What are the potential side effects of Enoxaparin (low molecular weight heparin)?

Side Effects of Enoxaparin

Hemorrhagic Complications

Bleeding is the most significant and common adverse effect of enoxaparin, occurring in approximately 17.4% of patients receiving prophylactic doses (40 mg/day), compared to 14.3% in placebo groups. 1

Major Bleeding Events

• Major bleeding occurs in 0.1% to 0.7% of patients undergoing orthopedic surgery, with rates comparable to unfractionated heparin 2
• Clinically relevant non-major bleeding events occur in 2.6% to 3.3% of patients 2
• Life-threatening hemorrhagic complications include:
  • Retroperitoneal hematomas requiring surgical evacuation and potentially causing abdominal compartment syndrome 3
  • Abdominal wall hematomas presenting with unexplained hematocrit drops and abdominal pain, which can be fatal in high-risk patients (e.g., those on hemodialysis) 4
  • Spinal/epidural hematomas when used concurrently with neuraxial anesthesia (over 40 reported cases since 1993) 4

Bleeding Risk Factors and Monitoring

• An unexplained fall in hematocrit or blood pressure should prompt immediate investigation for bleeding sites 4
• Intracranial hemorrhage risk increases significantly in elderly patients (>75 years) when enoxaparin is administered pre-hospital with fibrinolytic therapy 2
• Non-cerebral bleeding complications increase when enoxaparin is used with fibrinolytic agents, though net clinical benefit may still favor enoxaparin 2

Hematologic Complications

Thrombocytopenia

• Heparin-induced thrombocytopenia (HIT) is an antibody-mediated reaction that may cause arterial or venous thrombosis 2
• Enoxaparin is contraindicated in patients with thrombocytopenia and positive in vitro tests for antiplatelet antibodies 5
• Platelet counts should be monitored every 2-3 days from day 4 to day 14 of therapy in high-risk patients (orthopedic surgery) 6, 5
• Hospital-acquired thrombocytopenia (platelet counts <150,000) occurs in approximately 10-13% of patients receiving heparin-based regimens 2

Reactive Thrombocytosis

• Enoxaparin-induced reactive thrombocytosis is a rare but documented adverse reaction, with platelet counts potentially exceeding 800 × 10⁹/L 7
• This typically develops within 7-14 days of enoxaparin initiation and resolves within 16 days of discontinuation 7
• Switching to alternative anticoagulants (e.g., rivaroxaban) leads to gradual normalization of platelet counts 7

Local Injection Site Reactions

• Hematoma at injection site is a frequent adverse event 1
• Ecchymosis and petechiae at injection sites are common 1
• Abdominal bruising and superficial subcutaneous lumps may develop, requiring evaluation for hematoma formation and potential discontinuation 6

Non-Hemorrhagic Adverse Events

Gastrointestinal Effects

• Nausea, vomiting, and constipation are the most frequent drug-related adverse events, occurring in 12-20% of patients 2
• These rates are similar to those observed with unfractionated heparin 2

Other Systemic Effects

• Anemia (independent of bleeding) 1
• Fever 1
• Peripheral edema 1
• Edema at unspecified sites 1

Hepatic and Cardiovascular Safety

• No evidence of drug-associated liver toxicity in phase III trials lasting up to 5 weeks 2
• Elevated liver enzymes occur at low rates similar to enoxaparin comparators 2
• Cardiovascular events while on treatment range between 0.1% and 0.7%, similar to enoxaparin 2

Special Population Considerations

Renal Impairment

• Enoxaparin has delayed clearance in renal dysfunction due to its longer half-life compared to unfractionated heparin 2
• Dose adjustment to 1 mg/kg subcutaneously once daily is required for severe renal impairment (creatinine clearance <30 mL/min) 5
• Patients with severe renal impairment require cautious use due to increased bleeding risk 5

Elderly Patients

• Patients >75 years require reduced dosing (0.75 mg/kg subcutaneously every 12 hours without initial bolus) for acute coronary syndromes 5
• Pre-hospital administration in elderly patients significantly increases intracranial hemorrhage risk when combined with fibrinolytics 2

Critical Management Considerations

Reversal and Antidote Limitations

• Protamine sulfate has only 60% efficacy in reversing enoxaparin and can cause severe adverse effects 8
• Enoxaparin is unlikely to be dialyzable due to high plasma protein binding 2
• In cases of active bleeding, discontinuation and administration of blood products may be necessary 2

Drug Interactions

• Concomitant use of NSAIDs, aspirin, or other antiplatelet agents does not significantly increase bleeding rates in pooled analyses 2
• Adding additional anticoagulants to patients already on enoxaparin significantly increases bleeding risk and should be avoided 6
• Activated clotting time (ACT) should not be used to guide anticoagulation in enoxaparin patients, as low-molecular-weight heparins have minimal effect on ACT measurements 6