Coagulation cascade (diagram)

Case Discussion

The coagulation cascade is a process in which relatively few initiation factors culminate in the formation of thrombin and, subsequently, fibrin to form an insoluble fibrin polymer (clot) that stabilises platelet plug ^{1, 2}. The cascade acts as an amplification system; a million-fold higher concentration of factors is produced by the amplification phase than in the initiation phase ¹.

The coagulation cascade is initiated physiologically by exposing blood to tissue factor, which is expressed at biological boundaries and described as a haemostatic envelope, ensuring that following vascular injury, the blood is exposed to tissue factor ^{1, 2}. Once factor VII binds to tissue factor, it has proteolytic activity, which activates both factor IX and factor X ^{1, 2}. Factor Xa, without its activated cofactor (factor Va), produces only a small amount of thrombin. Still, this small amount of thrombin is enough to activate factor V, factor VIII, and factor XI which leads to the amplification phase of the cascades ^{1, 2}.

After thrombin activates factors V, VIII, and XI, factor XIa activates factor IXa, which forms a complex with factor VIIIa ^{1, 2}. This complex then further activates factor Xa, which forms a complex with factor Va, producing prothrombinase, which generates large amounts of thrombin and subsequently a fibrin clot ^{1, 2}. Factor XIII is also activated by thrombin, along with calcium, and acts to stabilise the fibrin by forming cross-links ².

Thrombin also leads to the activation of important inhibitors of the procoagulant response, namely tissue factor pathway inhibitors (TFPI), antithrombin, and the protein C pathway ². TFPI inhibits the complex formed by tissue factor VIIa as well as factor Xa by forming a quaternary inhibited complex with them ². Antithrombin has inhibitory effects on factors XI, Xa, IXa, and thrombin ². Protein C, after its activation, forms a complex with protein S and inactivates factors Va and VIIIa ².

Once polymerised fibrin is built up, it binds to both tissue plasminogen activator and plasminogen, leading to the activation of plasminogen to plasmin and its rapid degradation of the insoluble crosslinked fibrin to soluble fibrin degradation products, clearing clot ².

While the coagulation cascade is commonly depicted as having intrinsic and extrinsic pathways for thrombin generation, the contact system (activation of factor XII and its activation of factor XI) seems to have little to no role in initiating physiological haemostasis ^{1, 2}. Separating the two pathways, however, clarifies the common coagulation tests used in practice ². The tests commonly done are the activated partial thromboplastin time (APTT), the prothrombin time (PT), and the thrombin time (TT) ². The APTT tests for deficiencies in the intrinsic pathway by the addition of a contact activator to sample ². The PT tests for deficiencies in the extrinsic pathway by the addition of thromboplastin and phospholipids to sample ². The thrombin time (TT) tests for an inhibition of thrombin or issues with fibrin cleavage by the addition of thrombin to sample ².

Anticoagulation information from M. Heestermans et all ³.