What is anticoagulant

Anticoagulants are medicines that help prevent blood clots. Anticoagulants are sometimes called “blood-thinning” medicines, although they don’t actually make the blood thinner. Anticoagulants work by interrupting the process involved in the formation of blood clots. Anticoagulants given to people at a high risk of getting clots, to reduce their chances of developing serious conditions such as strokes and heart attacks.

Anticoagulants are used largely for the prevention and treatment of venous thromboses, although they have some activity against arterial thromboses. Their major clinical use is prevention and treatment of deep vein thrombosis (DVT) in high risk persons (such as after hip or knee replacement surgery or with prolonged immobilization), prevention and treatment of pulmonary embolism, and prevention of arterial embolism in patients with atrial fibrillation.

A blood clot is a seal created by the blood to stop bleeding from wounds. While they’re useful in stopping bleeding, they can block blood vessels and stop blood flowing to organs such as the brain, heart or lungs if they form in the wrong place.

The most commonly prescribed anticoagulant is warfarin.

Newer types of anticoagulants are also available and are becoming increasingly common. These include:

• rivaroxaban (Xarelto)
• dabigatran (Pradaxa)
• apixaban (Eliquis)
• edoxaban (Lixiana)

Warfarin and the newer alternatives are taken as tablets or capsules. There’s also an anticoagulant called heparin that can be given by injection.

Although they’re used for similar purposes, anticoagulants are different to antiplatelet medicines, such as low-dose aspirin and clopidogrel.

Antiplatelet vs Anticoagulant

Antiplatelet inhibits platelet function and is effective for the prevention and treatment of arterial thromboses (which are platelet rich).

The major classes of an antiplatelet agent based on the mechanism of action are as follows ¹:

• Platelet aggregation inhibitors such as:
  1. Aspirin and related cyclooxygenase inhibitors
  2. Oral thienopyridines such as clopidogrel, ticagrelor, ticlopidine, and prasugrel
• Glycoprotein platelet inhibitors (e.g., abciximab, eptifibatide, tirofiban) ²
• Protease-activated receptor-1 antagonists (e.g. vorapaxar)
• Miscellaneous (e.g., dipyridamole, cilostazol)

The antiplatelet drugs in current use are:

• Abciximab (intravenously administered glycoprotein IIb/IIIa receptor blockers)
• Aspirin (irreversible inhibitor of cyclooxygenase 1)
• Cangrelor
• Cilostazol
• Clopidogrel (thienopyridine inhibitors of P2Y-12)
• Dipyridamole
• Eptifibatide (intravenously administered glycoprotein IIb/IIIa receptor blockers)
• Prasugrel (thienopyridine inhibitors of P2Y-12)
• Ticagrelor
• Ticlopidine (thienopyridine inhibitors of P2Y-12)
• Vorapaxar (inhibitor of PAR-1)

Aspirin is the most commonly used oral antiplatelet drug. Aspirin is commonly used for treatment and prevention of coronary, cerebrovascular and other arterial thromboses (myocardial infarction, stroke, peripheral vascular disease). Aspirin works by irreversibly inhibiting cyclooxygenase 1 (COX-1) activity of the prostaglandin synthesis PGH2. This prostaglandin is a precursor of thromboxane A2 and PGI2. Thromboxane A2 works by inducing platelets aggregation and vasoconstriction, and COX-1 inhibits its production while PGI2 works by inhibiting platelets aggregation and induces vasodilation and inhibited by COX-2, which blocks platelet activation and aggregation for the life of the platelet. Low dose aspirin (75-150mg) can induce complete or near complete inhibition of COX-1 thus inhibits the production of TXA2 while larger doses are required to inhibit CoX-2 ³.

Dipyridamole has antiplatelet and vasodilating properties and inhibits platelet cyclic nucleotide phosphodiesterase. This enzyme is responsible for degradation of AMP to 5′ AMP which increases intra-platelet cyclic adenosine monophosphate (cAMP) accumulation and inhibits platelets aggregation. It also blocks the uptake of adenosine by the platelets which also increase cyclic AMP ⁴. The increased cAMP levels result in inhibition of platelet aggregation. Dipyridamole is used with or without aspirin for secondary prevention of myocardial infarction or stroke.

Oral thienopyridines, ticlopidine, clopidogrel and prasugrel selectively inhibit adenosine diphosphate receptor (also known as the purinergic receptor, P2Y-12) on platelets which blocks their activation and aggregation. These agents are used for secondary prevention of coronary and cerebrovascular thrombosis. These drugs convert to an active drug with the help of hepatic CYP450 system that inhibits the platelet P2Y12 receptor. Prasugrel is the most potent of all three drugs, has a rapid onset of action and is superior to clopidogrel in patients undergoing coronary stenting. Ticlopidine has fallen out of favor because of bone marrow toxicity. Cangrelor is a new intravenous platelet agrregation inhibitor, a reversible P2Y12 receptor antagonist and has a rapid onset of action and rapid half-life, making it an appropriate as therapy of acute cardiovascular events. It achieves a significant level of platelet inhibition compared with clopidogrel ⁵.

Ticagrelor is a non-thienopyridine platelet aggregation inhibitor with activity similar to the thienopyridines. Ticagrelor is used with aspirin (<100 mg daily) as secondary prevention of arterial thrombosis with acute coronary syndrome.

Vorapaxar is a inhibitor of the protease-activated receptor 1 (PAR-1) found on platelets that inhibits platelet aggregation and is used to reduct the risk of atherosclerotic events in high risk patients.

Glycoprotein platelets inhibitors work by inhibiting glycoprotein IIb/IIIa (GpIIb-IIIa) receptors on platelets, thus decrease platelet aggregation and most commonly used in an acute form of acute coronary syndrome ⁶. These drugs are only available in an intravenous form and thus used as short-term therapy. Glycoprotein IIb/IIIa receptor blockers have an immediate effect in preventing platelet aggregation, blocking the action of fibrinogen and von Willebrand factor on these platelet receptors; these agents are administered intravenously and are used to attain immediate platelet inhibition in acute coronary syndrome or percutaneous coronary artery intervention.

Cilostazol is also reported to have vasodilatory, antiplatelet properties and antiproliferative effects. It also reduces smooth muscle cell hyperproliferation and intimal hyperplasia after an injury to the endothelium ⁷.

