Rare Bleeding Disorder Research Articles

Mapping the Patient Experience in a Pediatric Hemophilia Unit: Our Patient Journey.

Background: Hemophilia is a rare X-linked bleeding disorder. Prophylaxis has improved outcomes, but there are still unmet needs to be addressed. The aim of this study was to develop a patient journey in pediatric patients with hemophilia, a visual tool that illustrates patients' relationship with the healthcare provider through time useful for identifying patient needs, potential concerns ("pain points"), and gaps in care. Methods: qualitative study in a pediatric hemophilia unit using a human-centered design methodology. First stage: discover and empathize: (a) semi-structured interviews to patients/families and stakeholders; (b) observation techniques ("shadowing") to patients/families and professionals. Second stage: analyzing the collected information to create the patient journey. Results: A preliminary "clinical journey" was built using information from eight interviews with professionals from the interdisciplinary hemophilia team. Interviews with patient association representatives, 13 patients/families, and six "shadowing" techniques with patients and professionals were used to compare the "clinical journey" with the patient's reported experience. Main "pain points" were detected before diagnosis, at diagnosis, during assimilation, at treatment initiation, during training, and when patients start asking about their condition. The empowerment process was detected as a potential moment to improve patient/family experiences. Conclusions: The patient journey helps to better understand patient/family experiences related to the disease in different scenarios. Caregivers and patient learning and empowerment processes are significant moments where the interdisciplinary team should focus to offer valuable solutions to improve outcomes. Further research is required in this area, particularly empirical research to amend or confirm the suggested patient journey.

Patient Experience With Efanesoctocog Alfa for Severe Hemophilia A: Results From the XTEND-1 Phase 3 Clinical Study Exit Interviews

PurposeHemophilia A is a rare bleeding disorder that leads to recurrent hemarthrosis, which can ultimately result in reduced mobility and poor quality of life. Qualitative exit interviews provide insights into patient perspectives and support the interpretation of quantitative trial data, such as patient-reported outcome measures. In the Phase 3 XTEND-1 study (NCT04161495) of efanesoctocog alfa in participants with severe hemophilia A, exit interviews were conducted to understand pre- and post-study experiences with pain and physical functioning and to evaluate participants’ treatment experiences. MethodsIn XTEND-1, participants (≥12 years old) received once-weekly efanesoctocog alfa prophylaxis 50 IU/kg for 52 weeks (Arm A) or on-demand efanesoctocog alfa 50 IU/kg for 26 weeks followed by 26 weeks once-weekly prophylaxis (50 IU/kg; Arm B). Optional qualitative exit interviews were conducted using a semi-structured guide in a subset of participants following study completion. Interviews included open-ended questions about participants’ pre- and post-study experiences with hemophilia A and targeted questions relating to improvements in patient-reported outcomes assessed during XTEND-1, including the Haemophilia Quality of Life Questionnaire for Adults Physical Health subscale (Haem-A-QoL PH). Content validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Intensity 3a measure was also assessed, particularly the worst pain item. FindingsExit interviews were conducted with 29 of 159 patients enrolled in XTEND-1 (mean [range] age 40 [16−73] years). Of 17 participants enrolled in Arm A, 13 (76.5%) reported a “wearing off” feeling with pre-study treatment, including more aches/pain, breakthrough bleeds, and limited physical activities. Joint pain was the most reported pre-study symptom (96.6%; n = 28/29), followed by a reduced ability to move without pain (89.7%, n = 26/29). Improvements following efanesoctocog alfa prophylaxis in ≥1 Haem-A-QoL PH domain were reported by 89.7% (n = 26/29) of participants, with improvements in joint pain, the ability to move without pain, and painful swellings reported by at least 21 (84%) participants. Participants reported that the PROMIS Pain Intensity 3a items were relevant, clear, and easy to answer. Most participants (96.6%) were “quite satisfied” or “very satisfied” with efanesoctocog alfa prophylaxis. All participants preferred efanesoctocog alfa over pre-study treatment. ImplicationsThe exit interviews demonstrated that once-weekly efanesoctocog alfa prophylaxis resulted in patient-relevant and meaningful improvements in pain and physical functioning, consistent with the quantitative findings from XTEND-1. These results support the validity of the Haem-A-QoL PH and PROMIS Pain Intensity 3a assessed during XTEND-1, demonstrating the potential for change with efficacious treatment. Trial RegistryClinicalTrials.gov Trial Registration NumberNCT04161495 Registry URLhttps://clinicaltrials.gov/study/NCT04161495

