Carriers Of Haemophilia Research Articles

Similar Pattern of Increase in FIX Levels in Female Carriers and Males with Hemophilia B Leyden

Hemophilia B is a congenital X-linked recessive bleeding disorder that occurs as a result of mutations at the long (q) arm of the X chromosome at position 27. Hemophilia B affects 1 in 30,000 males; however the incidence in Ireland is more than double the international incidence and affects 1 in 12,500 male births. Hemophilia B Leyden is a sub-type of hemophilia B first recognized in 1970 in Leyden in the Netherlands. There are more than 20 genetic mutations that result in hemophilia B Leyden. These mutations cluster at three regions within the proximal promoter region of the F9 gene including mutations in nucleotides c.-34 and c.-35 (-5 and -6 legacy numbering) in almost half the cases, mutations around nucleotide c.-49 (-20) and mutations around nucleotide c.-19 (+10). Point mutations associated with hemophilia B Leyden interfere with F9 gene transcription via binding of F9 promoter to ONECUT1 in patients with c.-35 mutation, HNF4a (hepatocyte nuclear factor 4 alpha) in patients with c.-19 mutation and C/EBPa (enhancer-binding protein alpha) in patients with c.-49 mutation. A characteristic feature of hemophilia B Leyden is progressive rise in FIX:C level from the time of puberty to reach lower normal level in young adults. This led to the widely accepted believe that the increase in FIX:C level in hemophilia B Leyden is due to the effect of the androgens surge at puberty. Androgens and anabolic steroids were used for prophylactic treatment in patients with hemophilia B Leyden in a limited number of patients. Recent evidence from animal studies using hypophysectomized hemophilia B Leyden mouse model convincingly demonstrated the pre-eminent role of growth hormone (GH) in regulating the age-dependent increase in FIX:C levels. FIX:C levels were only restored to 10% of pre-hypophysectomy levels by exogenous administration of dihydrotestosterone or oestrodiol but were restored to 80% of pre-hypophysectomy levels by exogenous administration of GH. We investigated the pattern of the increase in FIX:C in 14 male children and four female children from seven different Irish families attending the National Haemophilia Centre at Children's Health Ireland, Crumlin. The hemizygous presence of hemophilia B Leyden associated variant c.35G>A was confirmed by standard dideoxysequence analysis in all children. To evaluate the timing of increase in plasma FIX:C levels, we measured FIX:C levels using automated one stage assay. Serial measurement of FIX:C in male children with hemophilia B leyden demonstrated an increase of FIX:C from severe/moderate levels at the first year of life to mild FIX:C levels within the first 3 years of life. In all 14 male children with hemophilia B Leyden, FIX:C levels increased gradually throughout childhood with more pronounced increase in FIX:C at the time of puberty (Figure 1-A). The increase in FIX:C levels coincided with the known physiological increase in GH levels. Growth hormone level is low during infancy and increases but remains stable at low levels during early childhood, until just before puberty when GH secretion surges to the highest lifetime peak. All four female carriers of hemophilia B Leyden showed low levels of FIX:C at diagnosis associated with variable bleeding symptoms (Figure 1-B). One female child had very low FIX:C level at diagnosis in the moderate hemophilia range (0.04 iu/ml), while all other three female children had low FIX:C levels at the mild hemophilia range at diagnosis (0.13 iu/ml, 0.27 iu/ml and 0.46 iu/ml respectively). Low FIX:C level in those female carriers is likely due to skewed inactivation of the unaffected X chromosome during embryogenesis (lyonization) as no child had compound heterozygosity for the F9 gene mutation and none of the children showed clinical features of Turner syndrome or testicular feminization syndrome. Serial measurement of FIX:C levels in those symptomatic female carriers of hemophilia B Leyden showed similar gradual increase in FIX:C levels during childhood with more steep increase at puberty. Our findings further assert that gender and sex hormones has no influence in the increase of FIX:C level in hemophilia B patients. Figure 1 Disclosures Nolan: Sobi: Other: personal fees; Bayer, CSL Behring, and Sanofi.: Other: sponsorship; Sanofi: Other: PI for sponsor-(Sanofi-) led clinical trial.

