Coagulation Disorders

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In a process as complex as coagulation, it is not surprising that things can go wrong. Clotting deficiencies can result from causes as diverse as malnutrition, leukemia, and gallstones (see insight 18.4).

A deficiency of any clotting factor can shut down the coagulation cascade. This happens in hemophilia, a family of hereditary diseases characterized by deficiencies of one factor or another. Because of its sex-linked recessive mechanism of heredity, most hemophilia occurs predominantly in males. They can inherit it only from their mothers, however, as happened with the descendants of Queen Victoria.

Chapter 18 The Circulatory System: Blood 707

The lack of factor VIII causes classical hemophilia (hemophilia A), which accounts for about 83% of cases and afflicts 1 in 5,000 males worldwide. Lack of factor IX causes hemophilia B, which accounts for 15% of cases and occurs in about 1 out of 30,000 males. Factors VIII and IX are therefore known as antihemophilic factors A and B. A rarer form called hemophilia C (factor XI deficiency) is autosomal, not sex-linked, so it occurs equally in both sexes.

Before purified factor VIII became available in the 1960s, more than half of those with hemophilia died before age 5 and only 10% lived to age 21. Physical exertion causes bleeding into the muscles and joints. Excruciating pain and eventual joint immobility can result from intramuscular and joint hematomas24 (masses of clotted blood in the tissues). Hemophilia varies in severity, however. Half of the normal level of clotting factor is enough to prevent the symptoms, and the symptoms are mild even in individuals with as little as 30% of the normal amount. Such cases may go undetected even into adulthood. Bleeding can be relieved for a few days by transfusion of plasma or purified clotting factors.

_Think About It_

Why is it important for people with hemophilia not to use aspirin? (Hint: See p. 666.)

Insight 18.4 Clinical Application

Liver Disease and Blood Clotting

Proper blood clotting depends on normal liver function for two reasons. First, the liver synthesizes most of the clotting factors. Therefore, diseases such as hepatitis, cirrhosis, and cancer that degrade liver function result in a deficiency of clotting factors. Second, the synthesis of clotting factors II, VII, IX, and X require vitamin K. The absorption of vitamin K from the diet requires bile, a liver secretion. Gallstones can lead to a clotting deficiency by obstructing the bile duct and thus interfering with bile secretion and vitamin K absorption. Efficient blood clotting is especially important in childbirth, since both the mother and infant bleed from the trauma of birth. Therefore, pregnant women should take vitamin K supplements to ensure fast clotting, and newborn infants may be given vitamin K injections.

Far more people die from unwanted blood clotting than from clotting failure. Most strokes and heart attacks are due to thrombosis—the abnormal clotting of blood in an unbroken vessel. A thrombus (clot) may grow large enough to obstruct a small vessel, or a piece of it may break loose and begin to travel in the bloodstream as an embolus.25 An embolus may lodge in a small artery and block blood flow

Saladin: Anatomy & I 18. The Circulatory System: I Text I © The McGraw-Hill

Physiology: The Unity of Blood Companies, 2003 Form and Function, Third Edition

Insight 18.5 Clinical Application

708 Part Four Regulation and Maintenance from that point on. If that vessel supplies a vital organ such as the heart, brain, lung, or kidney, infarction (tissue death) may result. About 650,000 Americans die annually of thromboembolism (traveling blood clots) in the cerebral, coronary, and pulmonary arteries.

Thrombosis is more likely to occur in veins than in arteries because blood flows more slowly in the veins and does not dilute thrombin and fibrin as rapidly. It is especially common in the leg veins of inactive people and patients immobilized in a wheelchair or bed. Most venous blood flows directly to the heart and then to the lungs. Therefore, blood clots arising in the legs or arms commonly lodge in the lungs and cause pulmonary embolism. When blood cannot circulate freely through the lungs, it cannot receive oxygen and a person may die of hypoxia.

Table 18.10 describes some additional disorders of the blood. The effects of aging on the blood are described on pages 1110 to 1111.

Before You Go On

Answer the following questions to test your understanding of the preceding section:

25. What are the three basic mechanisms of hemostasis?

26. How do the extrinsic and intrinsic mechanisms of coagulation differ? What do they have in common?

27. In what respect does blood clotting represent a negative feedback loop? What part of it is a positive feedback loop?

28. Describe some of the mechanisms that prevent clotting in undamaged vessels.

29. Describe a common source and effect of pulmonary embolism.

Controlling Coagulation

For many cardiovascular patients, the goal of treatment is to prevent clotting or to dissolve clots that have already formed. Several strategies employ inorganic salts and products of bacteria, plants, and animals with anticoagulant and clot-dissolving effects.

Preventing Clots from Forming

Since calcium is an essential requirement for blood clotting, blood samples can be kept from clotting by adding a few crystals of sodium oxalate, sodium citrate, or EDTA26—salts that bind calcium ions and prevent them from participating in the coagulation reactions. Blood-collection equipment such as hematocrit tubes may also be coated with heparin, a natural anticoagulant whose action was explained earlier.

Since vitamin K is required for the synthesis of clotting factors, anything that antagonizes vitamin K usage makes the blood clot less readily. One vitamin K antagonist is coumarin21 (COO-muh-rin), a sweet-smelling extract of tonka beans, sweet clover, and other plants, used in perfume. Taken orally by patients at risk for thrombosis, coumarin takes up to 2 days to act, but it has longer-lasting effects than heparin. A similar vitamin K antagonist is the pharmaceutical preparation Warfarin'28 (Coumadin), which was originally developed as a pesticide—it makes rats bleed to death. Obviously, such anticoagulants must be used in humans with great care.

