Essence of this Article
The coagulation process that leads to haemostasis involves a complex set of reactions involving approximately 30 different proteins. These reactions convert fibrinogen to fibrin, which, together with platelets, forms a stable thrombus. Several coagulation cascade models have been proposed, including the intrinsic and extrinsic pathway model and the more recent cell-based model. Building on these models, ongoing research has elucidated a role for other components of the coagulation process including microparticles and the protein P-selectin. An inherited or acquired imbalance in the coagulation system that leads to an increased risk of thrombosis is called thrombophilia. Approximately one in three patients with venous thromboembolism (VTE) has an inherited thrombophilia.
The coagulation cascade
The coagulation process that leads to haemostasis involves a complex set of reactions involving approximately 30 different proteins.22 These reactions convert fibrinogen, a soluble protein, to insoluble strands of fibrin, which, together with platelets, forms a stable thrombus.
Several coagulation cascade models have been proposed, including the intrinsic and extrinsic pathway model and the more recent cell-based model.
The intrinsic and extrinsic pathway model
The intrinsic and extrinsic pathway model divides the initiation of coagulation into two distinct parts.19 The extrinsic pathway is thought to be responsible for the initial generation of activated Factor X (Factor Xa), whereas the intrinsic pathway leads to amplification of Factor Xa generation. Factor Xa plays a central role in the coagulation cascade because it occupies a point where the intrinsic and extrinsic pathways converge.
The cell-based model
The cell-based model better explains the mechanism of haemostasis in vivo and includes the important interactions between cells directly involved in haemostasis (i.e. tissue factor [TF]-bearing cells and platelets) and coagulation factors. This model more accurately represents the interaction between cellular activity and coagulation proteins that leads to thrombus formation and haemostasis.23
The cell-based model identifies the membranes of TF-bearing cells and platelets as the sites where activation of specific coagulation factors occurs.23 This model describes a three-phase process:
- Fibrin formation
Initiation occurs after vascular injury, when TF-bearing cells bind to and activate Factor VII. This leads to production of a small amount of thrombin, which then activates platelets and co-factors during the amplification phase. The prothrombinase complex (comprising Factor Xa and co-factors bound to activated platelets) is responsible for the burst of thrombin production leading to the third phase of fibrin formation.
The final step of the series of protease reactions leading to thrombus formation involves the conversion of the soluble protein fibrinogen to insoluble fibrin strands by thrombin. Thrombin also activates Factor XIII, which stabilizes the thrombus by cross-linking fibrin. The resulting fibrin mesh traps and holds cellular components of the thrombus (platelets and/or red blood cells).19
The central role of Factor Xa in thrombus formation
Factor Xa plays a central role in the coagulation process that leads to haemostasis in both the older, extrinsic/intrinsic model as well as the more recently proposed cell-based model.
- Factor Xa, with activated Factor V (Factor Va) as a co-factor, propagates coagulation by converting prothrombin (Factor II) to thrombin (Factor IIa)23
- Factor Xa is a crucial site of amplification in the coagulation process
- One molecule of Factor Xa catalyses the formation of approximately 1000 thrombin molecules24
Development of medications that inhibit Factor Xa is, therefore, an attractive area of pharmaceutical research.
Fibrinolysis: restoring blood flow
Fibrinolysis is the process that dissolves fibrin. By dissolving fibrin, fibrinolysis leads to dissolution of the thrombus.
Plasminogen is the precursor of plasmin, which breaks up fibrin in the thrombus. During initial thrombus formation, plasminogen activators are inhibited. Endothelial cells begin to secrete tissue plasminogen activators to start dissolving the thrombus as the structural integrity of the blood vessel wall is restored. Fibrinolysis must occur for normal blood flow to be reestablished.
Medications that convert plasminogen to plasmin are used to treat acute, life-threatening thrombotic disorders, such as myocardial infarction (MI) and ischaemic stroke.25
Beyond cells and coagulation factors: the role of microparticles and P-selectin
Ongoing research has elucidated other components of the coagulation process. These components include microparticles and P-selectin.
Microparticles are irregularly shaped vesicles that are smaller than platelets (i.e. less than 1 μm in diameter). These vesicles arise from the plasma membrane of blood-borne cells during cell activation, programmed cell death or exposure to shear stress.26 P-selectin is a cell adhesion molecule found on the inner surface of blood vessels and on activated platelets.27
Both microparticles and P-selectin promote thrombosis during the amplification phase of coagulation.27 During thrombus formation, platelets accumulate at the site of vascular injury, become activated and express P-selectin.27 P-selectin, in turn, binds to TF-bearing microparticles. One of the effects of this binding is to cause those microparticles to bind to activated platelets. TF from the microparticles then binds to and activates Factor VII. TF-bearing microparticles are also implicated in thrombosis associated with diabetes, metabolic syndrome, specific malignancies (e.g. cancer of the colon, pancreas, breast, ovary and lung) and inflammatory and haematological disorders.26
Imbalances in the coagulation system
‘Thrombophilia’ is an inherited or acquired imbalance in the coagulation system that leads to an increased risk of thrombosis.
Thrombophilia may be expected in:
- Patients with recurrent VTE or a life-threatening VTE
- Patients with VTE <45 years of age
- Patients with VTE and a family history of VTE
- Patients who develop VTE with no apparent exposing risk factors
- Women who experience multiple spontaneous abortions or stillbirths28
Approximately one in three patients with VTE has an inherited thrombophilia.29
- Common forms involve genetic mutations affecting Factor V (known as Factor V Leiden) and prothrombin (Factor II)
- Rare causes include deficiencies of the natural anticoagulants protein C, protein S and antithrombin28