An experimental model to study isolated effects of thrombin in vivo.
BACKGROUND
In addition to a recognized role in the coagulation cascade and haemostasis, thrombin is known to have multiple functions. We hypothesized that protracted intravenous infusion of thrombin at steady state will allow to study isolated thrombin effects in vivo.


METHODS
Thrombin (0.05-0.9U/kg/min) was continuously infused in Sprague Dawley rats over five hours (n=38). The study consisted of three parts: dose escalation (n=21), dose verification (n=5) and a parallel group study to investigate whether thrombin effects can be antagonised by concomitant infusion of lepirudin (n=12).


RESULTS
A thrombin dose of 0.9U/kg/min decreased platelet counts by 70% compared to the control group (median 230×10^9/L vs. 752×10^9/L; p=0.041). In accordance, infusion of 0.9U/kg/min of thrombin decreased fibrinogen level by 75% compared to the control group (56mg/dl vs. 220mg/dl; p=0.046). Cumulative thrombin doses of ≥0.1U/kg/min caused bleedings but not thromboembolic events. Thrombin at doses ≥0.15U/kg/min was lethal in four cases (30%). Platelet counts and fibrinogen levels after thrombin infusion correlated with bleeding events and mortality. Administration of thrombin at cumulative doses of 0.3-0.9U/kg/min was associated with a 3 to 6.5 -fold increase in IL-6 levels (139-306pg/ml vs. 47pg/ml, p<0.05). In contrast, thrombin infusion did not alter other markers of inflammation (IL-10, MCP-1 or TNF-alpha). In addition, lepirudin prevented thrombin- induced thrombocytopenia.


CONCLUSIONS
Protracted intravenous infusion of thrombin offers a new experimental model, where consumption of fibrinogen and platelets correlates with bleedings and mortality. Infusion of thrombin increased only IL-6 levels but not other cytokines.
Siller-Matula
Jolanta M
JM
Department of Clinical Pharmacology, Medical University of Vienna, Austria.
Bayer
Guenther
G
Bergmeister
Helga
H
Quehenberger
Peter
P
Petzelbauer
Peter
P
Friedl
Peter
P
Mesteri
Ildiko
I
Jilma
Bernd
B
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism; D005355:Fibrosis / Q000097:blood; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced; D007249:Inflammation / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D023421:Models, Animal; D010976:Platelet Count; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013917:Thrombin / Q000494:pharmacology / Q000502:physiology*
D015850:Interleukin-6; D005340:Fibrinogen; D013917:Thrombin