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The coagulation process

Thrombosis and embolism


How it works

Oral anticoagulants

Medical conditions and side effects

Recent advances


Anticoagulants are complex organic or synthetic compounds, often carbohydrates, which help prevent the clotting or coagulation of blood. Some commonly used anticoagulant drugs are dicumarol, warfarin (Coumadin®), dipyridamole (Persantine®), enoxaparin (Lovenox®) and heparin. The most widely used of these is heparin, which blocks the formation of thromboplastin, an important clotting factor in the blood. Most anticoagulants are used for treating existing thromboses (clots that form in blood vessels) to prevent further clotting. Oral anticoagulants, such as warfarin and dicumarol, are effective treatments for venous thromboembolisms (a blockage in a vein caused by a clot), but heparin is usually prescribed for treating the more dangerous arterial thrombosis.

Anticoagulants are often mistakenly referred to as blood thinners. Their real role is not to thin the blood but to inhibit the biochemical series of events that lead to the unnatural coagulation of blood inside unsevered blood vessels, a major cause of stroke and heart attack. Furthermore, this type of medicine will not dissolve clots that already have formed, although the drug stops an existing clot from worsening.

The coagulation process

In 1887, Russian physiologist Ivan Petrovich Pavlov (18491936) first postulated the existence of natural anticlotting factors in animals and humans. His extensive studies of blood circulation led him to the realization that when blood reaches the lungs, it loses some of its ability to coagulate, a process aided, he believed, by the addition of some anticlotting substance. In 1892, A.A. Schmidt, who pioneered the enzymatic theory of blood coagulation, published the first data proving the existence of coagulation-inhibiting agents in liver, spleen, and lymph node cells. He later isolated this agent from liver tissue and demonstrated its anticoagulant properties. In 1905, German internist and physiologist Paul Morawitz (18791936) hypothesized that thrombosis might be effectively controlled by reducing the coagulation properties of the blood using antithrombins found in plasma.

Most modern theories of coagulation are scientifically complex and involve numerous substances known as clotting factors. The major mechanism of clot formation involves the conversion of fibrinogen, a highly soluble plasma protein, into fibrin, a stringy protein. There are a number of steps in this conversion process. First, when blood vessels are severed, prothrombin activator is produced. This agents interaction with calcium ions causes prothrombin, an alpha globulin produced by the liver, to undergo conversion to thrombin. Next, thrombin, acting as an enzyme, triggers chemical reactions in fibrinogen, binding the molecules together end to end in long threads. Once these fibrin structures are formed, they adhere to the damaged area of the blood vessel, creating a mesh that traps blood cells and platelets. The resulting sticky mass, a clot, acts as a plug to seal the vessel and prevent further blood loss.

Thrombosis and embolism

Normally, clots form only in response to tissue injury. The natural flow of blood keeps thrombin from congregating in any one area. Clots can usually form only when the blood flows slowly or when wounds are opened. A clot that forms in a vessel abnormally is known as a thrombus; if the clot breaks free and is swept up along through the blood stream to another location, it is known as an embolus. These abnormal formations are thought to be caused by condition changes in the linings of blood vessels. Atherosclerosis and other diseases that damage arterial linings may lead directly to the formation of blood clots. Anticoagulants are used to treat these conditions.


The first effective anticoagulant agent was discovered in 1916 by a medical student, Jay McLean, at Johns Hopkins University, who isolated a specific coagulation inhibitor from the liver of a dog. This substance, known as heparin because it is found in high concentrations in the liver, could not be widely produced until 1933, when Canadian scientists began extracting the substance from the lungs of cattle. In 1937, researchers began using heparin to treat and prevent surgical thrombosis and embolism.

Heparin is a complex organic acid found in all mammalian tissues that contain mast cells (allergic reaction mediators). It plays a direct role in all phases of blood coagulation. In animals and humans, it is produced by mast cells or heparinocytes, which are found in the connective tissues of the capillaries, inside blood vessels, and in the spleen, kidneys, and lymph nodes. There are several types of heparin in widescale clinical use, all of which differ in physiologic activity. Various salts of heparin have been created, including sodium, barium, benzidine, and others. The most widely used form in medical practice is heparin sulfate.

How it works

Heparin works by inhibiting or inactivating the three major clotting factorsthrombin, thromboplastin, and prothrombin. It slows the process of thromboplastin synthesis, decelerates the conversion of prothrombin to thrombin, and inhibits the effects of thrombin on fibrinogen, blocking its conversion to fibrin. The agent also causes an increase in the number of negatively charged ions in the vascular wall, which helps prevent the formation of intravascular clots.

Heparin is administered either by periodic injections or by an infusion pump. The initial dose is usually 5,000 units, followed by 1,000 units per hour, depending on the patients weight, age, and other factors. The therapy usually lasts for seven to ten days. Heparin is also used in the treatment of deep vein thrombosis, a serious surgical complication which is also associated with traumatic injury. This condition can lead to immediate death from pulmonary embolism or produce long-term, adverse effects. Patients with pelvic or lower extremity fractures, spinal cord injuries, a previous thromboembolism, varicose veins, and those over age 40 years are most at risk. Low-dose heparin is a proven therapy and is associated with only a minimal risk of irregular bleeding.

