Anti-Clotting Drugs

As you might expect, anti-clotting drugs are widely used. They are important, for example, in preventing clots from forming that could lead to a myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism. They can also be essential when medical devices such as prosthetic heart valves are implanted in the body. Specific drugs target either platelet activation or the blood coagulation reactions.

Drugs Blocking Platelet Activation

Aspirin is the obvious first drug to mention here, since it blocks thromboxane A2 formation. Other NSAIDs, such as ibuprofen and naproxen, of course, do the same thing. But recall that aspirin forms a covalent bond with COX. Thus, if a cell treated with aspirin is to regain the activity of its COX, it must synthesize more enzyme. This influences the final result because platelets don't have nuclei, while endothelial cells do. Without a nucleus, platelets can't synthesize more COX.

Can you think why I brought up endothelial cells in the context of aspirin and other COX inhibitors and clotting? (HINT: Think about other substances that inhibit platelet activation.)

Where this question leads:

Thus, aspirin, because it forms a covalent bond with COX, has a larger effect on platelets than on endothelial cells, which can synthesize more COX due to their nuclei. This is a reason why a comparatively low dose of aspirin has lasting anti-clotting effects.

Clopidogrel (Plavix) is an oral drug used either along with aspirin or as an alternative to aspirin. It inhibits platelet activation by blocking the binding of ADP to its receptor. Both aspirin and clopidogrel are most commonly used to reduce the probability of clot formation in blood vessels damaged by atherosclerosis. Thus they are widely used in patients at risk of a myocardial infarction.

Dipyridamole has several effects that reduce activation of platelets. For example, it inhibits the uptake of adenosine by platelets, which increases the extracellular concentration of adenosine. Adenosine blocks the effect of ADP. (Incidentally, adenosine forms in the blood due to an enzyme that acts on ADP. Thus, more ADP in the blood leads to the formation of adenosine, a blocker of ADP.)

Abciximab(Reopro) is a monoclonal antibody that binds to the glycoprotein IIb/IIIa receptor, thereby interrupting platelet aggregation. Since abciximab is a protein, it must be injected. Thus, it is used during invasive medical procedures that might trigger clot formation, such as angioplasty for opening narrowed coronary arteries. There are some other drugs in this category too.

Drugs Blocking the Blood Coagulation Reactions

Warfarin (Coumadin) is a widely used anticoagulant drug. It acts as a vitamin K antagonist. Since vitamin K is required for the activity of prothrombin as well as several other blood coagulation proteins, warfarin decreases the formation of thrombin and thus fibrin. A patient on warfarin requires regular blood tests since warfarin has narrow therapeutic range; that is, its effect is quite sensitive to its exact concentration. The tests measure how fast the blood coagulates. One of the most common uses is in atrial fibrillation, in which stagnant blood in the atria of the heart tends to lead to the formation of clots. This is a very common condition in the elderly. But it is used in various other situations as well, such as deep vein thrombosis and implantation of artificial prosthetic devices such as heart valves.

Direct Inhibitors of Thrombin and Factor Xa are relatively new drugs and are an alternative to warfarin. While warfarin blocks the vitamin K necessary for their activity, these drugs block the active substances directly. One difference between warfarin and these drugs is that the effects of warfarin can be quickly reversed by injecting the missing factors. But the direct inhibitors continue working even if the factors are increased. However, fairly recently drugs have become available that compete with the direct inhibitors and reverse their effects. Clinical trials for the most part have shown that the direct inhibitors ultimately are as safe and effective as warfarin with atrial fibrillation, if not more so, depending on the circumstances. Morever, they do not require the constant blood testing. One example is dabigatran (Pradaxa), which is a thrombin inhibitor. Another is apixaban (Eliquis), which blocks factor Xa. (On the other hand, things are rarely simple, and dabigatran is less safe than coumadin when used with artificial heart valves.)

Heparin is another commonly used anticoagulant. It has the same effect as endothelial heparan proteoglycan in activating anti-thrombin, as described on the previous webpage. (The role of heparin normally in the body is not clear. It is released from mast cells.) Heparin is purified from sources such as pig intestine. The purified product contains many different chain lengths, and this is the form in which it is often used. But sometimes a further purified form called low molecular weight heparin (enoxaparin, etc) is used. The idea behind this drug is that the more refined product with only the smaller sized molecules provides a more measured effect (since it has a bigger effect on a blood coagulation factor than on prothrombin itself). Heparin is used for many of the same problems as warfarin. However, since it must be injected, it is used when a short term, rapid effect is desired. Heparin is also used to coat test tubes used in collecting blood, intravenous catheters, and similar devices.

Drugs That Break Down Clots

Sometimes it is important to rapidly break down a clot that has already formed. Important situations include, of course, following a myocardial infarction or a stroke. The most common drug used for this purpose is tissue plasminogen activator (tPA). This the enzyme that normally converts plasminogen to plasmin in the blood. Plasmin then is an enzyme that breaks down fibrin. Clots are temporary structures in the body, and plasmin is the normal enzyme that starts the destruction of a clot after it forms. Since it is a protein, tPA must be injected. It is important that it be as soon as possible after a myocardial infarction or stroke. This is usually said to be within four and one half hours. It may still be effective with a longer delay if delivered directly to the site of the clot with a catheter. Recombinant DNA technology is used to manufactor tPA.

Another option is streptokinase, which is a less expensive enzyme purified from bacteria.

Quick Quiz

Fill in Answer Correct False Correct Answer
What is the drug that activates anti-thrombin?
What drug described above binds to glycoprotein IIb/IIIa?
What is the product of the reaction promoted by tPA?
What regulatory molecule does clopidogrel block?
For what substance is warfarin an antagonist?
What monoclonal antibody given above might be given during coronary angioplasty?

(Spelling must be correct)
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