The World Federation of Hemophilia Annual Global Survey 1999-2018.

INTRODUCTION: The World Federation of Hemophilia (WFH) strives to achieve care for all patients with inherited bleeding disorders through research, advocacy, capacity building and education. The WFH developed and implemented the Annual Global Survey (AGS), through which comprehensive demographic and treatment data on bleeding disorders are collected each year from its constituent non-governmental national organizations. AIM: To describe the development, methodology and achievements of the WFH AGS over the past 20 years. METHODS: The AGS is a yearly cross-sectional survey. Data are collected using a standardized form (available online and on paper), quality checked and reviewed, and published in English, French and Spanish. Over time, the AGS has been modified in response to changes in treatment landscape or emerging new issues. RESULTS: Over the past 20 years, the AGS has reported an increase in the number of countries participating in the survey, a tripling in the number of people identified with rare bleeding disorders and an increase in the amount of factor used to treat people with haemophilia. Yet, a large treatment inequity gap still exists across the globe. In response to this gap, the WFH has analysed the AGS reports which has stimulated further development in quality of care indicators, estimates of the global prevalence of haemophilia, patient-level data collection efforts like the World Bleeding Disorders Registry and the Gene Therapy Registry. CONCLUSION: The AGS has provided evidence to support research, programme planning and development activities of the WFH.

Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.

BACKGROUND: Effective ways to prevent arthropathy in severe hemophilia are unknown. METHODS: We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor VIII (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totaling a minimum of 80 IU of factor VIII per kilogram of body weight at the time of a joint hemorrhage. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees, and elbows) by radiography or magnetic resonance imaging (MRI). RESULTS: Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P=0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups. CONCLUSIONS: Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597 [ClinicalTrials.gov].).

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.

Infectious disease in the blood supply and the public health response.

The consistent improvements in hemophilia care seen in the years 1960 to 1980 halted when human immunodeficiency virus (HIV) appeared in the blood supply. In the early 1980s, before HIV virulence was fully understood, a complacent blood therapy industry and its regulators waffled on an appropriate response. As a result, the period between the appearance of HIV and its effective elimination from the blood supply was lengthy and many recipients of blood therapies became infected, with devastating impact on their quality of life, quality of care, and longevity. As the decade wore on, even as they began to better understand the threat, industry and public health officials continued to stall, in part because development of interventions was costly and cumbersome. In order to protect the safety of the blood supply and blood-derived therapies, it must be recognized that new pathogens will continue to emerge. Agencies' and companies' decision-making processes in this regard must therefore be proactive rather than reactive, and should preferably implement a formalized risk-management approach. The ongoing safety of blood therapies and the blood supply will also depend on continued vigilance and research. Finally, the hemophilia community must be allowed to play an active and educated role in their own care.

Elevated factor VII as a risk factor for recurrent fetal loss. Relationship to factor VII gene polymorphisms.

Haemostatic abnormalities can be detected in a portion of the women who have recurrent fetal loss. We measured factor VII coagulant activity (FVII:C) in 65 women with 3 or more fetal losses (recurrent cases), 31 women with one 2nd or 3rd trimester loss (late loss cases), and 81 women with only live births (controls). FVII:C was greater than 2 standard deviations above the mean for controls in 9 recurrent cases (13.8%) and 2 controls (2.5%) for an odds ratio of 6.35 (95% CI 1.32-30.52, p=0.012). In recurrent cases, mean levels were significantly higher than controls for FVII:C (p=0.003), FVII antigen (p=0.024), and FVIIa (p=0.001). Late loss cases had an odds ratio of 4.23 (95% CI 0.67-26.67, p=0.098) with FVII:C, FVII antigen, and FVIIa not significantly different from the controls. DNA was examined for the presence of mutations or polymorphisms in the promoter region of the FVII gene, using denaturing HPLC. Abnormal patterns were confirmed with direct sequencing. A previously reported polymorphism, -402 G>A, was found to be present in 11/14 subjects with elevated FVII:C (79%) and 43% of those with normal levels (p=0.029). FVII:C, FVII antigen and FVIIa varied significantly with genotype; however, genotype frequencies did not differ between controls and either case group. No other promoter polymorphisms were identified. This is the first report of a significant elevation of FVII in a population with recurrent fetal loss. These data suggest the need for further investigation of this potential risk factor.