A Retrospective Cohort Study Evaluating the Safety and Efficacy of Peri-Partum Tranexamic Acid for Women with Inherited Bleeding Disorders

Background: Post-partum hemorrhage (PPH) is a major cause of maternal mortality. The risk of death from PPH is approximately 1 in 1000 deliveries(Carroli et al., 2008). Tranexamic acid (TXA) is a recommended treatment for women with severe PPH as it significantly reduces blood loss, need for surgical intervention and maternal mortality from hemorrhage (Abdul-Kadir et al., 2014; Ducloy-Bouthors et al., 2011; Li et al., 2017). Despite evidence supporting the use of TXA in this setting, there remain concerns and reluctance with its use stemming from the known increased risk of venous thromboembolism (VTE) in women post-partum (Tepper et al., 2014; James, 2009). Much of the data on TXA use has come from studies conducted on women without a bleeding disorder. Women with inherited bleeding disorders are at a substantially greater risk of PPH with maternal mortality from PPH estimated to be 10 times higher than average(Abdul-Kadir et al., 2014; James & Jamison, 2007). The safety and efficacy of peri-partum use of TXA in this population warrants study given their increased baseline risk of PPH and lower risk of thromboembolism (James & Jamison, 2007; Martin & Key, 2016). Methods: A retrospective cohort study was conducted on all women with inherited bleeding disorders known to our Multidisciplinary Clinic for Women with Inherited Bleeding Disorders (MCWBD) who received TXA peri-partum between July 2014 and December 2019. The primary objective was to evaluate the frequency of VTE amongst patients with inherited bleeding disorders who received peri-partum TXA. The secondary objective was to evaluate the frequency of primary and secondary PPH among those who did and did not receive TXA. Research ethics board approval was obtained. Descriptive statistical analyses were used. Results: There were no VTE events in all MCWBD patients who received TXA peri-partum. A total of 40 patients with inherited bleeding disorders were managed from the beginning of pregnancy to labour and delivery under the care of the MCWBD between July 2014 and December 2019. The distribution of primary bleeding disorder diagnoses is 37.5% (15/40) for von Willebrand disease, 30% (12/40) had platelet function disorders, 22.5% (9/40) were symptomatic hemophilia carriers and 10% (4/40) had a rare factor deficiency (see Figure 1). Of these patients, 25% (10/40) had a personal previous history of PPH and 13% (5/40) had a family history of PPH. Among the 40 women, 75% (30/40) gave birth vaginally. TXA was provided to 95% (38/40) of patients at the onset of the second stage of labour, during the postpartum period (minimum of 10 days of oral TXA treatment), or both. Primary PPH occurred in 13% (5/38) of women who received prophylactic TXA and in 1 out 2 (50%) women without prophylactic TXA (see Table 1). There were no reports of secondary PPH. Conclusions: TXA appears to be a safe preventative treatment for PPH in patients with inherited bleeding disorders based on our retrospective study, with no additional risks of thromboembolism observed. Prospective evaluation of peripartum TXA use in this patient population is warranted to further assess its efficacy. Disclosures Martin: Borden Ladner Gervais LLP: Consultancy. Sholzberg:NovoNordisk: Honoraria, Other: Scientific Advisory Board; Novartis: Honoraria, Other: Scientific Advisory Board; Takeda: Honoraria, Other: Scientific Advisory Board, Research Funding; Amgen: Honoraria, Other: Scientific Advisory Board, Research Funding; Octapharma: Honoraria, Other: Scientific Advisory Board, Research Funding.

X Chromosome inactivation: a modifier of factor VIII and IX plasma levels and bleeding phenotype in Haemophilia carriers.

Haemophilia A and B are X-linked hemorrhagic disorders caused by gene variants in the F8 and F9 genes. Due to recessive inheritance, males are affected, while female carriers are usually asymptomatic with a wide range of factor VIII (FVIII) or IX (FIX) levels. Bleeding tendency in female carriers is extremely variable and may be associated with low clotting factor levels. This could be explained by F8 or F9 genetic variations, numerical or structural X chromosomal anomalies, or epigenetic variations such as irregular X chromosome inactivation (XCI). The aim of the study was to determine whether low FVIII or FIX coagulant activity in haemophilia carriers could be related to XCI and bleeding symptoms. HUMARA assay was performed on 73 symptomatic carriers with low clotting activity ≤50 IU/dL. Bleeding Assessment Tool (BAT) from the International Society on Thrombosis and Haemostasis (ISTH) was used to describe symptoms in the cohort of carriers. In 97% of haemophilia carriers, a specific gene variant in heterozygous state was found, which alone could not justify their low FVIII or FIX levels (≤50 IU/dL). A statistical association between XCI pattern and FVIII and FIX levels was observed. Moreover, female carriers with low coagulant activity (≤20 IU/dL) and high degree of XCI ( ≥ 80:20) had a higher ISTH-BAT score than the carriers with the opposite conditions (>20 IU/dL and <80:20). In our cohort of haemophilia carriers, XCI was significantly skewed, which may contribute to the low expression of clotting factor levels and bleeding symptoms.

Women and girls with haemophilia: Lessons learned.

