Carriers Of Haemophilia Research Articles

Haemophilia testing of young girls in Canada: Describing the current recommendations for factor level and genetic testing and the experiences of Canadian parents.

It is widely acknowledged that haemophilia affects women and girls, yet current testing recommendations for factor level and genetic testing vary and do not universally incorporate updated research. Canadian parents have expressed frustration at inconsistent recommendations and reported instances where delayed testing led to missed diagnosis and preventable bleeding. Study aim was to explore and describe the practice of haemophilia-related testing of young girls in Canada. A mixed methods study was carried out with two populations: (1) Nurses working in haemophilia care completed a survey regarding the current testing recommendations of their Haemophilia Treatment Centre (HTC), (2) Parents of obligate or potential haemophilia carriers completed a structured interview with questions about their family experience of haemophilia and testing decisions for daughters. Twenty-six survey responses were received and showed wide variation in the usual recommendations of Canadian HTCs. Different factor level testing recommendations may be given to obligate and potential carriers despite no difference in bleeding risk. Only a minority of HTCs currently recommend an early baseline factor level (<10 years) to obligate carriers (27%) or potential carriers (15%). For genetic testing of potential carriers, 70% of HTC would approve a family request for genetic testing of a minor with specific conditions. The majority of parents interviewed felt dissatisfied with their testing experience (58%) and highlighted many issues related to delayed testing recommendations. Updated, nationally affirmed testing recommendations are needed that align with research on bleeding in women and girls affected by haemophilia.

A Comparative Analysis of the Bleeding Profile and Quality of Life Among Women With Hemophilia Genotype Compared to Other Bleeding Disorders.

Introduction Women with bleeding disorders continue to be underdiagnosed as well as undertreated. Women with bleeding disorders include those with genotype for hemophilia (traditionally named hemophilia carriers), von Willebrand disease (VWD), platelet function disorders, and rare bleeding disorders. Among these women, the carriers of hemophilia are usually considered asymptomatic. The present study compares the bleeding profile and quality of life (QOL) of women and girls with hemophilia and compares it to those diagnosed with VWD and rare bleeding disorders. Methods The present study is part of a prospective observational study (August 2023-July 2028) done on women and girls >12 years in two groups. Group 1 was mothers, sisters, or daughters of patients with hemophilia A who were proven carriers. Group 2 was girls and women registered at our center as following bleeding symptoms and diagnosed as either suffering from VWD or rare bleeding disorders. The bleeding profile was assessed by 1:1 interview using the International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT). Health-related QOL (HRQOL) was assessed using the EuroQOL five dimension (EQ5D5L) questionnaire. Results The baseline data collected in the first six months of this prospective study is being presented here. At the time of submission, the center caters to 970 patients with hemophilia and inherited bleeding disorders. Eighty girls (post pubertal) and women with either obligate carrier status for hemophilia (n=68) or a previously diagnosed bleeding disorder (10 VWD, one afibrinogenemia, one factor VII deficiency) were enrolled.The median age of Group 1 was 35 years (25-70 years), whereas that of Group 2 was 15.5 years (13-23 years). In Group 1 (women and girls with hemophilia (WGH)), 58 and 10 were carriers of hemophilia A and B, respectively. Additionally, 83% of WGH had more than one family member with bleeding disorder, whereas 75% of Group 2 had a positive family history. The number of family members with the same disorder ranged from 0-4. Among 68 hemophilia carrier women, 20 reported bleeding symptoms (29.4%), of which 18 reported menorrhagia, one antepartum hemorrhage, and one post-partum hemorrhage and two had joint/muscle bleeds and one each had ENT and gastrointestinal bleeding. Three of them were admitted for treatment of excessive bleeding and treated with plasma/red cells. Three women reported gynecological procedures for excessive bleeding, one was on treatment for ovarian cysts, and four received packed red cells after delivery. The BAT score above 6 was reported only in 10% of WGH. Eighteen patients had undergone a surgical procedure in their life, and three of these women required a transfusion during surgery. Only one woman reported similar complaints in her daughter. The comparative analysis of HRQOL showed a significantly worse score for Group 1 in EQ5D5L domains for pain and anxiety/depression compared to that of Group 2. Conclusions A significant proportion of previously asymptomatic women with hemophilia carrier status were recognized to have significant bleeding tendencies. The QOL of these carriers is comparable to girls with VWD and rare bleeding disorders and requires special attention.

The genetic analysis of eight families with hemophilia B in Mongolia: Identification of two novel mutation.