Antiplatelet medications divide into oral and parenteral agents. Oral agents subdivide further based on the mechanism of action. Aspirin is the first antiplatelet medication and is a cyclooxygenase inhibitor. Others oral antiplatelet include clopidogrel, ticagrelor, and prasugrel, pentoxifylline, cilostazol, and dipyridamole. Glycoprotein IIb/IIIa inhibitors such as tirofiban, eptifibatide are only available as parenteral agents and used in acute phases of acute coronary syndrome ⁸.

Following are a few indications of antiplatelet medications:

• Acute coronary syndrome
• Post Percutaneous coronary intervention with stenting
• Mechanical heart valves in combination with warfarin
• Acute Ischemic stroke
• Post percutaneous intervention of peripheral arterial disease
• Device closure such as post ASD (atrial septal defect) closure for at least six months
• Stable angina
• Post-coronary artery bypass grafting surgery
• Essential thrombocytosis
• Primary prevention of coronary artery disease
• Prevention of colon cancer
• Kawasaki disease
• Acute rheumatic disease
• Post PDA device closure for the first six months
• Acute pericarditis
• Atrial fibrillation with a CHAD2SVASc score of 1
• Primary prevention of venous thromboembolism

Following are the most common adverse effects associated with antiplatelet medications ⁹.

• Aspirin-induced asthma
• Nasal polyp
• Upper gastrointestinal bleeding because of chronic gastritis
• Ecchymosis
• Hematuria
• Epistaxis
• Ticagrelor-related dyspnea
• Hemorrhage
• Thrombocytopenia

Headache, nausea, diarrhea, pain, infection, upper respiratory symptoms, palpitations, arrhythmias, and peripheral edema are the most common side effects associated with cilostazol.

Anticoagulant medications

• Dabigatran, Desirudin
• Apixaban, Edoxaban, Fondaparinux, Rivaroxaban
• Heparins, Heparin, Dalteparin, Enoxaparin, Tinzaparin
• Warfarin

Apixaban

Apixaban is an oral anticoagulant and direct and reversible inhibitor of factor Xa (the rate controlling last step in the generation of thrombin), which is used to decrease the risk of venous thromboses, systemic embolization and stroke in patients with atrial fibrillation (a condition in which the heart beats irregularly, increasing the chance of clots forming in the body and possibly causing strokes) that is not caused by heart valve disease and lower the risk of deep vein thrombosis (DVT, a blood clot, usually in the leg) and pulmonary embolus (a blood clot in the lung) after knee or hip replacement surgery. Apixaban is also used to treat DVT and PE and may be continued to prevent DVT and PE from happening again after the initial treatment is completed.

Apixaban current indications are for prevention of stoke and systemic embolism in patients with nonvalvular atrial fibrillation, prevention of deep vein thrombosis after hip or knee replacement surgery, treatment of deep vein thrombosis and pulmonary embolism, and reduction in risk of recurrence of deep vein thrombosis or pulmonary embolism.

Apixaban is a direct and reversible inhibitor of factor Xa, the final intermediate in blood coagulation. Inhibiting thrombin prevents the conversion of fibrinogen to fibrin and subsequent cross linking of fibrin monomers, platelet activation and amplification of coagulation. Apixaban has been shown to be as effective as warfarin and more effective than aspirin in preventing stroke and systemic embolization in patients with atrial fibrillation. Clinical trials have also shown that apixaban therapy can decrease the risk of deep vein thrombosis and pulmonary embolism in patients undergoing hip or knee replacement surgery. Apixaban was approved for use in the United States in 2012.

Apixaban comes as a tablet to take by mouth. Apixaban is available in 2.5 and 5 mg tablets under the commercial name Eliquis. The usual dose is 2.5 or 5 mg twice daily and varies somewhat by indication. Unlike warfarin, apixaban and the other oral direct thrombin and factor Xa inhibitors do not require monitoring of bleeding time or INR. When apixaban is taken to prevent DVT and PE after hip or knee replacement surgery, the first dose should be taken at least 12 to 24 hours after surgery. Apixaban is usually taken for 35 days after a hip replacement surgery and for 12 days after knee replacement surgery. Take apixaban at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take apixaban exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

If you are unable to swallow the tablets, you can crush them and mix with water, apple juice, or applesauce. Swallow the mixture right after you prepare it. Apixaban can also be given in certain types of feeding tubes. Ask your doctor if you should take this medication in your feeding tube. Follow your doctor’s directions carefully.

Continue to take apixaban even if you feel well. Do not stop taking apixaban without talking to your doctor. If you stop taking apixaban, your risk of a blood clot may increase.

Apixaban side effects are not common, but can include bleeding, headache, dizziness, fatigue, gastrointestinal upset, nausea, arthralgias and rash. Uncommon, but potentially severe adverse events include severe bleeding episodes and hypersensitivity reactions.

Apixaban special precautions

Before taking apixaban:

• tell your doctor and pharmacist if you are allergic to apixaban, any other medications, or any of the ingredients in apixaban tablets. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Teril); clarithromycin (Biaxin, in Prevpac); itraconazole (Onmel, Sporanox); ketoconazole (Nizoral); phenytoin (Dilantin, Phenytek); rifampin (Rifadin, Rimactane, in Rifadin, in Rifater); ritonavir (Norvir, in Kaletra); selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), fluoxetine (Prozac, Sarafem, Selfemra, in Symbyax), fluvoxamine (Luvox), paroxetine (Brisdelle, Paxil, Pexeva), and sertraline (Zoloft); and serotonin and norepinephrine reuptake inhibitors (SNRIs) such as duloxetine (Cymbalta), desvenlafaxine (Khedezla, Pristiq), milnacipran (Fetzima, Savella), and venlafaxine (Effexor). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with apixaban, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor what herbal products you are taking, especially St. John’s wort.
• you should know that apixaban may interact with certain medications that may be used to treat you if you have a stroke or other medical emergency. In case of an emergency, you or a family member should tell the doctor or emergency room staff who treat you that you are taking apixaban.
• tell your doctor if you have an artificial heart valve or if you have heavy bleeding anywhere in your body that cannot be stopped. Your doctor will probably
• tell you not to take apixaban.
• tell your doctor if you have or have ever had any type of bleeding problem, or kidney or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking apixaban, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking apixaban. Your doctor may tell you to stop taking apixaban before the surgery or procedure. If you need to stop taking apixaban because you are having surgery, your doctor may prescribe a different medication to prevent blood clots during this time. Your doctor will tell you when you should start taking apixaban again after your surgery. Follow these directions carefully.
• Call your doctor right away if you fall or injure yourself, especially if you hit your head. Your doctor may need to check you.

