC. Twenty-three DIC patients diagnosed based on the Japanese Association for Acute Medicine (JAAM) DIC diagnostic criteria were treated with either high-dose (60 IU/kg/day) or low-dose (30 IU/kg/day) antithrombin concentrates for 3 days. The clinical conditions that cause DIC were restricted to systemic inflammatory response syndrome (SIRS) and sepsis. Data of antithrombin activity, platelet counts, coagulation and fibrinolytic markers, and DIC scores before antithrombin administration (day 0), on days 1 to 3, and on day 7 were retrospectively collected from computer-based records. Patients who met the JAAM DIC criteria were administered either high-dose (12 patients) or low-dose (11 patients) antithrombin. The patients’ backgrounds and antithrombin activity (high dose, 51.5 ± 14.5%; low dose, 62.6 ± 19.3%; P = .153) on day 0 were identical in the 2 groups. The JAAM DIC score and prothrombin time ratio on day 7 significantly improved when compared with those on day 0. However, mortality at 28 days as well as interaction within the antithrombin doses administered showed no difference. There were also no differences in the time course of the platelet counts, coagulation and fibrinolytic markers, and DIC scores in the 2 groups. The authors conclude that the effects of antithrombin on prognosis and coagulation and fibrinolytic parameters are independent of the doses administered in patients with SIRS/sepsis-associated DIC.
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In several animal experiments, high doses of antithrombin III concentrates have shown beneficial effects on mortality and reversal of coagulation abnormalities which had resulted from disseminated intravascular coagulation. Other experiments have suggested that antithrombin III infusion without heparin is effective in the treatment of organ failure. We clinically treated children suffering disseminated intravascular coagulation only with antithrombin concentrate. Four patients suffering disseminated intravascular coagulation with organ failure were selected. We started antithrombin III concentrate infusion as soon as the diagnosis was established. The dosage of antithrombin III was 120–250 units/kg/day for 2 or 3 days. Heparin was not used. All 4 patients recovered completely and quickly without any complications within 14 days. We suggest that the high-dose antithrombin III infusion without heparin is an effective and safe therapy for disseminated intravascular coagulation with organ failure. © 1996 Wiley-Liss, Inc.
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Objective To review the results of treatments for severe sepsis involving the protein C/activated protein C pathway. Data Source Published research and review articles (PubMed, from 1985 to 2003) relating to compounds involving the protein C pathway. Results Protein C is converted to activated protein C when thrombin complexes with thrombomodulin. Sepsis is associated with rapid depletion of protein C and blunted endogenous protein C activation. A phase III trial of recombinant human activated protein C (drotrecogin alfa [activated]) in severe sepsis demonstrated a 6.1% absolute reduction in 28-day mortality compared with placebo. The short- and long-term survival rates associated with drotrecogin alfa (activated) were better in patients at high risk of death associated with a better cost/effectiveness ratio. Treatment with drotrecogin alfa (activated) was associated with an increased risk of serious bleeding compared with placebo during the 28-day study period (3.5% vs. 2.0%). Conclusions Treatment with drotrecogin alfa (activated) leads to substantial reduction in mortality and has an acceptable risk/benefit ratio in septic patients at high risk of death. however, a large trial involving a high dose is required to determine its effect on mortality and morbidity.
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Human protein C is a serine protease that circulates in the blood as an inactive zymogen. It is converted to its active form by interaction with thrombomodulin on the endothelial wall.1, 2 Activated protein C has a significant role in maintaining haemostasis, and is a major mechanism of controlling microvascular thrombosis.1-6 Recent reports describe the use of drotrecogin alfa (recombinant activated protein C) in severe sepsis,7-11 a condition relevant to emergency medicine. This review describes the physiology of the protein C pathway and its importance in sepsis. It will also focus on the use of drotrecogin alfa in sepsis, and its use in the ED.
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The role of activated protein C (APC) in coagulation, inflammation, and fibrinolysis and the pharmacology, pharmacokinetics, and trials of recombinant human activated protein C (rhAPC), or drotrecogin alfa (activated), in sepsis are described. Protein C, a naturally occurring vitamin K-dependent serine protease in the blood, remains inactive until exposed to the thrombin-thrombomodulin complex. This change between the inactive and active forms occurs constantly in humans and serves to balance the coagulation cascade. APC functions in concert with protein S as an anticoagulant, a fibrinolytic agent, and an antiinflammatory agent. In response to serious infection, a procoagulant process is activated leading to thrombin and fibrin deposition in small vessels that results in decreased blood flow, decreased oxygen delivery, and organ failure. The body's natural defense during severe sepsis is to activate protein C through the thrombin-thrombomodulin complex in an attempt to restore the imbalance of the hemostatic systems. However, APC has a short half-life, and the pool of circulating protein C is rapidly depleted in severe sepsis. Low protein C levels have been correlated with poor outcome in patients with severe sepsis and in animal models. These observations led to a Phase III safety and efficacy trial of drotrecogin alfa (activated) that demonstrated a significant improvement in mortality compared with placebo (24.7% versus 30.8%). This 6.1% absolute difference in mortality translates to a 19.4% reduction in relative risk of death in the treated patients. The proper use of drotrecogin alfa (activated) will require careful consideration of appropriate patients to treat and further studies in patient populations that were excluded from the Phase III trial, as well as possible modification of dosing schemes on the basis of patient response.
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Purpose: Few reports have been made on the therapeutic effects as well as pathological features of an antithrombin preparation in patients diagnosed with septic disseminated intravascular coagulation (DIC) by the diagnostic criteria for acute DIC.Materials and Methods: A total of 88 sepsis patients who had received inpatient hospital care during the period from January 2000 through December 2008 were divided into two groups, an antithrombin group and a non-antithrombin group, to study the outcomes.Furthermore, the relationship between sepsis-related factors and DIC in 44 patients was studied.Results: The antithrombin group contained 34 patients, and the non-antithrombin group contained 54 patients.The outcomes were significantly better in the antithrombin group.The levels of protein C were low in DIC patients.Conclusion: Our results suggest that early administration of antithrombin might improve outcomes of septic DIC patients in the diagnostic criteria for Japanese Association for Acute Medicine acute DIC.
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