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

BACKGROUND: 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. OBJECTIVE: To assess the role of CAA in warfarin-associated ICH. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Plasma beta-amyloid peptide, transforming growth factor-beta 1, and risk for cerebral amyloid angiopathy.

Despite the documented association between apolipoprotein E genotype and cerebral amyloid angiopathy (CAA), a substantial proportion of CAA-related hemorrhages occur in patients without known risks for this disorder. Two other factors implicated in the pathogenesis of CAA are the amyloid-beta peptide (preferentially deposited in vessels as a 40-amino acid species) and the multifunctional cytokine transforming growth factor-beta 1 (a specific promoter of vascular amyloid deposition in transgenic models). We measured plasma concentrations of these factors in a series of 25 patients diagnosed with probable or definite CAA-related hemorrhage and compared them with 21 patients with hemorrhage due to probable hypertensive vasculopathy and 42 elderly control subjects without hemorrhage. We found no differences among the groups in concentrations of the 40- or 42-amino acid species of beta-amyloid or either the active or latent form of transforming growth factor-beta 1. While the data do not exclude important roles for these molecules as risks for CAA, they indicate that plasma measurements are not useful in its diagnosis.

Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage.

BACKGROUND: Recurrent lobar intracerebral hemorrhage is the hallmark of cerebral amyloid angiopathy. The factors that predispose patients to early recurrence of lobar hemorrhage are unknown. One candidate is the apolipoprotein E gene, since both the epsilon2 and the epsilon4 alleles of apolipoprotein E appear to be associated with the severity of amyloid angiopathy. METHODS: We performed a prospective, longitudinal study of consecutive elderly patients who survived a lobar intracerebral hemorrhage. The patients were followed for recurrent hemorrhagic stroke by interviews at six-month intervals and reviews of medical records and computed tomographic scans. RESULTS: Nineteen of 71 enrolled patients had recurrent hemorrhages during a mean follow-up period of 23.9+/-14.8 months, yielding a 2-year cumulative rate of recurrence of 21 percent. The apolipoprotein E genotype was significantly associated with the risk of recurrence. Carriers of the epsilon2 or epsilon4 allele had a two-year rate of recurrence of 28 percent, as compared with only 10 percent for patients with the common apolipoprotein E epsilon3/epsilon3 genotype (risk ratio, 3.8; 95 percent confidence interval, 1.2 to 11.6; P=0.01). Early recurrence occurred in eight patients, four of whom had the uncommon epsilon2/epsilon4 genotype. Also at increased risk for recurrence were patients with a history of hemorrhagic stroke before entry into the study (two-year recurrence, 61 percent; risk ratio, 6.4; 95 percent confidence interval, 2.2 to 18.5; P<0.001). CONCLUSIONS: The apolipoprotein E genotype can identify patients with lobar intracerebral hemorrhage who are at highest risk for early recurrence. This finding makes possible both the provision of prognostic information to patients with lobar hemorrhage and a method of targeting and assessing potential strategies for prevention.

MRI detection of new hemorrhages: potential marker of progression in cerebral amyloid angiopathy.

The authors used serial gradient-echo MRIs to detect new small hemorrhages in patients with previous lobar hemorrhage. Of 24 lobar hemorrhage patients (17 diagnosed with probable and 7 with possible amyloid angiopathy) who prospectively underwent repeat MRI 1.5 years after initial study, 9 (38%) demonstrated additional hemorrhages at follow-up. Interrater agreement was high. New hemorrhages were more frequent in patients with probable amyloid angiopathy (8 of 17, 47%) with more hemorrhages at baseline (p < 0.01). These results suggest a role for gradient-echo MRI in assessing disease progression in amyloid angiopathy.