Warfarin-associated hemorrhage and cerebral amyloid angiopathy - A geneticand pathologic study

Background: Intracerebral hemorrhage (ICH) is the most feared complication of warfarin therapy. The pathogenesis of this often-fatal complication rema ins obscure. Cerebral amyloid angiopathy (CAA) is a major cause of spontane ous lobar hemorrhage in the elderly and is associated with specific alleles of the APOE gene. Objective: To assess the role of CAA in warfarin-associa ted ICH. Methods: Clinical characteristics and APOE genotype were compared between 41 patients with warfarin-related ICH (from a cohort of 59 consecut ive patients aged greater than or equal to 65 years with supratentorial ICH on warfarin) and 66 randomly selected individuals aged greater than or equ al to 65 years without ICH taking warfarin. In addition, all neuropathologi c specimens from ICH patients were reviewed for the presence and severity o f CAA. Results: Hemorrhages tended to be in the lobar regions of the brain, and most (76%) occurred with an international normalized ratio of less tha n or equal to 3.0. The APOE epsilon 2 allele was overrepresented among pati ents with warfarin-associated lobar hemorrhage (allele frequency 0.13 versu s 0.04 in control subjects; p = 0.031). After controlling for other variabl es associated with ICH, carriers of the epsilon 2 allele had an OR of 3.8 ( 95% CI, 1.0 to 14.6) for lobar ICH. CAA was pathologically diagnosed as the cause of lobar hemorrhage in 7 of 11 patients with available tissue sample s. Conclusions: CAA is an important cause of warfarin-associated lobar ICH in the elderly. Although diagnosis of CAA before hemorrhage is not yet poss ible, these data offer hope that future patients at high risk for hemorrhag e may be identified before initiation of warfarin therapy.