Haemostasis

Haemostasis or normal blood clotting is essential for survival

The normal physiological response that prevents significant blood loss following vascular injury is called haemostasis.⁶ Familiarity with haemostasis lays the groundwork for a thorough understanding of the major disease states associated with thrombosis, such as venous thromboembolism (VTE), atherothrombosis (thrombosis triggered by plaque rupture), and cardioembolic stroke.

Blood vessel injury triggers the following sequence:

The vessel constricts to reduce blood flow
Circulating platelets adhere to the vessel wall at the site of trauma
Platelet activation and aggregation, coupled with an intricate series of enzymatic reactions involving coagulation proteins, produces fibrin to form a stable haemostatic plug

Vessel wall chart: clot initiation, formation and fibrinolysis

Haemostasis schematic

Haemostasis is a finely tuned process that serves to maintain the integrity of the circulatory system.¹⁰ However, the process can go out of balance, leading to significant morbidity and mortality.¹¹

Abnormal haemostasis

Excessive coagulation leads to the formation of a thrombus, potentially obstructing blood flow. This is a common problem, especially in hospitalised or immobilised patients. Venous thromboembolic disease, for example, is a major problem in the European Union, where it causes more than one million events or deaths every year.¹²

Excessive bleeding results when certain coagulation factors are lacking, as in patients with haemophilia.¹³

The coagulation cascade

The coagulation process that leads to haemostasis involves a complex set of protease reactions involving roughly 30 different proteins.¹⁴ The final result of these reactions is to convert fibrinogen, a soluble protein, to insoluble strands of fibrin. Together with platelets, the fibrin strands form a stable blood clot.

An evolving model

For decades, the coagulation cascade was conceptualised as having two distinct points of initiation, labelled the extrinsic and intrinsic pathways.¹⁵ Over time, however, it has become clear that these pathways do not function in the body as parallel, independent systems.

The finding that the tissue factor-factor VIIa complex from the extrinsic pathway activates factors in both systems suggests that they are linked. This discovery, combined with an evolving understanding of the role of different cells, in particular blood platelets, has led to a cell-based model of coagulation. Unlike the older, intrinsic/extrinsic cascade model, the cell-based model includes the important interactions between cells directly involved in haemostasis (ie, tissue factor-bearing cells and platelets) and coagulation factors. This model more accurately represents the interaction between cellular activity and coagulation proteins that leads to blood clot formation and haemostasis.¹⁵

The intrinsic and extrinsic pathway model

This model divides the initiation of coagulation into distinct parts: the extrinsic pathway and the intrinsic pathway.⁶ The extrinsic pathway is the primary initiator of coagulation, while the intrinsic pathway leads to the successive activation of Factors IX and X. Activated Factor X (Factor Xa) plays a central role in the coagulation cascade, as it occupies a point where the intrinsic and extrinsic pathways converge.

The cell-based model

The cell-based model identifies the membranes of tissue factor–bearing cells and platelets as the sites where activation of specific coagulation factors occurs.¹⁵ This model posits a three-phase process — initiation, amplification, and thrombin action. Initiation occurs after vascular injury, when tissue factor–bearing cells bind to and activate Factor VII. This leads to production of a small amount of thrombin. Thrombin then activates platelets and cofactors during the amplification phase. The prothrombinase complex (comprising Factor Xa and cofactors bound to activated platelets) is responsible for the burst of thrombin production leading to the third phase of clot formation.

Beyond cells and coagulation factors: the role of microparticles and P-selectin

Ongoing research in this field has uncovered other components of the coagulation process, including microparticles and P-selectin. Microparticles are irregularly shaped vesicles that are smaller than platelets (ie, less than a micron in diameter). These vesicles arise from the plasma membrane of blood-borne cells during cell activation, programmed cell death or exposure to shear stress.¹⁷⁸ P-selectin is a cell adhesion molecule found on the inner surface of blood vessels and on activated platelets.¹⁹⁵

Both microparticles and P-selectin promote thrombosis during the amplification phase of coagulation.¹⁹⁵ During thrombus formation, platelets accumulate at the site of vascular injury, become activated and express P-selectin.¹⁹⁵ P-selectin, in turn, binds to tissue factor (TF)-bearing cells. One of the effects of this binding is to cause those cells to shed TF-bearing microparticles. Microparticles then bind to and activate Factor VII. TF-bearing microparticles also are implicated in thrombosis associated with diabetes, metabolic syndrome, specific malignancies (eg, cancer of the colon, pancreas, breast, ovary and lung) and inflammatory and haematologic disorders.¹⁷⁸

Propagation of clotting: the central role of Factor Xa

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.