Oral anticoagulants

The development of oral anticoagulants can be linked directly to a widespread cattle epidemic in the United States and Canada during the mid-1920s. A scientist traced the cause of this outbreak to the cattle feed, a fodder containing spoiled sweet clover, which caused the cattle to bleed to death internally. Mixing alfalfa, a food rich in vitamin K, into the fodder seemed to prevent the disease. In 1941, research showed that the decaying sweet clover contained a substance that produced an anti-vitamin-K effect. The substance was isolated and called dicumarol. During the 1940s, the agent was synthesized and widely used in the United States to treat postoperative thrombosis. In 1948, a more powerful synthetic compound was derived for use, initially as a rodentcide. This substance, known as warfarin, is now one of the most widely prescribed oral anticoagulants. There are numerous other agents in clinical use. Acenocoumarol, ethyl biscoumacetate, and phenprocoumon, which are seldom used in the United States, are widely prescribed elsewhere in the world.

Most oral anticoagulants work by suppressing the action of vitamin K in the coagulation process. These agents are extremely similar in chemical structure to vitamin K and effectively displace it from the enzymatic process, which is necessary for the synthesis of prothrombin and other clotting factors. Indeed, one of the ways to treat irregular bleeding, the most common side effect of oral anticoagulants, is vitamin K therapy.

In addition to bleeding, another side effect of oral anticoagulant use is negative interaction with numerous other drugs and substances. Even unaided, oral anticoagulants can have serious effects. For example, use of warfarin during pregnancy can cause birth defects, fetal hemorrhages, and miscarriage. Dicumarol, the original oral anticoagulant, is seldom used today because it causes painful intestinal problems and is clinically inferior to warfarin.

Medical conditions and side effects

A physician must know about any existing medical conditions before prescribing anticoagulant drugs, because they can be dangerous in combination with certain conditions. Persons who take anticoagulants should see a physician regularly while taking these drugs. The physician will order periodic blood tests to check the bloods clotting ability.

These drugs can increase the risk of severe bleeding and heavy blood loss. Because of this risk, anyone taking an anticoagulant drug must take care to avoid injuries. Sports and other potentially hazardous activities should be avoided. Any falls, blows to the body or head, or other injuries should be reported to a physician, as internal bleeding may occur without any obvious symptoms.

The most common minor side effects of anticoagulant medicines are bloating or gas. These problems usually go away as the body adjusts to the drug and do not require medical treatment. Side effects that are more serious may occur, especially if too much of this medicine is taken. Anyone who has unusual symptoms while taking anticoagulant drugs should get in touch with his or her physician.

People who are taking anticoagulant drugs should tell all medical professionals who provide medical treatments or services to them that they are taking this medicine. They should also carry identification stating that they are using an anticoagulant drug.

Other prescriptions or over-the-counter medicineespecially aspirinshould not be taken without checking with the physician who prescribed the anticoagulant drug.

Diet also affects the way anticoagulant drugs work in the body. The reason that diet is so important is that vitamin K affects how the anticoagulant drugs work. Vitamin K is found in meats, dairy products, leafy, green vegetables, and some multiple vitamins and nutritional supplements. For the drugs to work properly, it is best to have the same amount of vitamin K in the body all the time.


Dicumarol The first mass-produced oral anticoagulant was derived from sweet clover.

Fibrinogen A soluble plasma protein that, in the presence of thrombin, is converted into a more insoluble protein, fibrin, during the coagulation process.

Heparin The most widely used and effective anticoagulant; it is found naturally in mammalian tissues.

Thrombin This plasma substance works as an enzyme to cause a reaction in fibrinogen, chemically changing it into fibrin.

Thrombus A blood clot that forms abnormally in a vessel.

Alcohol can change the way anticoagulant drugs affect the body. Anyone who takes these drugs should not have more than one to two drinks at any time and should not drink alcohol every day.

Anyone who has had unusual reactions to anticoagulants in the past should let his or her physician know before taking the drugs again. The physician should also be told about any allergies to foods, dyes, preservatives, or other substances.

Anticoagulants may cause many serious problems if taken during pregnancy. Birth defects, severe bleeding in the fetus and other problems are possible. The mother may also experience severe bleeding if she takes anticoagulants during pregnancy, during delivery, or even shortly after delivery. Some anticoagulant drugs may pass into breast milk.

Recent advances

Over the past three decades, the search for new, less toxic anticoagulants has led to the development and use of a number of synthetic agents, including fibrinlysin, thrombolytin, and urokinase. The enzyme streptokinase, developed in the early 1980s, is routinely injected into the coronary artery to stop a heart attack. Another new agent, tissue plasminogen activator, a blood protein, is being generated in large quantities using recombinant-DNA (deoxyribonucleic acid) techniques. The search is on for a natural anticlotting factor that can be produced in mass quantities.

See also Acetylsalicylic acid.



Hardman, J., et al. Goodman and Gillmans Pharmacological Basis of Therapeutics. New York: McGraw-Hill, 2001.

Porter, Roy. The Cambridge Illustrated History of Medicine. Cambridge, UK: Cambridge University Press, 2006.

Yang, Victor Chi-Min. Toxicity Control, Monitoring, and Novel Applications of Heparin and Protamine. Taipei, Taiwan: International Exchange Committee, Tamkang University, 2001.

Young, Vincent B. Blueprints Medicine. Philadelphia, PA: Lippincott Williams & Wilkins, 2007.

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