A number of retrospective studies have demonstrated conflicting data regarding the association of morbidity and mortality secondary to intracerebral hemorrhage (ICH) in patients being treated with antiplatelet agents.1-4 In addition, an association between the severity of ICH as well as the conversion of a minor head trauma to an ICH secondary to the prehospital use of antiplatelet agents has yet to be determined.
I was intrigued by this and evaluated a number of institutional protocols that have been developed for the reversal of antiplatelet therapies in the setting of life-threatening hemorrhage such as ICH. To my surprise, I found desmopressin (DDAVP) listed as a potential reversal agent across the board. This piqued my interest and as I dug a little deeper to learn more, I found the waters to be even murkier.
Let me backtrack a bit. DDAVP is an analog of vasopressin that acts by increasing plasma concentrations of factor VIII and von Willebrand factor (vWf) through endothelial stimulation, which leads to improvement in platelet adhesion resulting in a shortened activated partial thromboplastin time (aPTT) and bleeding time. For this, it is indicated for the treatment of hemophilia A and mild-to-moderate von Willebrand disease.
As we know, aspirin as well as ticlopidine, clopidogrel, and prasugrel irreversibly inhibit platelet aggregation through different mechanisms. Aspirin irreversibly binds to the cyclooxygenase-1 and -2 (COX-1 and COX-2) enzymes via protein acetylation, inhibiting the downstream production of thromboxane A2, which is necessary for platelet aggregation. Ticlopidine, clopidogrel, and prasugrel selectively inhibit the P2Y12 portion of ADP receptors, all of which irreversibly prevent the activation of the GPIIb/IIIa complex that is necessary for platelet aggregation.
So what is the rationale for the use of DDAVP in this setting?
It has been hypothesized that the production of vWf induced by DDAVP may directly crossbind and stimulate the GPIIb/IIIa receptor, which may induce platelet aggregation. However, there is little evidence to show that this can occur in the setting of irreversible inhibition of platelet aggregation secondary to antiplatelet agents. One case report demonstrated that an IV infusion of 0.3 mcg/kg of DDAVP partially reversed the antiplatelet activity of clopidogrel and aspirin after carotid endarterectomy, which was exhibited through the use of platelet mapping thromboelastography.
However, there have been no studies to date that have assessed the effectiveness of desmopressin for the reversal of ICH secondary to antiplatelet therapies.
Like any other drug, DDAVP is not without its risks. Although its effects are immediate, they are transient and last for approximately 24 hours. In addition, there is some debate in the literature regarding the increased risk of arterial thrombosis associated with its use.
Perhaps the IMPACT Proof of Concept study will shed some light regarding the utility of DDAVP in improving platelet activity and thereby reversing ICH secondary to antiplatelet therapy.
But for now, I am not totally convinced.
1. Mina AA, Knipfer JF, Park DY, et al. Intracranial complications of preinjury anticoagulation in trauma patients with head injury. J Trauma 2002; 53:668-672.
2. Jones K, Sharp C, Mangram AJ, et al. The effects of preinjury clopidogrel use on older trauma patients with head injuries. Am J Surg 2006; 192:743-745.
3. Sansing LH, Messe SR, Cucchiara BL, et al. Prior antiplatelet use does not affect hemorrhage growth or outcome after ICH. Neurology 2009; 72:1397-1402.
4. Ohm C, Mina A, Howells G, et al. Effects of antiplatelet agents on outcomes for elderly patients with traumatic intracranial hemorrhage. J Trauma 2005; 58:518-522.
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