Anne Dilley

von Willebrand disease and other inherited bleeding disorders in women with diagnosed menorrhagia

Objective To estimate the prevalence of von Willebrand disease and other bleeding disorders in women with and without diagnosed menorrhagia. Methods Women with menorrhagia were identified among members of a health maintenance organization in the southeastern United States through a computer search for appropriate International Classification of Diseases, 9th Revision codes. A random sample of members with no such code was selected as controls. The study included 121 women with menorrhagia and 123 controls. Subjects were interviewed in person, and blood was drawn for coagulation testing. Laboratory results for menorrhagia patients were compared with those in controls using race and blood type specific ranges developed from the control group. A test was considered abnormal if it exceeded two standard deviations below the control mean. Results Bleeding disorders (von Willebrand disease, factor deficiency, or a platelet abnormality) were diagnosed in 10.7% of menorrhagia patients and 3.2% of controls (P = .02). von Willebrand disease was present in eight menorrhagia patients (6.6%) and in one control (0.8%) (P = .02); separate analyses by race revealed a von Willebrand disease prevalence of 15.9% among white and 1.4% among black menorrhagia patients (P = .01). Women with bleeding disorders did not differ significantly from controls in other symptoms of bleeding. Conclusion The prevalence of inherited bleeding disorders among white women with menorrhagia was substantial, consistent with European data published recently. For unknown reasons, the prevalence of von Willebrand disease was lower among black women. These findings indicate the importance of considering inherited bleeding disorders as a cause of menorrhagia.

Platelet functional defects in women with unexplained menorrhagia

Summary.  Menorrhagia is a common clinical problem and is unexplained in more than 50% of women. Although studies suggest that von Willebrands Disease (VWD) is found in a substantial number of women with unexplained menorrhagia, the prevalence of platelet defects in women with menorrhagia is unknown. To determine the prevalence of platelet and other hemostatic defects, we evaluated women ages 17–55 diagnosed with unexplained menorrhagia. Seventy‐four women (52 white, 16 black, six other) were studied. Bleeding time was prolonged in 23 women (31.5%). Maximal percent platelet aggregation was decreased with one or more agonists in 35 (47.3%) women. The most commonly found platelet function defects were reduced aggregation responses to ristocetin in 22 women and to epinephrine in 16 women. Sixteen of 22 women with reduced ristocetin aggregation had von Willebrand ristocetin cofactor (VWF:RCo) and von Willebrand factor antigen (VWF:Ag) > 60%. Platelet ATP release was decreased with one or more agonists in 43 (58.1%) women. Of the black women studied, 11/16 (69%) had abnormal platelet aggregation studies compared with 20/52 white women (39%) (P = 0.06). Black women with menorrhagia had a higher prevalence of decreased platelet aggregation in response to ristocetin and epinephrine than did white women (P = 0.0075, P = 0.02). Ten women (13.5%) had VWF:RCo and/or VWF:Ag < 60%. Using race and blood group specific ranges, 5 (6.8%) women had decreased VWF:RCo, VWF:Ag and/or collagen binding (VWF:CB). Mild factor XI deficiency was found in two women and one woman with mild factor V deficiency and one hemophilia A carrier were identified. We conclude that the prevalence of platelet function defects and other inherited bleeding disorders is substantial in a multiracial US population of women with unexplained menorrhagia.

The epidemiology of venous thromboembolism in Caucasians and African-Americans: the GATE Study.

Summary.  The aim of this study was to assess, comprehensively, medical and genetic attributes of venous thromboembolism (VTE) in a multiracial American population. The Genetic Attributes and Thrombosis Epidemiology (GATE) study is an ongoing case–control study in Atlanta, Georgia, designed to examine racial differences in VTE etiology and pathogenesis. Between 1998 and 2001, 370 inpatients with confirmed VTE, and 250 control subjects were enrolled. Data collected included blood specimens for DNA and plasma analysis and a medical lifestyle history questionnaire. Comparing VTE cases, cancer, recent surgery, and immobilization were more common in caucasian cases, while hypertension, diabetes, and kidney disease were more prevalent in African‐American cases. Family history of VTE was reported with equal frequency by cases of both races (28–29%). Race‐adjusted odds ratios for the associations of factor V Leiden and prothrombin G20210A mutations were 3.1 (1.5, 6.7) and 1.9 (0.8, 4.4), respectively. Using a larger external comparison group, the odds ratio for the prothrombin mutation among Caucasians was a statistically significant 2.5 (1.4, 4.3). A case‐only analysis revealed a near significant interaction between the two mutations among Caucasians. We found that clinical characteristics of VTE patients differed across race groups. Family history of VTE was common in white and black patients, yet known genetic risk factors for VTE are rare in African‐American populations. Our findings underscore the need to determine gene polymorphisms associated with VTE in African‐Americans.

