Sidney F. Stein

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.

Analysis of Twenty-three Plasma Proteins in Ascites The Depletion of Fibrinogen and Plasminogen

The concentrations of 23 plasma proteins were measured by radial immunodiffusion in the plasma and ascites of 17 patients with cirrhosis and four patients with intraperitoneal malignancies, to learn whether there is a selectivity in the movement of proteins from plasma into ascites, analogous to that of proteinuria. Additionally, since some of the proteins are involved in coagulation, we hoped to clarify the coagulopathy frequently seen following peritoneovenous shunting of ascites. Analysis was by groups: group 1 consisted of nine patients with cirrhosis with an ascites-total protein content less than 2.5 g/dl; group 2 consisted of eight patients with cirrhosis with ascites-total protein content greater than or equal to 2.5 g/dl; and group 3 consisted of four patients with malignant ascites. The ratio of the plasma concentration/ascites concentration ([P]/[A]) for each protein was calculated for each patient. In each group the median [P]/[A] for each protein was plotted against the natural logarithm of its molecular weight (In MW). For 21 of the 23 proteins, [P]/[A] showed a close linear relationship to In MW. Fibrogen and plasminogen showed significant (p < 0.0002) elevation above the regression line relating [P]/[A] to In MW. This indicates depletion of fibrinogen and plasminogen in ascites. The ascites in group 1 showed moderate selectivity, defined as the slope of the regression line (1.59), while groups 2 and 3 were essentialy nonselective (0.35 and 0.50). Fibrin-split products were elevated in all ascites but not in plasma, indicating either fibrinolysis or fibrinogenolysis within the ascites. A normal ratio for prothrombin suggests fibrinogenolysis may be the dominant mechanism. Thus the coagulopathy induced by LeVeen valve insertion may be in part secondary to the infusion of plasmin or a plasminogen activator into the circulation.

The spectrum of haemostatic characteristics of women with unexplained menorrhagia

Summary.  While an estimated 13% of women with unexplained menorrhagia have von Willebrand disease (VWD), the frequency of other potential bleeding disorders has been uncertain. This study describes the relatively wide range of laboratory characteristics of women with unexplained menorrhagia and presents issues affecting diagnosis in this population. Women with pictorial blood assessment chart (PBAC) score >100 were identified at six U.S. sites and asked to remain drug free for 10 days prior to testing. Blood was collected on one of the first four menstrual cycle days and tested at a central laboratory for procoagulant factors, VWD and fibrinolytic factors. Platelet function testing by PFA‐100® (PFA) and platelet aggregation with ATP release (PAGG/ATPR) were performed locally using standardized methods. Among 232 subjects, a laboratory abnormality was found in 170 (73.3%), including 124 of 182 White (68.1%) and 34 of 37 Black (91.9%) subjects; 6.0% had VWD, 56.0% had abnormal PAGG/ATPR, 4.7% had a non‐VWD coagulation defect (NVCD) and 6.5% had an abnormal PFA only. AGG/ATPR was reduced in 58.9% of subjects, with multiple agonists in 28.6%, a single agonist in 6.1% and ristocetin alone in 24.2%. Frequencies of PAGG/ATPR defects varied by study site and race; frequencies of VWD and NVCD were similar. Laboratory abnormalities of haemostasis, especially platelet function defects, were common among women with unexplained menorrhagia across multiple U.S. sites. To what degree these abnormalities are clinically significant requires further study.

Evaluation of a screening tool for bleeding disorders in a US multisite cohort of women with menorrhagia.

OBJECTIVE The purpose of this study was to determine the usefulness of a simple screening tool for bleeding disorders in a multisite population of women with menorrhagia. STUDY DESIGN Women with menorrhagia between the ages of 18 and 50 years from 6 geographically diverse US centers underwent hemostatic testing for bleeding disorders, complete blood cell count, and ferritin. A questionnaire that contained all elements of the 8-question screening tool was administered. Sensitivity of the screening tool, a screening tool with a pictorial blood assessment chart (PBAC) score of >185, and a screening tool with serum ferritin were calculated for hemostatic disorders. RESULTS Two hundred and seventeen women who were identified with a PBAC score of ≥100 participated in the study. The sensitivity of the screening tool was 89% for hemostatic defects, and sensitivity increased to 93% and 95% with a serum ferritin level of ≤20 ng/mL and a PBAC score of >185, respectively. CONCLUSION This study confirms the usefulness of a short screening tool for the stratification of women with menorrhagia for hemostatic evaluation.