This study aimed to conduct molecular diagnostics among individuals with hemophilia B (HB) and carriers of hemophilia in Mongolia. Eight patients (six severe, two mild) with HB and their 12 female relatives were enrolled from eight families. Sanger sequence was performed for mutation identification. The questionnaire survey was conducted to evaluate carrier symptoms in female relatives. Two families had a history of HB. A total of five different variants (c.223C > T; c.344A > G; c.464G > C; c.187_188del; and c.1314_1314delA) were identified in six patients with severe HB. Of these, two (c.187_188del and c.1314_1314delA) were novel. No variant in the entire F9 was found in two patients with mild HB. Nonsense c.223C > T (p.Arg75*) mutation was detected in two unrelated patients. Carrier testing identified five mothers as carriers, while one younger sister was a non-carrier. The carrier status of six female relatives of the two mild patients remained undetermined. By questionnaire survey, only one of the five genetically identified carriers displayed noticeable symptoms of being a carrier. The novel variants c.187_188del and c.1314_1314delA can cause severe hemophilia B. This study did not observe a significant association between symptoms and carrier status in the five carriers.

Proactive systematic hemophilia carrier screening: a step toward gender equity in hemophilia care

AbstractDespite numerous efforts to raise awareness, many hemophilia carriers and female persons with hemophilia (PWHs) remain undiagnosed. Between May 2021 and April 2023, we identified potential and obligate carriers of hemophilia A (HA) and hemophilia B (HB) by updating pedigrees of all PWHs followed at the Cliniques universitaires Saint-Luc, Brussels. Retrospective data on previously screened females were collected, including bleeding history, coagulation factor levels, and testing for the proband’s pathogenic variant. In addition, a proactive approach involved sending 125 invitation letters to unscreened or incompletely screened individuals, through related PWHs. In pedigrees of 287 male PWHs (226 HA and 61 HB) and 7 female index patients from 236 families (184 HA and 52 HB), a total of 900 female individuals were identified. Of those, 454 were obligate and/or genetically proven carriers, and 118 were noncarriers. Genetic testing was conducted in 133 obligate, 237 potential, and 4 sporadic carriers, with 190 obligate and 328 potential carriers remaining untested. Among carriers with known factor levels (261/454), 42 HA (23.0%) and 23 HB carriers (29.5%) had a factor level <40 IU/dL. Carriers with a factor deficiency were screened on average 6 years earlier than other females (P = .034). This study, to our knowledge, represents the first systematic effort to identify potential carriers among families of all PWHs within a single center, emphasizing the challenges in comprehensive screening for female individuals genetically linked to one or more PWHs. Such initiatives are vital for achieving equitable access to hemophilia care for all potentially affected individuals, irrespective of gender. This trial was registered at www.ClinicalTrials.gov as #NCT05217992.

Primary postpartum hemorrhage in women with von Willebrand disease and carriers of hemophilia: a retrospective analysis

BackgroundBetween 2002 and 2011, the incidence of severe primary postpartum hemorrhage (PPH) in Dutch women with von Willebrand disease (VWD) and hemophilia carriers (HCs) was 8% vs 4.5% in the general population. ObjectivesTo determine the contemporary incidence of severe primary PPH in women with VWD and HCs. MethodsAll women with VWD or HCs who delivered between 2012 and 2017 were selected from all 6 Dutch hemophilia treatment centers. Data on patient and disease characteristics, peripartum hematologic and obstetric management, and outcomes were retrospectively collected. Incidence of severe primary (≥1000 mL of blood loss ≤24 hours after childbirth) and primary (≥500 mL within ≤24 hours after childbirth) PPH was compared with the (1) previous cohort and (2) general Dutch population and between (3) women with VWD and HCs with third-trimester coagulation activity levels <50 international units (IU)/dL vs ≥50 IU/dL and (4) women treated with vs without peripartum hemostatic prophylaxis. ResultsThree-hundred forty-eight deliveries (151 VWD, 167 hemophilia A, and 30 hemophilia B carriers) were included. The severe primary PPH incidence was 10% (36/348) and remained stable over time, whereas this incidence has increased in the general population (to 8%), leading to a similar risk (P = .17). Severe primary PPH risk was comparable between women with coagulation activity levels <50 and ≥50 IU/dL (11% [7/66] vs 10% [29/279]; odds ratio, 1.02; 95% CI, 0.43-2.44) and comparable between those with and those without prophylaxis (12% [11/91] vs 10% [25/254]; odds ratio, 1.26; 95% CI, 0.59-2.68). ConclusionSevere primary PPH in women with VWD and HCs remained stable and is comparable with the increasing prevalence in the general population. More research is needed to find the optimal pregnancy management strategy for safe delivery in VWD and HC.