Acquired hemophilia A as a disease of the elderly: A comprehensive review of epidemiology, pathogenesis, and novel therapy

AbstractAcquired hemophilia A (AHA) is a rare autoimmune bleeding disorder characterized by the development of neutralizing autoantibodies (inhibitors) against coagulation factor VIII (FVIII). This review provides an in-depth exploration of AHA, covering its epidemiology, pathogenesis, clinical presentation, diagnosis, complications, and treatment strategies, focusing on recent advancements. AHA can manifest in both men and women with no prior bleeding history. The annual incidence is estimated to be approximately 1 case per million individuals in the general population. The incidence increases significantly with age: the incidence among individuals aged 60 years or older is approximately 3 to 4 cases per million individuals per year. Typically, patients present with an acquired bleeding disorder that is characterized by an isolated, prolonged activated partial thromboplastin time stemming from FVIII deficiency. Diagnosis relies on the detection of neutralizing antibodies using the Nijmegen-modified Bethesda assay. Hemostatic control strategies involve bypassing agents like recombinant activated factor VII, activated prothrombin complex concentrate, and recombinant porcine FVIII for bleeding patients. Emicizumab, a novel bypassing agent, exhibits several potential advantages. In the realm of immunosuppressive treatment for inhibitor eradication, the CyDRi regimen emerged as a remarkable advancement, significantly enhancing the outlook for the management of AHA even in the elderly frail population.

A Phase 1b PK/PD Study to Demonstrate Antigen Elimination with RLYB212, a Monoclonal Anti-HPA-1a Antibody for FNAIT Prevention.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare bleeding disorder of the fetus/newborn caused by development of maternal alloantibodies against fetal human platelet antigens (HPAs), predominantly HPA-1a. Currently there are no treatments available to prevent maternal alloimmunization to HPAs or FNAIT. This proof-of-concept study (EudraCT Number: 2021-005380-49) was designed to assess the ability of subcutaneous (SC) RLYB212, a monoclonal anti-HPA-1a antibody, to eliminate HPA-1a-positive platelets in an antigen challenge model of a 30 mL fetal-maternal hemorrhage. Subjects were randomized to receive a single SC dose of RLYB212 or placebo on day 1 in a single-blinded manner, followed by transfusion of 10 × 109 HPA-1a-positive platelets on day 8. Four subjects received 0.09 mg SC RLYB212, five received 0.29 mg SC RLYB212, and two received placebo. RLYB212 achieved rapid elimination of HPA-1a-positive platelets in a concentration-dependent manner, with concentrations as low as 3.57 ng/mL meeting the prespecified proof-of-concept criterion of ≥90% reduction in platelet elimination half-life versus placebo. Following HPA-1a-positive platelet transfusion, a rapid decline was observed in the concentration of RLYB212 over a period of 2 to 24 hours, corresponding to the time needed for RLYB212 to bind to ∼10% of HPA-1a on cell surfaces. RLYB212 was well tolerated with no reports of drug-related adverse events. The data from this study are consistent with preclinical efficacy data and support the potential use of RLYB212 as a prophylactic treatment for FNAIT that prevents maternal HPA-1a alloimmunization during at-risk pregnancies.

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.

Clinical, Laboratory Aspects and Management of Factor X Deficiency.

