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.

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].).

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.

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.

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.

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.

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.

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.