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.

HIV Infection and thrombocytopenia.

Thrombocytopenia is a common complication of HIV infection. The low platelet count can be caused by multiple mechanisms including immune-mediated destruction, decreased platelet production, effects of drugs on progenitors, or by the development of a form of thrombotic thrombocytopenic purpura (TTP). Bleeding problems associated with the thrombocytopenia can be accentuated by the presence of platelet dysfunction produced by drugs used to treat HIV/AIDs or its complications. Therapy should be directed at reducing the load of the HIV virus of the patient supplemented by other therapies chosen depending on the specific underlying cause.

Cryptogenic stroke in relation to genetic variation in clotting factors and other genetic polymorphisms among young men and women.

BACKGROUND AND PURPOSE: The purpose of the present study was to compare the prevalences of genetic polymorphisms in persons with cryptogenic stroke with those among stroke patients with evidence of large-artery occlusive disease or an unequivocal cardioembolic source (noncryptogenic stroke). METHODS: We compared the prevalences of genetic polymorphisms thought to be related to thrombi formation in young stroke patients with evidence of large-artery occlusive disease or an unequivocal cardioembolic source (noncryptogenic stroke; controls; n=79) with those in young stroke patients without such sources (cryptogenic stroke; cases; n=67). Common variations in the genes encoding factor V, prothrombin, angiotensin I-converting enzyme, 5,10-methylenetetrahydrofolate reductase, endothelial cell nitric oxide synthase, tissue plasminogen activator, plasminogen activator inhibitor-1, and fibrinogen were evaluated. We also compared the allele prevalence of these genes among all stroke patients with those among a large pool of historical controls assayed for these genes. RESULTS: None of these genetic polymorphisms was statistically significantly related to cryptogenic stroke. With respect to a comparison of all ischemic stroke with historical controls, only the prevalence of tissue plasminogen activator D allele among stroke subjects was statistically significantly higher than that of the historical controls (P=0.0014). CONCLUSIONS: These findings generally do not support the hypothesis that genes associated with a prothrombotic state are risk factors among a subgroup of young people with stroke of undetermined cause. Except for the D tissue plasminogen activator allele, the findings also indicated that these genetic factors are unrelated, or only weakly related, to all ischemic stroke.

Demographics of hemophilia in developing countries.

Demographic datasets pertaining to populations are extremely valuable tools in healthcare planning. They are vital in setting priorities, allocation of resources, measurement of outcomes, and comparison of alternate approaches. Countries with emerging economies especially need information regarding targeted populations when initiating programs designed to deliver care to persons with chronic conditions such as hemophilia. The problems associated with data collection in these countries are huge but surmountable. The World Federation of Haemophilia (WFH) Global Survey provides a valuable synopsis of current global data on hemophilia patients and has provided insight into the extent of the problem with hemophilia worldwide. More and more countries recognize the uses of these data and have established or are in the process of establishing registries for persons with hemophilia to try and improve the quality of the information provided to the WFH. This information will most certainly assist in guiding the future of hemophilia care in these countries with emerging economies.

Prevalence and risk factors for heart disease among males with hemophilia.

