Clinical Responses to Thrombolysis in Acute Ischemic Stroke, and the Importance of the Microvasculature

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The development of arterial recanalization strategies using plasminogen activators for treatment of atherothrombotic and thromboembolic cerebral ischemia has exposed events which contribute to the limitation and extension of tissue injury. These include the presence of early ishemic injury, individualization of the potential window for treatment, edema formation, and the mechanisms underlying the hemorrhagic transformation. The appearance of early ischemic injury and the potential window for treatment seem tied to the patency of collateral channels and peculiarities of the microvascular bed of the individual patient. Hemorrhagic transformation, a common accompaniment of focal cerebral ischemia, is related to the time from symptom onset to exposure with the plasminogen activator, persistence of diastolic hypertension, a relative plasminogen activator dose-rate, extensive ischemic injury on CT, anticoagulation, and advanced age. Limited evidence suggests that a threshold of regional cerebral blood flow reduction is significantly associated with symptomatic intracerebral hemorrhage. These contributors suggest a common vascular target. The microvasculature is both a source of cerebral integrity and the target of ischemic injury. Activation of microvascular endothelial cells by ischemia leads to the expression of P-selectin, ICAM-1, and E-selectin which promote PMN leukocyte firm adhesion and transmigration. Obstruction of microvascular flow is a consequence. Activation of platelets, in relationship to PMN leukocytes, and intravascular fibrin formation contribute further to the loss of microvascular patency. Within the myointima of selected microvessels the integrin α_vβ₃, appears. Constituents of the basal lamina and extracellular matrix, whose loss contributes to hemorrhagic transformation, are affected significantly within the initial 24 hours following ischemic injury. Recently, significant aletrations in cell-matrix interactions between the endothelium and astrocyte end-feet, and their respective matrix partners, have been shown to occur most significantly in the region of severest neuron injury. Interventions which reduce the frequency and severity of these microvascular processes should enhance benefit in acute stroke patients.