When a blood vessel is injured, a number of physiological mechanisms are activated that promote hemostasis, or the cessation of bleeding (hemo = blood; stasis = standing). Breakage of the endothelial lining of a vessel exposes collagen proteins from the subendothelial connective tissue to the blood. This initiates three separate, but overlapping, hemostatic mechanisms: (1) vasoconstriction, (2) the formation of a platelet plug, and (3) the production of a web of fibrin proteins that penetrates and surrounds the platelet plug.
In the absence of vessel damage, platelets are repelled from each other and from the endothelial lining of vessels. The repulsion of platelets from an intact endothelium is believed to be due to prostacyclin, a type of prostaglandin (see chapter 11, fig. 11.34), produced within the endothelium. Mechanisms that prevent platelets from sticking to the blood vessels and to each other are obviously needed to prevent inappropriate blood clotting.
Damage to the endothelium of vessels exposes subendothelial tissue to the blood. Platelets are able to stick to exposed collagen proteins that have become coated with a protein (von Willebrand factor) secreted by endothelial cells. Platelets contain secretory granules; when platelets stick to collagen, they degranulate as the secretory granules release their products. These products include adenosine diphosphate (ADP), serotonin, and a prostaglandin called thromboxane A2. This event is known as the platelet release reaction.
Serotonin and thromboxane A2 stimulate vasoconstriction, which helps to decrease blood flow to the injured vessel. Phos-pholipids that are exposed on the platelet membrane participate in the activation of clotting factors.
The release of ADP and thromboxane A2 from platelets that are stuck to exposed collagen makes other platelets in the vicinity "sticky," so that they adhere to those stuck to the collagen. The second layer of platelets, in turn, undergoes a platelet release reaction, and the ADP and thromboxane A2 that are secreted cause additional platelets to aggregate at the site of injury. This produces a platelet plug in the damaged vessel, which is strengthened by the activation of plasma clotting factors.
In order to undergo a release reaction, the platelets must produce prostaglandins. Aspirin inhibits the cy-^ i ^ clooxygenase enzyme that catalyzes the conversion of arachidonic acid (a cyclic fatty acid) into prostaglandins (chapter 11; see fig. 11.34), and thereby inhibits the release reaction and consequent formation of a platelet plug. Since platelets lack nuclei and are not complete cells, they cannot regenerate new enzymes. Therefore, the enzymes remain inhibited for the life of the platelets. The ingestion of excessive amounts of aspirin can thus significantly prolong bleeding time for several days, which is why blood donors and women in the last trimester of pregnancy are advised to avoid aspirin. Slight inhibition of platelet aggregation by low doses of aspirin, however, can reduce the risk of atherosclerotic heart disease, and such a regimen is often recommended for patients diagnosed with this condition.
Clotting Factors: Formation of Fibrin
The platelet plug is strengthened by a meshwork of insoluble protein fibers known as fibrin (fig. 13.7). Blood clots therefore contain platelets and fibrin, and they usually contain trapped red blood cells that give the clot a red color (clots formed in arteries, where the blood flow is more rapid, generally lack red blood cells and thus appear gray). Finally, contraction of the platelet mass in the process of clot retraction forms a more compact and effective plug. Fluid squeezed from the clot as it retracts is called serum, which is plasma without fibrinogen, the soluble precursor of fibrin. (Serum is obtained in laboratories by allowing blood to clot in a test tube and then centrifuging the tube so that the clot and blood cells become packed at the bottom of the tube.)
The conversion of fibrinogen into fibrin may occur via either of two pathways. Blood left in a test tube will clot without
Heart and Circulation the addition of any external chemicals; the pathway that produces this clot is thus called the intrinsic pathway. The intrinsic pathway also produces clots in damaged blood vessels when collagen is exposed to plasma. Damaged tissues, however, release a chemical that initiates a "shortcut" to the formation of fibrin. Since this chemical is not part of blood, the shorter pathway is called the extrinsic pathway.
The intrinsic pathway is initiated by the exposure of plasma to a negatively charged surface, such as that provided by collagen at the site of a wound or by the glass of a test tube. This activates a plasma protein called factor XII (table 13.4), which is a protein-digesting enzyme (a protease). Active factor XII in turn activates another clotting factor, which activates yet another. The plasma clotting factors are numbered in order of their discovery, which does not reflect the actual sequence of reactions.
The next steps in the sequence require the presence of Ca2+ and phospholipids, the latter provided by platelets. These steps result in the conversion of an inactive glycoprotein, called pro-thrombin, into the active enzyme thrombin. Thrombin converts the soluble protein fibrinogen into fibrin monomers. These
■ Figure 13.7 Colorized scanning electron micrograph of a blood clot. The threads of fibrin have been colored green, the erythrocytes are shown red, and the platelets have been colored purple.
monomers are joined together to produce the insoluble fibrin polymers that form a meshwork supporting the platelet plug. The intrinsic clotting sequence is shown on the right side of figure 13.8.
A number of hereditary diseases involve the clotting system. Examples of hereditary clotting disorders include two different genetic defects in factor VIII. A defect in one subunit of factor VIII prevents this factor from participating in the intrinsic clotting pathway. This genetic disease, called hemophilia A, is an X-linked recessive trait that is prevalent in the royal families of Europe. A defect in another subunit of factor VIII results in von Willebrand's disease. In this disease, rapidly circulating platelets are unable to stick to collagen, and a platelet plug cannot be formed. Some acquired and inherited defects in the clotting system are summarized in table 13.5.
The formation of fibrin can occur more rapidly as a result of the release of tissue thromboplastin from damaged tissue cells. This extrinsic clotting pathway is shown on the left side of figure 13.8. Notice that the intrinsic and extrinsic clotting pathways eventually merge to form a final common pathway that results in the formation of insoluble fibrin polymers.
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