Related Experiment Video
Updated: Aug 12, 2025
A Microfluidic Flow Chamber Model for Platelet Transfusion and Hemostasis Measures Platelet Deposition and Fibrin Formation in Real-time
Published on: February 14, 2017
Thrombogenic potential of picomolar coagulation factor XIa is mediated by thrombin wave propagation
Leonid A Parunov1, Yideng Liang1, Qijin Lu2
1Center for Biologics Evaluation and Research (CBER), US Food and Drug Administration, Silver Spring, MD.
Abstract:
Inhibitors of coagulation factor XIa (FXIa) are currently being investigated as potential anticoagulant therapies. We hypothesize that circulating FXIa could be a potential target for these therapies. Using previous analyses of FXIa impurities in immune globulin products involved in thrombotic adverse events, we estimated that picomolar levels of FXIa can be thrombogenic. In an in vitro clot-growth assay, 0.1-3 pM of FXIa did not, by itself, activate clotting but increased the size of growing clots. Spatio-temporal reconstruction of thrombin activity inside the clot revealed that FXIa's effect was limited to the clot-plasma interface, in which FXIa produced a taller than standard wave of thrombin. Factor-depleted plasma and a panel of selective anti-FXIa antibodies showed that exogenous FXIa effects are (1) blocked by anti-FXIa antibodies, (2) independent of FXI activation inside the clot, and (3) larger than the contribution of in situ FXIa. In a thrombin generation (TG) assay, picomolar FXIa did not initiate TG but rather promoted TG triggered by tissue factor or thrombin, suggesting that the effect of FXIa on the thrombin wave is mediated by the elevation of thrombin-triggered TG. In circulating bovine blood, low doses of human FXIa did not initiate clotting but increased the size of stenosis-triggered thrombi. FXIa injection in mice enhanced TG in plasma for at least 6 hours ex vivo, confirming the persistence of circulating FXIa. Our findings suggest that picomolar levels of circulating FXIa may not be able to initiate thrombosis but can facilitate thrombus growth through the facilitation of TG inside the clot.
Insights
Picomolar levels of coagulation factor XIa (FXIa) do not initiate blood clots but can promote thrombus growth. This suggests FXIa may be a target for anticoagulants by facilitating thrombin generation within clots.
Area of Science:
- Hemostasis and Thrombosis
- Coagulation Cascade Research
- Pharmacological Anticoagulation
Background:
- Coagulation factor XIa (FXIa) inhibitors are explored as anticoagulants.
- Previous findings suggest FXIa impurities in immune globulin products correlate with thrombotic events.
- Picomolar concentrations of FXIa are hypothesized to be thrombogenic.
Purpose of the Study:
- To investigate the role of circulating FXIa in thrombosis.
- To determine if picomolar levels of FXIa can initiate or influence clot formation.
- To elucidate the mechanism by which FXIa affects thrombin generation and clot growth.
Main Methods:
- In vitro clot-growth assays using varying FXIa concentrations.
- Spatio-temporal reconstruction of thrombin activity within clots.
- Thrombin generation (TG) assays with exogenous FXIa.
- In vivo studies in bovine blood and murine models to assess FXIa's thrombotic potential and persistence.
Main Results:
- Picomolar FXIa (0.1-3 pM) did not initiate clotting but increased clot size in vitro.
- FXIa's procoagulant effect was localized to the clot-plasma interface, enhancing thrombin wave height.
- Exogenous FXIa effects were blocked by anti-FXIa antibodies and independent of intrinsic FXI activation.
- FXIa potentiated thrombin generation triggered by tissue factor or thrombin, rather than initiating it.
- In vivo, FXIa increased thrombus size in bovine blood and enhanced TG in mice for at least 6 hours.
Conclusions:
- Circulating FXIa at picomolar levels may not initiate thrombosis but can significantly facilitate thrombus growth.
- FXIa's prothrombotic activity appears mediated by enhancing thrombin generation within the clot.
- These findings support FXIa as a potential therapeutic target for anticoagulant therapies.
Related Concept Videos
01:30Anticoagulant Drugs: Low-Molecular-Weight Heparins
01:20Extrinsic and Intrinsic Pathways of Hemostasis
The Extrinsic Pathway
The extrinsic pathway of coagulation is typically initiated by tissue damage that exposes blood to tissue factor (TF), a protein released by the damaged tissue cells outside the blood vessels—this interaction with TF triggers biochemical reactions involving specific clotting factors. The key player here is Factor VII, which...
01:29Venous Thrombosis III: Interprofessional Care
01:16Clot Retraction and Fibrinolysis
01:09Coagulation
During the coagulation phase, clotting factors, or procoagulants, play a vital role in initiating and progressing the coagulation cascade. This cascade is a series of reactions...
01:30Venous Thrombosis I: Introduction