Impact of Replacement Therapy on Pregnancy Outcomes in Hemophilia Carriers: A Historical Cohort Study in Saudi Arabia.

This retrospective cohort study evaluates the safety and efficacy of replacement therapy with regard to pregnancy outcomes in hemophilia carriers. Hemophilia carriers face elevated bleeding risks during pregnancy, necessitating meticulous management, including replacement therapy with clotting factors. This research examines the records of 64 pregnant hemophilia carriers at King Fahad Medical City, Riyadh, from January 2010 to December 2023, analyzing their demographic details, hemophilia type and severity, replacement therapy specifics, and pregnancy outcomes. The study found that 62.5% of the participants had hemophilia A, with 43.8% categorized as severe. Most subjects (87.5%) received recombinant factor VIII at a median dosage of 30 IU/kg weekly. Adverse pregnancy outcomes included gestational hypertension (15.6%), preterm labor (18.8%), and postpartum hemorrhage (12.5%). The cesarean section rate was 28.1%. Neonatal outcomes were generally favorable, with median birth weights at 3100 g and mean Apgar scores of 8.2 and 9.1 at 1 and 5 min, respectively. Logistic regression analysis revealed no significant association between adverse events and therapy type or dosage, though a trend towards significance was noted with once-weekly administration (p = 0.082). The study concludes that replacement therapy is a viable method for managing hemophilia in pregnant carriers, leading to generally favorable maternal and neonatal outcomes. However, it underscores the importance of individualized treatment plans and close monitoring to effectively manage the risks associated with hemophilia during pregnancy.

Treatment of haemophilia in Austria

This guideline is intended to provide practical guidance for the diagnosis and treatment of haemophilia in Austria. Few randomized controlled interventional trials are available addressing the treatment of haemophilia, therefore recommendations are usually based on low level of evidence and represent expert consensus.This guideline is based on the WFH guideline, published in 2020, and adapted according to the national circumstances and experience.It includes recommendations and suggestions for diagnosis and follow-up visits and pharmacological therapies for treatment and prophylaxis. Further topics comprise special aspects in children and adults with severe haemophilia, outcome measurement, and management of trauma, special bleedings and interventions, including dental procedures, inhibitors, management of haemophilia carriers, and psychosocial aspects.

Clinical Analysis and Mental Health Survey of Hemophilia Carriers: a Cross-sectional Study.

Hemophilia carriers (HCs), who are heterozygous for mutations in the clotting factor VIII/clotting factor IX gene (F8 or F9), may have a wide range of clotting factor levels, from very low, similar to afflicted males, to the upper limit of normal, and may experience mental health issues. The purpose of this study was to provide genetic information on mothers of hemophilia patients and to understand the clotting factor activity and phenotype of HCs. Additionally, we aimed to investigate the mental health status of HCs in China. A total of 127 hemophilia mothers, including 93 hemophilia A (HA) mothers and 34 hemophilia B (HB) mothers, were enrolled in this study. Long distance PCR, multiplex PCR, and Sanger sequencing were used to analyze mutations in F8 or F9. Coagulation factor activity was detected by a one-stage clotting assay. The Symptom Checklist 90 (SCL-90, China/Mandarin version) was given to HCs at the same time to assess their mental health. A total of 90.6% of hemophilia mothers were diagnosed genetically as carriers, with inversion in intron 22 and missense mutations being the most common mutation types in HA and HB carriers, respectively. The median clotting factor level in carriers was 0.74 IU/mL (ranging from 0.09 to 1.74 IU/mL) compared with 1.49 IU/mL (ranging from 0.93 to 1.89 IU/mL) in noncarriers, of which 14.3% of HCs had clotting factor levels of 0.40 IU/mL or below. A total of 53.8% (7/13) of HA carriers with low clotting factor levels (less than 0.50 IU/mL) had a history of bleeding, while none of the HB carriers displayed a bleeding phenotype. The total mean score and the global severity index of the SCL-90 for surveyed HCs were 171.00 (±60.37) and 1.78 (±0.59), respectively. A total of 67.7% of the respondents had psychological symptoms, with obsessive-compulsive disorder being the most prevalent and severe. The pooled estimates of all nine factors were significantly higher than those in the general population (P<0.05). The detection rate of gene mutations in hemophilia mothers was 90.6%, with a median clotting factor level of 0.74 IU/mL, and 14.3% of HCs had a clotting factor level of 0.40 IU/mL or below. A history of bleeding was present in 41.2% of HCs with low clotting factor levels (less than 0.50 IU/mL). Additionally, given the fragile mental health status of HCs in China, it is critical to develop efficient strategies to improve psychological well-being.

