Thrombolytic therapy and TPA

Anatomy or system affected: Blood, blood vessels, circulatory system, heart, lungs, nervous system, respiratory system

Definition: The use of drugs to dissolve blood clots blocking an artery or vein (often in the heart, lungs, or brain); tissue plasminogen activator (TPA or tPA) is one of the best thrombolytic agents and is frequently administered to patients experiencing heart attacks

Physiology of Blood Clot Formation

In an undamaged, healthy blood vessel, blood flows smoothly past the lining of the vessel wall. If a blood vessel wall breaks or there is damage to its lining, however, a complex series of biochemical reactions occur to stop the flow of blood. The blood vessel spasms (vascular spasm), platelets in the bloodstream clump together to form a plug, and proteins form to cause the blood to clot (coagulate). This process is rapid, localized to the area of injury, and carefully controlled. It involves many clotting factors normally present in blood, as well as specialized clotting particles called platelets and some substances that are released by the injured tissues.

The most immediate response to a blood vessel injury is vasoconstriction, the narrowing of a blood vessel. Vasoconstriction decreases the diameter of a vessel, resulting in a decreased flow of blood at the site of damage. Some factors that cause vascular spasm, include direct injury, chemicals released by the cells that line a vessel wall, platelets, and nervous reflexes. When the cells that line the interior wall of a blood vessel are damaged, platelets are attracted to the site. They then swell and become sticky. The platelets adhere to the damaged area and release chemicals called prostaglandins, which attract more platelets to the area. Aspirin, in relatively low doses, is an effective inhibitor of prostaglandin synthesis and, therefore, an excellent therapy for some individuals who are susceptible to inappropriate blood clotting. The vascular spasm and platelet plug help stop the bleeding at the injury site. Blood-clotting proteins must be activated, however, to seal the damaged area of the blood vessel completely.

Once the platelet plug is formed, coagulation is triggered. Several clotting proteins are produced by the liver and released in their inactive form to the blood. Bacteria within the intestinal tract are responsible for synthesizing vitamin K, which is essential for normal production of the clotting proteins by the liver. Vitamin K is absorbed by intestinal blood vessels and transported to the liver.

The mechanism by which clotting proteins are activated is called a cascade. First, a substance called prothrombin activator is formed. Prothrombin activator converts prothrombin, a protein in the blood plasma, into thrombin, which in turn converts another plasma protein, fibrinogen, into fibrin. Fibrin molecules then combine to form a loose meshwork that fills in the gaps between the cells of the platelet plug, preventing blood loss at the site of injury.

A clot is not meant to be a permanent solution. If the clot completely occludes (stops the flow of blood to) a tissue, the tissue may die. A process called fibrinolysis removes clots that are no longer needed. Because small clots are continually formed in vessels throughout the body, clot dissolution is essential to reestablishing normal blood flow. Without fibrinolysis, blood vessels would gradually become completely occluded.

One essential component of this natural clot-reducing process is the enzyme plasmin, which is produced when the blood protein plasminogen is activated. A large amount of plasminogen, which binds to fibrin, is incorporated into a blood clot. The plasminogen remains inactive until it receives appropriate signals. Healing of the blood vessel and surrounding tissues will cause the release of a substance called tissue plasminogen activator (TPA or tPA). TPA then converts the plasminogen in the clot to plasmin. It is plasmin that breaks down the fibrin, and thus the clot, through fibrinolysis. Enzymes will quickly destroy any plasmin that escapes into the general circulation. Therefore, most of the fibrinolytic effect of plasmin occurs within the clot itself.

It is important to note that once a clot begins to form, something must limit its growth. A clot that was allowed to grow uncontrollably would eventually fill up all the vessels in the body. Several factors regulate the extent of clot formation. Any tendency toward clot formation in rapidly moving blood is usually unsuccessful because the activated coagulation factors are diluted and washed away, preventing them from accumulating to a concentration necessary for clotting. The second mechanism restricting clot formation is that as a clot forms, almost all the thrombin produced is absorbed into the fibrin. Therefore, fibrin effectively acts as an anticoagulant to prevent enlargement of the clot by holding onto thrombin so that it cannot act elsewhere. Any thrombin that escapes is bound by a substance in the blood called antithrombin III. Antithrombin III can be activated by a substance called heparin, a natural anticoagulant produced by some white blood cells and other undamaged cells that line blood vessels. Heparin acts to inhibit thrombin activity, and thus clotting, by stimulating antithrombin III.

Additional factors prevent clotting in undamaged blood vessels. The factors that normally ward off unnecessary clotting include both structural and chemical characteristics of the lining of blood vessels. As long as the cells lining the vessels remain undamaged, there is no vasospasm, no platelet plug forms, and no clot results. The cells on the wall lining can repel platelets using specialized chemicals on their surfaces. They also secrete heparin and a substance known as prostacyclin, both of which prevent platelet activation.

