Heparin Side Effects
Some side effects of heparin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.
For the Consumer
Applies to heparin: injectable, solution
Along with its needed effects, heparin may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor or nurse immediately if any of the following side effects occur while taking heparin:Less common
- Abdominal or stomach pain or swelling
- back pain or backaches
- bleeding from the gums when brushing teeth
- blood in the urine
- coughing up blood
- headaches, severe or continuing
- heavy bleeding or oozing from cuts or wounds
- joint pain, stiffness, or swelling
- menstrual bleeding, unexpected or unusually heavy
- unexplained bruising or purplish areas on the skin
- unexplained nosebleeds
- vomiting of blood or material that looks like coffee grounds
- Blood under the skin (blood blister) at the place of injection
- chest pain
- chills or fever
- fast or irregular breathing
- irritation, pain, redness, or ulcers at the place of injection
- itching and burning feeling, especially on the bottom of the feet
- nausea or vomiting
- numbness or tingling in the hands or feet
- pain, coldness, or blue color of the skin on the arms or legs
- peeling of the skin
- puffiness or swelling of the eyelids or around the eyes
- shortness of breath
- skin color change, especially near the place of injection or in the fingers, toes, arms, or legs
- skin rash, hives, or itching
- tearing of the eyes
- tightness in the chest
- trouble with breathing
After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:
- Black, tarry stools
- bleeding gums
- blood in the urine or stools
- pain in the chest, groin, or legs, especially calves of legs
- pinpoint red spots on the skin
- severe headaches of sudden onset
- sudden loss of coordination
- sudden shortness of breath for no apparent reason
- sudden slurred speech
- sudden vision changes
- unusual bleeding or bruising
For Healthcare Professionals
Applies to heparin: injectable kit, injectable solution, intravenous solution
Hematologic side effects including hemorrhage at any site have been reported the most frequently. These have included hematomas, melena, hematuria, and less frequently, ecchymoses, epistaxis, and hematemesis. Compression neuropathy and nerve paralysis from local bleeding and/or hematoma, fatal rectal sheath hematomas, intracranial hemorrhage, and other serious bleeding events have been reported. Adrenal hemorrhage, ovarian hemorrhage, and retroperitoneal hemorrhage have been reported. Thrombocytopenia has been reported in up to 30% of patients. Heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia and thrombosis (HITT), and delayed onset HIT and HITT have been reported.
The risk of bleeding has been reported to be increased in women over 60 years of age. Other risk factors have included administration by intermittent intravenous injection, a serious comorbid condition or history of alcohol abuse, concomitant use of aspirin, or advanced age. In addition, patients previously exposed to unfractionated heparin or a low-molecular-weight heparin appear to be more susceptible to developing heparin-induced thrombocytopenia (HIT) and HIT-related thromboembolic complications (e.g., transient ischemic attack, stroke) than those who were never exposed.
There are two types of heparin-induced thrombocytopenia (HIT). Type I, sometimes called heparin-associated thrombocytopenia, occurs in approximately 10% to 20% of patients treated with heparin and is a nonimmunogenic response to heparin. Type I is not progressive, not associated with bleeding or thrombosis, and does not require special treatment. Platelet counts usually recover within a few days even if heparin therapy is continued. Type II HIT is an immune-mediated, prothrombotic reaction that occurs in 0.5% to 5% of patients treated with unfractionated heparin and in less than 1% of patients treated with a low molecular weight heparin (LMWH). An overall mortality of 20% to 30% has been reported in patients who develop HIT type II. The decrease in platelet count associated with HIT usually begins 5 to 14 days after starting heparin. However, patients with a previous exposure (within past 100 days) to heparin may still have HIT antibodies circulating which can result in an abrupt (within 30 minutes of an IV bolus) decrease in platelets upon restarting heparin. Another phenomenon known as delayed-onset HIT can also occur 9 to 40 days after heparin is stopped. This typically occurs in patients exposed to heparin in the recent past (previous 2 weeks). Patients with LMWH-induced HIT exhibit a longer delay in the onset of symptoms compared with those who have heparin-induced HIT. Following discontinuation, platelet counts begin to recover within 4 days, but may take more than 2 weeks in patients with high-titer HIT antibodies. Thrombocytopenia is caused by heparin-dependent IgG antibodies that bind to a specific platelet protein, platelet factor 4 (PF4). The heparin-PF4-IgG immune complex binds to platelets causing platelet activation. The activated platelets cause release of platelet-derived procoagulant microparticles, which accelerate coagulation reactions and generates thrombin. LMWHs have a high cross-reactivity with circulating heparin-PF4-IgG immune complex. Complications associated with HIT include exacerbation of venous thromboembolism, arterial or venous thrombosis, limb gangrene, stroke, and skin necrosis. Approximately 50% to 75% of patients with HIT develop symptomatic thrombosis. The risk of HIT-associated thrombosis correlates with the magnitude of decrease in platelet count. Other factors associated with a higher risk for developing HIT-associated thrombosis include women, nonwhites, and lower body weight. In approximately 20% of HIT patients, thrombosis occurs 1 to 3 days before thrombocytopenia is detected. If HIT is suspected, treatment with the offending agent (e.g., heparin, LMWH, including heparin flushes) should be discontinued immediately and the patient should be given an alternative anticoagulant such as a direct thrombin inhibitor (i.e., argatroban, bivalirudin, lepirudin) or fondaparinux. Use of a vitamin K antagonist (i.e., warfarin) should be delayed until the platelet count returns to normal. The antibodies that cause HIT will usually disappear after approximately 3 months; therefore, use of heparin may be considered in a patient with a history of HIT if the antibody test is negative.