Women and girls with inherited bleeding disorders: Focus on haemophilia carriers and heavy menstrual bleeding.

Raising awareness and improving recognition, accurate classification, and enhanced access to new treatments represent current key challenges for carriers of haemophilia. Women and girls carrying genes for haemophilia often experience significant bleeding and/or low factor levels. The bleeding associated with female haemophilia is frequently overlooked, has a weak correlation with factor levels, and manifests differently than in males, with heavy menstrual bleeding being a predominant symptom. Recent changes in terminology now allow the diagnosis of haemophilia in females with low factor levels and differentiate between symptomatic and asymptomatic carriers of the gene. Observations from real-world experiences and limited clinical trial data have highlighted the positive impact of various new haemophilia treatments for women and girls with clotting factor deficiencies. There is an urgent need for initiatives that increase their access to these treatments and encourage well-designed clinical trials focusing on female-specific outcomes. In women with inherited bleeding disorders, early recognition and optimal management of heavy menstrual bleeding are crucial. However, treatment options and guidance from high-quality clinical trials are currently insufficient. Menstrual health assessment should be a regular part of monitoring women and girls with inherited bleeding disorders throughout their lives, emphasizing the importance of gathering data to improve future management.

Management of pregnant women who have bleeding disorders.

Bleeding disorders, including von Willebrand disease (VWD), hemophilia, other coagulation factor deficiencies, platelet disorders, defects of fibrinolysis, and connective tissue disorders, have both maternal and fetal implications. Successful management of bleeding disorders in pregnant women requires not only an understanding of bleeding disorders but also an understanding of when and how bleeding occurs in pregnancy. Bleeding does not occur during a normal pregnancy with a healthy placenta. Bleeding occurs during pregnancy when there is an interruption of the normal utero-placental interface, during miscarriage, during an ectopic pregnancy, or at the time of placental separation at the conclusion of pregnancy. Although mild platelet defects may be more prevalent, the most commonly diagnosed bleeding disorder among women is VWD. Other bleeding disorders are less common, but hemophilia carriers are unique in that they are at risk of bleeding themselves and of giving birth to an affected male infant. General guidance for maternal management of a woman who is moderately or severely affected includes obtaining coagulation factor levels at a minimum in the third trimester; planning for delivery at a center with hemostasis expertise; and anticipating the need for hemostatic agents. General guidance for fetal management includes pre-pregnancy counseling; the option of preimplantation genetic testing for hemophilia; delivery at a tertiary care center with pediatric hematology and newborn intensive care; consideration of cesarean delivery of a potentially severely affected infant; and avoidance of invasive procedures such as scalp electrodes and operative vaginal delivery in any potentially affected infant.

Rare within Rare: A Girl with Severe Haemophilia A and Turner Syndrome

A coincidental occurrence of severe haemophilia A and Turner syndrome in a female person is extremely rare (less than 10 cases published). In such challenging cases, a multidisciplinary approach based on medicine of precision with full access to genetic and bio-molecular exploration is indispensable. The article presents an eight-year-old girl, with a family history of haemophilia, without significant disease signs (only post-dental extraction bleeding and a shorter stature). Discordantly, however, the investigations revealed a challenging condition: a genotype of 46,X,i(Xq), with an Isochromosome Xq responsible for the Turner syndrome and simultaneously, for the detrimental transformation, interfering with X chromosome inactivation, of an obligate hemophilia carrier into a severe hemophilia case—two distinct and provocative diseases.

Comparison of Projected Hemophilia a Populations Residing in Hospital Referral Regions with and without Hemophilia Treatment Centers in the US