Measurement of von Willebrand factor activity: relative effects of ABO blood type and race

Summary.  Tests based on three different principles are reported to measure the activity of von Willebrand factor (VWF): ristocetin cofactor (VWF:RCo), collagen binding (VWF:CB), and the so‐called ‘activity ELISA’ (VWF:MoAb). We measured these and other diagnostic parameters in a population of 123 randomly selected female study controls, age 18–45 years. Type O subjects had significantly lower levels than non‐O subjects in each test. Race differences were seen in all tests except VWF:RCo, with Caucasians having significantly lower levels than African‐Americans. ABO differences accounted for 19% of the total variance in VWF:Ag (P < 0.0001) and race for 7% (P < 0.0001), for a total of 26%. Both effects were mediated through VWF:Ag and were independent. VWF:Ag level was the primary determinant of VWF function, accounting for approximately 60% of the variance in VWF:RCo and VWF:CB and 54% of the variance in factor VIII. The ratio VWF:RCo/VWF:Ag differed significantly by race within blood group. The median ratios were 0.97 for type O Caucasians vs. 0.79 for type O African‐Americans and 0.94 for non‐O Caucasians vs. 0.76 for non‐O African‐Americans. The ratio VWF:CB/VWF:Ag did not vary. This suggests racial differences in the interaction of VWF with GP1b but not with subendothelium. Alternatively, VWF:RCo may be regulated to maintain a relatively constant plasma level in the presence of excessive VWF:Ag. This heterogeneity within the normal population is partially responsible for the difficulty in defining diagnostic limits for von Willebrand disease.

The Role of the t-PA I/D and PAI-1 4G/5G Polymorphisms in African-American Adults With a Diagnosis of Myocardial Infarction or Venous Thromboembolism

To determine whether or not the PAI-1 4G/5G and t-PA I/D polymorphisms in African-Americans were linked to cardiovascular disease, the association of these polymorphisms to disease expression was analyzed in a recently completed case-control study of myocardial infarction or venous thromboembolism among African-Americans. All African-Americans patients with a history of venous thromboembolism attending an anticoagulant clinic, and patients with a history of a MI attending a cardiology clinic at a large local urban public hospital were eligible for inclusion as cases in the study. In this study it was observed that there was a statistically significant association between the D allele of the t-PA I/D polymorphism and venous thromboembolism and a nonsignificant association between the D allele and myocardial infarction among African-Americans. t-PA antigen levels were statistically significantly higher among both myocardial infarction and venous thromboembolism cases compared with control subjects. The genotypes were unrelated to t-PA plasma levels. There was no association between either myocardial infarction or venous thromboembolism and the 4G/5G PAI-1 genotype. It was also found that genotype frequencies for both PAI-1 4G/5G and t-PA I/D polymorphisms in African-American adults were different from those reported for both U.S. Causcians and Europeans.

Screening women with menorrhagia for underlying bleeding disorders: the utility of the platelet function analyser and bleeding time

Summary.  Menorrhagia is a very common clinical problem among women of reproductive age and recent studies have suggested that underlying bleeding disorders, particularly von Willebrands deficiency and platelet function defects, are prevalent in women presenting with menorrhagia. The objective of this study was to determine the utility of the platelet function analyser (PFA‐100) and bleeding time (BT) as initial screening tests for underlying bleeding disorders in women with menorrhagia. In this study, 81 women with a physician diagnosis of menorrhagia underwent PFA‐100 testing, BT and comprehensive haemostatic testing. The effectiveness of the PFA‐100 and BT as screening tools in women with menorrhagia was assessed using results of haemostatic testing for von Willebrands disease (VWD) and platelet dysfunction. In women presenting with menorrhagia, the PFA‐100 had a sensitivity 80%, specificity 89%, positive predictive value (PPV) 33%, negative predictive value (NPV) 98% and efficiency 88% for VWD. For platelet aggregation defects, the PFA‐100 closure time had a sensitivity 23%, specificity 92%, PPV of 75%, NPV of 52% and efficiency 55%. The data suggest that the PFA‐100 may be useful in stratifying women with menorrhagia for further von Willebrand testing; however, neither the PFA‐100 nor the BT tests are effective for purposes of classifying women for standard platelet aggregometry testing in women presenting with menorrhagia.

Mutations in the Genes Regulating Methylene Tetrahydrofolate Reductase (MTHFR C→T677) and Cystathione β-Synthase (CBS G→A919, CBS T→c833) Are Not Associated with Myocardial Infarction in African Americans

Moderate hyperhomocysteinemia is a putative risk factor for cardiovascular disease. Molecular studies have demonstrated increased plasma homocysteine levels in the presence of DNA mutations in either the methylenetetrahydrofolate reductase (MTHFR) enzyme found in the remethylation pathway or the enzyme cystathione beta-synthase (CBS) of the transsulfuration pathway. To determine whether the mutation C-->T677 in the MTHFR gene or the T-->C833/844ins68 and G-->A919 mutations in the CBS gene are associated with myocardial infarction (MI) in African Americans, DNA was analyzed from samples obtained from a case-control study conducted at a large, inner-city hospital. One-hundred ten African American subjects with a diagnosis of MI and 185 race- and age-matched controls were recruited. Our results demonstrated that 15% of the MI cases were heterozygous for the C-->T677 (MTHFR) mutation, while 1.8% were homozygous. When compared to the controls in which 15% were heterozygous and 2.1% were homozygous, no significant association with MI was observed. In addition, 34% of the cases were heterozygous for the T-->C833 (CBS) mutation while 6% were homozygous. This is compared to 32% and 5% of the controls having the heterozygous and homozygous genotype, respectively. No significant association was observed for the T-->C833 (CBS) mutation among the cases and controls. Although this mutation has no significant association with MI, the prevalence of the heterozygous state was higher than what has been reported for whites (12%). No mutations for G-->A919 (CBS) were detected in the cases or controls. The racial differences of the CBS T-->C833 polymorphism suggest that further investigation into the other areas of the CBS gene is needed.