Medications Used to Treat Clotting Disorders

In order to understand the different medications used to treat patients with clotting disorders, it is helpful to review the processes involved in blood clot formation. The figure entitled The Formation of a Clot at the end of this handout depicts the basic processes of hemostasis (clot formation). At this time, there are 3 primary classes of medications to treat patients with a thrombophilic disorder: 1) antiplatelet agents, 2) anticoagulants and 3) thrombolytic. The relative sites of action for these different types of medications is depicted on the figure entitled The Effects of Medicine on clotting. Each of these classes of medications will be discussed below along with the adverse effects (side effects) seen with these medications. It is important to understand that adverse effects may be seen with these medications, but do not always occur. The severity of the reactions can vary from mild to severe. An adverse reaction to a medication is not the same as an allergy. With all of the medications described below, bleeding is a possible side effect. Taking more than one of these agents at a time (for example taking warfarin and then taking an aspirin for a headache) can increase the risks of bleeding. Bleeding complications can range from mild bruising which is relatively commonly seen to severe gastrointestinal (stomach and intestine) bleeding and intracranial hemorrhages (bleeding in the brain). The latter two can lead to hospitalizations, the need for blood transfusions and even death. Changing the dose or frequency of any of these medications below could lead to an increased chance of bleeding or a decrease in the effectiveness of the anticoagulation. As a result, the choice of agent(s) to be used and/or decisions to combine medications and changes in the way the drugs are taken need to be discussed with ones health care providers. Of special note is the use of herbal medications, vitamin supplements and other natural remedies in combination with anticoagulant, antiplatelet or thrombolytic medications. Many of these medications have not been studied extensively and data regarding their safety and effects on other medications has not always been established. These medications can interact with other medications one is already taking or enhance the effects of other medications. It is recommended that patients taking anticoagulants such as warfarin or antiplatelet medications such as aspirin, NSAIDs (ibuprofen for example), clopidogrel, Aggrenox and ticlopidine avoid using alfalfa, chinchona bark, clove oil, ginkgo biloba, garlic, ginger, ginseng and feverfew. These agents have been shown to alter the clotting system in the body which could decrease the effectiveness of the medication one is taking or increase the chances of serious bleeding complications. It is recommended that a patient discuss any herbal medications or vitamins with a physician to minimize the chance of adverse reactions.

Antiplatelet Agents:
The function of platelets was discussed previously. In brief, platelets arrive at a site of injury, aggregate together and provide a phospholipid (fat) membrane upon which the reactions of the coagulation cascade can be carried out. There are several medications that are used to inhibit platelet aggregation (the process by which platelets clump together to plug the hole).