Introduction: Among the approximately 53,000 people with hemophilia A (PwHA) in the US, a majority receive care at federally supported hemophilia treatment centers (HTCs). PwHA treated at HTCs have more favorable outcomes and are more likely to receive advanced therapies than PwHA receiving care external to the HTC network. Identifying geographic, socioeconomic and racial disparities among populations residing in hospital referral regions (HRRs) with and without HTCs will support efforts to improve care access and advance health equity. The objective of this study was to evaluate geographic, socioeconomic and racial differences in modeled US populations of PwHA who reside within HRRs with and without HTCs. Methods: Characteristics of HRRs with and without HTCs were compared using the Centers for Disease Control and Prevention (CDC) HTC listings. The study cohorts included individuals who resided in HRRs with and without an HTC based on modeled US populations of projected PwHA (pPwHA). The number of males with hemophilia A in each HRR was calculated at a rate of 12 cases per 100,000 males in the region of interest based on CDC estimates, and the number of females who were carriers of hemophilia A was calculated at a rate of 0.6 female carriers per male case as defined by the International Society of Thrombosis and Haemostasis Scientific and Standardization Committee. Demographic characteristics for each HRR were derived from the 2020 5-year American Community Survey; zip code tabulation areas were crosswalked to 5-digit zip codes and aggregated to HRRs.Differences in population characteristics in HRRs with and without HTCs were evaluated for statistical significance using the Wilcoxon rank sum test. Results: In 307 HRRs in the US, 109 had an associated HTC, while 198 did not (Figure). However, larger mean (SD) populations comprised HRRs with HTCs than those without (3,183,191 [2,752,401] vs 906,047 [814,847]; P&amp;lt;0.001; Table). Findings from this modeling work indicate that 78% of pPwHA reside in HRRs with an HTC. HRRs with HTCs served populations with greater proportions of Asian (5.3% vs 3.0%) and Black (14% vs 11%) individuals than those without HTCs ( P&amp;lt;0.001 for both). Compared with those in HRRs without HTCs, individuals residing in HRRs with HTCs had a wider range of median incomes ($27,978-$184,456 vs $35,087-$138,168; P&amp;lt;0.001) and a greater likelihood of falling above the 150% federal poverty line (77.9% vs 76.3%; P=0.014). Additionally, those residing in HRRs with HTCs were less likely to drive to work (75.0% vs 79.0%) and more likely to take public transit (4.4% vs 1.7%) or walk (3.0% vs 2.1%) than people in HRRs without HTCs ( P&amp;lt;0.001 for all). Conclusions: This analysis estimated that in the US, 4 of 5 pPwHA reside in an HRR with HTC access. HRRs with HTCs served larger populations with greater racial and socioeconomic diversity than HRRs without HTCs. While it is possible that PwHA who reside in HRRs without HTCs can still receive adequate care via outreach clinics, mobile units or virtual appointments, this work highlights that geographic barriers to HTC access remain incompletely addressed. Future efforts should focus on accurately identifying US hemophilia A populations and their locations relative to HTCs and comparing the impact on care and outcomes in those who rely on outreach efforts or mobile programs.

Proactive Systematic Hemophilia Carrier Screening: A Step Towards Gender Equity in Hemophilia Care

Introduction Despite multiple awareness-raising initiatives, and in contrast with male persons with hemophilia (PwH), a considerable number of carriers and female PwH still go undiagnosed. We here present the findings of a proactive and extensive hemophilia carrier screening project. Methods From May 2021 until April 2023, potential and obligate carriers of hemophilia A (HA) and B (HB) were identified by updating family trees of all PwH regularly followed at the Cliniques universitaires Saint-Luc. Data from previously screened female individuals (bleeding history, coagulation factor assays and testing for the index patient's pathological genetic variant) were collected retrospectively through electronic medical records (EMRs). Female individuals who had not been previously screened or with missing data were provided with a total of 125 invitation letters by related index hemophilia patients. The study protocol received approval of the local ethics committee. Results All 287 male PwH (226 HA, 61 HB) from 228 families (180 HA, 48 HB) were included in the analysis. Seven female PwH (3 HA, 4 HB) were considered as index cases in their families. In total, based on the family trees, there were 900 females, among which 454 were obligate and/or genetically proven carriers of hemophilia and 118 were found to be non-carriers (Figure 1). Mean age at diagnosis was 30.7 years (range 1-82) in families with HA and 30.1 years (range 0.5-93) in families with HB, without significant difference between these two groups (p=0.809) or between families with severe, moderate or mild hemophilia (p=0.535). Genetic testing for pathological variants has been conducted in 133 obligate, 237 potential and 4 sporadic carriers, and remains to be performed in 190 obligate and 328 potential carriers. Eight females were obligate non-carriers. The group of mothers, sisters and daughters of PwH comprised 543 females, of which at least 178 (35.7% of those with known date of birth) were of reproductive age (18-49 years). Seventy-three percent of females in the latter group have had genetic testing. The proportion of female individuals genetically tested did not significantly differ between families of different severities of HA (p=0.132). In families with moderate HB, female individuals were more likely to be tested (genetic status known in 59.4%) than in other HB severity groups (p=0.01), yet this may be attributed to the presence of one large family comprising 6 male persons with moderate HB and 22 female individuals, of whom a large proportion (n=18, 82%) has had genetic testing. Among carriers with known coagulation factor levels (261/454), 42 (23.0%) and 23 (29.5%) carriers of HA and HB, respectively, had a factor level below 40 IU/dL, and 65 (35.5 %) and 32 (41.0%) had a factor level below 50 IU/dL. The proportion of carriers with a factor level below 40 IU/dL did not significantly differ between families with severe, moderate and mild hemophilia (22.6%, 34.7% and 22.7% respectively, p=0.213), neither did mean coagulation factor levels in carriers with a factor deficiency in these groups (26.2, 30.4 and 27.1 IU/dL in families with severe, moderate and mild HA and HB, p=0.344). Carriers with a coagulation factor deficiency of less than 40 IU/dL were screened earlier than other female individuals (mean age at diagnosis 25.8 and 31.8 years, respectively, p=0.034). Conclusions This study represents the first reported attempt to systematically identify all (potential) hemophilia carriers within families of all PwH followed at a single hemophilia treatment center. To date, this initiative has allowed 44% of the entire cohort to be screened, and carrier status to be genetically confirmed in 73% of mothers, sisters and daughters of PwH who are of childbearing age, based on the date of birth documented in their EMR. Although original and promising, these data reflect the major challenges and difficulties in reaching out and providing appropriate screening to all women genetically linked to one or more PwH. The carrier screening efforts that have been initiated in our center, and which should ideally be replicated across the hemophilia community globally, appear as a critical step towards providing equal access to haemophilia diagnosis and care to all potentially affected individuals, regardless of their gender.