Severe and moderate factor VIII (FVIII) or IX (FIX) deficiencies in female carriers of haemophilia are rarely observed, but mild deficiency is quite frequent, although insufficiently recognized and registered. The confusion between the genetic diagnosis of the carriership, mainly assessed at adult age and the diagnosis of the bleeding disorder for those who have low factor levels often prevents early diagnosis of a potential bleeding risk. The factor levels in obligate or potential carriers of haemophilia can be assessed during childhood, possibly apart from genetic assays. The absence of early recognition of the bleeding disorder precludes the anticipation of menarche and the prevention of potential heavy menstrual bleeding to heavy menstrual bleeding. Standardized bleeding assessment tools (BAT) have demonstrated that women and girls with haemophilia (WGWH) have increased bleeding scores as compared to the general female population, however weakly correlating with factor levels. More recent evidence has highlighted that hemarthroses affect 4% to 19% of carriers and that some of them could experience sub-clinical joint bleeding. Desmopressin for women with FVIII deficiency and abnormal ISTH-BAT scores had a significantly lower FVIII response to DDAVP compared to those with normal bleeding scores, which could at least partially explain more postsurgical bleeding. Management of delivery of haemophilia carriers requires attention to the risks of maternal bleeding, the risks of foetal bleeding, preconception and prenatal care, strategies to reduce maternal bleeding, choice of mode of delivery to reduce foetal/neonatal bleeding, and postpartum care. Either prior to pregnancy, or during early pregnancy, a plan should be developed that addresses the needs of both the mother and her unborn baby. If the unborn baby is a male proven to be or potentially affected by moderate or severe form of haemophilia, there is a risk of severe foetal bleeding, so a planned caesarean delivery may be preferred. If the unborn baby is a carrier, or potentially affected carrier, there is still the risk of non-severe bleeding so invasive foetal procedures and operative vaginal delivery (forceps or vacuum) should be avoided. Further studies based on large cohorts will help the community to favour earlier diagnosis, increase knowledge on WGWH and promote better care.

Bleeding complications during pregnancy and delivery in haemophilia carriers and their neonates in Western France: An observational study.

Pregnancy, delivery and the postpartum period expose haemophilia carriers, as well as their potentially affected neonates to a high risk of haemorrhagic complications. To describe bleeding complications in haemophilia carriers and their newborns throughout pregnancy and postpartum and to identify potential factors increasing the risk of bleeding in this population. The ECHANGE multicentre observational cohort study was conducted between January 2014 and February 2019 using the BERHLINGO database comprised of patients from seven French haemophilia centres. During the 5years study period, a total of 104 haemophilia carriers and 119 neonates were included, representing 124 pregnancies and 117 deliveries. Thirty-five (30%) bleeding events were observed, most of them (83%) occurred during the postpartum period, and 37% were reported during the secondary postpartum. Neuraxial anaesthesia was not complicated by spinal haematoma. Three (2.5%) neonates experienced cerebral bleeding. Caesarean section was associated with an increased risk of maternal bleeding in primary and secondary postpartum periods. Basal factor level <0.4IU/mL was also found to be associated with an increased risk of bleeding during secondary postpartum. In our cohort, bleeding events occurred in more than a third of haemophilia carriers mainly in the postpartum period, and a significant portion of this bleeding occurred during the secondary postpartum. Haemophilia carriers warrant specific attention during primary and secondary postpartum, in particular in case of caesarean section and low basal factor level. The ECHANGE study is registered at clinicaltrials.gov identifier: NCT03360149.

Postpartum bleeding in women with inherited bleeding disorders: a matched cohort study.

: Women with inherited bleeding disorders (IBDs) are reported to have higher rates of primary and secondary postpartum haemorrhage (PPH), even with optimal haemostatic management. We evaluated whether women with IBD have higher odds of PPH compared with those without, when controlled for mode of delivery with a control group of women without IBDs. The obstetric experiences and outcomes of all women with IBD delivering at a tertiary centre between 2008 and 2017, were compared with matched controls (1 : 1). Obstetric care was provided according to national guidelines to both women with IBD and controls. Primary PPH was defined as estimated blood loss at least 500 ml. There were 46 completed pregnancies in women with IBD: 16 haemophilia A carriers, eight haemophilia B carriers, eight factor XI deficiency patients and 14 von Willebrand disease patients (type 1 = 6; type 2 = 8). No peripartum haemostatic treatment was received by carriers of haemophilia A or B. There were 74 control pregnancies. Women with IBD had higher odds of primary PPH, in a model controlling for mode of anaesthesia (adjusted odds ratio 5.30, 95% confidence interval 1.02-27.59, P = 0.048). Carriers of haemophilia A had a higher, statistically nonsignificant, odds for primary PPH than controls (adjusted odds ratio 6.85, confidence interval 0.77-60.73, P = 0.084). An increase in primary PPH was observed in women with IBD, particularly in haemophilia A, despite management according to guidelines. These results warrant further investigation and consideration should be given as to which factor levels to target.