Apixaban side effects

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical treatment:

• bleeding gums
• nosebleeds
• heavy vaginal bleeding
• red, pink, or brown urine
• red or black, tarry stools
• coughing up or vomiting blood or material that looks like coffee grounds
• swelling or joint pain
• headache
• rash
• chest pain or tightness
• swelling of the face or tongue
• trouble breathing
• wheezing
• feeling dizzy or faint

Apixaban prevents blood from clotting normally, so it may take longer than usual for you to stop bleeding if you are cut or injured. This medication may also cause you to bruise or bleed more easily. Call your doctor right away if bleeding or bruising is unusual, severe, or cannot be controlled.

Apixaban may cause other side effects. Call your doctor if you have any unusual problems while taking apixaban.

Symptoms of apixaban overdose may include the following:

• unusual bleeding or bruising
• red, brown, or pink urine
• red or black, tarry stools
• coughing up or vomiting blood or material that looks like coffee grounds

Dabigatran

Dabigatran is a potent direct inhibitor of thrombin and anticoagulant which is used for prevention of stroke and venous embolism in patients with chronic atrial fibrillation. Dabigatran is used to treat deep vein thrombosis (DVT; a blood clot, usually in the leg) and pulmonary embolism (PE; a blood clot in the lung) in patients who have been treated with an injectable anticoagulant (”blood thinner”). Dabigatran is also used to reduce the risk of a DVT and pulmonary embolism from happening again after initial treatment is completed. Dabigatran is used to help prevent DVT and pulmonary embolism in people who have had hip replacement surgery. Dabigatran is also used to help prevent strokes or serious blood clots in people who have atrial fibrillation (a condition in which the heart beats irregularly, increasing the chance of clots forming in the body, and possibly causing strokes) without heart valve disease.

Dabigatran binds to the active site of thrombin and inactivates both fibrin-bound and unbound thrombin, unlike heparin that binds to the unbound thrombin only. Inhibiting thrombin prevents the conversion of fibrinogen to fibrin and subsequent cross linking of fibrin monomers, platelet activation and amplification of coagulation activation. Dabigatran itself is not absorbed from the gastrointestinal tract, but the prodrug dabigatran etexillate mesylate is absorbed and then converted to the active form by gut and plasma esterases. Dabigatran provides a reliable anticoagulant effect and monitoring of effect is not needed. Dabigatran etexilate was approved for use in the United States in 2010 and indications are for prevention of stroke and thromboembolic complications in patients with chronic atrial fibrillation not related to valvular heart disease. Thereafter, indications were extended to the treatment and prevention of deep venous thrombosis and pulmonary embolism.

Dabigatran is available in capsules of 75 and 150 mg under the brand name Pradaxa to be taken by mouth and the recommended dose in adults is 75 to 150 mg twice daily. When dabigatran is used to treat or prevent DVT or PE or to prevent strokes or serious blood clots in people who have atrial fibrillation, it is usually taken twice a day. When dabigatran is used to prevent a DVT or PE after hip replacement surgery it is usually taken 1 to 4 hours after surgery, and then once a day for another 28 to 35 days. Dabigatran may be taken with or without food. Take dabigatran at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take dabigatran exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the capsules whole with a whole glass of water; do not split, chew, or crush them. Do not open the capsules and sprinkle the contents on food or into drinks.

Dabigatran will help prevent strokes and blood clots only as long as you continue to take it. Continue to take dabigatran even if you feel well. Make sure to refill your prescription before you run out of medication so that you will not miss doses of dabigatran. Do not stop taking dabigatran without talking to your doctor. If you suddenly stop taking dabigatran, the risk that you will have clot or a stroke may increase.

Dabigatran, like other anticoagulants, is associated with bleeding adverse events, but these are not common and no more frequent than with low molecular weight heparins or warfarin. Dabigatran side effects not directly attributable to the anticoagulant activity are not common but can include nausea, abdominal discomfort, diarrhea, anorexia, fever, and skin rash. Rare, potentially severe adverse events include serious and fatal bleeding.

Dabigatran special precautions

Before taking dabigatran:

• tell your doctor and pharmacist if you are allergic to dabigatran, any other medications, or any of the ingredients in dabigatran capsules. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: dronedarone (Multaq), ketoconazole (Nizoral), and rifampin (Rifadin, Rimactane, in Rifamate, in Rifater). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  tell your doctor if you have had a valve in your heart replaced or if you have recently noticed any unusual bruising or bleeding. Your doctor probably will tell you not to take dabigatran.
• tell your doctor if you are 75 years of age or older; if you have or have ever had a bleeding problem, bleeding or an ulcer in your stomach or intestine; or kidney disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking dabigatran, call your doctor. Taking dabigatran may increase the risk that you will experience severe bleeding during labor and delivery.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking dabigatran.

Dabigatran side effects

Dabigatran may cause side effects. Tell your doctor if any of these symptoms occur:

• stomach pain
• upset stomach
• heartburn
• nausea

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• unusual bruising or bleeding
• pink or brown urine
• red or black, tarry stools
• coughing up blood
• vomiting material that is bloody or looks like coffee grounds
• bleeding from the gums
• frequent nosebleeds
• heavy menstrual bleeding
• bleeding from a cut that lasts longer than normal
• joint pain or swelling
• headache
• dizziness or feeling faint
• weakness
• hives
• rash
• itching
• difficulty breathing or swallowing
• chest pain or tightness
• swelling of the face, throat, tongue, lips, eyes, arms, hands, feet, ankles, or lower legs

Dabigatran may cause other side effects. Call your doctor if you have any unusual problems while taking dabigatran.