Female Hemophilia in a Set of Triplets

Female Hemophilia In A Set Of Triplets Introduction: Hemophilia A (HA) and B (HB) are the most common inherited bleeding disorders. Gene sequencing identifies specific mutations and their associations with plasma factor levels and clinical phenotypes. Both HA and HB are X-linked recessive disorders, where the female carriers pass the gene onto their descendants. Males who inherit the mutated gene from their mothers develop the disease, whereas females are carriers due to having one normal gene, they typically do not display the characteristic features of hemophilia and have moderately low factor VIII levels of less than 40%. Female carriers may have bleeding symptoms, yet they do not experience as severe morbidities as the male hemophilia patients, due to having higher plasma factor VIII levels. Rarely female carriers can be severely affected and may have plasma factor VIII activities comparable to those with severe hemophilia. Here we are presenting a set of triplets, where the male infant and one of his sisters have severe hemophilia while the other sister is a hemophilia carrier. Methods: A set of triplets a male and two female neonates were born after 33 weeks of gestation to a healthy mother. Female neonates were dichorionic but shared the same placenta. The male infant had a circumcision at six weeks of age, which was complicated with prolonged bleeding. He was brought to the hospital and was diagnosed with severe HA. (Table.1). Infant #2 was admitted to the hospital for skin rash at age 8 weeks. She had staphylococcal scalded skin syndrome and was treated with vancomycin and cephalexin. She was noted to have prolonged bleeding from needle puncture sites. She was diagnosed with severe HA. The bleeding was controlled with tight packing. After a week of treatment her rash cleared, and she was discharged home. (Table 1). Infant #3 She was a healthy baby with no bleeding problems. (Table 1). Results and conclusions: We presented three infant-triplets-with factor VIII deficiency; infant #1 and infant #2 have severe HA. Infant #3 is an asymptomatic carrier. They all have the same mutation as their asymptomatic carrier mother. Infant #1 the male infant developed severe HA due to having the hemophilia allele on his “X” chromosome. Infant #3 a female infant is an asymptomatic carrier. She inherited the hemophilia allele on the X chromosome from her carrier mother and has an X chromosome bearing the normal allele, thus is able to produce factor VIII of 40%. Infant #2 the other female infant had severe HA, with a factor VIII activity of &amp;lt;0.3%. Female hemophilia is rare occurrence. Hemophilia treatment center (HTT) population profile (PP) reported that of the 1,676 females attending to HTC, 47.6% of them had less than 40% factor level, 0.48% of them had severe, 1.4% had moderate and 17.9% had mild hemophilia[Haemophilia. 2021:27(6):1037-1044. Doi:10.1111}. This can occur, in the setting of monosomy X (Turner syndrome-XO), due to having one X chromosome carrying the hemophilic gene or in the setting of compound heterozygosity: the female product of a father with hemophilia and the mother being a carrier. Similarly, hemizygosity of the hemophilic gene on both parents would result in hemophilia in their daughters. Another mechanism that plays a role in the pathogenesis of female hemophilia is the “X chromosome inactivation (XCI). This has been described as the most common cause of female hemophilia. One of the two X chromosomes in females is randomly and permanently inactivated in cells to ensure the balance with one X chromosome of males and limit the overproduction of potentially toxic gene proteins. The degree of inactivation determines the plasma levels of the gene products, in hemophilia the factor levels. The chromosome analysis of infant #2 revealed normal 46XX. Structural chromosomal abnormality is ruled out as she did not have Turner syndrome “XO”, or “45XY” with androgen insensitivity syndrome, nor did she have compound heterozygosity or hemizygosity of the X chromosome. The father had normal coagulation studies and factor VIII activity. Therefore, we believe infant #2 had extremely skewed XCI and the inactivation is skewed in favor of hemophilic X chromosome. This mechanism resulted in severe HA in this infant. The infants are now seven months old and have no bleeding problems, as infant #1 and #2 are on prophylaxis with emicizumab (Hemlibra), they both have 1% factor activity by chromogenic assay and do not have inhibitors. (Table 1)