As explained in chapter 17, aspirin suppresses the formation of prostaglandins including thromboxane A2, a factor in platelet aggregation. Low daily doses of aspirin can therefore suppress thrombosis and prevent heart attacks.

Many parasites feed on the blood of vertebrates and secrete anticoagulants to keep the blood flowing. Among these are segmented

Table 18.10 Some Disorders of the Blood

Infectious mononucleosis

Thalassemia

Thrombocytopenia

Disseminated intravascular coagulation (DIC)

Septicemia

Disorders described elsewhere

Anemia 692

Embolism 708

Hematoma 198, 707

Hemolytic disease of the newborn 697

Hemophilia 707

Infection of B lymphocytes with Epstein-Barr virus, most commonly in adolescents and young adults. Usually transmitted by exchange of saliva, as in kissing. Causes fever, fatigue, sore throat, inflamed lymph nodes, and leukocytosis. Usually self-limiting and resolves within a few weeks.

A group of hereditary anemias most common in Greeks, Italians, and others of Mediterranean descent; shows a deficiency or absence of a or p hemoglobin and RBC counts that may be less than 2 million/pL.

A platelet count below 100,000/pL. Causes include bone marrow destruction by radiation, drugs, poisons, or leukemia. Signs include small hemorrhagic spots in the skin or hematomas in response to minor trauma.

Widespread clotting within unbroken vessels, limited to one organ or occurring throughout the body. Usually triggered by septicemia but also occurs when blood circulation slows markedly (as in cardiac arrest). Marked by widespread hemorrhaging, congestion of the vessels with clotted blood, and tissue necrosis in blood-deprived organs.

Bacteremia (bacteria in the bloodstream) accompanying infection elsewhere in the body. Often causes fever, chills, and nausea, and may cause DIC or septic shock. (see p. 765)

Hypoproteinemia 682 Hypoxemia 685 Leukemia 702 Leukocytosis 701 Leukopenia 699

Polycythemia 692 Sickle-cell disease 693 Thrombosis 707 Transfusion reaction 696

Saladin: Anatomy & I 18. The Circulatory System: I Text I © The McGraw-Hill

Physiology: The Unity of Blood Companies, 2003 Form and Function, Third Edition worms known as leeches. Leeches secrete a local anesthetic that makes their bites painless; therefore, as early as 1567 B.C.E., physicians used them for bloodletting. This method was less painful and repugnant to their patients than phlebotomy—cutting a vein—and indeed, leeching became very popular. In seventeenth-century France it was quite the rage; tremendous numbers of leeches were used to treat headaches, insomnia, whooping cough, obesity, tumors, menstrual cramps, mental illness, and almost anything else doctors or their patients imagined to be caused by "bad blood."

The first known anticoagulant was discovered in the saliva of the medicinal leech, Hirudo medicinalis, in 1884. Named hirudin, it is a polypeptide that prevents clotting by inhibiting thrombin. It causes the blood to flow freely while the leech feeds and for as long as an hour thereafter. While the doctrine of bad blood is now discredited, leeches have lately reentered medical usage (fig. 18.24). A major problem in reattaching a severed body part such as a finger or ear is that the tiny veins draining these organs are too small to reattach surgically. Since arterial blood flows into the reattached organ and cannot flow out, it pools and clots there. This inhibits the regrowth of veins and the flow of fresh blood through the organ and thus often leads to necrosis. Some vascular surgeons now place leeches on the reattached part. Their anticoagulant keeps the blood flowing freely and allows new veins to grow. After 5 to 7 days, venous drainage is restored and leeching can be stopped.

Anticoagulants also occur in the venom of some snakes. Arvin, for example, is obtained from the venom of the Malayan viper. It rapidly breaks down fibrinogen and may have potential as a clinical anticoagulant.

Dissolving Clots That Have Already Formed

When a clot has already formed, it can be treated with clot-dissolving drugs such as streptokinase, an enzyme made by certain bacteria (streptococci). Intravenous streptokinase is used to dissolve blood clots in coronary vessels, for example. It is nonspecific, however, and digests almost any protein. Tissue plasminogen activator (TPA) works faster, is

Chapter 18 The Circulatory System: Blood 709

Figure 18.24 A Modern Use of Leeching. Two medicinal leeches are being used to remove clotted blood from a postsurgical hematoma. These leeches grow up to 20 cm long.

more specific, and is now made by transgenic bacteria. TPA converts plasminogen into the clot-dissolving enzyme plasmin. Some anticoagulants of animal origin also work by dissolving fibrin. A giant Amazon leech, Haementeria, produces one such anticoagulant named hementin. This, too, has been successfully produced by genetically engineered bacteria and used to dissolve blood clots in cardiac patients.

26ethylenediaminetetraacetic acid

27coumaru, tonka bean tree

28acronym from Wisconsin Alumni Research Foundation

29phlebo = vein + tomy = cutting

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Responses

  • JARI
    Why is it important for people with hemophilia not to use aspirin?
    8 years ago
  • Findlay
    What are some of the mechanisms that prevent clotting in undamaged vessels?
    8 years ago

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