Lepirudin blunts endotoxin-induced coagulation activation

Area of Science:

• Hematology
• Pharmacology
• Critical Care Medicine

Background:

• Sepsis-induced disseminated intravascular coagulation (DIC) involves lipopolysaccharide (LPS) triggering coagulation via the tissue factor pathway, leading to excessive thrombin and fibrin generation.
• Animal studies indicate hirudin reduces fibrin deposition and mortality in LPS-induced DIC.
• The human efficacy of recombinant hirudin (lepirudin) in this context requires investigation.

Purpose of the Study:

• To compare the effects of lepirudin versus placebo on LPS-induced coagulation activation in healthy human volunteers.
• To evaluate lepirudin's anticoagulatory potency in an experimental human model of DIC.

Main Methods:

• A randomized, double-blind, placebo-controlled study involving 24 healthy males.
• Volunteers received intravenous LPS followed by placebo or lepirudin infusion to prolong activated partial thromboplastin time (aPTT) twofold.
• Coagulation activation markers including thrombin-antithrombin complexes (TAT), thrombus precursor protein (TpP), D-dimer, and prothrombin fragment F(1+2) were measured.

Main Results:

• LPS infusion markedly increased TAT, TpP, and D-dimer levels.
• Lepirudin significantly attenuated the rise in TAT, TpP, and D-dimer compared to placebo (P <.01).
• Lepirudin also reduced prothrombin fragment F(1+2) levels and blunted tissue factor expression on monocytes.

Conclusions:

• This study demonstrates the anticoagulatory efficacy of lepirudin in inhibiting LPS-induced coagulation activation in humans.
• The findings support further clinical trials to assess lepirudin's effectiveness in treating DIC.