There have been conflicting reports in the literature about the protective effect of hemophilia on the occurrence of ischemic heart disease (IHD). Circulatory disease has been reported as the second most common cause of death in persons with hemophilia in the United States. In addition to diabetes and hypertension, high levels of FVIII, as may occur during factor concentrate infusions, may increase IHD risk in this population. To estimate the prevalence of heart disease and examine factors associated with IHD and other heart diseases among persons with hemophilia, we analyzed data collected from the medical records of 3,422 males with hemophilia living in six U.S. states from 1993 to 1998. Heart disease cases were ascertained from among 2,075 persons who were hospitalized at least once during the 6-year period. Of these, 48 were diagnosed with IHD and 106, with other types of heart disease. The age-specific prevalence of IHD ranged from 0.05% in those under 30 years to 15.2% in those 60 years or older. Hospital discharge rates in males with hemophilia with IHD and other types of heart disease were lower compared to rates in age-matched U.S. males. In our cohort, as in the general population, IHD was independently associated with age, hypertension, diabetes, and hyperlipidemia. Other heart diseases were associated with HIV infection, hypertension, hemophilia B, and diabetes. In summary, persons with hemophilia have unique risk factors such as infusion of factor concentrates and infection with HIV that may predispose them to heart disease as their life expectancy increases.

Parvovirus B19 transmission by a high-purity factor VIII concentrate.

BACKGROUND: Parvovirus B19 (B19) is known to cause a variety of human diseases in susceptible individuals by close contact via the respiratory route or by transfusion of contaminated blood or blood products. In this study, whether a case of B19 transmission was causally related to the infusion of implicated lots of a solvent/detergent (S/D)-treated, immunoaffinity-purified factor VIII concentrate (antihemophilic factor [human][AHF]) was investigated. STUDY DESIGN AND METHODS: Anti-B19 (both immunoglobulin M [IgM] and immunoglobulin G [IgG]) and B19 DNA (by a nucleic acid testing [NAT] procedure) were assayed in two implicated product lots, a plasma pool, and a recipient's serum sample. Analysis of the partial B19 sequences obtained from sequencing clones or direct sequencing of the samples was performed. RESULTS: Only one of the two implicated lots was B19 DNA-positive. It contained 1.3 x 10(3) genome equivalents (geq or international units [IU]) per mL. The negative lot was derived from plasma screened for B19 DNA by NAT in a minipool format to exclude high-titer donations, whereas the positive lot was mostly from unscreened plasma. This high-purity AHF product had no detectable anti-B19 IgG. A 4-week postinfusion serum sample from a recipient, who received both lots and became ill, was positive for the presence of B19 antibodies (both IgM and IgG) as well as B19 DNA. The B19 sequences from the positive lot, its plasma pool, and the recipient's serum sample were closely related. CONCLUSION: These findings and the recipient's clinical history support a causal relationship between the implicated AHF product and B19 infection in this recipient. The seronegative patient became infected after receiving 2x10(4) IU (or geq) of B19 DNA, which was present in this S/D-treated, high-purity AHF product.

A survey of gynecologists concerning menorrhagia: perceptions of bleeding disorders as a possible cause.

We sought to determine perceptions and practices of American gynecologists when treating with a woman complaining of menorrhagia, specifically with regard to an underlying bleeding disorder as a potential cause. A mail survey of Georgia members of the American College of Obstetricians and Gynecologists was conducted. The survey response was 52%, and the analysis includes 376 physicians who reported seeing at least one gynecological patient per week. On average, respondents were in practice 20 years and reported that 8% of their patient population complain of menorrhagia. Virtually all physicians reported employing a menstrual history as a starting point for the workup for menorrhagia, and 95% order a hemoglobin/hematocrit determination. About 50% of physicians considered saturating three tampons/pads per 4 hours as excessive, although the criterion varied widely (range 0-24 per 4 hours, SD = 3). The diagnoses considered most likely among reproductive age women were anovulatory bleeding or benign lesions or that the heavy bleeding was within normal limits. Only 4% of physicians would consider von Willebrand disease (VWD) for this age group (women of reproductive age). Among girls near menarche, physicians overwhelmingly consider anovulatory bleeding or bleeding within normal limits the likely diagnoses, and 16% would consider VWD in this age group. Only rarely (3%) do surveyed physicians refer menorrhagia patients to other specialists. Most respondents believe that most menorrhagia is caused by anovulation or is within normal limits. Bleeding disorders are believed to be a rare cause of menorrhagia.

Relationship of venous thromboembolism and myocardial infarction with the renin-angiotensin system in African-Americans.

