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The biology of haemostasis and thrombosis 

The biology of haemostasis and thrombosis

The biology of haemostasis and thrombosis

Harold R. Roberts

and Gilbert C. White

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date: 30 March 2017

Haemostasis—a component of the wound defence mechanism—is a process by which vessel wall components and platelets act in concert with procoagulant and anticoagulant proteins to form a plug of cells and cross-linked fibrin. The plug is later remodelled and replaced by new tissue as part of wound healing. These processes are very complex and involve highly controlled pathways of interaction between cells, glycans, and membrane-bound and soluble proteins of coagulation and fibrinolysis, as well as their cognate inhibitors.

Thrombosis—this is an abnormal state leading to formation of a clot obstructing blood vessel flow; dislodgement leads to thromboembolism.

Blood-vessel wall

Endothelial cells—these make many contributions to haemostasis: (1) vascular tone—by production of (a) vasodilators, most notably nitric oxide (NO) and prostacyclin (PGI2), and (b) vasoconstrictors, particularly endothelin and angiotensin 2; (2) anticoagulant effects—by production of PGI2, NO, thrombomodulin, tissue factor pathway inhibitor, glycosaminoglycans, CD39, tissue plasminogen activator; (3) procoagulant effects—the dominant effect of endothelial cells is anticoagulant, but they store/produce Von Willebrand factor and tissue factor (TF); (4) expression of receptors—including thrombin receptors, endothelial cell protein C receptor, and a number of adhesive receptors that are important for the interaction of leucocytes and the vessel wall.

Other elements—these include (1) extracellular matrix—promotes platelet adhesion, cellular migration, cell proliferation, and endothelial and smooth muscle cell interactions; (2) smooth muscle cells; (3) adventitia.


Platelets are key components of the haemostatic plug. They adhere to damaged vessels where subendothelial matrix is exposed, aggregating to form an initial plug that prevents blood loss by occluding the breach in the vessel wall. Their involvement in haemostasis can broadly be divided into the following processes: (1) platelet adhesion—accomplished by a number of glycoprotein and other adhesion receptors on the platelet surface; (2) platelet activation—following adhesion and in response to soluble agonists, platelets undergo reactions (including changes in metabolism of membrane inositol phospholipids) that lead to generation of platelet coagulant activity, thrombin, and release of ADP, which lead to activation of additional platelets; (3) platelet aggregation—mediated by binding of activated platelet surface glycoprotein GPIIb–IIIa to fibrinogen or fibrin, which by virtue of its dimeric structure can bind to more than one platelet and thereby facilitate their aggregation, which serves to localize the haemostatic plug at the site of injury.

Blood coagulation

Blood coagulation depends on the presence of serial proenzymes that are sequentially activated in the presence of activators and cofactors, with key elements being (1) TF—this is constitutively produced in several extravascular tissues such as fibroblasts and smooth muscle cells, but not in cells exposed to the circulating blood; it functions as a receptor for factor VII and initiates the blood coagulation pathway after it binds to and activates factor VII; (2) TF–VIIa complex—this activates factors IX and X which, in the presence of their respective cofactors (VIII and V), rapidly convert prothrombin (factor II) to thrombin; (3) thrombin converts soluble fibrinogen to fibrin; (4) fibrin undergoes cross-linking by activated factor XIII to form the stable haemostatic plug.

Important aspects of the system include: (1) platelets are essential in several steps of the clotting mechanism and form the surface for activated clotting factors, which lead to the explosive generation of thrombin and subsequent clot formation; (2) the initial generation of relatively small amounts of thrombin is essential for feedback activation of factors V, VIII, XI, and XIII, as well as of platelets.

Inhibitors of the coagulation reactions—there are numerous inhibitors of the reactions involved in blood coagulation, which are essential for the time control and safety of the process. These include (1) TF pathway inhibitor—occurs in forms free within the circulation and anchored to cell surfaces; inhibits the VIIa–TF–Xa complex; (2) antithrombin—a serpin inhibitor of thrombin, factor X, and other proteases; (3) other inhibitors—these include α‎1-antitrypsin, C-1 esterase inhibitor, and protein Z-dependent protease inhibitor.

The fibrinolytic system

The fibrinolytic system depends on the activation of plasminogen in the circulation by tissue plasminogen activator to form plasmin, which degrades (1) fibrinogen and fibrin to form specific fibrin degradation products, and also (2) factors VIII and V, and von Willebrand factor.

Important aspects of the system include: (1) free plasmin in the circulation is inhibited by α‎2-antiplasmin; (2) plasminogen and tissue plasminogen activator associate in the circulation with fibrinogen, hence when fibrinogen is converted to fibrin, the clot is rich in both of these proteins, which are protected from the inhibitory action of antiplasmin, hence clots can be lysed without interference from inhibitors; (3) many other regulatory mechanisms, including plasminogen activator inhibitor I, urokinase plasminogen activator, and thrombin-activatable fibrinolytic inhibitor.

The balance of fibrinolysis and coagulation

Fibrinolysis and coagulation are interrelated: fibrin clots are normally lysed by plasmin locally released from plasminogen by the action of tissue plasminogen activator, and this process is enhanced by some procoagulant factors, e.g. activated factors XI and XII, protein C. This system, so delicately controlled and normally maintained in a dynamic equilibrium, is strongly influenced by components involved in inflammatory and other defence mechanisms in the host. An integrated understanding of these processes offers the potential for improved means to predict the adverse complications of many diseases and ultimately to prevent their occurrence.

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