Cross-modulatory effects of clopidogrel and heparin on platelet and fibrin incorporation in thrombosis

Abstract

Pharmacologic inhibition of platelet activation and aggregation is a mainstay for reducing the incidence of arterial thrombosis, whereas anticoagulation is the primary approach for preventing the development of venous thrombosis. The effect of standard pharmacologic agents on their reciprocal vessel - anticoagulants on arterial thrombosis and platelet inhibitor on venous thrombosis - is relatively understudied. This study was designed to evaluate murine large-vessel arterial or venous thrombosis under conditions of either fibrin or platelet inhibition. In this study, heparin and clopidogrel were used as standard anticoagulant and platelet inhibitor, respectively, evaluating both large artery and vein thrombosis in mice, using in-vivo fluorescence imaging to simultaneously measure fibrin and platelet levels at the thrombus induction site. Heparin reduced both fibrin and platelet development in both arteries and veins, with stronger influences on fibrin accrual. Clopidogrel had a stronger effect in arteries, reducing both platelet and fibrin accumulation. Clopidogrel also reduced platelet accumulation with venous thrombosis, but the reductions in fibrin formation did not reach statistical significance. These findings illustrate the interactive role of platelet activity and coagulation in the development of large-vessel thrombosis, with inhibition of one thrombotic component showing profound effects on the other component in both arterial and venous thrombosis.

New insights into the spatiotemporal localization of prothrombinase in vivo

“…[45][46][47] Differences with the cremaster laser injury model in different injury scenarios could also yield alternative outcomes in terms of prothrombinase distribution and contribution of platelets to thrombin generation. Interestingly, however, Cooley et al 48,49 have established parallels between some of our observations and the response to electrolytic injury in large veins. Pharmacologic inhibition of platelet adhesion had only a minor effect on fibrin levels at the injury site, again highlighting the importance of cells other than platelets contributing to thrombin generation.…”

Elevated Prothrombin Promotes Venous, but Not Arterial, Thrombosis in Mice

“…Thrombus formation in this model is reduced by heparin, consistent with the sensitivity of venous thrombosis to thrombin generation. 31 We tested 2 levels of prothrombin: 130% and 200% (final); these levels were chosen to approximate the mean and upper end of the pathophysiologic range. Neither prothrombin concentration significantly increased the rate or total amount of platelet accumulation in femoral vein thrombi (Figures 2B, 2D).…”

ACVIM consensus statement on the treatment of immune‐mediated hemolytic anemia in dogs

“…135,136 There is thus a rationale for the use of antiplatelet drugs in venous thrombosis. 132,[137][138][139][140] Experimental data support this proposition to some degree, 141 and evidence in humans suggests that antiplatelet drugs do decrease the risk of venous thrombosis. [142][143][144][145] However, this should be viewed in the context of the substantial body of evidence in humans supporting administration of anticoagulants as first line prophylactic drugs for venous thrombosis.…”