Stroke Classification: Critical Role of Unusually Large von Willebrand Factor Multimers and Tissue Factor on Clinical Phenotypes Based on Novel "Two-Path Unifying Theory" of Hemostasis.

Stroke is a hemostatic disease associated with thrombosis/hemorrhage caused by intracranial vascular injury with spectrum of clinical phenotypes and variable prognostic outcomes. The genesis of different phenotypes of stroke is poorly understood due to our incomplete understanding of hemostasis and thrombosis. These shortcomings have handicapped properly recognizing each specific stroke syndrome and contributed to controversy in selecting therapeutic agents. Treatment recommendation for stroke syndromes has been exclusively derived from the result of laborious and expensive clinical trials. According to newly proposed "two-path unifying theory" of in vivo hemostasis, intracranial vascular injury would yield several unique stroke syndromes triggered by 3 distinctly different thrombogenetic mechanisms depending upon level of intracranial intravascular injury and character of formed blood clots. Five major phenotypes of stroke occur via thrombogenetic paths: (1) transient ischemic attack due to focal endothelial damage limited to endothelial cells (ECs), (2) acute ischemic stroke due to localized ECs and subendothelial tissue (SET) damage extending up to the outer vascular wall, (3) thrombo-hemorrhagic stroke due to localized vascular damage involving ECs and SET and extending beyond SET to extravascular tissue, (4) acute hemorrhagic stroke due to major localized intracranial hemorrhage/hematoma into the brain tissue or space between the coverings of the brain associated with vascular anomaly or obtuse trauma, and (5) encephalopathic stroke due to disseminated endotheliopathy leading to microthrombosis within the brain. New classification of stroke phenotypes would assist in selecting rational therapeutic regimen for each stroke syndrome and designing clinical trials to improve clinical outcome.