Clotting Disorders

In clotting disorders, blood becomes more likely to clot when clotting is not needed.

A blood clot (thrombus) may form in a blood vessel (vein or artery) and block it. Or a clot may form in an artery or in the heart, travel through the bloodstream, and block an artery elsewhere (embolus). In most clotting disorders, veins are blocked more often than arteries. Veins in the legs are most commonly affected. If a critical blood vessel is blocked, the consequences may be serious. Examples are deep vein thrombosis, pulmonary embolism, strokes, heart attacks, and gangrene.

As people age, particularly after age 55 for men and age 60 for women, blockages in arteries and veins become more common. The reason for the increase is unclear. Atherosclerosis, which becomes more common as people age, may partly explain the increase of blockages in arteries, but not that in veins.

Normally, blood clots in response to injury. Clots form to plug breaks in blood vessels and prevent blood from leaking out of the blood vessels. Platelets are crucial to clotting. When a blood vessel breaks, platelets are activated. They become sticky and change from rounded to spiny. These changes enable platelets to stick to the broken blood vessel wall and to each other, helping form a plug at the break. At the same time, platelets release proteins and other substances that promote further clotting. These substances activate proteins called clotting factors, such as fibrinogen. Until activated, clotting factors are dissolved in the blood. When fibrinogen is activated, it is converted to fibrin, which consists of long strands. The strands are interwoven in the platelet plug and radiate from it. They form a net that entraps more platelets and red blood cells and thus help strengthen the clot. Platelets also release substances that cause the blood vessel to contract (constrict). This effect also helps reduce the bleeding.

After an injured blood vessel heals, other reactions help stop the clotting process and dissolve clots. These reactions also involve proteins dissolved in the blood. Without this control system, minor blood vessel injuries could trigger widespread clotting throughout the body, which occurs in some disorders.

Causes

Not moving around sufficiently can slow blood flow and cause blood to pool in the veins of the legs. Then, blood clots are more likely to form, particularly in the deep veins of the legs. Clots may form when people are paralyzed or have to stay in bed for a long time—for example, after surgery or a heart attack. Even sitting for a long time, especially in confined spaces as in a car or an airplane, can make clots more likely.

Certain disorders cause blood to clot more readily because the clotting factors become overactive. These disorders include disseminated intravascular coagulation and the antiphospholipid syndrome.

• Disseminated intravascular coagulation is usually triggered by surgery, severe injuries, or a substance that enters the bloodstream. For example, some types of bacteria release harmful substances (toxins) into the bloodstream, and many kinds of cancer cells release substances that stimulate clotting. Disseminated intravascular coagulation can cause both excessive clotting and excessive bleeding. The disorder usually begins with small blood clots developing throughout the bloodstream. A clot may block a vein deep in the leg, causing deep vein thrombosis. As more and more clots form, clotting factors, which help control bleeding, are used up. Then bleeding occurs.
• In antiphospholipid syndrome, abnormal proteins appear in the blood. The most common are anticardiolipin antibodies and lupus anticoagulant. Despite the name, lupus anticoagulant is really the opposite of an anticoagulant. Rather than make blood less likely to clot, lupus anticoagulant makes blood clot more readily, especially in arteries.

In some hereditary disorders, blood tends to clot more readily. Many people with such a disorder do not have symptoms until they are in their 60s. In some hereditary disorders, the body does not produce enough of a protein that helps control clotting, or one of these proteins is ineffective. These proteins include protein C, protein S, and antithrombin III. In all of these disorders, the production of fibrin, which helps clots form, increases. In activated protein C resistance (factor V Leiden mutation), one clotting factor does not respond when protein C signals to stop clotting. About 3% of people have this disorder. In another hereditary disorder (prothrombin G20210A polymorphism), production of prothrombin, another clotting factor, is increased, leading to increased clotting.

A high level of homocysteine in the blood (hyperhomocysteinemia) makes the blood in veins and especially arteries more likely to clot. A high level may result from a hereditary disorder or a deficiency of vitamin B₆, vitamin B₁₂, or folic acid. Chronic kidney failure and the use of certain drugs can also result in a high homocysteine level. These drugs include methotrexate (used to treat cancer), the anticonvulsants phenytoin and carbamazepine, some cholesterol-lowering drugs such as fibric acid derivatives and niacin, and the antibiotic isoniazid.

Sometimes the bone marrow produces too many platelets, making blood more likely to clot. This disorder is called thrombocythemia.

