Blood Clot Formation under Flow: The Importance of Factor XI Depends Strongly on Platelet Count

Abstract

A previously validated mathematical model of intravascular platelet deposition and tissue factor (TF)-initiated coagulation under flow is extended and used to assess the influence on thrombin production of the activation of factor XI (fXI) by thrombin and of the activation of factor IX (fIX) by fXIa. It is found that the importance of the thrombin-fXIa-fIXa feedback loop to robust thrombin production depends on the concentration of platelets in the blood near the injury. At a near-wall platelet concentration of ~250,000/μL, typical in vessels in which the shear rate is <200 s(-1), thrombin activation of fXI makes a significant difference only at low densities of exposed TF. If the near-wall platelet concentration is significantly higher than this, either because of a higher systemic platelet count or because of the redistribution of platelets toward the vessel walls at high shear rates, then thrombin activation of fXI makes a major difference even for relatively high densities of exposed TF. The model predicts that the effect of a severe fXI deficiency depends on the platelet count, and that fXI becomes more important at high platelet counts.

FXIa and platelet polyphosphate as therapeutic targets during human blood clotting on collagen/tissue factor surfaces under flow

“…Importantly, platelet concentrations in wallattached thrombi that form under flow are 50-to 200-fold greater than those found in whole blood, a complexity that distinguishes microfluidic flow studies from test tube studies. [24][25][26] Recently, a phase 2 trial demonstrated that FXI-antisense oligonucleotide (FXI-ASO) reduced FXI levels and decreased the incidence of deep vein thrombosis (DVT) after knee arthroplasty without increasing bleeding, thus providing evidence that FXIa can contribute to thrombosis in humans. 27 However, postoperative bleeding in knee arthroplasty is relatively uncommon, and the rate of bleeding with FXI-ASO was not significantly lower than that seen with enoxaparin.…”

A Mathematical Model of Venous Thrombosis Initiation

“…This model is adapted from our earlier models of arterial thrombosis (39)(40)(41) and shares numerous features of those models. The models involve the same set of coagulation enzyme reactions and the same reaction rate constants.…”

“…Assumptions 1 to 6 are essentially unchanged from assumptions in our arterial thrombosis models; see (39,41) for further discussion of them. Assumptions 7 to 10 are either completely new to the venous thrombosis situation or are substantial modifications to those in (39,41).…”

“…Assumptions 7 to 10 are either completely new to the venous thrombosis situation or are substantial modifications to those in (39,41).…”

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

“…This late stage participation of thrombin-mediated activation of FXI has also been theoretically predicted (54). The FXI antibody O1A6 inhibits FXIIa activation of FXI and disrupts the FXI-dependent thrombin amplification loop by inhibiting FXIa generation of FIXa and subsequent FXa activation (Fig.…”