Lepirudin blunts endotoxin-induced coagulation activation.
During sepsis, lipopolysaccharide (LPS) triggers the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation resulting in massive thrombin generation and fibrin polymerization. Recently, animal studies demonstrated that hirudin reduced fibrin deposition in liver and kidney and decreased mortality in LPS-induced DIC. Accordingly, the effects of recombinant hirudin (lepirudin) was compared with those caused by placebo on LPS-induced coagulation in humans. Twenty-four healthy male subjects participated in this randomized, double-blind, placebo-controlled, parallel group study. Volunteers received 2 ng/kg LPS intravenously, followed by a bolus-primed continuous infusion of placebo or lepirudin (Refludan, bolus: 0.1 mg/kg, infusion: 0.1 mg/kg/h for 5 hours) to achieve a 2-fold prolongation of the activated partial thromboplastin time (aPTT). LPS infusion enhanced thrombin activity as evidenced by a 20-fold increase of thrombin-antithrombin complexes (TAT), a 6-fold increase of polymerized soluble fibrin, termed thrombus precursor protein (TpP), and a 4-fold increase in D-dimer. In the lepirudin group, TAT increased only 5-fold, TpP increased by only 50%, and D-dimer only slightly exceeded baseline values (P <.01 versus placebo). Concomitantly, lepirudin also blunted thrombin generation evidenced by an attenuated rise in prothrombin fragment levels (F(1 + 2), P <. 01 versus placebo) and blunted the expression of tissue factor on circulating monocytes. This experimental model proved the anticoagulatory potency of lepirudin in LPS-induced coagulation activation. Results from this trial provide a rationale for a randomized clinical trial on the efficacy of lepirudin in DIC. (Blood. 2000;95:1729-1734)
Pernerstorfer
T
T
Department of Clinical Pharmacology-TARGET, Vienna General Hospital, Wien, Austria. thomas.pernerstorfer@univie.ac.at
Hollenstein
U
U
Hansen
J B
JB
Stohlawetz
P
P
Eichler
H G
HG
Handler
S
S
Speiser
W
W
Jilma
B
B
D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000032:analysis; D001798:Blood Proteins / Q000032:analysis; D003864:Depression, Chemical; D004211:Disseminated Intravascular Coagulation / Q000209:etiology / Q000517:prevention & control*; D004311:Double-Blind Method; D019446:Endotoxemia / Q000150:complications / Q000188:drug therapy*; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005246:Feedback; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D024764:Hirudin Therapy; D006629:Hirudins / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010314:Partial Thromboplastin Time; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000096:biosynthesis; D013925:Thromboplastin / Q000096:biosynthesis; D016896:Treatment Outcome
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D001798:Blood Proteins; D004731:Endotoxins; D005338:Fibrin Fibrinogen Degradation Products; D006629:Hirudins; D008074:Lipoproteins; D011994:Recombinant Proteins; C036309:fibrin fragment D; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin; D013917:Thrombin; C083544:lepirudin