Thrombin-induced leukopenia and thrombocytopenia are attenuated by PAF antagonist WEB 2086.
Thrombin has been shown to increase pulmonary transvascular permeability in vivo. This permeability change appears to be dependent on polymorphonuclear leukocytes (PMNs). In vitro, thrombin has been demonstrated to increase PMN adherence to endothelial cells coincident with generation of platelet activating factor (PAF) by endothelial cells. These observations have led to the suggestion that PAF mediates, in part, the attachment of PMNs to endothelial cells. We examined this hypothesis in vivo and in vitro with a specific PAF receptor antagonist, WEB 2086. Prior infusion of WEB 2086 into conscious sheep significantly attenuated the drop in peripheral blood PMN counts observed during and after infusion of alpha-thrombin (30 NIH U/kg). These data suggest that WEB 2086 prevented PMN margination on endothelial cells. WEB 2086 also attenuated the thrombocytopenia seen after thrombin infusion and ameliorated the thrombin-induced hypoxemia and hemoconcentration. WEB 2086 did not affect the thrombin-induced hemodynamic response, the degree of intravascular coagulation as assessed by fibrin degradation product generation, or thromboxane B2 generation. In vitro, WEB 2086 prevented the augmented adherence of sheep PMNs to sheep endothelial cell monolayers after thrombin stimulation. The results of the present study are consistent with the hypothesis that PAF mediates, at least in part, thrombin-induced leukopenia and thrombocytopenia in vivo.
van der Zee
H
H
Department of Physiology & Cell Biology, Albany Medical College, New York 12208.
Moon
D G
DG
Kaplan
J E
JE
Gudewicz
P W
PW
Fenton
J
J
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D002245:Carbon Dioxide / Q000097:blood; D002448:Cell Adhesion / Q000187:drug effects; D007958:Leukocyte Count / Q000187:drug effects; D007970:Leukopenia / Q000139:chemically induced* / Q000517:prevention & control; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D012756:Sheep; D013917:Thrombin / Q000494:pharmacology*; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000517:prevention & control; D013929:Thromboxane B2 / Q000097:blood; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C052518:WEB 2086; D002245:Carbon Dioxide; D013929:Thromboxane B2; D013917:Thrombin