Genetic polymorphisms/mutations associated with venous thrombosis have largely been confined to the genes that encode for proteins in either the coagulant or the anticoagulant pathway. Although genetic alterations in the renin-angiotensin system have been reported to have a role in myocardial infarction and hypertension, there is recent evidence to suggest that there may also be an association with venous thrombosis. To extend our earlier observation of an association between the ACE DD genotype in African-American males and venous thrombosis, other genes in the renin-angiotensin pathway were investigated for possible disease association and were compared with African-Americans with myocardial infarction. African-American patients with a documented history of venous thrombosis or a history of myocardial infarction were eligible for participation as cases in the study. Control subjects were African-American outpatients attending a clinical laboratory for routine blood tests who had comparable age and gender distributions to the cases. Persons with a history of myocardial infarction, stroke, or thrombosis were excluded. Genes that were analyzed for known polymorphisms included angiotensinogen, angiotensin-converting enzyme (ACE), and the angiotensin II type I receptor. Our results showed that the ACE DD genotype was also associated with MI in African-American males but not in females. Racial/ethnic and sex differences were also found with respect to the genotype distribution of the ACE 4656(CT)(2/3) polymorphism. It was observed that the 2/2 genotype had a protective effective in males for myocardial infarction and venous thrombosis. The data also demonstrated that the allele frequencies of the A1166C variant of the angiotensin II type I receptor were different in African-Americans as compared to Caucasians.

Human parvovirus B19 in young male patients with hemophilia A: associations with treatment product exposure and joint range-of-motion limitation.

BACKGROUND: To evaluate the risk of human parvovirus B19 (B19) transmission in recombinant antihemophilic factor, the seroprevalence among 798 two- to seven-year-old boys with hemophilia was compared. Also, data collected on joints were used to assess relations between B19 serostatus and joint range-of-motion (ROM) limitation. STUDY DESIGN AND METHODS: Staff at US hemophilia treatment centers collected data on product exposures and ROM of 10 joints and provided blood specimens as part of blood safety surveillance. Blood was tested for immunoglobulin G anti-B19. Associations between B19 seropositivity and treatment products and joint ROM limitations were examined in multivariate analyses. RESULTS: Compared to children who received no product, the odds of B19 seropositivity were 0.8 (p = 0.5), 1.9 (p = 0.05), and 7.6 (p < 0.001) for those children who received recombinant antihemophilic factor only, both recombinant antihemophilic factor and plasma-derived factor, and plasma-derived factor only, respectively. Children who were anti-B19 positive had an average 8 degrees less overall ROM (p = 0.002) than those who were B19 antibody negative after adjustment for other risk factors. CONCLUSION: The risk of B19 transmission by recombinant antihemophilic factor is low. Previous B19 infection is associated with ROM limitations in very young male patients with hemophilia. Virus inactivation techniques effective against B19 and other nonenveloped viruses are needed.

Joint range-of-motion limitations among young males with hemophilia: prevalence and risk factors.

Chronic joint disease from repeated bleeding into joints is a serious complication of hemophilia. To measure the extent of and to identify risk factors for deviations from normal in joint range of motion (ROM), we used cross-sectional data collected from 4343 males with hemophilia aged 2 to 19 years who received care at 136 US hemophilia treatment centers (HTCs). Factors examined included age, race/ethnicity, family history, insurance status, age at diagnosis and first HTC visit, frequency of HTC visits, hemophilia type, bleeding frequency, prophylaxis use, inhibitor status, body mass index (BMI), and recent orthopedic procedures. Trained personnel using a standard protocol obtained ROM measurements on 10 joints (hips, knees, shoulders, elbows, and ankles). Analyses used multiple linear regression to model overall ROM limitation separately by disease severity. For persons in all severity groups, joint ROM limitation was positively associated with older age, nonwhite race, and increased BMI. For those with severe disease, ROM limitation was also positively associated with number of bleeds and was greater for those with inhibitors or recent orthopedic procedures. We conclude that ROM limitations begin at an early age, especially for those with severe and moderate disease, and that BMI is an important, potentially modifiable risk factor.