Symptoms of dabigatran overdose may include the following:

• unusual bruising or bleeding
• pink or brown urine
• red or black, tarry stools
• vomiting material that is bloody or looks like coffee grounds
• coughing up blood

Desirudin

Desirudin is a parenterally administered, selective thrombin inhibitor that is used to decrease the risk of deep vein thrombosis and pulmonary embolus in patients undergoing hip replacement surgery. Current indications are limited to reduction of the risk of deep vein thrombosis and pulmonary embolization after elective hip replacement surgery.

Desirudin is a recombinant 65 amino acid peptide analogue of hirudin, the naturally occurring anticoagulant found in the salivary glands of leeches (Hirudo medicinalis). Hirudin is a mixture of similar peptides that actively bind to and inactivate thrombin. Like human antithrombin, hirudin binds to both circulating and fibrinogen bound thrombin and thus both prevents and dissolves clots and thrombi. In clinical trials, desirudin given during and after hip replacement surgery was equivalent or slightly better than heparin in decreasing the frequency of deep vein thrombosis and pulmonary emboli during the perioperative period. Desirudin was approved for use in the United States in 2003 and has been used in limited numbers of patients.

Desirudin is available in single use vials of 15.75 mg under the commercial name Iprivask. The usual dose is an injection of 15 mg subcutaneously immediately before surgery and twice daily for 8 to 12 days.

Desirudin most common side effect is bleeding; other side effects are not common, but can include hypersensitivity reactions, including anaphylaxis. Hypersensitivity reactions are particularly common and more likely to be severe in persons who have been previously treated with desirudin or other hirudin analogues such as bivalirudin.

Heparin

Standard or unfractionated heparin is a complex mixture of naturally occurring glycosaminoglycans and is used as an anticoagulant to treat venous thrombosis or to prevent thrombosis in high risk patients. Heparin has been used to treat or prevent venous thromboses for more than 50 years. Heparin is used to prevent blood clots from forming in people who have certain medical conditions or who are undergoing certain medical procedures that increase the chance that clots will form. Heparin is also used to stop the growth of clots that have already formed in the blood vessels, but it cannot be used to decrease the size of clots that have already formed. Heparin is also used in small amounts to prevent blood clots from forming in catheters (small plastic tubes through which medication can be administered or blood drawn) that are left in veins over a period of time.

Heparin is also sometimes used alone or in combination with aspirin to prevent pregnancy loss and other problems in pregnant women who have certain medical conditions and who have experienced these problems in their earlier pregnancies. Talk to your doctor or pharmacist about the risks of using this medication to treat your condition.

Heparin comes as a solution (liquid) to be injected intravenously (into a vein) or deeply under the skin and as a dilute (less concentrated) solution to be injected into intravenous catheters. Heparin should not be injected into a muscle. Multiple generic forms of heparin are available, usually in ampoules or vials of 1000 to 40,000 units per mL. Heparin is typically given initially as 5000 to 10,000 units intravenously (sometimes given as a slow, continuous injection into the vein), followed by intravenous or subcutaneous boluses every 4 to 12 hours to keep the activated partial thrombin time in the range of 1.5 to 2 times the control value.

When heparin is used to prevent blood clots from forming in intravenous catheters, it is usually used when the catheter is first put in place, and every time that blood is drawn out of the catheter or medication is given through the catheter.

Heparin may be given to you by a nurse or other healthcare provider, or you may be told to inject the medication by yourself at home. If you will be injecting heparin yourself, a healthcare provider will show you how to inject the medication. Ask your doctor, nurse, or pharmacist if you do not understand these directions or have any questions about where on your body you should inject heparin, how to give the injection, or how to dispose of used needles and syringes after you inject the medication.

If you will be injecting heparin yourself, follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Use heparin exactly as directed. Do not use more or less of it or use it more often than prescribed by your doctor.

Heparin solution comes in different strengths, and using the wrong strength may cause serious problems. Before giving an injection of heparin, check the package label to make sure it is the strength of heparin solution that your doctor prescribed for you. If the strength of heparin is not correct do not use the heparin and call your doctor or pharmacist right away.

Your doctor may increase or decrease your dose during your heparin treatment. If you will be injecting heparin yourself, be sure you know how much medication you should use.

Common side effects of standard heparin include dizziness, fatigue, headache, indigestion, nausea, excess bleeding, ecchymoses, rash and urticaria.

Heparin special precautions

Before using heparin:

• tell your doctor and pharmacist if you are allergic to heparin, any other medications, beef products,pork products, or any of the ingredients in heparin injection. Ask your doctor or pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: other anticoagulants such as warfarin (Coumadin); antihistamines (in many cough and cold products); antithrombin III (Thrombate III); aspirin or aspirin-containing products and other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn); dextran; digoxin (Digitek, Lanoxin); dipyridamole (Persantine, in Aggrenox); hydroxychloroquine (Plaquenil); indomethacin (Indocin); phenylbutazone (Azolid) (not available in the US); quinine; and tetracycline antibiotics such as demeclocycline (Declomycin), doxycycline (Monodox, Vibramycin), minocycline (Dynacin, Minocin) and tetracycline (Bristacycline, Sumycin). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have a low level of platelets (type of blood cells needed for normal clotting) in your blood and if you have heavy bleeding that cannot be stopped anywhere in your body. Your doctor may tell you not to use heparin.
• tell your doctor if you are currently experiencing your menstrual period; if you have a fever or an infection; and if you have recently had a spinal tap (removal of a small amount of the fluid that bathes the spinal cord to test for infection or other problems), spinal anesthesia (administration of pain medication in the area around the spine), surgery, especially involving the brain, spinal cord or eye, or a heart attack. Also tell your doctor if you have or have ever had a bleeding disorder such as hemophilia (condition in which the blood does not clot normally), antithrombin III deficiency (condition that causes blood clots to form), blood clots in the legs, lungs, or anywhere in the body, unusual bruising or purple spots under the skin, cancer, ulcers in the stomach or intestine, a tube that drains the stomach or intestine, high blood pressure, or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while using heparin, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are using heparin.
• tell your doctor if you smoke or use tobacco products and if you stop smoking at any time during your treatment with heparin. Smoking may decrease the effectiveness of this medication.

