LMWH, Unfractionated Heparin, and Hepatotoxicity
Enoxaparin, a low-molecular-weight heparin (LMWH), is widely used for the treatment and prophylaxis of thromboembolic disorders, such as deep vein thrombosis. Low-molecular-weight heparin products have smaller and more uniform molecular weights than unfractionated heparin, allowing them to exhibit a much greater affinity for factor Xa than factor IIa. Compared with traditional unfractionated heparin, LMWHs have proved to be equally efficacious and may be safer. The distinctive characteristics of LMWHs have resulted in decreased rates of bleeding and equivalent rates of thrombocytopenia compared with unfractionated heparin. This favorable safety profile has been identified in several studies and may have led clinicians to believe that LMWHs have lower frequencies of all common side effects. A 66-year-old woman developed increased hepatic transaminases during treatment with enoxaparin for a deep vein thrombosis; they returned to normal after enoxaparin discontinuation. A causal relationship between unfractionated heparin and asymptomatic, transient increases in hepatic transaminase levels has been documented; these increased levels also appear to be an underrecognized, adverse effect of LMWH therapy.
Enoxaparin is a low-molecular-weight heparin (LMWH) indicated for prophylaxis and treatment of thromboembolic disorders such as deep vein thrombosis (DVT) and pulmonary embolism. Enoxaparin has an average molecular weight of 4500 daltons (range 3000-8000 daltons) compared with 15,000 daltons (3000-30,000 daltons) for unfractionated heparin (UFH). Due to enoxaparin's more uniform, lower weight, it differs in its mechanism of anticoagulant activity, exhibiting a greater factor Xa:factor IIa affinity ratio compared with UFH (2.7:1 vs 1:1, respectively). Its enhanced effect at factor Xa and more uniform weight have resulted in more predictable antithrombotic effects and pharmacokinetics, allowing for standardized dosing without monitoring of antifactor Xa activity in most cases.
It is hypothesized that the more specific antifactor Xa activity of enoxaparin and all LMWHs results in an improved safety profile. When LMWHs were used to treat DVT, the most common adverse effects included major bleeding complications (1.5-2%), thrombocytopenia with a platelet count below 50,000/mm (0.1%), and hepatotoxicity, defined as serum hepatic transaminase elevations greater than 3 times the laboratory upper limit of normal. Hepatotoxicity during enoxaparin treatment was 6.1% for aspartate aminotransferase (AST) and 5.9% for alanine aminotransferase (ALT).
A recent meta-analysis compared the rates of adverse reactions of UFH with those of LMWHs and found lower mortality with LMWH therapy, a trend toward lower bleeding rates with LMWH therapy, and equivalent rates of thrombo-cytopenia in patients treated for DVT. These favorable outcomes associated with LMWH may have led clinicians to believe that LMWHs have lower frequencies of all common side effects.
Our patient had an increase in serum hepatic transaminases associated with the use of enoxaparin. Clinicians generally refer to texts to ensure a complete differential diagnosis; unfortunately, pharmacotherapy, general medicine, and hepatology texts, as well as the literature, do not mention what appears to be a common adverse effect of heparin products. In the context of our patient, we provide a comprehensive evidence-based review of heparin product-induced hepatic transaminase elevations, associated risk factors, possible mechanisms of action, and evidence suggesting the elevations are a class effect.
Enoxaparin, a low-molecular-weight heparin (LMWH), is widely used for the treatment and prophylaxis of thromboembolic disorders, such as deep vein thrombosis. Low-molecular-weight heparin products have smaller and more uniform molecular weights than unfractionated heparin, allowing them to exhibit a much greater affinity for factor Xa than factor IIa. Compared with traditional unfractionated heparin, LMWHs have proved to be equally efficacious and may be safer. The distinctive characteristics of LMWHs have resulted in decreased rates of bleeding and equivalent rates of thrombocytopenia compared with unfractionated heparin. This favorable safety profile has been identified in several studies and may have led clinicians to believe that LMWHs have lower frequencies of all common side effects. A 66-year-old woman developed increased hepatic transaminases during treatment with enoxaparin for a deep vein thrombosis; they returned to normal after enoxaparin discontinuation. A causal relationship between unfractionated heparin and asymptomatic, transient increases in hepatic transaminase levels has been documented; these increased levels also appear to be an underrecognized, adverse effect of LMWH therapy.
Enoxaparin is a low-molecular-weight heparin (LMWH) indicated for prophylaxis and treatment of thromboembolic disorders such as deep vein thrombosis (DVT) and pulmonary embolism. Enoxaparin has an average molecular weight of 4500 daltons (range 3000-8000 daltons) compared with 15,000 daltons (3000-30,000 daltons) for unfractionated heparin (UFH). Due to enoxaparin's more uniform, lower weight, it differs in its mechanism of anticoagulant activity, exhibiting a greater factor Xa:factor IIa affinity ratio compared with UFH (2.7:1 vs 1:1, respectively). Its enhanced effect at factor Xa and more uniform weight have resulted in more predictable antithrombotic effects and pharmacokinetics, allowing for standardized dosing without monitoring of antifactor Xa activity in most cases.
It is hypothesized that the more specific antifactor Xa activity of enoxaparin and all LMWHs results in an improved safety profile. When LMWHs were used to treat DVT, the most common adverse effects included major bleeding complications (1.5-2%), thrombocytopenia with a platelet count below 50,000/mm (0.1%), and hepatotoxicity, defined as serum hepatic transaminase elevations greater than 3 times the laboratory upper limit of normal. Hepatotoxicity during enoxaparin treatment was 6.1% for aspartate aminotransferase (AST) and 5.9% for alanine aminotransferase (ALT).
A recent meta-analysis compared the rates of adverse reactions of UFH with those of LMWHs and found lower mortality with LMWH therapy, a trend toward lower bleeding rates with LMWH therapy, and equivalent rates of thrombo-cytopenia in patients treated for DVT. These favorable outcomes associated with LMWH may have led clinicians to believe that LMWHs have lower frequencies of all common side effects.
Our patient had an increase in serum hepatic transaminases associated with the use of enoxaparin. Clinicians generally refer to texts to ensure a complete differential diagnosis; unfortunately, pharmacotherapy, general medicine, and hepatology texts, as well as the literature, do not mention what appears to be a common adverse effect of heparin products. In the context of our patient, we provide a comprehensive evidence-based review of heparin product-induced hepatic transaminase elevations, associated risk factors, possible mechanisms of action, and evidence suggesting the elevations are a class effect.
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