Coagulation factor X (FX), originally named Stuart-Prower factor, plays a pivotal role in the coagulation cascade, activating thrombin to promote platelet plug formation and prevent excess blood loss. Genetic variants in F10 may lead to FX deficiency and to impaired coagulation. FX variants are phenotypically classified as being type I, with the concomitant reduction of FX coagulant activity and FX antigen levels or type II, corresponding to a reduction in activity with normal antigen plasma levels. Patients affected with FX deficiency tend to be one of the most seriously affected among those with rare bleeding disorders. They show a variable bleeding tendency strongly associated with FX coagulant activity levels in plasma and may present, in the severe form of the deficiency, life-threatening symptoms such as gastrointestinal and umbilical stump bleeding and intracranial hemorrhages or central nervous system bleeding. Treatment of FX deficiency was originally based on the replacement of the missing factor using fresh frozen plasma, cryoprecipitate and prothrombin complex concentrates; however, a plasma-derived concentrate, shown to be safe and effective in clinical trials, is now available. In addition, novel nonreplacement therapy such as small interference RNA, gene therapy, drug repurposing, and gene editing may also represent novel therapeutic approaches for FX deficiency, but further, much focused studies are needed before considering this emerging therapy in such patients.

Clinical, Laboratory, and Molecular Aspects of Factor VII Deficiency.

Congenital factor VII (FVII) deficiency, the most frequent among the recessively inherited disorders of blood coagulation, is characterized by a wide range of symptoms, from mild mucosal bleeds to life-threatening intracranial hemorrhage. Complete FVII deficiency may cause perinatal lethality. Clinically relevant thresholds of plasma levels are still uncertain, and modest differences in low FVII levels are associated with large differences in clinical phenotypes. Activated FVII (FVIIa) expresses its physiological protease activity only in a complex with tissue factor (TF), which triggers clotting at a very low concentration. Knowledge of the FVIIa-TF complex helps to interpret the clinical findings associated with low FVII activity as compared with other rare bleeding disorders and permits effective management, including prophylaxis, with recombinant FVIIa, which, however, displays a short half-life. Newly devised substitutive and nonsubstitutive treatments, characterized by extended half-life properties, may further improve the quality of life of patients. Genetic diagnosis has been performed in thousands of patients with FVII deficiency, and among the heterogeneous F7 mutations, mostly missense changes, several recurrent variants show geographical distribution and identity by descent. In the general population, common F7 polymorphisms explain a large proportion of FVII level variance in plasma through FVII-lowering effects. Their combination with pathogenic variants may impact on the frequent detection of FVII coagulant levels lower than normal, as well as on mild bleeding conditions. In the twenties of this century, 70 years after the first report of FVII deficiency, more than 200 studies/reports about FVII/FVII deficiency have been published, with thousands of FVII-deficient patients characterized all over the world.

Clinical, Laboratory, and Molecular Aspects of Factor V Deficiency.

Factor V (FV) is a glycoprotein that plays a pivotal role in hemostasis, being involved in coagulant and anticoagulant pathways. Congenital FV deficiency is a rare bleeding disorder with an incidence of 1 per million live births, considering the most severe homozygous form. FV deficiency is diagnosed using routine coagulation tests and FV activity assays. Several mutations, including missense, nonsense, and frameshift, have been detected in the F5 gene. Clinical symptoms are variable, ranging from mild ecchymoses and mucosal bleeding to life-threatening intracranial hemorrhage. The mainstay of treatment includes fresh-frozen plasma, preferentially virus-inactivated. In this narrative review, we provide an update of the main laboratory, molecular, clinical, and therapeutic features of inherited FV deficiency.

A rare case of glanzmann thrombasthenia with concomitant factor VII deficiency.

Glanzmann thrombasthenia and clotting factor VII deficiency are rare autosomal recessive bleeding disorders. But the occurrence of both in the same person is an extremely rare phenomenon. Here, we present the case of a young female from Sindh, Pakistan that got diagnosed with Glanzmann thrombasthenia and concomitant moderate factor VII deficiency, a combination not previously reported in the country. The patient exhibited typical clinical manifestations including menorrhagia, nasal bleeds, and prolonged bleeding after minor injuries, compounded by a positive family history and consanguinity. Laboratory investigations revealed marked anemia, prolonged bleeding time, and abnormal platelet aggregation studies consistent with Glanzmann thrombasthenia. The identification of this rare combination relied on comprehensive clinical evaluation, emphasizing the importance of family history in suspected cases. Management involved platelet transfusions, tranexamic acid, and Factor VII replacement, resulting in clinical improvement.