Heparin side effects

Heparin may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• redness, pain, bruising, or sores at the spot where heparin was injected
• hair loss

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• unusual bruising or bleeding
• vomit that is bloody or looks like coffee grounds
• stool that contains bright red blood or is black and tarry
• blood in urine
• excessive tiredness
• nausea
• vomiting
• chest pain, pressure, or squeezing discomfort
• discomfort in the arms, shoulder, jaw, neck, or back
• coughing up blood
• excessive sweating
• sudden severe headache
• lightheadedness or fainting
• sudden loss of balance or coordination
• sudden trouble walking
• sudden numbness or weakness of the face, arm or leg, especially on one side of the body
• sudden confusion, or difficulty speaking or understanding speech
• difficulty seeing in one or both eyes
• purple or black skin discoloration
• pain and blue or dark discoloration in the arms or legs
• itching and burning, especially on the bottoms of the feet
• chills
• fever
• hives
• rash
• wheezing
• shortness of breath
• difficulty breathing or swallowing
• hoarseness
• painful erection that lasts for hours

Heparin may cause osteoporosis (condition in which the bones become weak and may break easily), especially in people who use the medication for a long time. Talk to your doctor about the risks of using heparin.

Symptoms of heparin overdose may include:

• nosebleed
• blood in urine
• black, tarry stools
• easy bruising
• unusual bleeding
• red blood in stools
• vomit that is bloody or looks like coffee grounds

Low Molecular Weight Heparin

The low molecular weight heparins are enoxaparin, dalteparin and tinzaparin. Low molecular weight heparins are purified fragments of natural heparins that have anticoagulant activity and are used to treat patients at high risk of venous thrombosis. Current indications include prevention of deep vein thromboses in high risk individuals (such as after surgery or during immobilization), prevention of ischemic complications in patients with unstable angina (in combination with aspirin), and active treatment of deep vein thrombosis with or without pulmonary embolism (in combination with warfarin).

• Enoxaparin was the first small molecular weight heparin (average 4,500 daltons) to be approved for use in the United States (1993) and is available in liquid solution in several forms (ampoules, syringes) generically and under the brand name Lovenox.
• Dalteparin (average 5,000 daltons) was approved in the United States in 1994 and is available in liquid solution in single or multidose vials under the brand name Fragmin.
• Tinzaparin (average 4,500-5,500 daltons) was approved for use in the United States in 2000 and has more restricted indications. Tinzaparin is available as solution for injection in multidose vials under the brand name Innohep.

Low molecular weight heparins are prepared from natural heparins isolated from porcine intestine or bovine lung by controlled depolymerization of the large natural heparin molecule (which has varying molecular weights averaging ~15,000 daltons) into smaller fragments and subsequent fractionation to obtain homogenous heparin fragments with biological activity and molecular weight averaging 4,000-5,000 daltons (range, 2,000-9,000 daltons). The low molecular weight heparins have the advantage of more favorable pharmacokinetics and fewer side effects, which allow for once daily administration and outpatient use. The onset of anticoagulation may be slower with low molecular weight compared to standard heparin, but the degree of anticoagulation is easier to maintain and manage. The mechanism of action of low molecular weight heparins is similar to that of standard heparin and involves binding to antithrombin III and inhibition of activated coagulation factors including thrombin and Factor IX.

Low molecular weight heparins common side effects include dizziness, fatigue, headache, indigestion, nausea, bleeding, ecchymoses, rash and urticaria. The dose regimen of the low molecular weight heparins varies by product, concentration units (mg vs anti-Factor IX IU) and indication. The typical regimen of treatment is once daily for 7 to 14 days, but longer term treatment is sometimes used in high risk situations including during cancer chemotherapy where there is a high risk of venous thomboses.

Warfarin

Warfarin is a commonly used oral anticoagulant with anti-vitamin K activity. Warfarin is used to prevent blood clots from forming or growing larger in your blood and blood vessels. It is prescribed for people with certain types of irregular heartbeat, people with prosthetic (replacement or mechanical) heart valves, and people who have suffered a heart attack. Warfarin is also used to treat or prevent venous thrombosis (swelling and blood clot in a vein) and pulmonary embolism (a blood clot in the lung). Warfarin therapy is associated with rare instances of idiosyncratic, clinically apparent liver injury that are usually mild and rapidly reversible on stopping.

Warfarin was discovered after identification of the hemorrhagic activity that caused toxicity and bleeding in cattle after eating spoiled, sweet clover silage. Once the active component was shown to be bis-hydroxycoumarin, synthetic derivatives were developed and found to be effective rodenticides. Only thereafter were coumarin derivatives shown to be useful as anticoagulants in humans, and only with careful monitoring. Importantly, coumarin itself does not have anticoagulant activity but is used as an antineoplastic agent, and has different effects and side effects than its derivatives. Coumarin derivatives include warfarin, dicumarol, phenprocoumon and acenocoumarol. These compounds act by blocking the enzymatic reduction of vitamin K to its active form, which is responsible for the final steps of synthesis of several clotting factors (Factors II, VII, IX and X). The coumarin derivatives cause a prolongation of the prothrombin time which is beneficial in preventing progression or recurrence of deep vein thrombosis and pulmonary embolism. Oral anticoagulation is also used to prevent arterial or venous embolization after acute myocardial infarction, atrial fibrillation and prosthetic heart value placement.

Warfarin was approved for use in the United States in 1961 and remains in wide use with more than 30 million prescriptions filled yearly.

Warfarin comes as a tablet to take by mouth. It is usually taken once a day with or without food. The typical dose is 5 mg daily for 2 to 4 days followed by 2 to 10 mg daily, based upon measurements of prothrombin time aiming at an international normalized ratio (INR) value of 2 to 3. Monitoring of the INR is essential during warfarin therapy, because bleeding is a common side effect and can be life-threatening and fatal.

Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take warfarin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Call your doctor immediately if you take more than your prescribed dose of warfarin.

Your doctor will probably start you on a low dose of warfarin and gradually increase or decrease your dose based on the results of your blood tests. Make sure you understand any new dosing instructions from your doctor.

Continue to take warfarin even if you feel well. Do not stop taking warfarin without talking to your doctor.

