Reversal of Anticoagulation After Cerebral Hemorrhage

FIGURE 2.1 Serial CT scans show expansion of the thalamic hematoma and development of acute hydrocephalus.

Ongoing anticoagulation in a patient with a cerebral hematoma is a serious concern. As expected, warfarin causes larger cerebral hemorrhages and increases the chance of poor outcome. Avoiding this expansion—and even reduction of size by 2 teaspoons could make a difference—may reduce the morbidity from additional brain tissue destruction or prevent brainstem injury from displacement. Everyone would agree that a first step would be to quickly correct the INR to a normal value (INR < 1.5). However, it is not well established that rapid reversal of the anticoagulant effects of warfarin effectively reduces enlargement of the hematoma.

The approach is to reverse the antagonistic effect of warfarin on vitamin K, and vitamin K will then reactivate factors II, VII, IX, and X. Using both intravenous vitamin K and fresh frozen plasma (FFP) accomplishes that, but only after several hours. Moreover, vitamin K alone is not sufficient and may even take 6–24 hours to take full effect; therefore by itself vitamin K has no substantial effect on expansion of the hematoma occurring usually in the first hours after the initial hemorrhage. FFP further replaces the depleted coagulation factors, but multiple studies have shown that target INR is not reached within 2–4 hours in the majority of patients (compatibility testing and thawing of plasma lasting 30–60 minutes adds to the delay). Equally problematic is when INR is not corrected rapidly with FFP, since it may lead physicians to infuse more units of FFP, since leading to transfusion-associated circulatory overload, pulmonary edema, and in the worst-case scenario endotracheal intubation and mechanical ventilation. There is no consensus on the number of FFP units needed, although weight-based calculation may reduce complications. As a general rule, a dose of 10–20 mL of FFP/kg of body weight will produce a sufficient 10% increase in coagulation factors. A typical unit is 250 cc, thus 3 to 4 units are often needed. Finally and most concerning, one should not be surprised to find out that some emergency departments may not have fresh frozen plasma readily available. This delay in treatment is obviously unacceptable.

The best alternative options for correction of warfarin are prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa). PCCs contain human derived clotting factors and rFVIIa is bioengineered. PCCs are basically a concentrate of factor IX and smaller amounts of II, X, and VII. Neither PCC nor rFVIIa is universally available.

There is a tendency to prefer PCC (Table 2.1). There are several reasons for that: it is easy to use and quickly prepared, there is a minimal infused volume, it nearly completely replaces clotting factors, and the most convincing argument for some physicians is that it lasts longer than rFVIIa and less additional FFP may be needed. But thrombotic events using PCC may not be different from rFVIIa, and there are very few studies that have assessed this risk with PCC. The risk of arterial and venous occlusive events in rFVIIa was 26% with a low dose (20 mcg/kg) and almost 50% with higher dose (80 mcg/kg) in the largest cerebral hematoma trial although most of these events were inconsequential. This is consistent with our experience in daily practice. A recent detailed analysis of several clinical trials in multiple conditions found these increased risks, particularly in patients over 65 years of age, often resulting in venous occlusions.

Patients with severe thrombocytopenia need platelet transfusions. An unresolved issue is whether platelet infusion in a patient with prior use of antiplatelet agents reduces hematoma expansion or improves outcome. Clinical trials are underway, and there is yet no definite evidence that platelet infusion can impact on progression of the hemorrhage or even outcome.

A new problem will be introduced when the use of dabigatran (a thrombin or factor II inhibitor) or apixaban (a factor Xa inhibitor) becomes more commonplace, because no reversal strategy is available other than stopping the drug. The anticoagulation effect of these newer drugs reverses many hours (half life 12–15 hours) after discontinuation and thus not soon enough. FFP would not have any major effect, but PCC or rFVIIa may help. Research on antibodies against these drugs is ongoing. Finding an antidote will be important because these new expensive drugs may replace warfarin in the long run.

TABLE 2.1 Reversal of Warfarin