Efficacy and Safety of Tifacogin (Recombinant Tissue Factor Pathway Inhibitor) in Severe Sepsis

Abraham, Edward; Reinhart, Konrad; Opal, Steven M.; Demeyer, Ignace; Doig, Christopher J.; Rodriguez, Angel Lopez; Beale, Richard; Svoboda, Petr; Laterre, Pierre François; Simon, Stuart H.; Light, Bruce; Spapen, Herbert; Stone, Judith V.; Seibert, Allan; Peckelsen, C.; Deyne, C. De; Postier, Russell G.; Pettilä, Ville; Sprung, Charles L.; Artigas, Antonio; Percell, Sandra; Shu, Vincent; Zwingelstein, Christian; Tobias, Jeffrey; Poole, Lona; Stolzenbach, James C.; Creasey, Abla A.

doi:10.1001/jama.290.2.238

Cited by 900 publications

(514 citation statements)

References 19 publications

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“…Based on the studies presented here, release of polyP by infectious microorganisms could have potent procoagulant and antifibrinolytic effects, enhancing the host defense role of the blood clotting and fibrinolytic systems. In addition, the ability of polyP released by activated platelets and͞or bacteria to severely abrogate TFPI function might limit the effectiveness of TFPI as a drug (Tifacogin) in combating disseminated intravascular coagulation in sepsis (24). Instability of polyP in plasma and serum.…”

Section: Resultsmentioning

confidence: 99%

Polyphosphate modulates blood coagulation and fibrinolysis

Smith

Mutch

Baskar

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

497

623

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Inorganic polyphosphate is an abundant component of acidocalcisomes of bacteria and unicellular eukaryotes. Human platelet dense granules strongly resemble acidocalcisomes, and we recently showed that they contain substantial amounts of polyphosphate, which is secreted upon platelet activation. We now report that polyphosphate is a potent hemostatic regulator, accelerating blood clotting by activating the contact pathway and promoting the activation of factor V, which in turn results in abrogation of the function of the natural anticoagulant protein, tissue factor pathway inhibitor. Polyphosphate was also found to delay clot lysis by enhancing a natural antifibrinolytic agent, thrombin-activatable fibrinolysis inhibitor. Polyphosphate is unstable in blood or plasma, owing to the presence of phosphatases. We propose that polyphosphate released from platelets or microorganisms initially promotes clot formation and stability; subsequent degradation of polyphosphate by blood phosphatases fosters inhibition of clotting and activation of fibrinolysis during wound healing.factor V ͉ platelets ͉ tissue factor pathway inhibitor ͉ acidocalcisomes ͉ dense granules P olyphosphate (polyP) is widely distributed in biology, being found in bacteria, fungi, plants, and animals (1). The biologic functions of polyP have been studied most extensively in prokaryotes and unicellular eukaryotes, in which high levels of polyP accumulate in acidic organelles known as acidocalcisomes. PolyP in these organisms can reach chain lengths of several hundred phosphate units. In unicellular organisms, polyP has been shown to play essential roles in stress responses and virulence (1, 2), although its function in higher eukaryotes, including man, has not been extensively investigated. Recently, we reported that dense granules of human platelets strongly resemble acidocalcisomes and contain millimolar levels of polyP (with chain lengths of Ϸ70-75 phosphate units), making acidocalcisomes the only known class of organelle conserved during evolution from bacteria to humans (3). Human platelets each have three to eight dense granules (also called ␦ granules), a type of secretory granule that contains serotonin, ADP, ATP, and PP i in addition to polyP. Patients with dense granule defects exhibit bleeding diatheses, underscoring the role of these secretory granules in hemostasis (4). Platelets contain Ϸ0.74 nmol polyP per 10 8 platelets, which is secreted after stimulation by platelet agonists such as thrombin (3). Therefore, released polyP could readily attain a concentration of 3 M in whole blood, and this could be far higher in platelet-rich thrombi. (Concentrations of polyP are expressed in this paper as phosphate monomer.)The importance of platelets in hemostasis suggested to us that polyP may play an important role in the blood clotting system. In this study, we found that polyP of the size released from activated platelets has a strongly net procoagulant effect, which is exerted at several levels in the clotting͞fibrinolysis system: PolyP activate...

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Section: Resultsmentioning

confidence: 99%

Polyphosphate modulates blood coagulation and fibrinolysis

Smith

Mutch

Baskar

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

497

623

View full text Add to dashboard Cite

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“…Over the past few decades, although some anticoagulant agents, such as antithrombin (AT), tissue factor pathway inhibitor, and activated protein C, have been investigated for use in patients by international large randomized controlled trials (RCTs), no remarkable effect on the mortality rate has been reported 4, 5, 6, 7. However, the post‐hoc subgroup analyses of those RCTs indicated that the anticoagulant therapies resulted in improved mortality rates in patients with sepsis‐induced DIC 8, 9.…”

