Hemostasis

Platelets are key players in hemostasis, the process by which the body seals a ruptured blood vessel and prevents further loss of blood. Although rupture of larger vessels usually requires medical intervention, hemostasis is quite effective in dealing with small, simple wounds.

There are three steps to the process: Vascular spasm, The formation of a platelet plug, and Coagulation (blood clotting).Failure of any of these steps will result in hemorrhage—excessive bleeding.

1.Vascular Spasm: When a vessel is severed or punctured, or when the wall of a vessel is damaged, vascular spasm occurs. In vascular spasm, the smooth muscle in the walls of the vessel contracts dramatically. This smooth muscle has both circular layers; larger vessels also have longitudinal layers. The circular layers tend to constrict the flow of blood, whereas the longitudinal layers, when present, draw the vessel back into the surrounding tissue, often making it more difficult for a surgeon to locate, clamp, and tie off a severed vessel. The vascular spasm response is believed to be triggered by several chemicals called endothelins that are released by vessel-lining cells and by pain receptors in response to vessel injury. This phenomenon typically lasts for up to 30 minutes, although it can last for hours.
2. Formation of the Platelet Plug: In the second step, platelets, which normally float free in the plasma, encounter the area of vessel rupture with the exposed underlying connective tissue and collagenous fibers. The platelets begin to clump together, become spiked and sticky, and bind to the exposed collagen and endothelial lining. This process is assisted by a glycoprotein in the blood plasma called von Willebrand factor, which helps stabilize the growing platelet plug. As platelets collect, they simultaneously release chemicals from their granules into the plasma that further contribute to hemostasis. A platelet plug can temporarily seal a small opening in a blood vessel. Plug formation, in essence, buys the body time while more sophisticated and durable repairs are being made. In a similar manner, even modern naval warships still carry an assortment of wooden plugs to temporarily repair small breaches in their hulls until permanent repairs can be made.
3. Coagulation: Those more sophisticated and more durable repairs are collectively called coagulation, the formation of a blood clot. The process is sometimes characterized as a cascade, because one event prompts the next as in a multi-level waterfall. The result is the production of a gelatinous but robust clot made up of a mesh of fibrin—an insoluble filamentous protein derived from fibrinogen, the plasma protein introduced earlier—in which platelets and blood cells are trapped.

This figure details the steps in the clotting of blood. Each step is shown along with a detailed text box describing the steps on the left. On the right, a signaling pathway shows the different chemical signals involved in the clotting process.

Figure 1: Three steps of hemostasis.

Clotting Factors Involved in Coagulation

In the coagulation cascade, chemicals called clotting factors (or coagulation factors) prompt reactions that activate still more coagulation factors. The process is complex, but is initiated along two basic pathways:

  • The extrinsic pathway, which normally is triggered by trauma.
  • The intrinsic pathway, which begins in the bloodstream and is triggered by internal damage to the wall of the vessel.

Both of these merge into a third pathway, referred to as the common pathway . All three pathways are dependent upon the 12 known clotting factors, including Ca2+ and vitamin K. Clotting factors are secreted primarily by the liver and the platelets. The liver requires the fat-soluble vitamin K to produce many of them. Vitamin K (along with biotin and folate) is somewhat unusual among vitamins in that it is not only consumed in the diet but is also synthesized by bacteria residing in the large intestine. The calcium ion, considered factor IV, is derived from the diet and from the breakdown of bone.

Disorders of Clotting

Either an insufficient or an excessive production of platelets can lead to severe disease or death. As discussed earlier, an insufficient number of platelets, called thrombocytopenia, typically results in the inability of blood to form clots. This can lead to excessive bleeding, even from minor wounds.

Another reason for failure of the blood to clot is the inadequate production of functional amounts of one or more clotting factors. This is the case in the genetic disorder hemophilia, which is actually a group of related disorders, the most common of which is hemophilia A, accounting for approximately 80 percent of cases. This disorder results in the inability to synthesize sufficient quantities of factor VIII. Hemophilia B is the second most common form, accounting for approximately 20 percent of cases. In this case, there is a deficiency of factor IX. Both of these defects are linked to the X chromosome and are typically passed from a healthy (carrier) mother to her male offspring, since males are XY. Females would need to inherit a defective gene from each parent to manifest the disease, since they are XX. Patients with hemophilia bleed from even minor internal and external wounds, and leak blood into joint spaces after exercise and into urine and stool. Hemophilia C is a rare condition that is triggered by an autosomal (not sex) chromosome that renders factor XI nonfunctional. It is not a true recessive condition, since even individuals with a single copy of the mutant gene show a tendency to bleed. Regular infusions of clotting factors isolated from healthy donors can help prevent bleeding in hemophiliac patients. At some point, genetic therapy will become a viable option.

In contrast to the disorders characterized by coagulation failure is thrombocytosis, also mentioned earlier, a condition characterized by excessive numbers of platelets that increases the risk for excessive clot formation, a condition known as thrombosis. A thrombus(plural = thrombi) is an aggregation of platelets, erythrocytes, and even WBCs typically trapped within a mass of fibrin strands. While the formation of a clot is normal following the hemostatic mechanism just described, thrombi can form within an intact or only slightly damaged blood vessel. In a large vessel, a thrombus will adhere to the vessel wall and decrease the flow of blood, and is referred to as a mural thrombus. In a small vessel, it may actually totally block the flow of blood and is termed an occlusive thrombus. Thrombi are most commonly caused by vessel damage to the endothelial lining, which activates the clotting mechanism. These may include venous stasis, when blood in the veins, particularly in the legs, remains stationary for long periods. This is one of the dangers of long airplane flights in crowded conditions and may lead to deep vein thrombosis or atherosclerosis, an accumulation of debris in arteries. Thrombophilia, also called hypercoagulation, is a condition in which there is a tendency to form thrombosis. This may be familial (genetic) or acquired. Acquired forms include the autoimmune disease lupus, immune reactions to heparin, polycythemia vera, thrombocytosis, sickle cell disease, pregnancy, and even obesity. A thrombus can seriously impede blood flow to or from a region and will cause a local increase in blood pressure. If flow is to be maintained, the heart will need to generate a greater pressure to overcome the resistance.

When a portion of a thrombus breaks free from the vessel wall and enters the circulation, it is referred to as an embolus. An embolus that is carried through the bloodstream can be large enough to block a vessel critical to a major organ. When it becomes trapped, an embolus is called an embolism. In the heart, brain, or lungs, an embolism may accordingly cause a heart attack, a stroke, or a pulmonary embolism. These are medical emergencies.

Among the many known biochemical activities of aspirin is its role as an anticoagulant. Aspirin (acetylsalicylic acid) is very effective at inhibiting the aggregation of platelets. It is routinely administered during a heart attack or stroke to reduce the adverse effects. Physicians sometimes recommend that patients at risk for cardiovascular disease take a low dose of aspirin on a daily basis as a preventive measure. However, aspirin can also lead to serious side effects, including increasing the risk of ulcers. A patient is well advised to consult a physician before beginning any aspirin regimen.