Despite the body’s protective mechanisms to prevent inappropriate blood clots, clotting sometimes does occur. A clot that forms in an undamaged vessel is called a thrombus. If the thrombus is large, it may block blood flow to the tissue beyond the occlusion and starve the tissue to death. This starvation process is called ischemia, and if it lasts long enough, it may result in necrosis, or irreversible tissue damage due to cell death. A relatively common site for a thrombus to occlude a vessel is in the heart. If the blockage occurs in a coronary artery, a vessel that supplies the heart with blood, the consequences may be death of this tissue and even death of the affected individual.

A thrombus (or any other type of matter, such as lipids) that breaks away from a vessel and floats freely in the bloodstream is called an embolus. An embolus becomes a problem if it enters a blood vessel that is too narrow for it to pass through. For example, emboli that become trapped in a blood vessel going to the lungs can significantly alter an individual’s ability to obtain oxygen. An embolus that occludes a vessel feeding the brain will cause a stroke.

What would cause a clot to form in the body when there is no trauma to a vessel? Several factors are known to cause clot formation, even when there is no bleeding. Anything that causes the lining of a blood vessel to become roughened or irregular will allow platelets to gain a foothold and cling to the vessel wall, starting the clotting process.

Arteriosclerosis, in which there is an abnormal accumulation of fatty plaques in the wall of an artery, and blood-vessel inflammation are the most common causes of irregularities in the lining of blood vessels. Anything that causes the flow of blood to slow and pool enhances clot formation. In this case, clotting factors are not washed away and diluted, so they tend to accumulate until their concentrations are high enough to initiate clotting. Conditions in which this may occur include atrial fibrillation, aneurysms, and varicose veins. Atrial fibrillation is the abnormally rapid beating of the upper chambers (atria) of the heart. Because the contractions that normally force blood into the lower chambers (ventricles) are inefficient, blood pools and clots may form. Aneurysms occur when there is a weakening of an artery wall. This causes the blood vessel wall to bulge out and form a pocket where blood can pool. Thus, aneurysms provide a potential site for inappropriate clotting. Varicose veins are relatively common and usually occur in the veins returning blood from the legs. When the valves in a vein weaken, the flow of returning blood slows and the vein swells. As a result, clotting factors may accumulate in the vein and be returned to the heart or forced into the lungs.

Indications and Procedures

If inappropriate clotting occurs in blood vessels supplying critical tissues, such as the brain, heart, lungs, or kidneys, the resulting tissue damage can be debilitating or even life-threatening. Fortunately, physicians have a few options for treating patients with clotting problems.

A blood clot in the arteries supplying oxygen and nutrients to the heart can cause numerous symptoms. Sudden pain, pressure, squeezing, and fullness in the chest that last longer than fifteen minutes may indicate a heart attack. The pain may be excruciating, or it may be mild, resembling heartburn or indigestion. In general, Older adults tend to have less pain during a heart attack. Heart-attack pain does not go away with rest and may radiate across the chest to the shoulders (usually on the left side), neck, arms, jaw, or even the middle of the back. Because the pumping mechanism and efficiency of the heart have been impaired, patients often feel dizzy or light-headed. They may even faint, become nauseated or vomit, have difficulty breathing, or begin to sweat.

Various drugs are used to prevent undesirable clotting in persons at risk for a heart attack. Aspirin is a common drug whose action blocks the production of chemicals called prostaglandins, which cause platelets to adhere to one another. Heparin helps prevent clot formation. Warfarin is a drug that interferes with the action of vitamin K in the formation of clotting proteins. If a clot has already formed, some drugs are available that will dissolve clots, including TPA, streptokinase, and urokinase. These drugs are known as thrombolytic agents and are often administered in an emergency room to people experiencing heart attacks.

In 2003, researchers announced a breakthrough in the treatment of persons prone to blood clots. Since the 1950s, warfarin has been given to patients for a period of three to six months. Studies showed an increased risk of severe bleeding with longer use of warfarin, thus preempting its use after six months. However, without warfarin, nearly one-third of patients will form another blood clot within eight years. The findings showed that after several months of full doses of warfarin, moderate doses of the medicine can follow and can reduce the risk of further clots without introducing the risk of hemorrhage. This treatment became commonplace in the twenty-first century.

The period in which thrombolytic agents are effective is relatively brief; the sooner these drugs are given, the greater the benefit. To be effective, these potent drugs must be given before irreversible damage occurs. For heart-attack victims, this means within six hours after the onset of symptoms. Most studies indicate that thrombolytic therapy can be given safely and effectively before heart attack victims reach the emergency room and that early treatment reduces the likelihood of death. Therefore, it is important for individuals to contact a physician or emergency medical team promptly after experiencing suspicious symptoms that may indicate a heart attack.

Uses and Complications

Most patients who are thought to be experiencing a heart attack are given TPA or streptokinase intravenously to reverse or at least halt damage. Like all drugs, however, thrombolytic agents have potentially adverse effects. Because these medications can increase bleeding, patients are not given thrombolytic therapy if they are at high risk for hemorrhage (abnormal bleeding). Some of the factors that may increase the risk of bleeding include surgery within the past six weeks, severe hypertension, diabetic eye disease, recent head trauma, recent stroke, stomach or duodenal ulcers, or recent cardiopulmonary resuscitation (CPR).

