(USMLE topics) The 3 stages of hemostasis, blood clotting, bleeding disorders and formation of unwanted blood clots (thrombosis).
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Hemostasis is the process that controls bleeding at the site of injury. Blood loss is stopped by formation of blood clots that seal the breaks in blood vessels. Hemostatic mechanisms involve small cell fragments known as platelets and a dozen of soluble clotting factors. These elements are always present in the blood in their inactive form, ready to activate, typically within seconds of an injury. When blood vessels are damaged, blood is exposed to components of the surrounding tissue. Some of these components bind to and activate platelets. Activated platelets are involved in all stages of hemostasis:
- First, they secrete chemicals that induce blood vessels to constrict, thereby reducing blood loss. This is known as vascular spasm, the most immediate response to tissue injury. Vascular spasm is also triggered by local pain receptors, and by substances released by endothelial cells.
- Second, activated platelets become adhesive to each other and to the endothelium; they clump together, forming a platelet plug. They also secrete substances that attract other nearby platelets, activating them in a positive feedback loop, speeding up the formation and propagation of the plug.
- Third, the surface of activated platelets serves as the site for coagulation - the formation of blood clots. A clot is essentially a platelet plug reinforced with strands of a protein called fibrin - the final product of the coagulation cascade. Coagulation is a complex chain reaction where one clotting factor activates the next in the multi-step pathway.
There are 2 activation pathways for coagulation:
- The extrinsic pathway starts with the exposure of blood clotting factors to the tissue factor, TF, in the extravascular tissue. This pathway is induced by injuries to blood vessels.
- The intrinsic pathway, which involves only factors within blood vessels, is thought to serve as a positive feedback loop, amplifying coagulation.
The 2 pathways converge into a common pathway producing thrombin and ultimately fibrin. Thrombin has the central role in the coagulation cascade. It cleaves soluble fibrinogen to generate insoluble fibrin. Thrombin also further activates platelets, and initiates a positive feedback loop that is essential for clot propagation.
Blood clots prevent blood loss during wound healing, but once the vessels are repaired, they must be dissolved to restore blood flow. This process, called fibrinolysis, is a small cascade that produces the enzyme plasmin. Plasmin cleaves fibrin and dissolves the clot.
Because most clotting factors are produced in the liver and their production requires vitamin-K, liver diseases such as cirrhosis, and vitamin-K deficiency may cause excessive bleeding. The main bleeding disorders, however, are inherited. These conditions are caused by gene mutations that lead to deficiency of a certain clotting factor. They are usually treated with replacement therapy, using purified factors produced by recombinant technology, or frozen platelets.
While formation of blood clots is critical to control bleeding, inappropriate coagulation can be dangerous. In fact, far more people die from unwanted blood clotting than from clotting failure. Unwanted blood clot formation, known as thrombosis, is the most common cause of blocked arteries in heart attacks, strokes and pulmonary embolism.
Factors that prevent inappropriate coagulation include:
- Platelet-repellent property of the endothelium,
- Anticoagulant factors - enzymes that prevent clot formation,
- and the fibrinolysis cascade that dissolves blood clots after they are formed,
Fluidity of normal blood flow also helps dilute the small amount of thrombin that forms spontaneously. Decreased flow or stagnation of blood may increase risks for thrombosis.
People with high risks of unwanted blood clotting are treated with drugs that inhibit platelet aggregation, such as aspirin; or drugs that inhibit coagulation, such as heparin or warfarin.