Warfarin-associated hemorrhage and cerebral amyloid angiopathy: a genetic and pathologic study

Intracerebral hemorrhage (ICH) is the most feared complication of warfarin therapy. The pathogenesis of this often-fatal complication remains obscure. Cerebral amyloid angiopathy (CAA) is a major cause of spontaneous lobar hemorrhage in the elderly and is associated with specific alleles of the APOE gene.

To assess the role of CAA in warfarin-associated ICH.

Clinical characteristics and APOE genotype were compared between 41 patients with warfarin-related ICH (from a cohort of 59 consecutive patients aged > or = 65 years with supratentorial ICH on warfarin) and 66 randomly selected individuals aged > or = 65 years without ICH taking warfarin. In addition, all neuropathologic specimens from ICH patients were reviewed for the presence and severity of CAA.

Hemorrhages tended to be in the lobar regions of the brain, and most (76%) occurred with an international normalized ratio of < or = 3.0. The APOE epsilon2 allele was overrepresented among patients with warfarin-associated lobar hemorrhage (allele frequency 0.13 versus 0.04 in control subjects; p = 0.031). After controlling for other variables associated with ICH, carriers of the epsilon2 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 samples.

CAA is an important cause of warfarin-associated lobar ICH in the elderly. Although diagnosis of CAA before hemorrhage is not yet possible, these data offer hope that future patients at high risk for hemorrhage may be identified before initiation of warfarin therapy.