Intrinsic Pathway of Coagulation and Arterial Thrombosis

Abstract

Abstract-Formation of a fibrin clot is mediated by a group of tightly regulated plasma proteases and cofactors. While this system is essential for minimizing blood loss from an injured blood vessel (hemostasis), it also contributes to pathologic fibrin formation and platelet activation that may occlude vessels (thrombosis). Many antithrombotic drugs target key elements of the plasma coagulation mechanism such as thrombin and factor Xa, based on the premise that plasma elements contributing to thrombosis are primarily those involved in hemostasis. Recent studies with genetically altered mice raise questions about this paradigm. Deficiencies of the intrinsic pathway proteases factor XII and factor XI are not associated with abnormal hemostasis in mice, but impair formation of occlusive thrombi in arterial injury models, indicating that pathways not essential for hemostasis participate in arterial thrombosis. If factor XII or factor XI make similar contributions to thrombosis in humans, these proteases could be ideal targets for drugs to treat or prevent thromboembolic disease with minimal risk of therapy-associated bleeding. (Arterioscler Thromb Vasc

Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI

“…These activities ultimately promote coagulation, platelet activation, and preservation of fibrin clot integrity. 6,7 Thrombin also increases the density of fibrin networks 8 and indirectly inhibits fibrinolysis through activation of carboxypeptidase B (thrombin-activatable fibrinolysis inhibitor, TAFI). 9 Thus, FXI may support thrombus propagation and clot stability by increasing thrombin generation.…”

A descriptive investigation of the ultrastructure of fibrin networks in thrombo-embolic ischemic stroke

“…Formation of a fibrin clot is controlled by a group of tightly regulated plasma proteases and cofactors [6]. While this system plays an important role in controlling blood loss, it also contributes to pathologic fibrin formation and platelet activation that may occlude vessels [6].…”

“…Formation of a fibrin clot is controlled by a group of tightly regulated plasma proteases and cofactors [6]. While this system plays an important role in controlling blood loss, it also contributes to pathologic fibrin formation and platelet activation that may occlude vessels [6]. According to Muszbek and co-workers (2008), haemostatic clot formation entails thrombin-mediated cleavage of fibrinogen to fibrin, and thrombin concentration present during clot formation dictates the ultimate fibrin structure.…”

Thymus Peptides (Thymulin, Thymosin Alpha 1 and Thymosin Beta 4) Inhibiting Effects on the Intrinsic Blood Coagulation Pathway in Rats

“…An "internal tanase complex" (FIXa/FVIIIa) is formed as a result leading to activation of FX. Activation of FX is the first step of the end common pathway of blood coagulation leading to thrombin generation terminating with blood clot formation [7] The elements of the intrinsic system FIXa (in a combination of FVIIIa) and FXIa participate in reactions providing both blood clot formation and its resistance to fibrinolysis [8]. Dysregulation of the upper pathways modifies the haemostatic balance with the manifestation of clinical tendencies of either thrombosis or haemorrhage [9].…”