Medical and Scientific Information

Physiological hemostasis results from the harmonious balance between coagulation (clot formation) and fibrinolysis (clot resolution). This finely tuned process serves to maintain the integrity of the circulatory system. The human body, through a complex mechanism that causes blood to clot if a wound occurs, protects itself from excessive blood loss (bleeding) on one hand and from excessive clotting (thrombosis) on the other hand.

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 hemostatic plug

Coagulation involves a complex set of protease reactions involving roughly 30 different proteins. The final outcome 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.

Primary hemostasis - white thrombus

Blood vessels (arteries and arterioles) contract and so constrict the flow of blood. At the same time, damaged endothelial cells release substances that attract thrombocytes and activate clotting factors. The thrombocytes accumulate around the edges of the wound, aggregate and so close the wound up (white thrombus). The vascular and cellular components of blood coagulation are referred to as primary hemostasis.

Secondary hemostasis - stabilizing the thrombus

To stop the thrombus being washed away in the blood stream, a second mechanism is simultaneously activated: activated clotting factors circulating in the blood stabilize the white thrombus with a network of protein fibers (fibrin), to which other blood cells adhere. The stable blood clot (red thrombus) that then forms permanently closes the damaged blood vessel. This process is known as secondary hemostasis which includes the formation of fibrin from fibrinogen through activation of the coagulation cascade.

Following thrombus formation, the contraction of vessels in the injured area declines.
In healthy humans this process takes about 1-3 minutes.

Clotting factors - plasmatic coagulation

Clotting factors are mainly produced in the liver and are released into the plasma. Vitamin K plays a crucial role in the synthesis of factors II, VII, IX and X.

This is the rationale for treatment of thromboembolic diseases with coumarins (also called Vitamin K antagonists - VKAs), which antagonize the action of vitamin K and so inhibit blood clotting. This process is termed anticoagulation. The PT test measures the factors that make up the extrinsic and common pathways: VII, X, V, II and Fibrinogen.

Lack of some coagulation factors may lead to bleeding (e.g., factor VIII or IX in hemophilia)

Coagulation cascade:

The coagulation cascade is classically divided into three pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin.

1) The Traditional (outdated) vision:

traditional vision

on the basis of King, M.W. (1996)


In 1964, the "cascade" theory of McFarlane and the "waterfall" theory of Davie and Ratnoff separated the known coagulation factors into two pathways, the intrinsic and the extrinsic, which converge at the activation of factor X (FX) with the subsequent generation of thrombin proceeding through a single, "common" pathway.

The intrinsic system is the longer route, as it involves all of the coagulation factors and is activated by surface contact. Contact with a negatively charged surface, such as collagen, triggers the intrinsic system by activating factor XII. Also, if blood comes into contact with glass or a foreign surface, such as a prosthetic heart valve or mechanical valve, the intrinsic coagulation pathway may be triggered.

The extrinsic system is the shorter route and is initiated when blood comes into contact with tissue thromboplastin. For example, when there is a tear or an injured site in a vessel, tissue thromboplastin is exposed and forms a complex with factor VII and calcium, triggering the extrinsic system by activating factor X.

2) The "new" coagulation cascade:

simplified coagulation

Simplified "new" coagulation cascade


Over time, however, it has become clear that these pathways described above do not function in the body as parallel, independent systems.

The new coagulation cascade model is seen as 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.

3) Fibrinolysis

Fibrinolysis

Fibrinolysis


By dissolving fibrin, the fibrinolytic system helps to keep open the lumen of an injured blood vessel.

After the wound has healed, the fibrin itself is dissolved in a process known as fibrinolysis (.the process that dissolves fibrin). The fibrin clot is sometimes replaced by a permanent framework of scar tissue but mostly completely resolves.

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. Medications that convert plasminogen to plasmin are used to treat acute, life-threatening thrombotic disorders, such as myocardial infarction.

Under physiological conditions blood coagulation and fibrinolysis always occur simultaneously in the blood stream, normally being in a dynamic equilibrium, ensuring that blood remains liquid within the vascular system. An upset in this delicate balance can lead to bleeding as a result of diminished coagulation or increased fibrinolysis and, conversely, formation of blood clots as a result of increased coagulation and diminished fibrinolysis.


References

Lutze G. Useful facts about coagulation. Mannheim: Roche Diagnostics GmbH, 2000. (data on file)

Broze GJ Jr, Girard TJ, Novotny WF: Perspectives in biochemistry: Regulation of coagulation by a multivalent Kunitz-type inhibitor. Biochemistry 1990;29:7539-7546.

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

Colman RW, Clowes AW, George JN, Goldhaber SZ, Marder VJ. Overview of hemostasis. In: Colman RW, Clowes AW, George JN, Goldhaber SZ, Marder VJ, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006:1-16

Hoffman M, Monroe DM. Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin North Am. 2007;21(1):1-11.