Of the classes of agents below, aspirin, dypyridamole, ticlopidine and clopidogrel are all available as oral agents (by mouth). NSAIDs come in both oral and intravenous (IV) forms. The GP IIB/IIIA agents are currently only available in IV forms. Unlike the other medications discussed here, aspirin and many NSAIDs are available over the counter without a prescription. It is important to always inform your health care providers of all, including over the counter, medications you are taking as they can have significant effects on blood clotting as well as other aspects of your overall health. Aspirin and NSAIDs (non-steroidal anti-inflammatory drugs): Aspirins ability to alter clot formation has been known and studied since the 1960s. It is now known that aspirin inhibits an enzyme (protein) known as COX1. COX1 in the platelet is involved in the formation of chemicals that increase a platelets ability to cause platelet aggregation. By inhibiting this enzyme, platelet aggregation is disrupted. This results in a decreased ability to form clots. Once a platelet is effected, its COX1 enzyme is inhibited for the lifetime of that platelet (approximately 7 days). Other NSAIDs (such as ibuprofen) inhibit platelet aggregation in the same way, but the effect is not as long lasting. At this time, aspirin has the longest anti-platelet action in this group of drugs. The use of aspirin in the treatment and prevention of myocardial infarctions (heart attacks) has been well studied and it is commonly used as benefits have been clearly shown. Similarly, benefits have been shown in patients who have had or are at risk from cerebrovascular accidents (strokes) or peripheral vascular disease. Dipyridamole (Persantine): This medication was first used in the early 1960s for patients with chest pain, as it has the effect of dilating blood vessels (making the larger). It was reported to have antiplatelet activity in 1968. The mechanism by which it inhibits platelet aggregation is not entirely clear. Currently, the use of a long-acting form of dipyridamole in combination with aspirin (Aggrenox) has been approved and shown to be effective in preventing strokes. Side effects of dipyridamole, besides the risk of bleeding, include: dizziness, hypotension (low blood pressure), headache, nausea, flushing, abdominal discomfort and rashes. Side effects noted with the aspirin and dipyridamole combination (Aggrenox) include: acute renal failure (kidney failure), liver problems, thrombocytopenia (low platelets), severe hypotension (low blood pressure) in addition to the less severe side effects noted above for dipyridamole. Ticlopidine (Ticlid) and Clopidogrel (Plavix): Both ticlopidine (Ticlid) and clopidogrel (Plavix) are antiplatelet agents. The mechanism by which these agents work is different from that of aspirin and the NSAIDs. Platelets require a molecule called ADP to bind to the platelet in order to facilitate aggregation. Studies show that ticlopidine and clopidogrel inhibit the ability of ADP to bind to platelets. As a result, platelet aggregation is inhibited. Ticlopidine and clopidogrel have been shown to be effective in reducing the risk of strokes. Clopidogrel has also been shown to be effective in preventing heart attacks and peripheral vascular disease. Because serious side effects are less common with clopidogrel, it is more commonly used than ticlopidine. Side effects of clopidogrel: nausea, upset stomach, diarrhea, itching, rash, fatigue, headache, dizziness, flu-like symptoms. Rarely a serious medical condition known as TTP (thrombotic thrombocytopenic purpura) can occur.

Side effects of ticlopidine: In addition to the side effects noted for clopidogrel, nephrotic syndrome (a form of kidney disease), hyponatremia (low sodium in the blood), blood cell disorders (low platelets, low white blood cells and even lowering of all three types of blood cells (red, white and platelets)). TTP can also occur. GPIIB/IIIA Inhibitors: These medications have been approved for use in treating the acute presentation of heart disease (patients with unstable angina or an evolving heart attack). As with the other medications discussed above, these agents all work by inhibiting platelet aggregation. Glycoprotein (GP) IIB/IIIA is the final common step required for platelet aggregation. These medications, which include abciximab (Reopro), tirofiban (Aggrastat), lamifiban and eptifibatide (Integrilin) are currently only available through an IV and are administered in the hospital. Multiple studies have shown that these medications are beneficial in properly selected patients. Research is underway looking at the possibility of oral versions of these medications, including xemilofiban and sibrafiban, but these have not been proven to be safe or effective at this time and are not available for use.

Anticoagulants:
Anticoagulant medications work by inhibiting or altering steps in the coagulation cascade. The figure below depicts the sites at which these medications act in the coagulation cascade. Medications such as warfarin (Coumadin) are available in oral forms, whereas heparin and the low-molecular-weight heparins require either IV or subcutaneous (injections below the skin) routes for treatment.