Warfarin side effects not directly attributable to the anticoagulant activity of warfarin are not common, but can include nausea, abdominal discomfort, diarrhea, anorexia, fever, alopecia, skin necrosis and bluish discoloration. Finally, warfarin is very sensitive to drug-drug interactions involving its metabolism or function and great care must be given to starting or stopping concurrent medications in patients on warfarin therapy. Severe bleeding episodes can be caused by administration of another medication that prolongs its half-life or activity.

Warfarin special precautions

Before taking warfarin:

• tell your doctor and pharmacist if you are allergic to warfarin, any other medications, or any of the ingredients in warfarin tablets. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• do not take two or more medications that contain warfarin at the same time. Be sure to check with your doctor or pharmacist if you are uncertain if a medication contains warfarin or warfarin sodium.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take, especially acyclovir (Zovirax); allopurinol (Zyloprim); alprazolam (Xanax); antibiotics such as ciprofloxacin (Cipro), clarithromycin (Biaxin, in Prevpac), erythromycin (E.E.S., Eryc, Ery-Tab), nafcillin, norfloxacin (Noroxin), sulfinpyrazone, telithromycin (Ketek), and tigecycline (Tygacil); anticoagulants such as argatroban (Acova), dabigatran (Pradaxa), bivalirudin (Angiomax), desirudin (Iprivask), heparin, and lepirudin (Refludan); antifungals such as fluconazole (Diflucan), itraconazole (Onmel, Sporanox), ketoconazole (Nizoral), miconazole (Monistat), posaconazole (Noxafil), terbinafine (Lamisil), voriconazole (Vfend); antiplatelet medications such as cilostazol (Pletal), clopidogrel (Plavix), dipyridamole (Persantine, in Aggrenox), prasugrel (Effient), and ticlopidine (Ticlid); aprepitant (Emend); aspirin or aspirin-containing products and other nonsteroidal anti-inflammatory drugs such as celecoxib (Celebrex), diclofenac (Flector, Voltaren, in Arthrotec), diflunisal, fenoprofen (Nalfon), ibuprofen (Advil, Motrin), indomethacin (Indocin), ketoprofen, ketorolac, mefenamic acid (Ponstel), naproxen (Aleve, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene), and sulindac (Clinoril); bicalutamide; bosentan; certain antiarrhythmic medications such as amiodarone (Cordarone, Nexterone, Pacerone), mexiletine, and propafenone (Rythmol); certain calcium channel blocking medications such as amlodipine (Norvasc, in Azor, Caduet, Exforge, Lotrel, Twynsta), diltiazem (Cardizem, Cartia XT, Dilacor XR, Tiazac) and verapamil (Calan, Isoptin, Verelan, in Tarka); certain medications for asthma such as montelukast (Singulair), zafirlukast (Accolate), and zileuton (Zyflo); certain medications used to treat cancer such as capecitabine (Xeloda), imatinib (Gleevec), and nilotinib (Tasigna); certain medications for cholesterol such as atorvastatin (Lipitor, in Caduet) and fluvastatin (Lescol); certain medications for digestive disorders such as cimetidine (Tagamet), famotidine (Pepcid), and ranitidine (Zantac); certain medications for human immunodeficiency virus (HIV) infection such as amprenavir, atazanavir (Reyataz), efavirenz (Sustiva), etravirine (Intelence), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir, nelfinavir (Viracept), ritonavir (Norvir), saquinavir (Invirase), and tipranavir (Aptivus); certain medications for narcolepsy such as armodafinil (Nuvigil) and modafinil (Provigil); certain medications for seizures such as carbamazepine (Carbatrol, Equetro, Tegretol), phenobarbital, phenytoin (Dilantin, Phenytek), and rufinamide (Banzel); certain medications to treat tuberculosis such as isoniazid (in Rifamate, Rifater) and rifampin (Rifadin, in Rifamate, Rifater); certain selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) such as citalopram (Celexa), desvenlafaxine (Pristiq), duloxetine (Cymbalta), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, in Symbyax), fluvoxamine (Luvox), milnacipran (Savella), paroxetine (Paxil, Pexeva), sertraline (Zoloft), venlafaxine (Effexor) corticosteroids such as prednisone; cyclosporine (Neoral, Sandimmune); disulfiram (Antabuse); methoxsalen (Oxsoralen, Uvadex); metronidazole (Flagyl); nefazodone (Serzone), oral contraceptives (birth control pills); oxandrolone (Oxandrin); pioglitazone (Actos, in Actoplus Met, Duetact, Oseni); propranolol (Inderal) or vilazodone (Viibryd). Many other medications may also interact with warfarin, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Do not take any new medications or stop taking any medication without talking to your doctor.
• tell your doctor and pharmacist what herbal or botanical products you are taking, especially coenzyme Q10 (Ubidecarenone), Echinacea, garlic, Ginkgo biloba, ginseng, goldenseal, and St. John’s wort. There are many other herbal or botanical products which might affect your body’s response to warfarin. Do not start or stop taking any herbal products without talking to your doctor.
• tell your doctor if you have or have ever had diabetes. Also tell your doctor if you have an infection, a gastrointestinal illness such as diarrhea, or sprue (an allergic reaction to protein found in grains that causes diarrhea), or an indwelling catheter (a flexible plastic tube that is placed into the bladder to allow the urine to drain out).
• Tell your doctor if you are pregnant, think you might be pregnant, or plan to become pregnant while taking warfarin. Pregnant women should not take warfarin unless they have a mechanical heart valve. Talk to your doctor about the use of effective birth control while taking warfarin. If you become pregnant while taking warfarin, call your doctor immediately. Warfarin may harm the fetus.
• tell your doctor if you are breast-feeding.
• if you are having surgery, including dental surgery, or any type of medical or dental procedure, tell the doctor or dentist that you are taking warfarin. Your doctor may tell you to stop taking warfarin before the surgery or procedure or change your dosage of warfarin before the surgery or procedure. Follow your doctor’s directions carefully and keep all appointments with the laboratory if your doctor orders blood tests to find the best dose of warfarin for you.
• ask your doctor about the safe use of alcoholic beverages while you are taking warfarin.
• tell your doctor if you use tobacco products. Cigarette smoking may decrease the effectiveness of this medication.

