Abstract
The contributions of coagulation factor XI (FXI) and FXII to human clot formation is not fully known. Patients with deficiency in FXI have a variable mild bleeding risk, whereas FXII deficiency is not associated with bleeding. These phenotypes make FXII and FXI attractive target proteins in anticoagulant therapy. Here, we studied the mechanisms of fibrin clot formation, stability, and fibrinolytic degradation in patients with severe FXI or FXII deficiency. Thrombin generation was triggered in platelet-poor (PPP) and platelet-rich plasma (PRP) with the biological FXII trigger sulfatides. Intrinsic and extrinsic thrombus formation and degradation in whole blood were determined with rotational thromboelastometry (ROTEM). Clot formation under flow was assessed by perfusion of whole blood over collagen microspots with(out) tissue factor (TF). Thrombin generation and clot formation were delayed in FXII- and FXI-deficient patients triggered with sulfatides. In FXI-deficient plasma, this delay was more pronounced in PRP compared to PPP. In whole blood of FXII-deficient patients, clots were smaller but resistance to fibrinolysis was normal. In whole blood of FXI-deficient patients, clot formation was normal but the time to complete fibrinolysis was prolonged. In flow chamber experiments triggered with collagen/TF, platelet coverage was reduced in severe compared with moderate FXI deficiency, and fibrin formation was impaired. We conclude that quantitative defects in FXII and FXI have a substantial impact on contact activation-triggered coagulation. Furthermore, FXI deficiency has a dose-dependent suppressing effect on flow-mediated and platelet/TF-dependent clot formation. These last data highlight the contribution of particularly FXI to hemostasis.
Highlights
Thrombosis is a critical element in the pathogenesis of ischemic cardiovascular disease as well as in venous thromboem-Ã These authors contributed to this study.bolism
Limited and conflicting information is available on how reduced levels of factor XI (FXI) and factor XII (FXII) can protect against thrombosis in man, since subjects with a congenital deficiency in either factor still experience cardiovascular events
Plasma levels/activities of prothrombin, fibrinogen, antithrombin, and FXIII were within normal ranges and were comparable for patients and controls; the same applied to fibrinolysis parameters
Summary
Both epidemiological and animal studies indicate that the intrinsic coagulation factors, factor XI (FXI) and factor XII (FXII), contribute to the development of pathological thrombus formation.. Congenital deficiency of either F11 or F12 protected against experimentally induced arterial thrombosis.. Congenital deficiency of either F11 or F12 protected against experimentally induced arterial thrombosis.5–7 Since these deficiencies are not associated received November 27, 2018 accepted after revision June 7, 2019. With bleeding (FXII) or with a mild bleeding phenotype (FXI), respectively, the contribution of these intrinsic factors in normal hemostasis is limited. Limited and conflicting information is available on how reduced levels of FXI and FXII can protect against thrombosis in man, since subjects with a congenital deficiency in either factor still experience cardiovascular events.. Antibody-, antisense-, or aptamer-based inhibitors of FXI or FXII showed promising, suppressive effects in several in vivo models of arterial thrombosis. in primate thrombosis models, immunological inhibition of FXI or FXII appeared to be thromboprotective. Limited and conflicting information is available on how reduced levels of FXI and FXII can protect against thrombosis in man, since subjects with a congenital deficiency in either factor still experience cardiovascular events. A recent trial indicated that antisense FXI treatment reduced postoperative venous thromboembolism without increasing bleeding in patients undergoing knee replacement surgery. the collective data point to a more prominent role of human FXI and FXII in thrombosis than in hemostasis, it is important to better understand the mechanisms and processes that are regulated by these contact activation factors
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