Warfarin (Coumadin): Discovered at the University of Wisconsin, studies of warfarins use as an anticoagulant were first published in 1942. Warfarin is an oral medication that provides anticoagulation by inhibiting the effects of vitamin K on several clotting factors. These clotting factors are referred to as the vitamin K dependent clotting factors and they are factor II (prothrombin), factor VII, factor IX and factor X. In addition, protein C and protein S are also vitamin K dependent. Vitamin K is required in order to facilitate a reaction that allows these clotting factors to function properly. When this reaction can not occur because of a lack of vitamin K (either from inadequate intake or because one is taking warfarin), the activity of the clotting factors is decreased. At adequate doses, the activity of these clotting factors can be brought down to a level offering clinical benefit. It generally takes at least 48 hours before warfarin begins to have a measurable effect on coagulation. As a result, heparin or other agents may be started initially, while a patient is being started on warfarin (see below). Warfarin is used in patients that have had deep venous thrombosis (DVTs) to prevent recurrence or progression. It is generally continued for 3-6 months. Continuation of warfarin in this setting depends on other risk factors that have been previously discussed. Warfarin is also used in some settings for patients with strokes, heart attacks and peripheral vascular disease. Side effects of warfarin include: rash, diarrhea, skin necrosis, hepatitis, abdominal pain, nausea. Warfarin interacts with a large number of medications including many antibiotics. Because of these interactions, it is very important that all patients taking warfarin inform all health care providers that they are taking warfarin prior to taking any new prescription medications. In some cases, the dose of warfarin will need to be changed in order to accommodate a new medication. Unlike the antiplatelet agents discussed above, patients taking warfarin need to have regular monitoring. This is done to make sure that the amount of warfarin (and thus the amount of anticoagulation) is at the right level. Over anticoagulation (too much) leads to an increased risk of severe and even fatal bleeding and under anticoagulation (too little) will minimize or even eliminate the potential benefits of the anticoagulation. This monitoring is accomplished by a blood test. This may need to be done weekly or even more frequently initially, but generally can be done monthly once a regular dose has been achieved. Warfarin Antidote: Because warfarin is a vitamin K antagonist (works against the effects of vitamin K), vitamin K is an antidote to the effects of warfarin. Even dietary intake of vitamin K (for example spinach) can lower the anticoagulant effect of warfarin. In emergencies, patients can be given vitamin K and or fresh frozen plasma (FFP which is a human blood product) to reverse the effects of warfarin. Heparin: Heparin is available for IV or subcutaneous (injection under the skin) administration and anticoagulates by enhancing the effects of antithrombin. Antithrombin inhibits factors in the coagulation cascade, including factor IIa (thrombin) and factor Xa. Heparin is available in an unfractionated form (UF heparin) and a lowmolecular-weight form (LMW heparin), both of which are widely used. Patients with acute coronary syndromes including heart attacks or unstable angina are frequently started on heparin or low-molecular-weight heparins. Heparin is also

frequently started in patients having a stroke or transient ischemic attack (symptoms of a stroke that resolve in less than 24 hours) and studies are underway to look at the potential benefits of low-molecular-weight heparins in stroke. In addition, prior to beginning oral anticoagulation with warfarin (as would be done for patients with a deep venous thrombosis (DVT), a patient is generally started on IV heparin or a low-molecular-weight heparin. IV or subcutaneous heparin as well as low-molecular-weight heparins can be used in hospitalized patients to help prevent the formation of a deep venous thrombosis. Heparin achieves its anticoagulation effect rapidly upon administration. As with warfarin, a patient on heparin needs to be monitored with regular blood tests to ensure the proper level of anticoagulation. Upon initiating heparin, blood tests are required every 6 hours. Once the proper dose has been established, these may be changed to once or twice per day blood tests. Side effects of heparin include: itching, irritation at the site of infusion, fever, chills, runny nose, osteoporosis (with prolonged use) and thrombocytopenia (low platelets). Thrombocytopenia is relatively uncommon, but when it occurs, heparin must be discontinued. If anticoagulation is still required, patients will need to be started on alternative medications (discussed below). Low-Molecular-Weight Heparins: Low-molecular-weight heparins are available as subcutaneous (below the skin) injections. As with heparin, these molecules enhance the effects of antithrombin. Because of the different mechanisms by which antithrombin and heparin inhibit factor IIa and factor Xa, low-molecular-weight heparins do not enhance the inhibition of factor IIa, but do enhance inhibition of factor Xa. There are several low-molecular-weight heparins available: enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep), nadroparin (Fraxiparine), reviparin (Clivarin) and certoparin (Sandoparin). Patients with acute coronary syndromes including heart attacks or unstable angina are frequently started on heparin or low-molecular-weight heparins. Heparin is also frequently started in patients having a stroke or transient ischemic attack (symptoms of a stroke that resolve in less than 24 hours) and studies are underway to look at the potential benefits of low-molecular-weight heparins in stroke. In addition, prior to beginning oral anticoagulation with warfarin (as would be done for patients with a deep venous thrombosis (DVT), a patient is generally started on IV heparin or a low-molecular-weight heparin. IV or subcutaneous heparin as well as low-molecular-weight heparins can be used in hospitalized patients to help prevent the formation of a deep venous thrombosis. Unlike unfractionated (UF) heparin, regular monitoring of blood tests is not required with the low-molecular-weight heparins. The dose is determined by body weight and correlates well with the desired anticoagulation effect. Because the low-molecularweight heparins are cleared from the body by the kidneys, patients with kidney disease will need to have the dosing altered or may need to avoid these medications. Because these medications are given by subcutaneous injection, it is possible to have patients continue these medications outside of the hospital if necessary. Side effects for the low-molecular-weight heparins are similar to those of heparin. Of note, the low-molecular-weight heparins can also cause heparin induced thrombocytopenia (low platelets).