Developing an Algorithm to Better Identify Pregnant Women with Inherited Bleeding Disorders within Electronic Health Records

Background: When using electronic health records (EHRs) to conduct population-based studies on inherited bleeding disorders (IBDs), multiple studies demonstrated that using diagnoses codes alone result in a high number of false positive identifications (J Blood Med. 2017 Aug 30;8:131-139). To improve data integrity, in-depth chart reviews are often required which typically can only be done from a local institutional level. This limits the potential to use national research infrastructure such as the National Patient-Centered Clinical Research Network (PCORnet) which draws its data from millions of EHRs across healthcare institutions in the United States. Objective: The objective of this study was to test the diagnostic accuracy of an algorithm that utilized common data definitions and multiple data elements in EHR to identify pregnant women with IBDs. Methods: We used data for pregnant women with IBDs who delivered at our institution from January 1, 2016 to December 31, 2020 to test the accuracy of the algorithm. Women with IBD included those with the following diagnoses: hemophilia and hemophilia carriers, von Willebrand disease and rarer bleeding disorders including factor II, V, VII, X, XI and XIII deficiencies. We did not include the following diagnoses: Platelet function disorder, fibrinogen disorder or hereditary hemorrhagic telangiectasia. We used EHR data elements from EPIC Clarity data model that conformed to those from the PCORnet Common Data Model (CDM). The PCORnet CDM can help ensure consistent data definitions and formats across multiple sites to facilitate large-scale patient-centered research. The original version of our algorithm included the following: (i) ICD-9/10 codes for an inherited bleeding disorder (Table 1) based on discharge diagnosis of any patient encounter visit types including inpatient, outpatient and emergency visits (criterion 1); (ii) Medications used for management of IBD (criterion 2); and (iii) Coagulation factor test and results (criterion 3). A validated diagnosis of IBD required fulfilling either criteria (1) and (2) or criteria (1) and (3). To develop our algorithm in an iterative fashion, we ran sequential queries (queries 1.0-1.1) with revisions to our initial criteria. The results of our retrospective queries were confirmed to have an IBD (true positive) using our local registry and by manual chart review. The local registry is a clinical database that is housed with EPIC and includes accurate demographic, phenotypic, and laboratory data of all persons with a confirmed diagnosis of IBD seen at our federally-funded adult hemophilia treatment center. Sensitivity and the positive predictive value of the algorithm to identify pregnant women with IBDs were calculated. Results: Using our original algorithm (query 1.0), there were 301 pregnant women who fulfilled criterion 1 and had at least one live birth or fetal death (&amp;gt;20 weeks gestation) at our institution during the study period. Of these, only 25 fulfilled criteria 2 and/or criteria 3. For the 276 cases that did not fulfill criteria 2 or 3, we verified the diagnosis through our local registry or through a manual review of the charts. We found that the following ICD-diagnosis codes for IBD - Z14.8; 286.9/D68.8/D68.9; 286.3/D68.2 - resulted in contamination and could not be used to diagnose carriers of IBD or the rarer bleeding disorders. These diagnoses codes were removed and we added a fourth criteria in our revised algorithm (Table 2). For cases that did not fulfill criteria 2 or 3, a case was considered as having a diagnosis of IBD if they had at least two identical ICD diagnosis code for an IBD in at least 2 separate patient encounter visit types (criterion 4). The revised algorithm (query 1.1) identified 35 pregnant women with IBD, of which 32 were confirmed to be true positive. The 3 women incorrectly identified (false positive) by our revised algorithm had seen a hematologist for work-up for a possible IBD which was eventually ruled out. From the original cohort of 301 pregnant women who had an ICD diagnosis code of an IBD, one patient who was a carrier for hemophilia A was missed (false negative) by our revised algorithm. The sensitivity of the revised algorithm was 97.0% and the PPV was 91.4% Conclusion: This study demonstrates the feasibility of an algorithm to accurately identify pregnant women with specific types of IBD within an EHR.