Registry of patients with congenital bleeding disorders and COVID-19 in Madrid.

IntroductionWe present the first registry of patients with congenital bleeding disorders and COVID‐19. The study has been carried out in the Community of Madrid, which has the highest number of cases in Spain. The objective is to understand the incidence of COVID‐19, the course of the disease if it occurs and the psychosocial and occupational impact on this population.MethodsWe included 345 patients (246 of haemophilia, 69 of von Willebrand Disease, two rare bleeding disorders and 28 carriers of haemophilia). A telephone survey was used to collect the data.ResultsForty‐two patients presented symptoms suggestive of infection by COVID‐19, and in six cases, the disease was confirmed by RT‐PCR. The cumulative incidence of our series was 1.73%. It is worth noting the complexity of the management of COVID‐19 in two patients on prophylaxis with non‐factor replacement therapy. Adherence to the prescribed treatment was maintained by 95.5% of patients. Although 94% were independent for daily living activities, 42.4% had a recognized disability and 58% required assistance, provided by the Madrid Haemophilia Association (Ashemadrid) in 75% of cases. Only 4.4% of consultations were held in person.ConclusionsPatients with congenital bleeding disorders infected with SARS‐CoV‐2 presented a mild course of the disease that did not require admission. Their identification and treatment by a specialist team from a Haemophilia Treatment Center are essential to make a correct assessment of the risk of haemorrhage/thrombosis. COVID‐19 had a major impact on the psychosocial aspects of these patients which must be remedied with recovery plans.

The experiences and attitudes of hemophilia carriers around pregnancy: A qualitative systematic review

BackgroundHemophilia carriers (HCs) face specific psychosocial challenges related to pregnancy, caused by their inherited bleeding disorder. Optimal support from healthcare providers can only be realized by exploring medical and psychological healthcare requirements. ObjectiveTo review all published evidence on the experiences and attitudes of HCs regarding reproductive decision‐making, prenatal diagnosis, pregnancy, childbirth, and puerperium to provide an accessible overview of this information for health care providers. Study selectionCochrane library, PubMed/MEDLINE, EMBASE, CINAHL, and PsycINFO were searched for original qualitative data. Two authors performed study selection, risk‐of‐bias assessment, data extraction, and data analysis through meta‐summary. The extracted themes were discussed within the research team. FindingsFifteen studies with an overall moderate quality were included. The following findings were identified: (a) Quality of life of family members with hemophilia influences reproductive decision‐making; (b) Genetic counselling is generally considered useful; (c) The development of a specialized carrier clinic is considered valuable; (d) HCs describe prenatal diagnosis as beneficial yet psychosocially challenging; and (e) noninvasive prenatal diagnosis and preimplantation genetic diagnosis are predominantly considered beneficial. These findings are limited by the overall moderate quality of included studies and the possibly partly outdated results in the current era of hemophilia treatment. ConclusionsAvailable qualitative literature on HCs around pregnancy focuses on genetic counselling and prenatal diagnosis. Future studies are needed on the experiences and needs of HCs through pregnancy and puerperium as well as in light of emerging hemophilia diagnosis and treatment options.

Perinatal Management of Haemophilia.

The aim of this review is to provide practical guidance for the treatment of carriers of haemophilia and newborns presenting with haemophilia. Both mother and newborn have an increased risk for clinically relevant bleeding. An experienced team should manage genetic counselling, prenatal diagnosis, pregnancy, delivery and the newborn presenting with haemophilia. Published and regularly updated guidelines must guide this team. Vaginal and caesarean deliveries before labour entail a comparable bleeding risk. Haemophilia carriers should receive factor concentrate (FC) at the time of delivery if their factor level is below normal. Evidence remains insufficient to recommend systemic desmopressin and tranexamic acid for the prevention of peripartum haemorrhage. Primary prophylaxis with FC for all newborns with severe haemophilia is not justified. The pattern of bleeding seen in the affected newborns is essentially different from that seen in older children. Estimated frequency of intracranial haemorrhage (ICH) is 2 to 3%. Cranial ultrasound is a good screening method for ICH in newborns. Many neonatal bleeds are iatrogenic in origin. The most prominent concerns regarding neonatal factor replacement are the risk for inhibitor development, followed by local bleeding and issues related to poor vascular access. The preference for plasma-derived FC and recombinant FC differs widely between centres and countries. Replacement therapy should be monitored since newborns may require higher doses of FC. Emicizumab, licensed for all age groups since 2019, should not be used in newborns with severe haemophilia A and acute bleeding, although "non-factor" agents are expected to revolutionise haemophilia therapy.

