Claire S. Philipp

Age and the prevalence of bleeding disorders in women with menorrhagia.

OBJECTIVE: A study was conducted to evaluate the frequency and types of hemostatic defects occurring in adolescent and perimenopausal-age women diagnosed with menorrhagia. METHODS: A total of 115 women with a physician diagnosis of menorrhagia, including 25 adolescent women, 25 perimenopausal-age women, and 65 women between the ages of 20 and 44, underwent comprehensive hemostatic testing for possible bleeding disorders. Frequencies of bleeding disorders were calculated and compared. RESULTS: Forty-seven percent of women were found to have hemostatic abnormalities, including platelet dysfunction, von Willebrand’s disease, and coagulation factor deficiencies. Adolescents and perimenopausal-age women with menorrhagia were just as likely to have hemostatic abnormalities as were women aged 20 to 44. CONCLUSION: These results demonstrate that underlying bleeding disorders are frequently found in adolescent, postadolescent reproductive age, and perimenopausal-age women presenting with menorrhagia and suggest that women with menorrhagia should be considered for further hemostatic evaluation. LEVEL OF EVIDENCE: II-2

Multisite management study of menorrhagia with abnormal laboratory haemostasis: A prospective crossover study of intranasal desmopressin and oral tranexamic acid

The optimal management of menorrhagia among women with abnormal laboratory haemostasis is uncertain. In a crossover study, 116 women with menorrhagia [pictorial blood assessment chart (PBAC) score >100], negative gynaecological evaluation and abnormal laboratory haemostasis were randomly assigned to either intranasal desmopressin (IN‐DDAVP) or tranexamic acid (TA) therapy for two menstrual cycles. The subjects then crossed over to the second study drug for two additional cycles. Menstrual blood loss (MBL) was measured by PBAC scores at baseline and after each menstrual cycle. Quality of life (QOL) was assessed with four validated instruments. There was a statistically significant decrease in PBAC scores for both treatments. On average, the estimated decrease in the PBAC from baseline was −64·1 [95% confidence interval (CI) = −88·0, −40·3] for IN‐DDAVP and −105·7 (95% CI = −130·5, −81·0) for TA. The decrease in PBAC score was greater for TA than IN‐DDAVP (a difference of 41·6, P‐value = 0·0002, 95% CI = 19·6, 63·6). The test for treatment‐type effect was significant (P < 0·0001) suggesting a greater reduction in PBAC score with TA. Use of both IN‐DDAVP and TA improved QOL by all four instruments. We conclude that both medications reduced MBL and improved QOL among females with menorrhagia and abnormal laboratory haemostasis, but TA proved more effective.

Comparison of characteristics from White‐ and Black‐Americans with venous thromboembolism: A cross‐sectional study

When compared with Whites, Black‐Americans may have a 40% higher incidence venous thromboembolism (VTE) incidence. However, whether other VTE characteristics and risk factors vary by race is uncertain. To compare demographic and baseline characteristics among White‐ and Black‐Americans with VTE, we used data prospectively collected from consecutive consenting adults enrolled in seven Centers for Disease Control (CDC) Thrombosis and Hemostasis Centers from August 2003 to March 2009. These characteristics were compared among Whites (n = 2002) and Blacks (n = 395) with objectively diagnosed VTE, both overall, and by age and gender. When compared with Whites, Blacks had a significantly higher proportion with pulmonary embolism (PE), including idiopathic PE among Black women, and a significantly higher proportion of Blacks were women. Blacks had a significantly higher mean BMI and a significantly lower proportion with recent surgery, trauma or infection, family history of VTE, and documented thrombophilia (solely from reduced factor V Leiden and prothrombin G20210A prevalence). Conversely, Blacks had a significantly higher proportion with hypertension, diabetes mellitus, chronic renal disease and dialysis, HIV, and sickle cell disease. When compared with White women, Black women had a significantly lower proportion with recent oral contraceptive use or hormone therapy. We conclude that Whites and Blacks differ significantly regarding demographic and baseline characteristics that may be risk factors for VTE. The prevalence of transient VTE risk factors and idiopathic VTE among Blacks appears to be lower and higher, respectively, suggesting that heritability may be important in the etiology of VTE among Black‐Americans. Am. J. Hematol. 85:467–471, 2010