Efficacy and safety of recombinant porcine factor VIII in Japanese patients with acquired hemophilia A

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies inhibiting human factor VIII (hFVIII). This phase II/III open-label study evaluated the safety and efficacy of recombinant porcine factor VIII (rpFVIII, susoctocog alfa) in adults with AHA and severe bleeding episodes in Japan (NCT04580407). The initial rpFVIII dose was 200 U/kg, with subsequent doses based on clinical measures including plasma FVIII activity. The primary efficacy endpoint was the proportion of severe bleeding episodes with a positive response to rpFVIII therapy 24 h after treatment initiation. Five patients were eligible for, and completed, rpFVIII treatment (age group: 60s–80s; median hFVIII inhibitor: 52 BU/mL; porcine FVIII [pFVIII] inhibitor: 3/5 patients). The median (range) total dose/patient was 548.4 (198–1803) U/kg with a median 3.0 infusions/patient. All patients responded positively to rpFVIII therapy at 24 h regardless of baseline pFVIII inhibitor status. rpFVIII treatment was well tolerated with no adverse events of special interest such as thromboembolic events or de novo pFVIII inhibitors. This study supports the use of rpFVIII as a novel therapy in the clinical management of patients with AHA in Japan. rpFVIII was approved for treating bleeding episodes in adults with AHA in Japan in 2024.

Hereditary coagulation factor VII deficiency caused by novel compound heterozygous mutations c.572-1G>A and c.1037A>C in a Chinese pedigree

Hereditary coagulation factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder. The aims of this study were to identify and verify the pathogenic mutation sites in a family with hereditary coagulation FVII deficiency, and preliminarily explore the underlying mechanisms. We identified a novel combination of compound heterozygous mutations, c.572-1G>A and c.1037A>C in F7 gene, associated with FVII deficiency. The splice site mutation c.572-1G>A led to a truncation, resulting in the loss of the essential catalytic domain of the FVII protein. The c.1037A>C missense mutation has not been previously reported. Our study revealed that this mutation leads to steric hindrance between residues, causing significant changes in the energy and structure of the FVII protein, ultimately affecting its function. These changes disrupt the normal function of the FVII protein, accelerating the development of inherited FVII deficiency. Moreover, the mRNA expression of the F7 gene and the protein expression of the FVII antigen (FVII: Ag) were significantly lower in the proband, as well as in the proband's parents, compared to the healthy control (P<0.05). Our findings not only elucidate the genetic underpinning of FVII deficiency in the family studied but also contribute a new mutation to the known disease spectrum, potentially assisting in future diagnostic and therapeutic approaches.

Acquired Hemophilia A (AHA): A Rare Bleeding Disorder In a Tertiary Care Hospital In Dhaka, Bangladesh

Acquired Hemophilia A (AHA) is a rare bleeding disorder. This results from autoantibodies to factor VIII (FVIII) that neutralizes the ability of factor VIII. This causes potentially severe bleeding episodes that carries a high risk of morbidity and mortality. Acquired Hemophilia usually occurs over 60 years of age or in postpartum period and associated with other autoimmune conditions. The diagnosis should be suspected when patients with new onset of bleeding without prior personal or family history of bleeding. The hallmark of this condition is mucocutaneous bleeding leading to ecchymosis, malena, hematoma, hematuria and spontaneous oozing from wounds. Management should uphold both hemostatic therapies to minimize bleeding and immune modulation strategies to re-establish immune tolerance to factor VIII. Here we present an older male case of such Acquired Hemophilia A without history of previous anticoagulant therapy as well as family history or personal history of bleeding episodes. The patient has got hemiarthroplasty with prosthesis with bone cementing due to fracture neck of femur. After 10th post-operative day he was diagnosed with clot retention in catheter in-situ and oozing from wound site after 12th post-operative day. His laboratory reports showed prolongation of Prothrombin Time (PT) and Activated Partial Prothrombin Time (APTT). His factor VIII was very low level and factor VIII inhibitor showed the time depended inhibitor presence. Thus diagnosed as Acquired Hemophilia A (AHA), the rare case in Bangladesh. He was managed with medications that resulted in normalization of factor VIII level. J MEDICINE 2024; 25: 173-175