Atherosclerosis, polyarteritis nodosa, and giant cell arteritis make blood more likely to clot in arteries. These disorders cause inflammation of or injury to arteries, stimulating clot formation.

Heart failure increases the risk of clots. Because the heart cannot pump blood adequately, blood backs up in the heart and blood vessels. Clots are more likely to form when blood is not moving (stagnates) or is moving too slowly. Atrial fibrillation also increases the risk of clots. The reason is similar to that for heart failure. In atrial fibrillation, one of the heart's chambers (left atrium) does not empty completely because the heart beats irregularly and too fast. So clots tend to form in the blood that remains in the atrium.

Obesity increases the risk of clots because it puts pressure on veins, slowing the flow of blood.

The use of tamoxifen (used to treat breast cancer) or estrogen can make blood clot more readily. Also, people with cancer are more likely to develop blood clots.

Symptoms

Symptoms depend on which blood vessels are blocked by the clots. For example, an arm or a leg may swell or become painful and red. If a leg remains severely swollen, the skin on the lower leg may become itchy and turn a reddish brown. This skin is easily injured, often resulting in an ulcer. These symptoms may result when clots permanently damage the deep veins in a leg (a disorder called chronic venous insufficiency). Less commonly, the abdomen or face swells.

People with disseminated intravascular coagulation can have symptoms related to both clotting and bleeding. Shortness of breath may develop as small blood vessels of the lungs leak or clots form in them. The skin, lining of the mouth, and whites of the eyes (sclera) may become yellowish (jaundice) if clotting and bleeding occur in the liver. Often, many tiny red dots appear in the skin on the lower legs. People may bruise easily. The gums may bleed, and blood may appear in the stool or urine. Small blackened areas may develop in the fingers and toes if fibrin, a component of clots, is deposited in the blood vessels there. Gangrene can result.

When disseminated intravascular coagulation appears suddenly (as it may after surgery), it can cause uncontrollable, life-threatening bleeding. If it develops more slowly (as it may in people with cancer), clots in veins are more common than bleeding. This form is milder and tends to be chronic.

Diagnosis and Treatment

A blood clot may be detected when it causes symptoms or when a routine examination is done. An imaging test is usually needed to confirm the presence of clots. If clotting in veins is suspected, ultrasonography is useful for confirming clotting and for locating the clots. Magnetic resonance imaging (MRI) may be done if ultrasonography results are unclear. If results are still unclear, venography may be needed. For this test, special x-rays are taken after contrast dye is injected into a vein. When clotting in arteries is suspected, clotting may be confirmed using blood tests or arteriography. For arteriography, special x-rays are taken after contrast dye is injected into arteries.

The cause must be identified. Blood tests can help. The amount and activity of different proteins that control clotting are measured. The platelet count and the time blood takes to clot may be determined. These tests are usually done after a blood clot has been treated.

If the cause is another disorder or a drug, the clotting problems may subside when the disorder is treated or the drug is discontinued.

If a hereditary disorder is the cause, people who have had one or more clots are often advised to take the anticoagulant warfarin for the rest of their life. Sometimes people who have had only one clot are advised to take warfarin or another anticoagulant, heparin, only when the risk of clots is high. For example, they should take an anticoagulant when they need bed rest for a long time. Because taking anticoagulants increases the risk of excessive bleeding, people who take them must have blood tests periodically to check whether blood is taking too long to clot. Doctors then adjust the dose of the anticoagulant if needed.

People with a high homocysteine level may be advised to take vitamin supplements with folic acid, vitamin B₆, and vitamin B₁₂, which may lower the homocysteine level.

Clotting in arteries may be treated with a drug that makes platelets less likely to clump and thus makes blood clots less likely to form. These drugs, called antiplatelet drugs, include aspirin, clopidogrel, and dipyridamole. If a clot is still present or if a person has atrial fibrillation, heparin or warfarin is used.

If a clot causes blood pressure to fall dangerously low or blocks blood flow to the brain or other vital organs, emergency treatment is needed. Treatment may involve giving drugs to dissolve clots (thrombolytic drugs) or, rarely, performing surgery to remove a clot from a blood vessel. However, these treatments can have dangerous, even life-threatening side effects, especially in older people.

If disseminated intravascular coagulation develops suddenly, it requires emergency treatment for clotting and bleeding. If bleeding is severe, transfusions of red blood cells, platelets, and clotting factors are given to replace those that are used up and to stop the bleeding. If clotting is more of a problem than bleeding, heparin may be given.

See the sidebar Using Drugs to Control Clotting.

See the table When a Clot Blocks a Blood Vessel.