There are data which support an increased risk of thrombocytopenia with bovine heparin.
Cardiovascular side effects have included new or recurrent arterial and venous thrombosis in association with thrombocytopenia. This paradoxical effect, known as the "white clot syndrome", has resulted in cerebral vascular accident, pulmonary embolism, myocardial infarction, loss of limbs, and may be fatal. Gangrene of the limbs, fulminant hepatic failure following liver transplantation, and cutaneous necrosis, some fatal, have been reported. Constrictive pericarditis following heparin induced hemopericardium and fatal cardiac tamponade have been reported. Hypotension associated with heparin administration in patients undergoing cardiac surgery has been reported.
Dermatologic side effects have included extensive skin necrosis, necrotic lesions at subcutaneous injection sites, erythematous, indurated, nonnecrotic plaques at injection sites, as well as eczema and generalized pruritic, erythematous rash. Cutaneous necrosis has often been preceded by a burning sensation, localized erythema, and bullae formation. Alopecia has been reported.
Hypersensitivity side effects have included pruritic, inflammatory, papular, and vesicular lesions, urticaria, drug fever, asthma, rhinitis, and anaphylaxis. Eosinophilia and delayed type hypersensitivity have also been reported. Hypersensitivity is thought to play a role in the pathogenesis of Type II heparin induced thrombocytopenia and thrombosis as well as skin necrosis. A case of adult respiratory distress syndrome in which hypersensitivity was suspected has been reported.
In one study of 86 patients, elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in 59.3% and 26.7% of patients, respectively. The average maximum increase was 3.6 times baseline for ALT and 3.1 times baseline for AST. Lactate dehydrogenase abnormalities were observed in 35.7% of patients. Isoenzyme determinations in seven patients showed elevated hepatic fractions. In no case was there clinical evidence of hepatotoxicity.
Hepatic side effects reported in up to 60% of patients have included elevations in liver function enzymes.
Endocrine side effects have included increased free thyroxine levels. Acute adrenal insufficiency caused by heparin induced adrenal hemorrhage has been reported. Hypoaldosteronism has been reported.
The mechanism for increased free thyroxine levels appears to be displacement of thyroxine from binding sites by free fatty acids and may be more significant in patients with hypertriglyceridemia.
Metabolic side effects have included hyperkalemia, hyponatremia, and hypertriglyceridemia.
Musculoskeletal side effects have included osteoporosis.
A study of 39 women given prophylactic heparin therapy during pregnancy revealed an almost 5% reduction in trabecular bone mass during treatment. Although limited data are available, the osteoporotic effects of heparin are believed to be reversible.
In a study involving pregnant women (n=120) requiring thromboprophylaxis, clinically significant bone loss (i.e., 10% or greater) in the femur occurred in approximately 2% to 2.5% of patients regardless if they received enoxaparin (68.4 mg/day) or unfractionated heparin (17,380 units/day) for approximately 26 to 27 weeks.
Renal side effects have been reported rarely. A case of hemolytic uremic syndrome has been reported.
Genitourinary side effects have been reported rarely. Several cases of priapism have been reported.
Local side effects have included injection site irritation, erythema, mild pain, hematoma, or ulceration.
General side effects have been reported the most frequently. These have included bleeding or hemorrhage at any site.
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