If the thrombolytic drug is administered and bleeding becomes a significant problem, a drug called aminocaproic acid can be used to help correct the problem. Aminocaproic acid inhibits the thrombolytic effects of TPA, streptokinase, and urokinase by preventing their action and inhibiting plasmin. In life-threatening situations, the physician may have to give the patient blood transfusions or fibrinogen infusions to reverse the effects of thrombolysis. The adverse effects of thrombolytic agents are relatively rare, however, and should not discourage physicians from the appropriate use of these agents.

Thrombolytic therapy is used in nearly 300,000 patients in the United States each year. Tissue plasminogen activator is the fastest-acting thrombolytic agent. It is produced naturally in the body but can be manufactured in large amounts using genetic engineering techniques. Streptokinase, on the other hand, is produced by bacteria and at about one-tenth the cost of TPA. When these two thrombolytic agents were compared in 41,000 heart attack patients, TPA showed a slightly greater effectiveness. In a one-month follow-up study, researchers found that there were 14 percent fewer deaths among heart attack patients given TPA and intravenous heparin (to help keep blood clots from re-forming) than among heart attack patients treated with streptokinase and heparin.

In addition to their use as therapeutic agents for heart attacks, thrombolytic drugs are also used to treat abnormal blood clots in the blood vessels of the lungs. These clots, known as pulmonary emboli, usually originate in a leg vein, a condition called venous thrombosis. Part or all of the thrombus breaks away, forms an embolus, and travels to the heart, which then pumps it into the pulmonary arteries. If the embolus is large enough to block the main pulmonary artery leading from the heart to the lungs, or if there are many clots, the condition can be life-threatening. Pulmonary embolism is responsible for more than 50,000 deaths in the United States each year.

The symptoms that a patient with pulmonary embolism may experience depend on the size of the obstructing clot. If an embolus is so large that it blocks the main pulmonary artery, an affected individual will die. Smaller emboli may cause severe shortness of breath, rapid heart rate, dizziness, sharp chest pains when breathing, and coughing up blood.

Physicians treat pulmonary emboli with similar medical therapy as that used for heart attacks. Anticoagulant drugs such as heparin and warfarin are usually administered to reduce the clotting ability of the blood and to reduce the chance of more clots occurring. Thrombolytic agents, including urokinase and streptokinase, can also be used to destroy the clot in much the same way that they are used in heart attack victims.

The third major use of thrombolytic agents is to clear intravenous catheters of blood clots. A catheter may be placed into a person’s vein if healthcare workers need to draw frequent blood samples or administer drugs at frequent intervals. Because the catheter is in direct contact with the blood, it is a site for potential clot formation. Urokinase can be used to reopen an occluded catheter.

Perspective and Prospects

In 2022, 805,000 Americans experienced a heart attack. An attack lasts longer than most people realize. It is actually a four- to six-hour process that begins when one of the arteries supplying the heart muscle becomes blocked, usually by a blood clot. The pain that one experiences is partially attributable to a cramping of the heart muscle from lack of oxygen and an accumulation of waste products. As a result, heart muscle is destroyed, which interferes with the heart’s function. If the amount of muscle destruction is severe, it can lead to the patient’s death.

Studies show that individuals treated within one to two hours of the onset of heart-attack symptoms have significantly less heart damage than those treated later. However, half of all heart attack patients wait more than two hours before getting medical attention. The American Heart Association estimated that 697,000 Americans die of heart attacks each year before reaching a hospital. This number could be greatly reduced if people responded more quickly to the symptoms of a heart attack.

The goal in treating a heart attack is to stop it and, if possible, reverse the clotting process. Treatment with thrombolytic agents helps minimize or even reverse the damage to heart tissue. As with most diseases, however, it is better to prevent heart attacks entirely. Individuals who exercise regularly, maintain a diet relatively low in fat, and do not smoke have a low incidence of heart attacks and may never need drug therapy to unclog their arteries. Yet, it is comforting to know that these agents are available if the need ever arises.

Because of the success of thrombolytic agents in the treatment of coronary artery disease, these agents began being used in patients showing early symptoms of stroke. Strokes and heart attacks occur for similar reasons. In a stroke, blood clots in the arteries that supply the brain prevent the delivery of oxygen and nutrients to the sensitive nerve cells and cause an accumulation of waste products. As a result, these sensitive brain cells die. As in heart-attack treatment, timing is critical. In heart-attack patients, agents that dissolve clots work best when given within six hours after the onset of symptoms. For stroke patients, it appears that treatment with a thrombolytic drug must begin within three hours to have maximal effectiveness. Therefore, awareness of the early symptoms of stroke is even more important. These symptoms develop rapidly and depend on the region of the brain that is damaged. Some common symptoms include muscle weakness, loss of touch sensations, speech disturbances, and visual disturbances.

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