Bone health in symptomatic carriers of haemophilia A: a protocol for a multicentre prospective matched-cohort study

IntroductionHaemophilia A is an X linked inherited bleeding disorder, caused by a decrease in coagulation factor VIII. Persons with haemophilia experience repeated musculoskeletal bleeding, which can lead to decreased range...

Bleeding assessment in haemophilia carriers-High rates of bleeding after surgical abortion and intrauterine device placement: A multicentre study in China.

An increased bleeding tendency has been shown in female haemophilia carriers compared to healthy females. Bleeding assessment tools (BATs) have mainly been performed in western cultures. It is unclear how they perform in populations with different healthcare, health/wellness concepts and awareness, as well as family planning practices. To (a) describe and compare the bleeding symptoms in carriers with healthy females, particularly for bleeding after surgical abortion and intrauterine device (IUD) placement which are performed frequently for family planning in China; (b) quantify scores of International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) and Chinese-BAT (C-BAT) developed to include surgical abortion and IUD placement as separate categories in Chinese haemophilia carriers; (c) correlate bleeding scores (BS) with factor levels. We conducted a multicentre, cross-sectional study on obligate haemophilia carriers and healthy controls using ISTH-BAT and C-BAT. We enrolled 125 haemophilia carriers and 106 controls. Carriers, compared to controls, had significantly higher median BS (3 vs 1 by both ISTH-BAT and C-BAT) and lower factor level (63.5 vs 101.8IU/dL). Bleeding after surgical abortion and IUD placement was significantly associated with carrier status. Bleeding scores from neither ISTH-BAT nor C-BAT showed significant correlation with factor levels. Haemophilia carriers in China experienced abnormal bleeding. Unique to the Chinese carriers is significant bleeding after surgical abortion (3rd highest incidence of bleeding symptom) and IUD placement (4th highest). However, both ISTH-BAT and C-BAT exhibited no correlation between BS and factor levels in this population and neither could identify carriers with low factor level (of <50IU/dL).

Impaired Bone Health and Wound Dehiscence in Carriers of Hemophilia a and B

Introduction: FVIII and FIX have a well-established pivotal role in the promotion and maintenance of hemostasis. There is emerging evidence, however, for a role of FVIII and FIX in regulating processes beyond thrombin generation, such as bone health and macrophage function affecting wound healing. Previous studies on bone mineral density (BMD) and fractures have primarily investigated persons with hemophilia A (PwHA) and hemophilia B (PwHB), but not hemophilia carriers. It has been estimated that 35% of hemophilia carriers have FVIII and FIX levels below 40IU/dL. However, it is not known if hemophilia carriers have a similar potential to develop decreased BMD and poor wound healing as PwHA or PwHB. This study aims to assess the prevalence of bone health issues and wound healing among women who are hemophilia carriers comparing them to control women in the general population. Methods: A commercial database (Explorys Inc, Cleveland, OH, USA), an aggregate of electronic health record data from 26 major integrated US healthcare systems, was queried for data, using Systematized Nomenclature of Medicine (SNOMED) clinical terms or codes. Cases were defined as female patients of any age, with a diagnosis of Hemophilia carrier. Controls were defined as female patients of any age, with at least one medical encounter, and who did not have a diagnosis of Hemophilia Carrier. The prevalence rates of osteoporosis, osteoarthritis, fractures and wound dehiscence among cases and controls were estimated based on binomial distribution theory. The prevalence rates of the comorbidities were compared in the Hemophilia Carrier group and control group using chi-square or Fisher's exact test, and relative risk calculations for bone health issues were adjusted for age &amp;gt; 50, as the risk of osteoporosis and osteoporotic fractures is higher in post-menopausal women above the age of 50. Results: Our database search identified 740 hemophilia carriers and 34,129,790 women in the control group (Table 1). Among the hemophilia carrier group, there was increased prevalence of osteoporosis (7% vs 3.6%, p&amp;lt;0.0001), osteoarthritis (26% vs 11%, p&amp;lt;0.0001), and fractures (12% vs 6%), p&amp;lt;0.0001) as compared to the control group. Wound dehiscence had a prevalence of 270 cases per 10,000 in the hemophilia carrier group, vs 120 per 10,000 in the control group. The age-adjusted relative risk of osteoporosis, osteoarthritis, and fractures due to hemophilia was 2.72 (95% CI 2.20 to 3.41), 2.85 (95% CI: 2.55 to 3.17), and 2.57 (95% CI: 2.16 to 3.05), respectively (Table 2). Conclusions: Our study suggests an association between hemophilia carrier state and poor bone health and wound healing. Prospective studies are required to confirm these findings, including the role of factor levels in these patients in relation to bone turnover markers and macrophage function. This data may also have relevance for the importance of exposure to factor in the era of emerging non-factor therapies in hemophilia. Disclosures Ahuja: Genentech: Consultancy; Biovertiv Sanofi: Consultancy; Bayer: Consultancy; Rainbow Children's Foundation: Research Funding; XaTexk Inc.: Consultancy, Patents &amp; Royalties, Research Funding.