PB0220 Clinical Presentation and Bleeding Severity in Women with Autosomal Inherited Bleeding Disorders and Hemophilia Carriers: Real-Life Data from the Spanish Registry

PB0220 Clinical Presentation and Bleeding Severity in Women with Autosomal Inherited Bleeding Disorders and Hemophilia Carriers: Real-Life Data from the Spanish Registry

PB1272 Impact of the Difference in the Cutoff Point of the Values of Clotting Factors VIII and IX in the Definition of Women with Hemophilia and Hemophilia Carrier

PB1272 Impact of the Difference in the Cutoff Point of the Values of Clotting Factors VIII and IX in the Definition of Women with Hemophilia and Hemophilia Carrier

PB1531 Management and Outcomes of Pregnancy and Childbirth in Known and Unknown Haemophilia Carriers: A Retrospective Analysis from a Reference Center in Italy

PB1531 Management and Outcomes of Pregnancy and Childbirth in Known and Unknown Haemophilia Carriers: A Retrospective Analysis from a Reference Center in Italy

Building a haemophilia-specific navigator in Epic® Electronic Health Records: Single-centre preliminary experience.

With the increasing complexity of haemophilia care and the advent of numerous therapeutic innovations, there is an unmet need for documentation and data collection tools tailored to people with haemophilia (PwH). To date, no fully integrated haemophilia-specific electronic health record (EHR) has been described in the literature. To evaluate the feasibility of integrating a haemophilia-specific navigator into the Epic EHR. Based on clinical experience and registry datasets, we identified key variables describing both PwH and carriers of haemophilia. These were then incorporated into a REDCap database, which served as a starting point for the development of a comprehensive haemophilia flowsheet. We built a dedicated haemophilia navigator within Epic that includes a flowsheet featuring up to 212 variables, as well as customised note templates and patient lists integrating data from the haemophilia flowsheet. It was feasible to develop a haemophilia navigator within Epic over the course of 12 months. The navigator's flowsheet enables systematic and comprehensive clinical assessment of PwH and carriers, while customised patient lists provide a quick summary of each patient's profile to the haemophilia treatment centre staff and highlight issues that require an intervention. In our clinical practice, patients actively participated in the new documentation process and responded positively to the navigator. Adapting EHRs to the needs of PwH and carriers promotes holistic care for this population and provides an opportunity for patient empowerment. Such haemophilia-specific EHRs are expected to promote standardisation of care and facilitate the collection of registry data on a national and international level.

Factor activity levels and bleeding scores in pediatric hemophilia carriers enrolled in the ATHNdataset.

Multiple studies have now shown that a significant proportion of hemophilia carriers meet the criteria for having hemophilia and/or report abnormal bleeding. However, to date, investigations of hemophilia carriers have almost exclusively involved women over 18 years of age. Little is known about factor activity levels and bleeding scores in carriers during childhood. We queried a large deidentified database of subjects with bleeding disorders residing in the United States to determine factor activity levels and bleeding scores. The ATHNdataset was queried for hemophilia carriers under 18 years of age. Collected information included demographics, factor activity levels, and bleeding scores. Over 700 carriers in the pediatric age group were identified, of which 626 submitted factor activity levels. Nearly half had factor activity levels less than 40IU/dL, thereby meeting criteria for having hemophilia. Of those reporting bleeding scores, only 13.5% reported an abnormal bleeding score for age. The proportion reporting abnormal bleeding scores was higher in those with factor levels less than 40IU/dL (23%) than those greater than 40IU/dL (9.7%). The proportion of pediatric carriers with hemophilia was double of that previously reported for adults. Of those with hemophilia reporting a bleeding score, the majority (77%) did not report an abnormal bleeding score for age. However, nearly 10% of pediatric carriers not meeting criteria for having hemophilia reported abnormal bleeding scores for age. Similar results are reported in adults suggesting that factor activity levels may not be predictive of bleeding symptoms in carriers.