A rare bleeding disorder with severe haemorrhagic manifestation

Factor V is a major part of the coagulation system and maintains a balance in pro-coagulant and anticoagulant pathways. Any deficiency or mutation can lead to disequilibrium in coagulation. Factor V deficiency can be congenital or acquired. Congenital factor V deficiency (parahemophilia or Owren’s disease) is a rare autosomal recessive condition. We present a case of an adolescent unmarried girl presenting with an acute abdomen and deranged coagulation parameters. It was confirmed that the bilateral haemorrhagic ovarian cysts and hemoperitoneum were due to factor V deficiency. In her case, the bleeding was likely due to a ruptured corpus luteum during ovulation. She was successfully managed conservatively with red cells and fresh frozen plasma transfusions, tranexamic acid and combined oral contraceptive pills (COCP) with instructions to continue the use of COCP to prevent such bleeding manifestations.

Acquired Hemophilia A after SARS-CoV-2 Immunization: A Narrative Review of a Rare Side Effect.

Acquired hemophilia A (AHA) is a rare bleeding disorder (1.4 per million inhabitants per year) caused by neutralizing antibodies against factor VIII. Although uncommon, these autoantibodies can cause a high rate of morbidity and mortality. Several conditions are linked with AHA; based on an EACH2 study, 3.8% of AHA could be connected to infection. In the last four years, most humans have contracted the SARS-CoV-2 infection or have been vaccinated against it. Whether or not COVID-19 immunization might induce AHA remains controversial. This review aims to evaluate the evidence about this possible association. Overall, 18 manuscripts (2 case series and 16 case reports) were included. The anti-SARS-CoV-2 vaccination, as also happens with other vaccines, may stimulate an autoimmune response. However, older individuals with various comorbidities are both at risk of developing AHA and of COVID-19-related morbidity and mortality. Therefore, the COVID-19 vaccine must always be administered because the benefits still outweigh the risks. Yet, we should consider the rare possibility that the activation of an immunological response through vaccination may result in AHA. Detailed registries and prospective studies would be necessary to analyze this post-vaccine acquired bleeding disorder, looking for possible markers and underlying risk factors for developing the disease in association with vaccination.

Patient Perspective on Disease Burden and Gene Therapy for Hemophilia A and B: The "Haemvolution for Patients" Italian Survey.

Hemophilia is a rare X-linked congenital bleeding disorder due to a deficiency of factor VIII (hemophilia A [HA]) or factor IX (hemophilia B [HB]). Replacement and nonreplacement treatments are available but have limitations. Gene therapy (GT) provides an effective, long-term, single-dose treatment option, now approaching clinical practice. This study aimed to understand patient perspectives on GT for HA and HB in Italy using a qualitative questionnaire distributed through Italian patient associations, addressing patient views on daily life, treatments, unmet needs, quality of life (QoL), and GT for hemophilia. In total, 141 participants had HA, and 14 had HB (severe 78.6%). Daily life was most affected by pain and/or joint function limitations (57.5% of participants), high infusion frequency (42.5%), management of breakthrough bleeding episodes (40.3%), and anxiety/fear of severe or sudden bleeding (38.8%). Despite current treatments, about half of the participants experienced three or more annual bleeding episodes. Most participants knew of GT (87.2%) and expected improvements in QoL (60.5%), reduced frequency of current treatments (53.5%), and a permanent cure (49.1%); 46.4% were unaware of its once-off dosage and 46.4% were not concerned about the costs they anticipated to be associated with GT. Although several fears were reported, 25.0% of participants were willing to undergo GT with the support of a multidisciplinary team. This survey provided valuable insight into patient perspectives on hemophilia and GT in Italy. Overall, relevant proportions of patients still experience limitations affecting their daily life. Most were positive about GT and anticipated improvements in their clinical outcomes and QoL.