Mothers' intentions and behaviours regarding providing risk communication to their daughters about their possibility of being haemophilia carriers: A qualitative study.

Prophylactic replacement therapy has enabled improvements in the quality of life of patients with haemophilia. However, these patients and their families continue to report psychosocial problems regarding pregnancy and childbirth. In a situation where there is little medical support for haemophilia carriers (HCs), parents must inform their children regarding their possibility of being HCs. This study aimed to elucidate intentions and challenges among mothers with daughters who may be HCs, regarding providing them with carrier risk communication (RC). Study participants were mothers with daughters who have the possibility of being HCs. Semi-structured interviews were conducted with 20 mothers and were fully transcribed. The analysis was undertaken using a grounded theory-informed approach, through a process of repeated inductive and deductive qualitative coding. The study included 14 mothers who had already provided RC to their daughters, five who had not yet provided RC but who intended to do so, and one with no intention of providing RC. Mothers who had already provided RC included those who were not troubled and those who experienced psychological difficulties regarding the RC. Participants who had not provided RC experienced difficulties with 'not knowing what to do' and feelings of 'anxiety due to uncertainty' and reported not knowing the best RC method or timing. The study revealed a need for support for persons experiencing difficulties with informing their daughters of their possibility of being HCs. Healthcare professionals can advise parents to reduce the burden of providing carrier RC to their daughters.

Joint comorbidities among Swedish carriers of haemophilia: A register-based cohort study over 22years.

A significant fraction of women with an impaired factor VIII or IX gene in the X chromosome, carriers of haemophilia, will have clotting factor activities corresponding to those seen in males with non-severe haemophilia, hence, experience an increased bleeding tendency. Data describing the long-term joint outcomes among carriers are limited. We compared the age at onset, frequency of joint-related diagnoses as well as joint surgery and related hospitalizations among carriers of haemophilia with sex- and birthdate-matched controls from the general population. Carriers of haemophilia born 1941-2008 were identified through the haemophilia treatment centres' (HTCs) databases and the National Patient Register of Sweden. For each carrier, we included up to five individuals using the Swedish population register as comparisons. Data for the period 1987-2008 were obtained. Among 539 potential carriers identified, 213 had a known factor activity. Carriers with reduced factor activity and those with unknown factor activity had received their first joint-related diagnosis at a significantly earlier age than their comparisons. The same subgroups showed an overall 2.3- and 2.4-fold higher hazard for joint-related diagnoses compared with the general population. In addition, the hazards of joint-related outpatient hospitalization were 3.2-fold (95% CI: 1.2, 9.1) and 2.5-fold (95% CI: 1.6, 3.7). This was not observed for those with normal factor activity. Carriers of haemophilia suffer a significant risk for joint comorbidities. This risk seems to correlate to the factor activity. Our findings underline the importance of regular clinical follow-up of carriers at HTCs.

Development and evaluation of appropriate, culturally adapted educational tools for Ivoirian patients with haemophilia, haemophilia carriers and their families.

Patient education is the cornerstone of the management of chronic diseases like haemophilia. The education of patients with haemophilia (PWH), haemophilia carriers and their families requires educational materials adapted to their socio-cultural situations for maximum effectiveness. These tools are currently lacking in developing countries like Côte d'Ivoire. We sought to develop educational materials adapted to the Ivoirian context, assess their short- and long-term impacts on knowledge about haemophilia and evaluate the participants' motivation and their satisfaction with the tools. Following their elaboration, the materials were administered to 71 participants (37 PWH, 29 carriers and 5 fathers), whose level of knowledge was assessed before (T0), just after (T1), and 1year following the intervention (T2). We evaluated, analysed and compared the scores at T0, T1 and T2 and evaluated motivation at T0 and satisfaction at T1. All participants significantly improved their skills at T1 (P<0.001), maintaining a sustained and significant improvement at T2 in comparison with T0 (P<0.001). In all participants, we observed a high degree of motivation towards improving their knowledge and a high degree of satisfaction with the materials. Appropriate, culturally adapted educational tools focused on haemophilia are now available in Côte d'Ivoire. These materials will likely contribute to improving haemophilia awareness, to implementing screening, prevention and self-management of the disease and to positively impacting the outcomes of Ivoirian PWH in the long term.

The national blueprint for pregnancy/birth longitudinal cohorts to study factor VIII immunogenicity: NHLBI State of the Science (SOS) Workshop on factor VIII inhibitors.