Warfarin side effects

Warfarin may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• gas
• abdominal pain
• bloating
• change in the way things taste
• loss of hair
• feeling cold or having chills

If you experience any of the following symptoms, or those listed in the IMPORTANT WARNING section, call your doctor immediately:

• hives
• rash
• itching
• difficulty breathing or swallowing
• swelling of the face, throat, tongue, lips, or eyes
• hoarseness
• chest pain or pressure
• swelling of the hands, feet, ankles, or lower legs
• fever
• infection
• nausea
• vomiting
• diarrhea
• extreme tiredness
• lack of energy
• loss of appetite
• pain in the upper right part of the stomach
• yellowing of the skin or eyes
• flu-like symptoms

You should know that warfarin may cause necrosis or gangrene (death of skin or other body tissues). Call your doctor immediately if you notice a purplish or darkened color to your skin, skin changes, ulcers, or an unusual problem in any area of your skin or body, or if you have a severe pain that occurs suddenly, or color or temperature change in any area of your body. Call your doctor immediately if your toes become painful or become purple or dark in color. You may need medical care right away to prevent amputation (removal) of your affected body part.

Warfarin may cause other side effects. Call your doctor if you have any unusual problems while taking warfarin.

Symptoms of warfarin overdose may include the following:

• bloody or red, or tarry bowel movements
• spitting or coughing up blood
• heavy bleeding with your menstrual period
• pink, red, or dark brown urine
• coughing up or vomiting material that looks like coffee grounds
• small, flat, round red spots under the skin
• unusual bruising or bleeding
• continued oozing or bleeding from minor cuts

When anticoagulants are used

Anticoagulants are used if you’re at risk of developing blood clots that could potentially block a blood vessel and disrupt the flow of blood around your body. If a blood clot blocks the flow of blood through a blood vessel, the affected part of the body will become starved of oxygen and will stop working properly.

Depending on where the clot forms, this can lead to serious problems such as:

• Strokes – where a blood clot restricts the flow of blood to your brain, causing brain cells to die and possibly resulting in permanent brain damage or death
• Transient ischaemic attacks (TIAs) – also called “mini-strokes”, these have similar symptoms to a stroke, but the effects usually last less than 24 hours
• Heart attacks – where a blood clot blocks a blood vessel supplying your heart, starving it of oxygen and causing chest pain and sometimes death
• Deep vein thrombosis (DVT) – where a blood clot forms in one of the deep veins in your body, usually your legs, causing pain and swelling
• Pulmonary embolism – where a blood clot blocks one of the blood vessels around the lungs, stopping the supply of blood to your lungs

Treatment with anticoagulants may be recommended if your doctor feels you’re at an increased risk of developing one of these problems. This may be because you’ve had blood clots in the past or you’ve been diagnosed with a condition such as atrial fibrillation that can cause blood clots to form.

You may also be prescribed an anticoagulant if you’ve recently had surgery, as the period of rest and inactivity you need during your recovery can increase your risk of developing a blood clot.

Who should take anticoagulants?

Your doctor may recommend anticoagulants to help prevent the above conditions if they feel you’re at risk.

This may be because you have:

• developed blood clots in the past
• recently had surgery that means you’re unable to move around much while you recover, such as a hip replacement or knee replacement
• had an aortic valve replacement – as blood clots can form on the surface of the new heart valve
• atrial fibrillation – a type of irregular heartbeat (arrhythmia) that can cause blood clots to form in the heart
• a condition where the blood has an increased tendency to form clots (thrombophilia), such as Factor V Leiden
• antiphospholipid syndrome – where the immune system attack fats and proteins in the blood vessels, causing the blood to clot

Anticoagulants are also sometimes used to treat blood clots, such as DVT or a pulmonary embolism, by stopping the clot getting bigger while your body slowly reabsorbs it.

How long you’ll need to take anticoagulants for will depend on why they’re needed. You might only need to take them for a short time after a hip or knee replacement, but treatment may be lifelong if you have a long-term condition that increases your risk of blood clots.

Things to consider when taking anticoagulants

There are several things you need to be aware of when taking anticoagulant medicines.

If you’re going to have surgery or a test such as an endoscopy, make sure your doctor or surgeon is aware that you’re taking anticoagulants, as you may have to stop taking them for a short time.

Speak to your doctor, anticoagulant clinic or pharmacist before taking any other medications, including prescription and over-the-counter medicines, as some medications can affect how your anticoagulant works.

If you’re taking warfarin, you’ll also need to avoid making significant changes to what you normally eat and drink, as this can affect your medication.

Most anticoagulant medicines aren’t suitable for pregnant women. Speak to your GP or anticoagulant clinic if you become pregnant or are planning to try for a baby while taking anticoagulants.

Anticoagulant special precautions

If you’re prescribed anticoagulants, always follow the instructions of your doctor or another healthcare professional.

Some of the main issues you’ll need to consider while taking your medication are outlined below.

Having surgery

If you’re taking anticoagulants and you need to have surgery or any kind of invasive procedure, make sure that the healthcare professionals treating you are aware of your medication.

This includes procedures used to diagnose other conditions, such as an endoscopy or cystoscopy.

As anticoagulants reduce the ability of your blood to clot, there’s a risk you could experience heavy bleeding if any kind of cut (incision) is made during a procedure.

You may therefore be advised to stop taking your medication before surgery.

If you’re having a dental procedure, such as having a tooth removed, tell your dentist that you take anticoagulants.

You may not need to stop taking your medication, but you might need to have a blood test before the procedure to make sure your blood clots at the right speed.

Only stop taking your medication on the advice of your doctor or another healthcare professional.

Pregnancy

Warfarin isn’t normally given to pregnant women because it can affect the unborn baby. It can cause birth defects or excessive bleeding from the placenta or foetus.

It may sometimes be used in the second trimester, but should never be taken during the first trimester and should ideally be avoided in the third trimester as well.

The newer anticoagulant medications apixaban (Eliquis), dabigatran (Pradaxa) and rivaroxaban (Xarelto) also are not recommended in pregnancy.

If you’re taking any of these medications, you should make sure you use contraception when having sex to avoid becoming pregnant.

If you’re on anticoagulants and find out you’re pregnant or plan to start trying for a baby, speak to your doctor or anticoagulant clinic about stopping or changing your prescription.

Injections of an anticoagulant called heparin can be given while you’re pregnant if necessary.

Breastfeeding

You can usually take warfarin while you’re breastfeeding, but you should discuss this with your doctor or midwife first.