Psychometrics of patient-reported outcomes measurement information system in von Willebrand disease, inherited platelet function disorders, and rare bleeding disorders

BackgroundPatient-reported outcomes measurement information system (PROMIS) measures can be used to measure patient-reported outcomes. PROMIS measures, including computer adaptive tests (CATs) and short forms, have demonstrated the ability to adequately assess outcomes in patients with hemophilia. It is, however, unclear if PROMIS measures are suitable for patients with von Willebrand disease (VWD), inherited platelet function disorders (IPFDs), and rare bleeding disorders (RBDs). ObjectivesTo evaluate the feasibility, measurement properties, and relevance of PROMIS measures in adults with VWD, IPFDs, and RBDs. MethodsIn this cross-sectional multicenter study, adults with VWD, IPFDs, and RBDs completed 9 PROMIS measures and the Short Form-36 version 2 (SF-36v2) electronically. Feasibility was determined by the number of completed items and floor/ceiling effects. Measurement properties included construct validity based on a multitrait–multimethod analysis and reliability using the reliability coefficient and greatest lower bound. Relevance was evaluated based on comparison with the Dutch general population. ResultsIn total, 111 patients (median age, 57 years [IQR, 44-67]; 60% VWD, 16% IPFD, 24% RBD) participated. Mean number of items answered varied from 5.3 to 8.7 (range, 4-12) per PROMIS CAT in patients with VWD. Construct validity was supported for all CATs and all instruments had a good reliability (≥0.70). The PROMIS measures had less ceiling effects than the SF-36v2. ConclusionThe PROMIS measures are a feasible, valid, and reliable alternative for the SF-36v2 in patients with primarily nonsevere forms of VWD. The relevance of the selected measures was limited. Additional research is necessary to evaluate the PROMIS measures in adults with IPFDs and RBDs.

Targeted exome analysis in patients with rare bleeding disorders: data from the Rare Bleeding Disorders in the Netherlands study

BackgroundRare coagulation factor deficiencies and disorders of fibrinolysis (defined as rare bleeding disorders [RBDs]) present with a heterogeneous bleeding phenotype, and bleeding severity is difficult to predict. ObjectivesDescribe underlying rare genetic variants in the Dutch RBD population and investigate the relationship between genotype, laboratory phenotype, and clinical phenotype. MethodsThe Rare Bleeding Disorders in the Netherlands is a cross-sectional, nationwide study conducted between October 1, 2017, and November 30, 2019. Bleeding scores and blood samples were collected during a single study visit. Coagulation factor levels were measured centrally, and targeted exome analysis was performed on 156 genes involved in thrombosis and hemostasis. Pathogenicity was assigned according to the Association for Clinical Genetic Science guidelines. ResultsRare genetic variants specific to the diagnosed RBD were found in 132 of 156 patients (85%). Of the 214 rare genetic variants identified, 57% (n = 123) were clearly pathogenic, 19% (n = 40) were likely pathogenic, and 24% (n = 51) were variants of unknown significance. No explanatory genetic variants were found in patients with plasminogen activator inhibitor type 1 deficiency or hyperfibrinolysis. A correlation existed between factor activity levels and the presence of a genetic variant in the corresponding gene in patients with rare coagulation factor deficiencies and alpha-2-antiplasmin deficiency. Co-occurrence of multiple genetic variants was present in a quarter of patients, but effect on phenotype remains unclear. ConclusionTargeted exome analysis may offer advantages over single-gene analysis, emphasized by a number of combined deficiencies in this study. Further studies are required to determine the role of co-occurring hemostasis gene variants on the bleeding phenotype in RBDs.

Clinical and molecular characteristics of hemophilia A affected individuals and carriers: A 24 years experience from three centers.

