Coagulation procofactor activation by factor XIa

Abstract

Summary. Background: In the extrinsic pathway, the essential procofactors factor (F) V and FVIII are activated to FVa and FVIIIa by thrombin. In the contact pathway and its clinical diagnostic test, the activated partial thromboplastin time (APTT) assay, the sources of procofactor activation are unknown. In the APTT assay, FXII is activated on a negatively charged surface and proceeds to activate FXI, which activates FIX upon the addition of Ca 2+. FIXa feeds thrombin generation through activation of FX. FIXa is an extremely poor catalyst in the absence of its FVIIIa cofactor, which, in the intrinsic FXase complex, increases FXa generation by 10 7 . One potential APTT procofactor activator in this setting is FXIa. Objective: To test the hypothesis that FXIa can activate FVIII and FV. Methods: Recombinant FVIII and plasma FV were treated with FXIa, and the activities and integrities of each procofactor were measured using commercial clotting assays and sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE). Results: Kinetic analyses of FXIa-catalyzed activation and inactivation of FV and FVIII are reported, and the the timing and sites of cleavage are defined. Conclusions: FXIa activates both procofactors at plasma protein concentrations, and computational modeling suggests that procofactor activation during the preincubation phase of the APTT assay is critical to the performance of the assay. As the APTT assay is the primary tool for the diagnosis and management of hemophilias A and B, as well as in the determination of FVIII inhibitors, these findings have potential implications in the clinical setting.

Activated factor XI increases the procoagulant activity of the extrinsic pathway by inactivating tissue factor pathway inhibitor

“…2,3 Moreover, FXIa has been shown to promote thrombin generation by direct activation of FV and FVIII. 3,6 These observations suggest that the role of FXIa in hemostasis and thrombus formation may include activities that bypass the FIX-mediated intrinsic pathway of thrombin generation. Here we show that FXIa binds to TFPI and inhibits its anticoagulant activity.…”

“…2 Because FXII deficiency does not affect hemostasis, the hemostatic function of FXI may well be manifested through feedback activation by thrombin generated by the exposure of blood to tissue factor (TF). 3 In addition to activation of FIX, FXIa can also promote thrombin generation through direct activation of FX, FV, and FVIII, [4][5][6] suggesting it can support hemostasis even in the absence of FIX.…”

Activation of factor XI by products of prothrombin activation

“…13,14 FXIa, in turn, sustains ␣-IIa generation by converting FIX to FIXa␤, 15 and possibly by activating FV and FVIII. 16 In the original cascade/ waterfall hypotheses of coagulation, FXI is activated by FXIIa 17,18 ; however, current models deemphasize this reaction based on the observation that FXI deficiency is associated with abnormal bleeding, whereas FXII deficiency is not. 18 FXI activation by ␣-IIa would explain the phenotypic differences between FXI and FXII deficiency.…”

APC Resistance

“…A lifting of these restraints by removal of the B-domain allows the availability of discrete binding interactions between FVa and its binding partners FXa and prothrombin (Kane, 1990;Keller 1995;Toso, 2004). Activation of FV and FVIII is essentially a positive feedback reaction since the potential activators are alpha-thrombin (Kane et al, 1981;Suzuki et al, 1982), meizothrombin (Tans et al, 1994), FXa (Monkovic & Tracy, 1990), FXIa (Whelihan et al, 2010) and tissue factor-FVIIa . Of these, activation by alpha-thrombin, the very enzyme that is produced by the prothrombinase complex, is regarded as most important.…”