Management of Large Intentional Overdose of Enoxaparin with Protamine Sulfate

Enoxaparin, a low molecular weight heparin (LMWH), is used for prophylaxis and treatment of venous and arterial thromboembolism. Due to its safety profile, there has been little literature regarding management and treatment of overdoses. Two reports of enoxaparin overdose have been described in the literature; a neonate received a 10-fold overdose and a 64-year old man received an extra daily dose. Both cases were treated with an approximate 1 to 1 ratio of protamine sulfate to LMWH (30 mg and 20 mg, respectively) and showed incomplete reversal of anticoagulation. Plasma levels of LMWH can be monitored by measuring anti-factor Xa levels; however, studies correlating large overdoses have not been performed. Peak plasma levels of LMWH are found 3–4 hours after administration, and the half-life of the drug is 4.5–7 hours. Anti-factor Xa levels, however, are not readily available at most institutions. We report a challenging case of a large overdose of LMWH, successfully treated despite the lack of appropriate laboratory monitoring tests.

A 50-year old Caucasian man with a past medical history significant for bipolar disorder, schizophrenia, hypertension, and pulmonary embolism secondary to a hypercoagulable state caused by tetrahydrofolate reductase deficiency was found unresponsive and transported to the emergency department. Upon admission, he reported self-administration of 20 subcutaneous injections of 100 mg of enoxaparin (2000 mg) and 8 tablets of quetiapine (400 mg/tablet) in an attempt to commit suicide. He was somnolent but arousable with bruising noted around multiple injection sites on his abdomen. The remainder of his physical exam was unremarkable, and he exhibited no overt signs of bleeding. Initial laboratory assessment, approximately 2 hours post-suicide attempt, revealed an elevated aPTT of >150 seconds (reference range 23–38 seconds). Anti- factor Xa levels were not available at the time of treatment. An initial dose of protamine sulfate, 250 mg mixed in 500 ml of 0.9% sodium chloride, was infused over 3–4 hours. Repeat aPTT was 61 seconds. A second infusion of protamine sulfate was administered 2 hours later, and the aPTT decreased further to 49 seconds. Rebound phenomenon was noted 3–8.5 hours later as the aPTT increased (70 to 89 seconds), however, no additional protamine sulfate was given. At 24 hours, the aPTT was 46 seconds. The patient did not exhibit any signs of bleeding during treatment, and tolerated the infusions of protamine sulfate without any adverse effects. Subsequent testing for anti-factor Xa revealed an initial level of 4.72 IU/mL upon admit (therapeutic range 0.50 – 1.10 IU/mL), decreasing to 4.52 and 3.82 IU/mL after the infusions of protamine sulfate. The anti-factor Xa level at 24 hours was 1.39 IU/mL.

The reversal of an enoxaparin overdose is challenging and frequently difficult to manage. Reversal with protamine sulfate is often incomplete, and infusion of the recommended dosage of 1 mg for each 1 mg of enoxaparin can be risky in large dosages. Ideally, Factor Xa levels, when available, can assist in management decision, however in emergency situations as described here, the aPTT and clinical symptoms must be used to guide treatment.

No relevant conflicts of interest to declare.