Coated-Platelets in Ischemic Stroke – Potential Insight into the Etiology of Stroke Subtypes

The role of platelets in ischemic stroke is not questioned. Ample evidence supporting their involvement is provided by studies demonstrating the effectiveness of antiplatelet therapies in reducing the rate of recurrent stroke, a conclusion reflected in current guidelines for stroke management (1). Nevertheless, it is not clear if platelets play an identical role in all subtypes of ischemic strokes or if platelet hyperor hyporeactivity contributes to stroke susceptibility. For example, why do patients with identical vascular risk factors present with strokes in different arterial territories due to presumably different mechanisms? Do hyper-reactive platelets promote both cortical and lacunar stroke? Is it appropriate to use the same antiplatelet regimen in all forms of ischemic stroke? When these questions are fully answered, significant changes can be foreseen for the treatment and prevention of stroke. One persistent obstacle in understanding the role of platelet reactivity in stroke has been the difficulty of quantitating that reactivity. Numerous studies have examined platelet aggregation or platelet activation markers, e.g. P-selectin exposure, to establish a role for platelet reactivity. The results of these studies have, however, been inconsistent (2). Perhaps the technical procedures utilized are inadequate or perhaps aggregation and granule release do not reflect the most relevant aspects of platelet reactivity. Towards this goal of understanding the relationship between platelet reactivity and stroke susceptibility, the recent description of coated-platelets has allowed a unique and more quantitative approach to the evaluation of platelet reactivity. Coated-platelets are a subpopulation of activated platelets initially described in this laboratory (3). Formation of coatedplatelets requires simultaneous, dual agonist stimulation with both thrombin and collagen. Unlike single agonist activated platelets, the hallmark of coated-platelets is their coating of procoagulant proteins, including factor V, fibrinogen, fibronectin, thrombospondin, von Willebrand factor, and the expression of surface phosphatidylserine (3). The combination of bound procoagulant proteins and exposed phosphatidylserine defines the single most important characteristic of coated-platelets, their ability to support a robust prothrombinase activity. Because thrombin generation is the central event in coagulation, coated-platelets are very likely to be prothrombotic. In most individuals, the percentage of platelets converted into coated-platelets averages B30% (3); however, even among normal blood donors, there is a large range of coated-platelet potential (ca. 10–55%). The impact of a deficiency of coated-platelets has recently been documented in dogs where a rare bleeding diathesis was found to result from an absence of coated-platelet production (4). On the other hand, the consequences of over production of coated-platelets are still uncertain. Considering the prothrombotic profile of these platelets, it is logical to ask if elevated coated-platelet levels are a risk factor for thrombosis. It was with this background in mind that we investigated the role of coatedplatelets in ischemic stroke. In a recent study of 60 ischemic stroke patients, we measured coated-platelet levels in patients with lacunar vs. cortical stroke (5). The results showed a marked divergence in coated-platelet levels between the two subtypes of ischemic stroke. Compared with a population of controls (31.6713.2% coated-platelets; mean71 SD), patients with cortical stroke had higher levels of coated-platelets (39.4712.7%). This observation was consistent with our initial expectation that the prothrombotic nature of coated-platelets would result in their increased abundance in the thrombotic setting of ischemic stroke. What was unexpected was the low level of coated-platelets observed in patients with lacunar strokes (21.8711.4%), a level that is significantly below not only that of the cortical stroke patients but also that of the control population (5). A visual presentation of coated-platelet levels in ischemic stroke patients, distributed as quartiles, emphasizes the differences between lacunar and nonlacunar patients in terms of their coatedplatelet production (Fig. 1). While neurologists have known for some time that clinical, neuropathological and imaging features distinguish lacunar from nonlacunar strokes (6–9), biochemical support for these differences has been lacking. The observed divergence in coated-platelet levels between patients with lacunar vs. cortical stroke not only provides some of that missing biochemical evidence, but also suggests the existence of distinct mechanisms involved in the pathogenesis of these two stroke subtypes. Whether additional differences in coated-platelet levels reside Correspondence: George L. Dale , 941 Stanton Young Blvd, BSEB-302, Oklahoma City, OK 73104, USA. Tel: 1405 271 8541; e-mail: george-dale@ouhsc.edu VA Medical Center, Oklahoma City, OK, USA Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA