Do all pathways lead to clotting?

By Clément Naudin
Researcher at TREC

Coagulation is essential to prevent blood loss at sites of vascular injury and to maintain the integrity of the circulatory system (haemostasis). However, uncontrolled coagulation may contribute to vascular occlusions with obstruction of blood flow, resulting in tissue damage. This is thrombosis. Thrombosis may occur in the veins leading to venous thromboembolism. In the western world, thromboembolic diseases remain the primary cause of morbidity and mortality. A thrombus is constituted of activated platelets, leukocytes and fibrin fibers.

Fibrin is the result of the activation of tightly regulated plasma proteases and cofactors, the plasma coagulation system. Its formation can be initiated by two pathways of proteases, the extrinsic pathway and the intrinsic pathway. Both pathways meet to trigger the activation of thrombin that cleaves fibrinogen to insoluble fibrin.

The intrinsic pathway is initiated by factor XII in association with high molecular weight kininogen, plasma kallikrein and factor XI, representing the plasma contact system. Contact with negatively charged surfaces induces the activation of factor XII, which in turn activates plasma kallikrein and factor XI. Then factor XI triggers fibrin formation through activation of factor IX.

              Figure: Plasma kallikrein (PK) can activate FIX directly in absence of FXI.

Recently, several alternative pathways, which bypass the regular cascade of activation have been identified. In this new research article, Visser and colleagues demonstrate in plasma and in a mouse model that plasma kallikrein can activate FIX directly in absence of FXI. Under the absence of FXI, using natural and synthetic factor XII activator, deficient plasma and plasma kallikrein inhibitor, they show plasma kallikrein-dependent activation of FIX. These findings may explain, in part, the difference we observe in people who lack FXI and FIX. These data support the in vitro research done with purified proteases “in tube” published 42 years ago by our colleague Bjarne Østerud (Osterud et al, J. Biol. Chem., 1978).

The discovery of alternative pathways could explain phenotypes observed in patients deficient for cascade factors and is critical for safe target in prevention and treatment of thromboembolic diseases.

Reference: Visser M. et al. Arteriosclerosis, Thrombosis, and Vascular Biology (2019):

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