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A 60-year-old woman with a history of Crohn’s disease, factor V Leiden thrombophilia, and significant vascular and thrombotic disease in her left leg presents with headache. She has been maintained on 80 mg of enoxaparin bid for years without a new thrombotic complication. One week prior to the admission, she fell and had minor head trauma. For the ensuing 3 days, she had headache, and on the fourth day she developed severe nausea and projectile vomiting. A noncontrast computed tomography (CT) scan of her brain shows acute hemorrhage in the right cerebellar hemisphere with minimal mass effect.
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What are available antidotes for reversal of low-molecular-weight heparin?
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The issue of low-molecular-weight heparin (LMWH) use is commonly seen with patients and presents clinicians with a significant dilemma. It is common practice to stop all anticoagulation and antiplatelet agents once intracerebral hemorrhage (ICH) is detected. However, the diagnosis can sometimes be delayed, and the situation would be quite different if she had continued her LMWH. Reversal of anticoagulation, in the setting of continued, active bleeding, must be done on an emergent basis. The half-life of LMWH is 12 to 24 hours. There is no antidote that completely reverses the effect of LMWH, and such reversal reports are mostly anecdotal in the literature. Protamine sulfate is used intravenously to reverse unfractionated heparin and leads to full reversal. It is thought that protamine reverses approximately 60% of the effect of LMWH1,2 based on in vitro studies.
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It is unclear why protamine does not fully neutralize the anti-Xa activity of LMWH. One milligram of protamine is given for every 100 units of active unfractionated heparin, and per 1 mg of LMWH.3 The maximum dose of protamine is 50 mg, with a maximum infusion rate of 5 mg/min. Hypotension, severe anaphylaxis, and death have been reported with protamine use.4 These adverse reactions can often be minimized by premedication with antihistamines and steroids, as well as a slow rate of administration. If given in excess dose, protamine can have a paradoxical anticoagulant effect.
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There are small studies describing recombinant activated factor VII (rFVIIa) for LMWH reversal, with some success. Doses in these studies ranged from 20 to 90 μg/kg.5,6 The use of rFVIIa in the setting of spontaneous and warfarin-associated bleeding will be discussed later in this chapter.
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When can anticoagulation therapy be resumed, as this patient could easily require amputation of her left leg if thrombosis occurs again?
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A safe time to reinitiate full anticoagulation is determined on a case-by-case basis. If hematoma expansion does not occur and the patient does not receive decompressive surgery, in general, full anticoagulation may be resumed approximately 10 to 14 days after the bleeding episode. The decision as to when reinitiation of anticoagulation can occur in this setting must be decided with risk-benefit stratification.
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