FXI is a plasma zymogen in the intrinsic pathway of blood coagulation that contributes to the generation of thrombin. Individuals with FXI deficiency, also known as Hemophilia C, have a mild increase in bleeding. FXI is thought to be activated by either FXIIa in the intrinsic pathway or thrombin generated through the extrinsic pathway (tissue factor (TF)-FVIIa) via a feedback loop. This ability of FXI to amplify thrombin generation may explain the mild bleeding phenotype observed in FXI deficient individuals as the absence of FXI would lead to decreased thrombin generation and a less stable hemostatic plug. We decided to investigate the degree of activation of FXI via the extrinsic pathway using an enzyme-linked immunosorbent assay (ELISA) to detect activated FXIa in complex with its endogenous negative regulator C1 inhibitor (C1INH) in human plasma. FXIa-C1INH complexes were measured in human plasma activated with different concentrations of TF. Complex formation in plasma was also evaluated with FXIIa inhibitors and a fibrin depolymerizing agent. Increased FXIa-C1INH complex formation was observed in the presence of TF. However, when FXIIa activity was blocked no measurable increase in FXIa levels were detected in plasma in the presence of TF. This work raises questions about if thrombin-mediated activation of FXI takes place in human plasma.
Sophia Dhrolia (Sat,) studied this question.