No adverse effects from protamine sulfate were reported among previously published cases of LMWH overdose, even with continuous infusions and cumulative doses up to 500 mg. 11 However, the dose required to treat LMWH overdose (1 mg per 100 anti-Xa units, with 1 mg of enoxaparin equal to 100 anti-Xa units) often far exceeds this threshold. Second, given concerns regarding hypotension and anaphylaxis, the product monograph recommends a maximum single dose of 50 mg infused over a minimum of 10 minutes and cautious use in patients with fish allergy. This is illustrated by our patient, in whom LMWH anti-Xa levels decreased from 3.08 U/mL (before protamine sulfate) to 1.79 U/mL (after the final dose of protamine sulfate), but rose again to 2.06 U/mL 4 hours later. Our case illustrates 3 potential indications for protamine sulfate: to prevent bleeding after LMWH overdose, to treat intramuscular bleeding, and as prophylaxis before emergency fasciotomy.īecause the half-life of protamine sulfate is 7 minutes, its effect is transient unless continuously infused. 10 Among reported cases of LMWH overdose, protamine sulfate was administered prophylactically in 6 cases, therapeutically in 2 cases, and both prophylactically and therapeutically in 2 cases when bleeding developed during hospital stay, as occurred in our patient. American College of Chest Physicians guidelines suggest using protamine sulfate to neutralize LMWH when necessary, although they give no specific recommendations on managing LMWH overdose. Protamine sulfate forms a stable complex with heparin, neutralizing its anticoagulant effect. He underwent an uncomplicated wound closure 15 days later. Two days after fasciotomy, we started the patient on VTE prophylaxis with dalteparin 5000 units subcutaneous daily, given his high thrombotic risk. During the period before and after the fasciotomy, the patient received three 50 mg doses of protamine sulfate, with the third dose in response to bleeding from the surgical site, after which hemostasis occurred. The plastic surgery service measured the pressure in his left anterior arm compartment, finding it to be elevated at 30 (normal 0–8) mm Hg, confirming a diagnosis of anterior compartment syndrome, which we attributed to a hematoma after veni-puncture, and subsequently performed an urgent bedside fasciotomy.įigure 1 shows a timeline of clinical events, coagulation blood tests and treatment. Examination showed arm edema, antecubital fossa ecchymosis surrounding a venipuncture site and a weak radial pulse. The internal medicine service admitted the patient, with support from the hematology and thrombosis service, and treated him with prophylactic intravenous protamine sulfate 50 mg every 6 hours and oral tranexamic acid 500 mg every 8 hours.Įighteen hours after his overdose, the patient developed progressive left arm pain. The patient’s rivaroxaban level, measured by a drug-specific anti-Xa assay (Diagnostica Stago, Asnières sur Seine, France), was 351 (expected therapeutic range 182–408) ng/mL. Initial blood work results showed hemoglobin of 121 (normal 130–180) g/L, creatinine of 99 (normal 60–110) μmol/L, estimated glomerular filtration rate (GFR) of 81 (normal > 60) mL/min, international normalized ratio of 1.6 (normal 0.8–1.2), activated partial thromboplastin time (aPTT) of > 150 (normal 22–35) seconds, and LMWH anti-Xa level of 8.94 (therapeutic range 0.5–1.0) U/mL. The patient’s vital signs were stable, and we observed no evidence of bleeding other than bruising around multiple abdominal injection sites. He had taken his last dose of rivaroxaban 3 days before the current presentation. The injected dalteparin was left over from a previous prescription for 15 000 units daily. Previously, he had switched among several anti-coagulants owing to intolerance or breakthrough thrombosis, including warfarin, various preparations of low-molecular-weight heparin (LMWH) and, most recently, rivaroxaban. The patient’s medical history included depression, heterozygous factor V Leiden mutation and recurrent venous thromboembolism (VTE). Serial monitoring of LMWH anti-Xa levels or activated partial thromboplastin time or both may help to guide therapy.Ī 42-year-old man presented to the emergency department 2 hours after self-injecting 225 000 units of dalteparin (15 prefilled 15 000-unit vials) with intent to self-harm. Protamine sulfate partially reverses the anticoagulant effect of LMWH and may prevent bleeding from LMWH overdose. Bleeding in low-molecular-weight heparin (LMWH) overdose is unpredictable and may develop insidiously in deep tissues such as retroperitoneal and intramuscular spaces.
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