[Coagulation inhibitors in severe sepsis: state of the art].
OBJECTIVE
To present and discuss the rationale and the results of clinical trials using supplementation with physiologic anticoagulants (Tissue Factor Pathway Inhibitor (TFPI), AntiThrombin (AT), and Protein C (PC) in patients with severe sepsis.


BACKGROUND
An early activation of the coagulation cascade occurs in severe sepsis. TFPI, AT, and PC are major inhibitors of the coagulation cascade, and additionally modulate inflammatory and vascular reactions. They are consumed or inhibited in the sepsis pathologic process. Therapeutic supplementation with these inhibitors could improve the sepsis-induced organ failures and mortality.


RESULTS
Randomized controlled studies were recently completed. No effect on the mortality rate could be documented after treatment with recombinant TFPI. AT concentrates neither improve mortality, but a biological interaction with heparin therapy could have biased the study results. Treatment with recombinant activated PC (alpha-drotrecogin) was associated with a significant reduction in the mortality rate of severely ill patients and received recently the approval from FDA and EC authorities in this indication. An increase in the rate of hemorrhagic adverse effects has been observed with these compounds, justifying a strict observance of contraindications and of patients selection. PROSPECTIVE: Additional studies are needed to give confirmation of the positive effects of activated PC supplementation in less severely ill patients, children and specific clinical situations. The effects of new anticoagulant compounds are currently evaluated in preclinical studies.
Fourrier
F
F
EA 2689, université Lille 2, Lille, France. f-fourrier@chru-lille.fr
D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D000991:Antithrombins / Q000187:drug effects / Q000502:physiology; D001778:Blood Coagulation Disorders / Q000188:drug therapy* / Q000382:microbiology* / Q000401:mortality; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D016903:Drug Monitoring; D006493:Heparin / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation; D009102:Multiple Organ Failure / Q000382:microbiology; D018579:Patient Selection; D011486:Protein C / Q000037:antagonists & inhibitors / Q000502:physiology / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000627:therapeutic use; D018805:Sepsis / Q000097:blood / Q000150:complications* / Q000276:immunology; D012720:Severity of Illness Index; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
D000925:Anticoagulants; D000991:Antithrombins; D011486:Protein C; D011994:Recombinant Proteins; D006493:Heparin; D013925:Thromboplastin; C421124:drotrecogin alfa activated