Development of a screening tool for identifying women with menorrhagia for hemostatic evaluation

OBJECTIVE A study was conducted to develop a short, easy to administer screening tool useful for stratifying women with unexplained menorrhagia for hemostatic testing for underlying bleeding disorders. STUDY DESIGN One hundred forty-six women with a physician diagnosis of menorrhagia underwent comprehensive hemostatic testing for the diagnosis of bleeding disorders, including von Willebrand disease, platelet dysfunction, and coagulation factor deficiencies. A 12 page questionnaire of bleeding symptoms was administered. Bleeding symptoms with high predictive values for laboratory hemostatic abnormalities were combined and used as single variables to calculate sensitivity, specificity, and positive and negative predictive values in order to develop a short screening tool to identify females for testing and evaluation. RESULTS A combination of 8 questions in 4 categories resulted in a sensitivity of 82% (95%CI 75-90) for bleeding disorders. Adding a pictorial blood assessment chart score > 100 increased the sensitivity of the screening tool to 95% (95%CI 91-99). CONCLUSION These results demonstrate the feasibility of a simple questionnaire based screening tool to identify females for testing and evaluation for bleeding disorders.

Evaluation and management of acute menorrhagia in women with and without underlying bleeding disorders: consensus from an international expert panel

Acute menorrhagia is a common gynecological disorder. Prevalence is high among women with inherited bleeding disorders and recent guidance for optimal management is lacking. Following a comprehensive review of the literature, an international expert panel in obstetrics, gynecology and hematology reached consensus on recommendations regarding the management of acute menorrhagia in women without a diagnosed bleeding disorder, as well as in patients with von Willebrand disease, platelet function disorders and other rare hemostatic disorders. The causes and predictors of acute menorrhagia are discussed and special consideration is given for the treatment of women on anticoagulation therapy. This review and accompanying recommendations will provide guidance for healthcare practitioners in the emergency management of acute menorrhagia.

Acquired factor VIII inhibitors in non‐haemophilic patients: clinical experience of 15 cases

Summary.  We retrospectively analysed 15 non‐haemophilic patients with acquired factor VIII inhibitors seen in our regional haemophilia centre. The median age was 55 years (range: 21–80). About 70% of patients older than 50 were male, while all five patients younger than 50 were female. The most common underlying condition was pregnancy or postpartum status (20%). About 27% of cases had no identifiable underlying condition. About 27% of patients had medical conditions that were unlikely to be related to acquired inhibitors. The most frequent presenting symptom was spontaneous haemorrhage of soft tissues, skin or joints. Twelve of 13 (92.3%) evaluable patients achieved complete remission (CR) with prednisone alone and/or combined prednisone and cyclophosphamide, but their clinical courses were highly variable. The median time to response was 21.5 weeks (range: 2–176) and the median treatment duration was 9 months (range: 1.25–66). All six patients treated with prednisone initially, and then combined prednisone/cyclophosphamide if no response (NR) to prednisone within 3–4 months (three patients), achieved CR; while four of five patients treated initially with combined prednisone/cyclophosphamide had CR. Patients older than 50 years had a similar response rate, median time to response and median treatment duration as did patients younger than 50 years (83% vs. 100%; 21.5 vs. 32 weeks, and 8 vs 16.5 months, respectively). Furthermore, the differences in the median time to response and treatment duration for patients with high or low baseline or peak inhibitor titres were negligible. Only one patient died of a treatment‐related pulmonary aspergillosis 18 months after an acquired inhibitor was diagnosed. None of these patients died of bleeding complications.

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.

Association of hemostatic factors with peripheral vascular disease.

