Abstract

Primary hemorrhagic stroke is an uncommon but serious complication of sickle cell disease (SCD) with mortality from 20 to 65%. Proposed risk factors include previous ischemic stroke, aneurysms, low steady-state hemoglobin, high steady-state leukocyte count, acute chest syndrome, and transfusion. We performed a retrospective case-control study to evaluate risk factors for primary hemorrhagic stroke in adults (age >18 years) with SCD from Johns Hopkins and Barnes- Jewish Hospitals and Duke University Medical Center from January 1989 to April 2008. Cases had SCD and intraparenchymal (IPH), subarachnoid (SAH), or intraventricular (IVH) hemorrhage confirmed by neuroimaging or analysis of cerebrospinal fluid; traumatic hemorrhages and hemorrhagic conversion of ischemic strokes were excluded. Controls had SCD and ischemic stroke (focal neurological deficits with corresponding cerebral infarcts by neuroimaging). Both were identified by searching the hospital discharge database using ICD-9 codes for acute stroke and SCD and reviewing divisional records. We compared continuous variables by Student’s t-test and calculated odds ratios with exact methods. We identified 19 cases (mean age 29 years, range 18 – 66, 42% male) and 18 controls (mean age 34 years, range 19 – 61, 39% male). Most cases (14/18) had sickle cell anemia (HbSS) and 22% had a prior overt stroke; controls had HbSS (9/17), HbSB0thalassemia (1), or HbSC (7) and 41% had a history of overt stroke. Cases presented with headache (89%) and seizure (37%) and less frequently hemiparesis (27%). Controls presented with hemiparesis (78%), headache (57%), and rarely seizure (11%). Twelve cases had IPH including those with extension to the ventricles (1), subarachnoid (2) or both (2); six had SAH including ventricular extension (1). Potential causes of hemorrhagic stroke included moyamoya (4), aneurysms (3), anticoagulation (1) and ateriovenous malformation (1). Four cases (21%) and no controls died during the initial hospitalization. More cases (82%) than controls (44%, P<0.05) had elevated systolic blood pressure at the time of stroke. At steady-state, cases had lower hemoglobin (mean ± SEM 8.5 ± 0.6 g/dl vs. 9.7 ± 0.6 g/dl), lower blood pressures (systolic 121 ± 4 vs. 127 ± 6 mm Hg, diastolic 71 ± 4 vs. 72 ± 9 mm Hg) and higher platelet counts (399,231 ± 74,024/ul vs. 362,200/ul ± 39,927/ul) than controls, but these differences were not statistically significant. Mean hemoglobin concentration at the time of stroke increased 1.3 g/dl (19%) from steady-state in cases and 0.01 g/dl (2%) in controls (p<0.05). Seven cases had simple transfusions (between 1 and 11 days before their primary hemorrhagic stroke) in preparation for surgery (3), and for aplastic crisis (1), bacteremia (1), acute renal failure (1), or suspected acute chest syndrome (1). Only 1 control was transfused; and 1 with HbSS had a hemoglobin of 14.5 g/dl at the time of stroke (from excessive erythropoietin administration). In this group of adults with SCD, primary hemorrhagic stroke was associated with antecedent transfusion. Identifiable causes include moyamoya from obstructive cerebral vasculopathy, aneurysms and other vascular malformations, and rarely coagulopathy. Mortality was similar to that previously described. The association of recent transfusion and cerebral vasculopathy with hemorrhagic stroke suggests caution in the use of simple transfusion in adults with SCD and moyamoya or cerebral aneurysms.

Table 1: Associations with Primary Hemorrhagic Stroke

Variable Odds Ratio (95% CI) P-value 
Genotype (HbSS vs. other) 3 (0.6 – 17) NS 
Moyamoya 5 (0.4 – 260) NS 
Transfusion in the last 14 days 13 (1.3 – 630) <0.02 
NSAID in the last 14 days 2.9 (0.3 – 36) NS 
Variable Odds Ratio (95% CI) P-value 
Genotype (HbSS vs. other) 3 (0.6 – 17) NS 
Moyamoya 5 (0.4 – 260) NS 
Transfusion in the last 14 days 13 (1.3 – 630) <0.02 
NSAID in the last 14 days 2.9 (0.3 – 36) NS 

Disclosures: No relevant conflicts of interest to declare.

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