Patients with haemophilia can develop inhibitors to exogenous coagulation factors. Some patients are tolerant to factor, while those who develop inhibitors do so early in life. Genetics and environmental factors are known to contribute to inhibitor risk. However, it is not yet possible to predict inhibitor formation or treatment responsiveness in individuals. We hypothesize that factors in the antenatal/neonatal period inform inhibitor risk development. To consider the design of longitudinal studies beginning in the antenatal/neonatal period and the use of new technologies to better understand haemophilia inhibitors. A working group was formed for the NHLBI State of the Science Workshop: Factor VIII Inhibitors: Generating a National Blueprint for Future Research to solicit input from the US haemophilia community and international collaborators to consider design of pregnancy/birth longitudinal cohorts that leverage -omics, existing phenotypic data, and in silico modelling to study inhibitors. An antenatal/neonatal longitudinal cohort should begin with enrolment of pregnant genetic carriers of haemophilia and span the at-risk period for inhibitor development in the child. Data and samples from the mother, placenta, neonate and young child can be obtained that are amenable to existing assays, genomics and other -omics studies. Data can inform in silico prediction and mathematical models. A longitudinal study beginning before birth offers the unique opportunity to study factors that influence inhibitor development prior to exposure. Advances in -omics and computational biology can study complex phenotypes in this rare disease. This study could be accomplished through interdisciplinary efforts and patient community engagement.

PF330 MODE OF DELIVERY IN NEWBORNS WITH HEMOPHILIA: ASSOCIATION WITH FAMILY HISTORY/MATERNAL CARRIER STATUS, SEVERITY OF HEMOPHILIA AND INCIDENCE OF INTRACRANIAL/EXTRACRANIAL HEMORRHAGE

Background:Intracranial hemorrhage (ICH) in neonates is one of the most severe clinical conditions often associated with neurological complications. The incidence of ICH in hemophilic neonates compared to healthy term infants is referred higher (2–4% versus 0.04%, respectively). Nevertheless, mode of delivery in cases of known history of hemophilia or maternal carriership still remains under debate.Aims:To correlate mode of delivery (vaginal delivery‐VD or cesarean section‐CS) of newborns with hemophilia having had family history of hemophilia/maternal carriership with the severity of the disease, birth order and incidence of intracranial/extracranial hemorrhage.Methods:Patients with severe, moderate and mild haemophilia A/B (FVIII/IX &lt;1, 1–5, ≥5–25 u/dl, respectively) born between 1/1/2000 and 31/12/2017 were retrospectively included. Data presented with absolute and percentage distributions and the comparison of variables were made using Fisher's exact test. A cut‐off p‐value of 0.05 was considered statistically significant.Results:Of a total of 134 neonates, 115 (85.8%) had been diagnosed as hemophilia A and 19 (14.2%) as hemophilia B, whereas 56.7% had severe, 15.7% moderate and 27.6% mild hemophilia. Seventy four neonates (55.2%) were born by VD and 60 (44.8%) by CS, while 54.5% were delivered from nulliparous mothers. At delivery, family history of hemophilia/maternal status was known in 27.6% of cases. Higher percentage of children with severe/moderate hemophilia was born by VD in comparison to children with mild hemophilia (63% vs 35%, p &lt; 0.01), whereas 67.6% of neonates with family history/maternal carriership were born by CS. Positive family history and/or maternal carriership at delivery were found in 17.5 % of neonates with severe/moderate hemophilia, in contrast to 54.1% of them with mild hemophilia (p &lt; 0.01). Knowledge of carriership influenced significantly the decision for CS only in cases of non primigravidae mothers, in contrast to deliveries with unknown hemophilia history (88.2% vs 25%, p &lt; 0.01). Among all children, 4 (3%) had been presented with cephalohematoma. One of them with hemophilia B had also cerebral hemorrhage (0.8%). All patients were born by VD from primiparae mothers (2 with assisted VD). ICH occurred in one of the two children born by instrumental vaginal delivery using vacuum extraction. Maternal carriership of hemophilia A was known only in one neonate with cephalohematoma, born by spontaneous vaginal delivery.Summary/Conclusion:In our study, the choice of cesarean section seems to be the preferable way for delivery in cases of potential hemophilia, if the mother, especially multipara, is carrier of mild hemophilia. On the contrary, in cases of severe hemophilia, vaginal delivery is more frequently performed, probably because there is no knowledge of hemophilia carriership at the time of delivery, because of the presence of a de novo mutation in the factor VIII gene, since in previously known carriership prenatal diagnosis had been performed. In any case, it has to be mentioned that neonates with severe hemophilia born by vaginal delivery, especially assisted with vacuum extraction or forceps, are at greater risk of extracranial or intracerebral hemorrhage.

