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Thrombin-induced leukopenia and thrombocytopenia are attenuated by PAF antagonist WEB 2086
H van der Zee1, D G Moon, J E Kaplan
1Department of Physiology & Cell Biology, Albany Medical College, New York 12208.
Abstract:
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.
Insights
Platelet activating factor (PAF) partially mediates thrombin-induced changes in pulmonary permeability. A PAF receptor antagonist, WEB 2086, reduced thrombin
Area of Science:
- Pulmonary Circulation
- Inflammation
- Hemostasis
Background:
- Thrombin increases pulmonary transvascular permeability, a process linked to polymorphonuclear leukocytes (PMNs).
- In vitro studies suggest Platelet Activating Factor (PAF) mediates PMN adherence to endothelial cells stimulated by thrombin.
Purpose of the Study:
- To investigate the in vivo and in vitro role of PAF in thrombin-induced pulmonary effects.
- To assess the efficacy of a specific PAF receptor antagonist, WEB 2086, in mitigating these effects.
Main Methods:
- Conscious sheep received infusions of alpha-thrombin with or without prior administration of WEB 2086.
- Measurements included peripheral blood PMN counts, platelet counts, oxygen saturation, hematocrit, and coagulation markers.
- In vitro experiments assessed PMN adherence to endothelial cells after thrombin stimulation in the presence of WEB 2086.
Main Results:
- WEB 2086 significantly attenuated thrombin-induced decreases in PMN counts (leukopenia) and platelet counts (thrombocytopenia).
- The antagonist ameliorated thrombin-induced hypoxemia and hemoconcentration but did not affect hemodynamic responses or coagulation.
- In vitro, WEB 2086 blocked the increased adherence of PMNs to endothelial cells stimulated by thrombin.
Conclusions:
- Platelet activating factor (PAF) plays a significant role in mediating thrombin-induced leukopenia and thrombocytopenia in vivo.
- WEB 2086 effectively inhibits PAF-mediated PMN adherence to endothelial cells, suggesting a therapeutic potential.