Gender, Race, and Diet Affect Platelet Function Tests in Normal Subjects Contributing to a High Rate of Abnormal Results

To assess sources of variability in platelet function tests in normal subjects, 64 healthy young adults were tested on 2–6 occasions at 2 week intervals using four methods: platelet aggregation (AGG) in platelet‐rich plasma (PRP) in the Bio/Data PAP‐4 Aggregometer (BD) and Chrono‐Log Lumi‐Aggregometer (CL); and AGG in whole blood (WB) in the CL and Multiplate Platelet Function Analyser (MP), with ATP release (REL) in CL‐PRP and CL‐WB. Food and medication exposures were recorded prospectively for 2 weeks prior to each blood draw. At least one AGG abnormality was seen in 21% of 81 drug‐free specimens with CL‐PRP, 15% with CL‐WB, 13% with BD‐PRP and 6% with MP‐WB, increasing with inclusion of REL to 28% for CL‐PRP and 30% for CL‐WB. Epinephrine AGG and REL were significantly reduced in males (P < 0·0001). Ristocetin AGG and collagen and thrombin REL were significantly reduced in Blacks (P < 0·0001). One‐third of specimens drawn following flavonoid‐rich food exposures had aberrant results, compared to 8·5% of specimens without such exposures (P = 0·0035). PRP tests had less intra‐individual variation than WB tests. Gender, race, diet and test system affected results of platelet function testing in healthy subjects, suggesting caution when interpreting the results of platelet function testing in patients.

Bone density in haemophilia: a single institutional cross-sectional study.

Haemophilia has been associated with low bone mineral density (BMD). However, prior clinical studies of this population have neither clearly elucidated risk factors for development of low BMD nor identified who may warrant screening for osteoporosis. The aim of the study was to evaluate the relationship between BMD and haemophilic arthropathy and other demographic and clinical variables. We undertook a cross‐sectional study of BMD in adult men with haemophilia. Measures of predictor variables were collected by radiographic studies, physical examination, patient questionnaires and review of medical records. Among 88 enrolled subjects, the median age was 41 years (IQR: 20); median femoral neck BMD (n = 87) was 0.90 g cm−2 (IQR: 0.24); and median radiographic joint score was 7.5 (IQR: 18). Among subjects <50 years (n = 62), after controlling for BMI, alcohol, HIV and White race, BMD decreased as radiographic joint score increased (est. β = −0.006 mg cm−2; 95% CI −0.009, −0.003; partial R2 = 0.23). Among subjects ≥50 years (n = 26), 38% had osteoporosis (T score less than or equal to −2.5) and there was no association between BMD and arthropathy. Risk factors for low BMD in men with haemophilia <50 years include haemophilic arthropathy, low or normal BMI and HIV. Men with haemophilia over age 50 years should have routine screening for detection of osteoporosis.

Physical activity and functional abilities in adult males with haemophilia: a cross-sectional survey from a single US haemophilia treatment centre.

Physical activity and functional ability are important determinants of quality of life and these metrics are affected by both haemophilia and ageing. Outside haemophilic arthropathy, risk factors leading to reduced physical activity and function in people with haemophilia (PWH) are under‐explored. The purpose of this analysis was to determine risk factors for reduced physical activity and functional limitations in PWH. A secondary analysis was conducted on data indexing physical activity and functioning of 88 PWH using data originally collected as part of a cross‐sectional study at a single large haemophilia treatment centre. The Framingham Physical Activities Index (PAI), the Hemophilia Activities List (HAL) and the Timed Up‐and‐Go Test (TUG) were the outcome measures. The World Federation of Haemophilia (WFH) orthopaedic joint score was used as a measure of arthropathy. Multiple linear regression analysis was used to assess the relationship between the outcome measures and covariates. Worsening WFH joint score was independently associated with all three outcome measures (P < 0.05). Increasing age was associated with reduced PAI and increased TUG time (P < 0.05). The HAL summary score was decreased in patients with chronic liver disease (P = 0.006). The adjusted R2 for each model was ≤0.35. This study provides evidence for the relationship between arthropathy and reduced physical functioning/activity, but also highlights that much of the variation in physical functioning/activity is not explained by haemophilia‐related characteristics.

Distress in patients with bleeding disorders: a single institutional cross-sectional study.

Distress may affect a patients ability to cope with and manage disease.

Physician trust and depression influence adherence to factor replacement: a single‐centre cross‐sectional study

Poor adherence to factor replacement therapy among patients with haemophilia can lead to joint bleeding and eventual disability.

Viral infections among patients with hemophilia in the state of Georgia.

This analysis evaluated the extent to which infections with selected blood‐borne viruses, specifically infection with hepatitis B virus, hepatitis C virus, and/or the human immunodeficiency virus (HIV), continue to contribute to the morbidity of persons with hemophilia. The Georgia Hemophilia Surveillance System collected information on 336 state residents with hemophilia A or B who were followed by a physician in 1994. Data abstracted from medical records included information on demographics, sources of hemophilia care, clinical characteristics, joint range of motion measurements, hospitalization, and results of laboratory testing for hepatitis B, hepatitis C, and the human immunodeficiency virus. Prevalence of infection with one or more of these viruses was determined, and relationships with disease severity, bleeding frequency, and amount of clotting factor prescribed were explored. No child under the age of ten was positive for the human immunodeficiency virus; hepatitis infection was also uncommon in this age group, in contrast to the very high frequency of such infections among older subjects. There was a strong association between HIV positive status and infection with one of the hepatitis viruses. The likelihood of all types of viral infection increased with frequency of bleeding and with amount of clotting factor received. Efforts to prevent transmission of lipid‐enveloped viruses via clotting factor have been extremely effective. However, currently infected hemophilia patients will likely experience significant morbidity and mortality due to chronic liver disease and AIDS‐related complications. Am. J. Hematol. 59:36–41, 1998.