Hemophilia carrier\u2019s awareness, diagnosis, and management in emerging countries: a cross-sectional study in C\xf4te d\u2019Ivoire (Ivory Coast)

BackgroundLittle data is available on awareness of hemophilia carrier condition or associated bleeding risk and management in Sub-Saharan African countries. This study sought to identify hemophilia carriers in Côte d’Ivoire in order to collect data on demographics, bleeding phenotype, and laboratory results. Another purpose was to provide Ivorian hemophilia carriers with counseling on their risk of bleeding and of having children with hemophilia. A 12-month prospective study was conducted involving Ivorian hemophilia carriers recruited trough pedigree analysis pertaining to 81 hemophilia patients followed-up at the Yopougon Hemophilia Treatment Center in Abidjan. They were assessed using in-depth interviews, pedigree analysis, and laboratory testing.ResultsSixty-one subjects comprising 27 obligate and 34 possible carriers were recruited. None had previously been assessed, with 64% unaware of their carrier status despite a familial history of hemophilia in 69%. The most frequently reported bleeding symptom was menorrhagia (31%). Prolonged bleeding was reported after vaginal delivery in 19.6%, post-surgery in 4.9%, and post-dental extraction in 4.9%. Only one carrier was treated with tranexamic acid, with no other hemostatic therapy recorded. The median (range) clotting FVIII was 0.85 IU/mL (0.24–1.90 IU/mL) and FIX 0.60 IU/mL (0.42–1.76 IU/mL) in hemophilia A and B carriers, respectively. HA carriers had a FVIII < 0.5 IU/mL in 12.5%.ConclusionsThis study highlights the need of implementing care for hemophilia carriers in developing countries, and the high value of pedigree analysis for carrier identification, along with the relevance of diagnosis, treatment, and education of carriers, families, and caregivers.

Medical care for carriers of hemophilia —carrier testing, carrier check-up and perinatal management

Medical care for carriers of hemophilia —carrier testing, carrier check-up and perinatal management

Are There Inequities in Access to Care Amongst Women with Inherited Bleeding Disorders? a Systematic Review

Introduction: Despite the manifold symptoms women with inherited bleeding disorders experience, whether they receive timely screening and specialist referral remains unclear. While literature on this topic is sparse, studies have found that, irrespective of the hemostatic challenges women face, they are often unlikely to be referred to hematologists, subsequently remaining undiagnosed and under-treated. Recognition and early diagnosis remain paramount for management and avoidance of complications, particularly as women with bleeding disorders are at increased risk for heavy menstrual bleeding, anemia, post-partum hemorrhage, and decreased quality of life. However, to our knowledge, no studies have systematically assessed whether women face unique barriers to receiving specialist care and timely treatment. This systematic review sought to better characterize literature on access to care for women with inherited bleeding disorders.Methods: A systematic review was conducted to assess the literature on access to care for women with inherited bleeding disorders. This was conducted following the Cochrane Handbook, and reported as per Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In consultation with a health services librarian, we designed a search strategy in order to identify published papers reporting on all forms of bleeding diatheses. Inclusion criteria included all studies examining bleeding disorders and equity of care in women after the year 2000; exclusion criteria included studies written in a non-English language or only enrolling men. Two review authors independently extracted data and assessed included studies for risk of bias. Risk of bias was assessed using the Newcastle-Ottawa guidelines. The GRADE approach was used to assess quality of evidence. If required, additional data was sought from study authors.Results: Of 526 screened abstracts, only a small subset (N=12) explicitly focused on women's health, with the majority focusing on gynecologic and obstetric complications associated with von Willebrand Disease (VWD). There was significant heterogeneity in study methodology and populations enrolled. Only two studies explicitly studied self-reported barriers to hemophilia care, with one study largely enrolling men with hemophilia A of moderate-severe severity. Within the literature investigating barriers to care, themes that emerged included greater difficulties surrounding access to treatment for women, a tendency for hemophilia carriers to encounter dismissive healthcare provider attitudes, and ignorance around bleeding disorders in women. These studies proposed that unmet needs, particularly for women with inherited bleeding disorders, require further evaluation. However, risk of bias was found to be high, and grade of evidence low.Discussion: We sought to better characterize the literature on access to care for women with inherited bleeding disorders, and found that literature on this topic is particularly sparse. Given our lack of understanding of women's experiences, and particularly the experiences of hemophilia carriers, ongoing efforts are needed to appreciate where inequities in care may exist. Using qualitative research methodology, we will explore the experiences of women, as well as other understudied populations, who live with bleeding disorders. By identifying possible demographic, geographic, and systems level factors hindering patients' access to care, we hope to increase healthcare provider awareness around existing barriers and, through targeted interventions, promote patient self-advocacy. DisclosuresNo relevant conflicts of interest to declare.