Hemophilia A is a rare bleeding disorder with variable expressivity and allelic heterogeneity. Despite the advancement of prenatal diagnostics and molecular studies, the number of studies reviewing the reproductive choices of hemophilia A carriers and affected individuals remains limited. Through this retrospective review, we hope to gain a deeper understanding of hemophilia A-affected individuals' clinical and molecular characteristics, as well as the reproductive choices of the at-risk couples. A total of 122 individuals harboring likely causative F8 gene alterations from 64 apparently unrelated families attending three centers between 3/2000 and 3/2023 were included in this study. Their clinical and molecular findings as well as reproductive choices were gathered in a clinical setting and verified through the electronic medical record database of the public health system. Forty-seven affected males and 75 female heterozygous carriers were included in the analysis. Among 64 apparently unrelated families, 36 distinct pathogenic/likely pathogenic variants were identified, of which 30.6% (11/36) of variants were novel. While the majority of clinical findings and genotype-phenotype correlations appear to be in accordance with existing literature, female carriers who had no fertility intention were significantly more likely to have affected sons than those who had fertility intention (5/19 vs. 4/5; p = 0.047). Through this retrospective review, we summarized the clinical and molecular characteristics of 122 individuals harboring pathogenic/likely pathogenic F8 variants, as well as their fertility intentions and reproductive outcomes. Further studies are required to look into the considerations involved in reproductive decision-making.

Severe haemorrhages leading to a diagnosis of rare bleeding disorder occur at a very young age: A study from the FranceCoag network.

In the context of severe unexplained haemorrhage (SH), it is usual to seek haematological evaluation and investigate for an inherited rare bleeding disorder (IRBD). In such circumstances, appropriate screen can discriminate between IRBD and suspected child abuse. Yet, little information is available about the frequency of SH in the population of patients with IRBD. To collect epidemiologic data about SH and IRBD. The database of the FranceCoag network has collected information about IRBD since January 2004. Based on data gathered up to 16 March 2022, a retrospective search was conducted for of SH events having occurred before or at the time of IRBD diagnosis. Demographics and diagnosis circumstances were retrieved, as well as information about SH, defined as any life-threatening bleeding or intracranial haemorrhage. Among the 13,433 patients of the database, 109 (0.8%) fulfilled inclusion criteria including a known date of IRBD diagnosis, haemophilia A or B (HA/HB) being the most frequent (82.5%). IRBD was discovered as a consequence of an SH event in 82.6% of the cases while CNS was involved in 55%. Severe and moderate HA/HB and other severe IRBD presented significantly more intracranial haemorrhage (p<.02) and a lower age at diagnosis (p=.03). These data support that any unusual SH should raise a suspicion of IRBD. Particularly before 1-year of age, it is suggested to first confirm moderate or severe haemophilia and severe IRBD by standard coagulation tests (APTT, PT and fibrinogen), combined with a clotting FXIII assay as first-line investigation. Subsequent assays of coagulation factors should be performed in the case of abnormal values, in second-line investigation.

Rare bleeding disorders in Egyptian females presented with heavy menstrual bleeding: single-center study

BackgroundHeavy menstrual bleeding is an important health problem in women of reproductive age and is also one of the most common symptoms in women with bleeding disorders. Data about the frequency of rare bleeding disorders are limited, and population-based studies are lacking, so we aimed to determine the frequency of rare bleeding disorders among women presented with heavy menstrual periods that cannot be attributed to obvious problems.MethodsComplete blood count and bleeding profiles include activated partial thromboplastin time, prothrombin time, factor VIII activity assay, ristocetin cofactor activity, von Willebrand antigen assay, platelet aggregation tests and other factor assays in 100 out of 300 females presented with unexplained heavy menstrual period, pictorial bleeding assessment chart (PBAC) > 100 as a screening tool for heavy menstrual periods, and or International Society of Thrombosis and Hemostasis-Bleeding Assessment Tool (ISTH-BAT) > 6.ResultsA total of 300 women with heavy menstrual periods without an obvious explained cause were included in our study. Among them, we found 100 (30%) females with a mean PBAC of 234 ± 147 and mean ISTH-BAT of 9 ± 5 denoting HMB may be due to underlying bleeding disorders. Among them, the most common diagnosis was VWD in 30 (30%). Other disorders were as follows: 28 (28%) cases with clotting factor deficiencies, 24 (24%) cases were found to have platelet dysfunction, and in 18% of our studied cases, we did not find a clear cause of their bleeding disorders (unknown).ConclusionRare bleeding disorders are not uncommon and require comprehensive hemostatic evaluation as well as simple tools like PBAC and ISTH-BAT questionnaires for the identification of females presented with unexplained HMB.