Hemostatic risk factors have been well established in coronary artery disease but less well studied in peripheral vascular disease. The relationship of coagulation and fibrinolytic proteins to lower limb arterial occlusive disease and other vascular risk factors remains poorly defined. Fibrinogen, factor VII coagulant activity, von Willebrand factor (vWf) antigen, and plasminogen activator inhibitor-1 (PAI-1) activity were measured in 46 adult participants in the Arterial Disease Multiple Intervention Trial (ADMIT) and in 76 control subjects and related to ankle-brachial systolic pressure index (ABI), a measure of lower limb arterial stenosis. The primary inclusion criterion for the ADMIT study population was an average of two ABIs <0.85. Fibrinogen and PAI-1 in ADMIT subjects were significantly higher than in control subjects (331 +/- 52 mg/dl vs 273 +/- 46 mg/dl, p < 0.0001; 18.7 +/- 10 units/ml vs 13.5 +/- 8.9 units/ml, p < 0.04). There were significant correlations of fibrinogen with ABI, factor VII coagulant activity, and systolic and diastolic blood pressures; PAI-1 with body mass index and age; and factor VII coagulant activity with cholesterol levels. Logistic regression analysis, considering hemostatic variables and several known nonhemostatic risk factors of peripheral arterial disease, showed that fibrinogen and systolic blood pressure were independently associated with ABI status in this population. The results demonstrate a strong independent correlation between fibrinogen levels and the presence of lower limb arterial stenosis. PAI-1 levels were elevated in ADMIT participants, but multivariate analysis did not demonstrate an independent relationship between PAI-1 and ABI.

Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres

Summary.  Inherited bleeding disorders are especially problematic for affected girls and women due to the monthly occurrence of menstrual periods and the effects on reproductive health. Although heavy menstrual bleeding (HMB) is the most common manifestation, females with inherited bleeding disorders (FBD) experience other bleeding symptoms throughout the lifespan that can lead to increased morbidity and impairment of daily activities. The purpose of this article is to describe the utility of a female‐focused surveillance effort [female Universal Data Collection (UDC) project] in the United States Haemophilia Treatment Centres (HTCs) and to describe the baseline frequency and spectrum of diagnoses and outcomes. All FBD aged 2 years and older receiving care at selected HTCs were eligible for enrolment. Demographic data, diagnoses and historical data regarding bleeding symptoms, treatments, gynaecological abnormalities and obstetrical outcomes were analysed. Analyses represent data collected from 2009 to 2010. The most frequent diagnoses were type 1 von Willebrand’s disease (VWD) (195/319; 61.1%), VWD type unknown (49/319; 15.4%) and factor VIII deficiency (40/319; 12.5%). HMB was the most common bleeding symptom (198/253; 78.3%); however, 157 (49.2%) participants reported greater than four symptoms. Oral contraceptives were used most frequently to treat HMB (90/165; 54.5%), followed by desmopressin [1‐8 deamino‐D‐arginine vasopressin (DDAVP)] (56/165; 33.9%). Various pregnancy and childbirth complications were reported, including bleeding during miscarriage (33/43; 76.7%) and postpartum haemorrhage (PPH) (41/109; 37.6%). FBD experience multiple bleeding symptoms and obstetrical‐gynaecological morbidity. The female UDC is the first prospective, longitudinal surveillance in the US focusing on FBD and has the potential to further identify complications and reduce adverse outcomes in this population.

Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis

The aim of this study was to elucidate the fall in von Willebrand factor (VWF) and factor VIII activity (FVIII) after childbirth in women with and without von Willebrand disease (VWD). VWF:RCo, VWF:Ag, and FVIII were obtained in the third trimester of pregnancy, on admission for childbirth, and 10 times postpartum. Specimens were processed within 4 h and analysed centrally. Means were calculated at each time point. Forty women (40 pregnancies) without VWD and 32 women (35 pregnancies) with VWD were enrolled. 15/32 with VWD were treated (30% of those with type 1 and all of those with type 2) in 17 pregnancies. Treatments prior to delivery consisted of desmopressin (2/17), VWF concentrate (15/17) and after delivery VWF concentrate (16/17). Duration of treatment was 0–21 days (median 6). VWF levels peaked at 250% of baseline – 4 h postpartum in women with VWD and 12 h postpartum in women without VWD. Thereafter, VWF levels fell rapidly, approached baseline at 1 week and reached baseline at 3 weeks. Except immediately postpartum, when the levels among treated cases were higher, levels among women with VWD appeared to parallel, but were lower than those among women without VWD. Levels were lowest among those who received treatment. VWF levels fall rapidly after childbirth. Except immediately postpartum, current treatment strategies do not raise VWF levels to the levels of women without VWD or even to the levels of women with milder, untreated VWD. Consequently, women with VWD may be at risk of postpartum haemorrhage despite treatment.