Background: Recent studies of the hemostatic response show that in some vascular contexts thrombin activity is sequestered to the extravascular compartment. This finding raises questions about the importance of activated Protein C (APC) as an anticoagulant during hemostasis, since APC generation requires a thrombin mediated activation step occurring on the surface of endothelial cells.

Aims: To determine the relationships among thrombin spatial distribution, Protein C activation and APC anticoagulant function during hemostasis and thrombosis in multiple vascular contexts.

Methods: We examined the contribution of Protein C anticoagulant activity during the hemostatic response in both microvascular and macrovascular injury models, utilizing a combination of pharmacologic, genetic, and intravital imaging approaches. Computational studies were used to test hypotheses regarding thrombin and APC spatial distribution in different vascular contexts.

Results: We found that inhibition of the effects of APC in vivo, either in Factor V-Leiden mice or in the presence of an APC blocking antibody, significantly increased intravascular fibrin formation and platelet activation following vascular injury in the mouse microcirculation, consistent with its role as an anticoagulant. In contrast, after a penetrating injury in the jugular vein, inhibition of APC activity had no effect on the hemostatic response. Computational simulations revealed that the different contribution of APC in these contexts can be explained by effects of local physical forces on thrombin spatial distribution and subsequent Protein C activation following injury. To confirm computational predictions in vivo, we found that inhibition of APC significantly increased fibrin formation in the jugular vein when thrombin generation was initiated intravascularly, as occurs in settings of thrombosis.

Conclusions: Taken together, these studies provide new insights regarding the contribution of the Protein C system during hemostasis and thrombosis. They show that APC-mediated regulation of thrombin generation depends on local hemodynamic conditions and the spatial distribution of thrombin activity.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/thrombin-spatial-distribution-determines-the-contribution-of-activated-protein-c-to-endogenous-anti-coagulant-activity-during-hemostasis-and-thrombosis-in-vivo/