The coagulation cascade is triggered when injury to a blood vessel allows blood to come in contact with TF–bearing cells. Factor Xa, with activated Factor V (Va) as a cofactor, propagates coagulation by converting prothrombin (Factor II) to thrombin (Factor IIa).¹⁵ Factor Xa is the primary site of amplification in the process: one molecule of Factor Xa catalyses the formation of approximately 1000 thrombin molecules.¹⁶ For this reason, development of medications that inhibit Factor Xa is an active and promising area of pharmaceutical research.¹⁷

Final step: fibrin formation

In the final step of the series of protease reactions leading to clot formation, thrombin triggers conversion of the soluble protein fibrinogen to insoluble fibrin strands. Thrombin also activates Factor XIII, which stabilises the clot by cross-linking the fibrin. The resulting fibrin mesh traps and holds cellular components of the clot (platelets and/or red blood cells).⁶

Fibrinolysis: restoring blood flow

Fibrinolysis, as the term implies, is the process that dissolves fibrin. It leads to clot dissolution. Plasminogen is the precursor of plasmin, which breaks up fibrin clots. During initial clot formation, plasminogen activators are inhibited. Over time, endothelial cells begin to secrete tissue plasminogen activators to start dissolving the clot as the structural integrity of the blood vessel wall is restored. Fibrinolysis must follow the initial stages of haemostasis in order for normal blood flow to be re-established. Medications that convert plasminogen to plasmin are used to treat acute, life-threatening thrombotic disorders, such as myocardial infarction.⁶

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Article references

6 - Colman RW, Clowes AW, George JN, Goldhaber SZ, Marder VJ. Overview of hemostasis. In: Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006:3-16.
10 - Adams GL, Manson RJ, Turner I, Sindram D, Lawson JH. The balance of thrombosis and hemorrhage in surgery. Hematol Oncol Clin North Am. 2007;21(1):13-24.
11 - Heit JA. Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost. 2005;3(8):1611-1617.
12 - Cohen AT, Agnelli G, Anderson FA, et al; VTE Impact Assessment Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost. 2007;98(4):756-764.
13 - Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol. 2003;23(1):17-25.
14 - Colman RW, Marder VJJ, Clowes AW. Overview of coagulation, fibrinolysis and their regulation. In: Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ, eds. iHemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006:17-20.
15 - Hoffman M, Monroe DM. Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin North Am. 2007;21(1):1-11.
178 - Davizon P, López JA. Microparticles and thrombotic disease. Curr Opin Hematol. 2009;16(5):334-341.
195 - Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008;359(9):938-949.
16 - Mann KG, Brummel K, Butenas S. What is all that thrombin for? J Thromb Haemost. 2003;1(7):1504-1514.
17 - Turpie AG. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases. Arterioscler Thromb Vasc Biol. 2007;27(6):1238-1247.

Haemostasis: The prevention of blood loss, either by the physiological properties of vasoconstriction and coagulation or by surgical means.
Vascular injury: Damage to the endothelial layer (inner surface) of a blood vessel. This damage causes the release of tissue factor, which subsequently activates Factor X. Vascular injury can be caused, for example, by incisions made during surgery, the use of catheters, or the use of a tourniquet.
Venous thromboembolism: A condition in which a blood clot (thrombus) forms in a vein, which in some cases then breaks free and enters the circulation as an embolus, finally lodging in and completely obstructing a blood vessel, e.g., in lungs causing a PE. The term encompasses both DVT and PE.
Fibrin: The primary end product of the coagulation cascade. Fibrin links itself into strands to form a net. This net traps blood cells and tightens itself through cross-linkages, resulting in a dense blood clot.
Coagulation factors: Group of plasma protein substances (Factor I to XIII) contained in the plasma, which act together to bring about blood coagulation.
Coagulation cascade: Series of reactions by which a small stimulus is amplified to produce rapid coagulation.
Factor Xa: The activated form of Factor X. It catalyses the conversion of prothrombin to thrombin in conjunction with other cofactors.
Prothrombinase complex: The prothrombinase complex consisting of the coagulation factors Xa and Va, phospholipid and calcium catalyzes the conversion of prothrombin (Factor II) to thrombin (Factor IIa).
Thrombin: Also called Factor IIa, thrombin performs two functions in the coagulation cascade: activating platelets, and catalysing the conversion of soluble fibrinogen into insoluble fibrin. It is formed from prothrombin by a reaction that is catalysed by Factor Xa.
Tissue factor: Tissue factor is the cell surface receptor for Factor VIIa. The complex of tissue factor with Factor VIIa catalyses the conversion of Factor X into Factor Xa.
Prothrombin: Factor II, also called prothrombin, is converted into thrombin as part of the coagulation cascade.
Myocardial infarction: Destruction of heart tissue due to reduced blood flow to the heart. Also known as a heart attack. It usually results from coronary artery disease and is more severe than angina.
Plasmin: A component (enzyme) of the fibrinolytic system that breaks fibrin into small pieces.