Coagulation Factor XI Promotes Distal Platelet Activation and Single Platelet Consumption in the Bloodstream Under Shear Flow

Abstract

Objective Coagulation factor XI (FXI) has been shown to contribute to thrombus formation on collagen or tissue factor (TF)-coated surfaces in vitro and in vivo by enhancing thrombin generation. Whether the role of the intrinsic pathway of coagulation is restricted to the local site of thrombus formation is unknown. This study was aimed to determine whether FXI could promote both proximal and distal platelet activation and aggregate formation in the bloodstream. Approach and Results Pharmacological blockade of FXI activation or thrombin activity in blood did not affect local platelet adhesion, yet reduced local platelet aggregation, thrombin localization and fibrin formation on immobilized collagen and TF under shear flow, ex vivo. Downstream of the thrombus formed on immobilized collagen or collagen and 10 pM TF, platelet CD62P expression and microaggregate formation and progressive platelet consumption were significantly reduced in the presence of FXI-function blocking antibodies or a thrombin inhibitor in a shear rate- and time-dependent manner. In a non-human primate model of thrombus formation, we found that inhibition of FXI reduced single platelet consumption in the bloodstream distal to a site of thrombus formation. Conclusions This study demonstrates that the FXI-thrombin axis contributes to distal platelet activation and procoagulant microaggregate formation in the blood flow downstream of the site of thrombus formation. Our data highlights FXI as a novel therapeutic target for inhibiting distal thrombus formation without affecting proximal platelet adhesion.

Dynamics of Thrombin Generation and Flux from Clots during Whole Human Blood Flow over Collagen/Tissue Factor Surfaces

“…Our previous work indicated that participation of the TF-triggered extrinsic pathway was required to generate enough thrombin to initiate the FXIa-dependent thrombin amplification mechanism, which can be interrupted by O1A6 (5). This FXI functionblocking antibody also reduced platelet aggregation downstream of thrombi formed on collagen/TF, suggesting a role of the FXI-thrombin axis in distal thrombi formation (57). Therefore, thrombin flux after 500 s is most likely augmented by the FXIa-dependent thrombin amplification loop.…”

Fibrinogen and Fibrin in Hemostasis and Thrombosis

“…Pharmacologic FXI inhibition does not reduce local platelet adhesion in tissue factor and collagen-coated capillary tubes, but reduces platelet activation and aggregation downstream of the growing thrombus. 52 Similarly, in an arteriovenous shunt model of thrombosis in non-human primates, neither anti-FXI antibodies nor ASOs alter platelet deposition on a collagen-rich segment of graft, but both decrease thrombus propagation (platelet accumulation and fibrin deposition) downstream of the collagen-rich region. 53,54 A promising phase I clinical trial demonstrated success of anti-FXI ASO treatment in humans undergoing elective total knee arthroplasty; ASO-mediated reduction of plasma FXI levels decreased symptomatic or asymptomatic venous thrombosis/thromboembolism (VTE) incidence, and the higher ASO dose tested was superior to enoxaparin.…”

Biorheology of Platelet Activation in the Bloodstream Distal to Thrombus Formation

“…Moreover, our work suggests that activation of the coagulation factors XI and X play a key role in promoting thrombin generation, platelet activation and microaggregate formation in the bloodstream. 23 …”