Section: Introductionmentioning

confidence: 99%

A summary of the Japan septic disseminated intravascular coagulation study

Hayakawa

Ono

2018

Acute Medicine & Surgery

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Over the past few decades, the large, international, randomized controlled trials of anticoagulant therapies for patients with sepsis have not yielded any improvement in mortality rates. However, in Japan, anticoagulant therapies are administered for sepsis patients with disseminated intravascular coagulation (DIC), but not for sepsis patients without DIC. Furthermore, epidemiological data regarding sepsis in Japan are scarce. Therefore, a nationwide multicenter retrospective observational study, the Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study, was undertaken. The JSEPTIC DIC study enrolled 42 intensive care units and included 3,195 patients with sepsis. The results of the JSEPTIC DIC study indicated the following: (i) anticoagulant therapy may be effective in sepsis‐induced DIC patients at high risk for death, (ii) recombinant human soluble thrombomodulin administration and antithrombin supplementation are associated with survival benefits in patients with sepsis‐induced DIC.

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“…Although the DIC subcommittee of the Scientific Standardized Committee (SSC) in the ISTH emphasized vascular endothelial cell injury as a definition of DIC [3], scoring system based on these three diagnostic criteria do not reflect vascular endothelial cell injury. Recent clinical trials for severe sepsis [5][6][7] showed that the mortality rate of patients with severe sepsis was 35-45% and was even higher in patients with DIC than patients without DIC. The frequency of DIC in patients with severe sepsis was 40.7% according to the KyberSept trial results (antithrombin; AT) [5] and 22.4% in the PROWESS study (recombinant activated protein C; APC) [6].…”

Section: Introductionmentioning

confidence: 99%

Modified non‐overt DIC diagnostic criteria predict the early phase of overt‐DIC

et al. 2010

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of Thrombosis Hemostasis/DIC subcommittee Diagnostic criteria for non-overt disseminated intravascular coagulation (DIC) have been proposed by the International Society of Thrombosis and Hemostasis, but are not useful for the diagnosis of early phase of overt-DIC (pre-DIC). Therefore, in the current study the non-overt DIC diagnostic criteria were modified using the global coagulation tests, the change rate in the global coagulation tests and molecular hemostatic markers to detect the pre-DIC state and were prospectively evaluated in 613 patients with underlying DIC disease. The frequencies of patients with DIC (DIC positive), late onset DIC, and without DIC (DIC absent) were 29.5%, 7.2%, and 63.3%, respectively. The modified non-overt-DIC criteria can correctly predict 43/44 patients (97.7%) who were DIC absent at admission and became DIC positive, within a week (late onset DIC state). The mortality rate was higher in DIC positive compared with pre-DIC (37.6% vs. 22.7%, P < 0.05) or DIC negative (37.6 vs. 13.7%, P < 0.01). It was also significantly higher in pre-DIC compared with DIC negative (P < 0.05). Thus, these modified non-overt DIC diagnostic criteria might therefore be useful for the diagnosis of early-phase DIC. Am. J. Hematol. 85:691-694, 2010. V V C 2010 Wiley-Liss, Inc. IntroductionSeveral diagnostic criteria for disseminated intravascular coagulation (DIC) have been proposed by Colman et al. [1], the Japanese Ministry Health and Welfare (JMHW) [2], and the International Society of Thrombosis and Hemostasis (ISTH) [3], among others. In these diagnostic criteria, global coagulation tests such as the prothrombin time (PT), platelet count, fibrinogen and fibrin and fibrinogen degradation products (FDP) or D-dimer are primarily used for scoring for hemostatic abnormalities. A retrospective study [4] showed that the concordance rate between the JMHW and ISTH diagnostic criteria was 67.4%, and that the ISTH overt-DIC diagnostic criteria were less sensitive for DIC diagnosis than the JMHW criteria. Although the DIC subcommittee of the Scientific Standardized Committee (SSC) in the ISTH emphasized vascular endothelial cell injury as a definition of DIC [3], scoring system based on these three diagnostic criteria do not reflect vascular endothelial cell injury. Recent clinical trials for severe sepsis [5][6][7] showed that the mortality rate of patients with severe sepsis was 35-45% and was even higher in patients with DIC than patients without DIC. The frequency of DIC in patients with severe sepsis was 40.7% according to the KyberSept trial results (antithrombin; AT) [5] and 22.4% in the PROWESS study (recombinant activated protein C; APC) [6]. The patients with severe sepsis have a poor prognosis and the septic patients who also have DIC have an even worse outcome.The treatment efficacy in relation to the JMHW DIC score at the beginning of treatment showed that a greater efficacy was achieved in pre-DIC patients than in DIC patients [8]. The patient prognosis was progressively worse with increasing DIC sc...

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Efficacy and Safety of Tifacogin (Recombinant Tissue Factor Pathway Inhibitor) in Severe Sepsis

Cited by 900 publications

References 19 publications

Polyphosphate modulates blood coagulation and fibrinolysis

Polyphosphate modulates blood coagulation and fibrinolysis

A summary of the Japan septic disseminated intravascular coagulation study

Modified non‐overt DIC diagnostic criteria predict the early phase of overt‐DIC

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