title: Inherited DNA mutations contributing to thrombotic complications in patients with sickle cell disease.
abstract: Thrombosis may play an important role in the pathophysiology of certain complications of sickle cell disease (SCD), including stroke and avascular necrosis (AVN). Currently there is no laboratory or clinical parameter that can identify patients who are at highest risk of developing these thrombotic complications. We hypothesized that some patients with SCD have an inherited hypercoagulable state that results in an increased risk of developing stroke or AVN. We examined the role of two common inherited thrombophilic mutations that, in other populations, have been associated with arterial and venous thrombosis and are amenable to screening with DNA restriction enzyme analysis. The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and the C1565T mutation in the platelet glycoprotein IIIa (GPIIIa) gene were evaluated. We analyzed genomic DNA from 86 children and adults with SCD, including 16 patients with a history of a clinical stroke and 14 patients with AVN, for the presence of these mutations. The C677T MTHFR mutation was found in 19% of patients with stroke, 14% of patients with AVN, and 14% of patients with neither complication (P = NS). The C1565T GPIIIa mutation was found in 25% of patients with stroke, 14% of patients with AVN, and 18% of patients with neither complication (P = NS). Although each of these mutations is relatively common in patients with SCD, neither is independently associated with an increased risk of developing stroke or AVN.
authors.affiliation: Duke-UNC Comprehensive Sickle Cell Center, Duke University Medical Center, Durham, North Carolina 27710, USA. Zimme008@mc.duke.edu
authors.forename: S A
authors.initials: SA
authors.lastname: Zimmerman
authors.forename: R E
authors.initials: RE
authors.lastname: Ware
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications* / Q000235:genetics; D002561:Cerebrovascular Disorders / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005271:Femur Head Necrosis / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006811:Humerus / Q000473:pathology; D007511:Ischemia / Q000235:genetics / Q000473:pathology; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D009336:Necrosis; D010020:Osteonecrosis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics*; D017354:Point Mutation; D012306:Risk; D019851:Thrombophilia / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D017086:beta-Thalassemia / Q000150:complications / Q000235:genetics
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)