LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

Heparin is a naturally occurring, complex glycosaminoglycan that has anticoagulant activity and has been used for decades as an antithrombotic agent in management of patients at high risk for thromboses. Heparin is synthesized in mast cells as a polymer from glucuronic acid and glucosamine residues, 10 to 15 of which are attached to a core protein resulting in a large proteoglycan of 750,000 to 1,000,000 daltons. This complex is then modified extensively and then degraded into glycosaminoglycan chains of 5000 to 30,000 daltons. Heparin for therapeutic use in humans is generally made from extracts of bovine lung or porcine intestinal mucosa and consists of a heterogeneous mixture of glycosaminoglycans of slightly different structures and molecular weights. Commercial preparations of heparin are standardized as USP units/mg. Low molecular weight heparins (1000 to 10,000 daltons) are isolated from standard heparin preparations, which are then partially depolymerized and purified by gel chromatography and alcohol precipitation. Commercial preparations of low molecular weight heparins are standardized in a bioassay based upon inhibition of coagulation factor Xa. Heparin is a large glycosaminoglycan and is not absorbed through the gastrointestinal mucosa and must be given intravenously or by subcutaneous injection. Heparin is used as the initial treatment of venous thrombosis and pulmonary embolism because of its rapid onset of action, while awaiting the slower onset of activity of oral anticoagulants (such as warfarin). Heparin is also used in the setting of acute myocardial infarction and unstable angina and in prophylaxis of venous thrombosis during and/or after surgery. In addition, heparin is used to maintain patency of intravenous indwelling catheters (“heparin lock”), usually in low doses (10 to 100 units), and is not meant for therapeutic purposes. Recently, low molecular weight heparins have replaced standard heparin in many situations, their advantage being a more predictable pharmacokinetics which allows for subcutaneous administration and outpatient management. The major side effects of heparin therapy are related to excessive bleeding and anticoagulation. However, heparin (both standard and low molecular weight forms) also has somewhat idiosyncratic side effects which includes hypersensitivity reactions, thrombocytopenia and serum enzyme elevations. Indeed, a large proportion of patients given standard or low molecular weight heparin intravenously develop serum ALT and AST elevations arising after 4 to 8 days of therapy that are usually asymptomatic and self-limited, lasting only 4 to 20 days and resolving sometimes even with continuation of treatment. The cause of these elevations is not known, but they are rarely associated with any symptoms. Serum alkaline phosphatase levels are elevated in a small proportion of cases but bilirubin levels are rarely above normal. For obvious reasons, the liver histological changes accompanying the aminotransferase elevations during heparin therapy has not been described.