Heparin is also safe to take while you’re breastfeeding.

Apixaban, dabigatran and rivaroxaban aren’t recommended if you’re breastfeeding because it’s not clear if they’re safe for the baby.

If you’re on anticoagulants and are breastfeeding or planning to breastfeed, speak to your doctor, anticoagulant clinic or midwife to find out if you need to change your prescription.

Avoiding injury

Taking anticoagulant medicines can make you more prone to bleeding if you’re injured.

Try to avoid minor injuries and cuts and grazes by:

• taking care when brushing your teeth and shaving (consider using a soft toothbrush and an electric razor)
• using insect repellent to avoid insect bites or stings
• using protection when gardening, sewing or playing sports

Your doctor or anticoagulant clinic may advise you to avoid contact sports because of the risk of excessive bleeding.

Drug interactions

If you’re taking anticoagulants, you should speak to your doctor, anticoagulant clinic or pharmacist before taking any other medication, remedy or supplement.

This includes prescription medicines, medicines bought over the counter without a prescription (such as aspirin), and any herbal remedies (such as St John’s Wort).

Some treatments can stop anticoagulants working or can increase the effect they have, which can be dangerous.

Some of the medicines that can affect anticoagulants include certain:

• antibiotics
• antidepressants
• corticosteroids (medications used to reduce inflammation)
• anticonvulsants (medications used to treat epilepsy)
• non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (take paracetamol instead if you need pain relief)

For a full list of medicines that you should avoid, check the patient information leaflet that comes with your medicine.

Food and drink

It’s important to have a healthy, balanced diet that includes lots of fruit and vegetables if you’re taking anticoagulants.

But you should avoid making frequent changes to the amount of green vegetables you eat and cranberry juice you drink if you’re taking warfarin.

Foods with a lot of vitamin K, such as leafy green vegetables, chickpeas and liver, can interfere with how warfarin works.

You can still include these in your diet while taking warfarin, as the clinic will adjust your dose accordingly, but it’s important to be consistent in the amount you eat.

Do not drink cranberry juice while you’re taking warfarin. It can increase the blood-thinning effect of warfarin.

You should also seek advice before taking supplements containing vitamin K.

The effect of warfarin is also affected by alcohol. If you’re taking warfarin, do not drink more than 1 or 2 alcoholic drinks a day and never binge drink.

These food and drink restrictions don’t usually apply if you’re taking apixaban, dabigatran and rivaroxaban, but you should check with your doctor, anticoagulant clinic or pharmacist if you’re not sure.

Anticoagulant side effects

A possible side effect of anticoagulants is excessive bleeding (hemorrhage), because these medicines increase the time it takes for blood clots to form.

The main side effect of anticoagulant is that you can bleed too easily, which can cause problems such as:

• passing blood in your urine
• passing blood when you poo or having black poo
• severe bruising
• prolonged nosebleeds (lasting longer than 10 minutes)
• bleeding gums
• vomiting blood or coughing up blood
• sudden severe back pain
• difficulty breathing or chest pain
• in women, heavy or increased bleeding during your periods, or any other bleeding from your vagina

For most people, the benefits of taking anticoagulants will outweigh the risk of excessive bleeding.

If you notice any severe or recurrent bleeding, seek medical attention immediately. Contact your doctor or go to your nearest accident and emergency department.

You should also seek immediate medical attention if you:

• are involved in a major accident
• experience a significant blow to the head
• are unable to stop any bleeding

If you’re taking warfarin, you’ll have regular blood tests to check if you’re at a high risk of excessive bleeding by measuring how quickly your blood clots. If your blood clots too slowly, your dose may be increased.

Other side effects

Other side effects of anticoagulants vary depending on which medication you’re taking.

For a full list of potential side effects for your medicine, check the leaflet that comes with it.

Possible other side effects include:

• diarrhoea or constipation
• feeling and being sick
• indigestion
• dizziness
• headaches
• rashes
• itchy skin
• hair loss
• jaundice (yellowing of the skin and whites of the eyes)

Speak to your doctor or anticoagulant clinic if you have any persistent troublesome side effects. Contact them immediately if you develop jaundice.

1. Krötz F, Sohn HY, Klauss V. Antiplatelet drugs in cardiological practice: established strategies and new developments. Vasc Health Risk Manag. 2008;4(3):637-45[↩]
2. Hashemzadeh M, Furukawa M, Goldsberry S, Movahed MR. Chemical structures and mode of action of intravenous glycoprotein IIb/IIIa receptor blockers: A review. Exp Clin Cardiol. 2008 Winter;13(4):192-7[↩]
3. Warner TD, Nylander S, Whatling C. Anti-platelet therapy: cyclo-oxygenase inhibition and the use of aspirin with particular regard to dual anti-platelet therapy. Br J Clin Pharmacol. 2011 Oct;72(4):619-33[↩]
4. Harker LA, Kadatz RA. Mechanism of action of dipyridamole. Thromb. Res. Suppl. 1983;4:39-46.[↩]
5. Kubica J, Kozinski M, Navarese EP, Tantry U, Kubica A, Siller-Matula JM, Jeong YH, Fabiszak T, Andruszkiewicz A, Gurbel PA. Cangrelor: an emerging therapeutic option for patients with coronary artery disease. Curr Med Res Opin. 2014 May;30(5):813-28[↩]
6. Hashemzadeh M, Furukawa M, Goldsberry S, Movahed MR. Chemical structures and mode of action of intravenous glycoprotein IIb/IIIa receptor blockers: A review. Exp Clin Cardiol. 2008 Winter;13(4):192-7.[↩]
7. Goto S. Cilostazol: potential mechanism of action for antithrombotic effects accompanied by a low rate of bleeding. Atheroscler Suppl. 2005 Dec 15;6(4):3-11[↩]
8. Goto S. Cilostazol: potential mechanism of action for antithrombotic effects accompanied by a low rate of bleeding. Atheroscler Suppl. 2005 Dec 15;6(4):3-11.[↩]
9. Kalyanasundaram A, Lincoff AM., Medscape. Managing adverse effects and drug-drug interactions of antiplatelet agents. Nat Rev Cardiol. 2011 Sep 13;8(10):592-600[↩]