Toxicity and Management of Overdose

Treatment of the toxic effects of anticoagulants is aimed at reversing the underlying cause. Although the toxic effects of heparin, LMWH, and warfarin are hemorrhagic in nature, the management is different for each drug. Symptoms that may be attributed to toxicity or an overdose of anticoagulants are hematuria, melena (blood in the stool), petechiae, ecchymoses, and gum or mucous membrane bleeding. In the event of heparin or warfarin toxicity, the drug is to be stopped immediately. In the case of heparin, stopping the drug alone may be enough to reverse the toxic effects because of the drug’s short half-life (1 to 2 hours). In severe cases or when large doses have been given intentionally (i.e., during cardiopulmonary bypass for heart surgery), IV injection of protamine sulfate is indicated. This drug is a specific heparin antidote and forms a complex with heparin, completely reversing its anticoagulant properties. This occurs in as few as 5 minutes. In general, 1 mg of protamine can reverse the effects of 100 units of heparin. Protamine may also be used to reverse the effects of LMWHs. A 1-mg dose of protamine is administered for each milligram of LMWH given, (e.g., 1 mg protamine for 1 mg enoxaparin). If the heparin overdose has resulted in a large blood loss, replacement with packed red blood cells may be necessary.

In the event of warfarin toxicity or overdose, the first step is to discontinue the warfarin. As with heparin, the toxicity associated with warfarin is an extension of its therapeutic effects on the clotting cascade. However, because warfarin inactivates the vitamin K–dependent clotting factors and because these clotting factors are synthesized in the liver, it may take 36 to 42 hours before the liver can resynthesize enough clotting factors to reverse the warfarin effects. Giving vitamin K₁ (phytonadione) can hasten the return to normal coagulation. The dose and route of administration of the vitamin K depend on the clinical situation and its acuity (i.e., how quickly the warfarin-induced effects must be reversed and whether the patient is having significant bleeding). High doses of vitamin K (10 mg) given IV will reverse the anticoagulation within 6 hours. Current recommendations are to use the lowest amount of vitamin K possible, based on the clinical situation. This is because once vitamin K is given, warfarin resistance will occur for up to 7 days; thus the patient cannot be anticoagulated by warfarin during this period. In such cases, either heparin or an LMWH may need to be added to provide adequate anticoagulation. In acute situations in which bleeding is severe and the time it would take for the vitamin K to take effect is too long, it may be necessary to administer transfusions of human plasma or clotting factor concentrates. Depending on the clinical situation, oral vitamin K is usually the preferred route. However, when the international normalized ratio (INR) is very elevated and/or the patient is bleeding, vitamin K is given IV. There is a risk of anaphylaxis when it is given by the IV route. The risk is diminished by diluting it and giving it over 30 minutes. Some institutions allow it to be given via IV push. Vitamin K is available in 5-mg tablets and in 10-mg and 1-mg injections. It is common to give the injectable form orally.

Transfusions may be indicated for overdoses of direct thrombin inhibitors and the selective factor Xa inhibitor fondaparinux, which both lack specific antidotes. These drugs may also be removed with hemodialysis.

♦ warfarin

Warfarin sodium (Coumadin) is a pharmaceutical derivative of the natural plant anticoagulant known as coumarin. Warfarin is the most commonly prescribed oral anticoagulant and is available oral and IV; however, it is used almost exclusively in the oral form. Use of this drug requires careful monitoring of the prothrombin time/international normalized ratio (PT/INR), which is a standardized measure of the degree to which a patient’s blood coagulability has been reduced by the drug. A normal INR (without warfarin) is 1.0, whereas a therapeutic INR (with warfarin) ranges from 2 to 3.5, depending on the indication for use of the drug (e.g., atrial fibrillation, thromboprevention, prosthetic heart valve). Patients older than 65 years of age may have a lower INR threshold for bleeding complications and may need to be monitored accordingly. Elderly patients should be started on lower dosages initially. Recently, it has been shown that about one third of patients receiving warfarin metabolize it differently than expected, based on variations in certain genes, CYP2CP and VKORC1. Genetic testing for these genes is helpful in determining the appropriate initial dosage of warfarin. The maintenance dosage is still determined by the INR.

Warfarin has significant interactions with many drugs, including amiodarone, fluconazole, erythromycin, metronidazole, sulfonamide antibiotics, and cimetidine. Although many more drugs can interact with warfarin, the aforementioned are by far the most common. Combining warfarin and amiodarone will lead to a 50% increase in the INR. When amiodarone is added to warfarin therapy, it is recommended that the warfarin dose be cut in half.

Because warfarin inhibits vitamin K–dependent clotting factors, foods that are high in vitamin K may reduce warfarin’s ability to prevent clots. Common foods rich in vitamin K include leafy green vegetables (kale, spinach, collard greens). The most important aspect of these food-drug interactions is consistency in diet. Educate patients to maintain consistency in their intake of leafy green vegetables. Many patients are under the misconception that they must avoid all leafy green vegetables. However, this is not true. Once their maintenance warfarin dose is established, patients may still eat greens, but they need to be consistent in their intake of green vegetables, because increasing or decreasing their intake can affect the INR. Herbal products that interact with warfarin and result in increased risk of bleeding include dong quai, garlic, ginkgo, and St. John’s wort.

♦ enoxaparin

Enoxaparin (Lovenox) is the prototypical LMWH and is obtained by enzymatically cleaving large unfractionated heparin molecules into small fragments. These smaller fragments of heparin have a greater affinity for factor Xa than for factor IIa and have a higher degree of bioavailability and a longer elimination half-life than unfractionated heparin. Laboratory monitoring, as done with heparin therapy, is not necessary when enoxaparin is given because of its greater affinity for factor Xa. It is available only in injectable form. Other anticoagulants with comparable pharmacology and indications include danaparoid and dalteparin. Enoxaparin is the most frequently used LMWH and is commonly given for both prophylaxis and treatment. All LMWHs have a distinct advantage over heparin in that it does not require any laboratory monitoring and can be given at home for the treatment of DVT or pulmonary embolism. This allows patients to be discharged from the hospital sooner. It is also used at home after major orthopedic surgery.

A potentially deadly medication error is to give heparin in combination with enoxaparin (or any LMWH, dabigatran, or rivaroxaban). Always double-check that enoxaparin and heparin are never given to the same patient.