Heparin Antidote: For patients that have bleeding problems with heparin or require rapid neutralization of the heparin anticoagulation effect, protamine sulfate is available. This is generally used only for severe bleeding. Other Anticoagulants: There are a number of other agents either available or being studied to alter coagulation. Danaparoid is a heparin-related medication that can be given either intravenously or by subcutaneous injection. Like heparin and the low-molecularweight heparins, heparin induced thrombocytopenia is a potential side effect. For patients with heparin induced thrombocytopenia, there are several medications that inhibit factor IIa (thrombin) that can be used. These include hirudin, lepirudin (Refludan) and bivalirudin (Hirulog) as well as Argatroban.

Thrombolytic medications (Clot-Busters):

Thrombolytic (clot busting) medications serve to break up the fibrin clot (depicted in the figure below). The fibrinolytic system is the bodys system for breaking down a clot that has formed. There are 3 primary agents available to enhance fibrinolysis in a patient. These are streptokinase, urokinase-type plasminogen activator (UPA) and tissue-type plasminogen activator (TPA). These 3 medications all serve to cleave (break apart) fibrin; this serves to break up the clot after it has formed. Streptokinase will bind together with plasminogen and together this complex can ultimately form streptokinase and plasmin complexes. These complexes are more efficient than plasmin alone at breaking down a clot. Urokinase-type plasminogen activator and tissue-type plasminogen activator both enhance the formation of plasmin from plasminogen, which in turn breaks down fibrin. These medications all require intravenous administration and can only be done as an inpatient in the hospital. Because these medications are not specific toward one clot or another, bleeding is a major risk and some patients will have life-threatening and even fatal bleeding complications with these medications. These medications can be used in patients with heart attacks, strokes and other blood clots, however the window of opportunity for their use is generally limited. A patient with a stroke is not eligible for thrombolytic medications if the stroke began more than 3 hours before the patient presented to the emergency department or physicians office because of the risk of intracranial hemorrhage (bleeding in the brain), which becomes too high and outweighs the benefits. Similar time constraints exist for patients receiving thrombolytics for heart attacks as well, although the time window is a bit larger. Because of the need for rapid intervention in these conditions, it is important that patients experiencing strokes or heart attacks seek medical attention rapidly to maximize therapeutic options. Along with the time limitations, there are several other circumstances that need to be considered prior to administering thrombolytic medications. Recent major surgeries, strokes, brain tumors or bleeding problems are among the contraindications (circumstances that, if present, suggest the medication should not be used). All of these factors and many others need to be weighed prior to administering the medications as they can cause serious bleeding. Unfortunately, serious bleeding can occur even under the ideal circumstances for using these medications.

Further Information: For further information, please visit the University of Illinois Urbana/Champaign and Carle Cancer Center webpages on coagulation disorders at: www-admin.med.uiuc.edu/hematology. This information is provided as a resource to patients and health care providers. The information contained above represents common diagnostic and treatment modalities, but individual circumstances may require additional or different tests or medications. All medical decisions should be made with the advice and consultation of a physician or other health care provider.