Diagnosis Of Hemophilia Research Articles

Concurrent diagnosis of severe haemophilia A and acute lymphoblastic leukemia in a child: First report in Greece

Haemophilia A is a congenital bleeding disorder resulting by deficiency of coagulation factor VIII and Acute Lymphoblastic Leukemia (ALL) Is the most common cancer type in children. The concurrence of hemophilia and ALL in pediatric patients is quite rare. We report a case of a 2.5 year old boy, with an uneventful past history, which presented with pallor, petechiae, ecchymoses and lethargy to the emergency department. A full blood count on admission revealed severe leukocytosis, anemia and thrombocytopenia. Diagnosis of ALL was confirmed and the patient was put on chemotherapy. Excessive bleeding from the site of entry of the central venous catheter led to complementary testing, which revealed very low levels of Factor VIII and severe Haemophilia A was also diagnosed. The patient suffered from minor gastrointestinal bleeds and a severe intrabdominal hemorrhage due to an abcess eruption during his treatment for ALL. To date, very few cases of ALL and Haemophilia have been reported in children, and due to this rarity there are no guidelines concerning the adjustments in treatment in this small population of patients.

Diagnosis of hemophilia b after free gingival graft operation

Diagnosis of hemophilia b after free gingival graft operation

Hemophilia A in a male cat with intermittent lameness

A 3-month-old domestic shorthair tomcat born on a farm was unsuccessfully treated with meloxicam for alternating lameness, fever and inappetence. On presentation, there was lameness (grade 2/4) of the right forelimb with mild swelling of the soft tissue. Rectal temperature was 39.9°C, a moderate anemia developed. Inadequate bleeding occurred during arthrocentesis performed on suspicion of polyarthritis. Coagulation tests revealed an isolated prolonged activated partial thromboplastin time (aPTT). Activity of factor VIII was 5% (reference range: 70-125%), of factor IX 55% (80-130%), and of factor XII 73% (50-140%).In a genetic study, exons and adjacent intron sequences of the feline F8-gene were sequenced and compared with the reference (ENSFCAT000078256.1). While no non-synonymous variants were found in coding sequences, intron 19 revealed the variant c.6073+2 T>C. This variant likely results in splice site alteration, atypical splicing, and thus an altered mRNA for FVIII.The patient was treated symptomatically (metamizole, buprenorphine, tranexamic acid) and clinical signs improved. Chemical castration with a GnRH implant was performed at 8 and 18 months of age, whereby minor bleeding at the implantation site occurred after the second implantation. After 3.5 years, the cat lives nearly without clinical signs of bleeding.aPTT prolongation with normal PT indicated a factor deficiency. Determination of factor activity led to the diagnosis of hemophilia A. Genetic testing detected a splice variant in the F8-gene.

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.

The Role of Clot Waveform Analysis and Related Parameters in the Diagnosis and Treatment of Hemophilia A.

Hemophilia A (HA) is an inherited bleeding disorder caused by a deficiency or defect in factor VIII (FVIII). We investigated the role of clot waveform analysis (CWA) of activated partial thromboplastin time in the diagnosis and therapeutic monitoring of HA. The changes in CWA parameters the maximum clotting velocity (|Min1|), maximum clotting acceleration (|Min2|), and maximum clotting deceleration (|Max2|) were detected among mild, moderate, and severe HA groups. As the severity of HA subtypes increased, the levels of |Min1|, |Min2|, and |Max2| progressively decreased (p < 0.05). Receiver operating characteristic curve analysis showed that |Max2| and |Min2| were more effective than |Min1| in distinguishing different types of HA patients, with higher diagnostic efficacy. The standard curves based on Actin FSL reagent for normal and low levels of FVIII:C-|Max2| were established, with R2 values of 0.98 and 0.99, respectively. These curves can be utilized for monitoring during replacement therapies involving full-length recombinant FVIII and B-domain-deleted FVIII. Thirty cases of HA patients utilized the FVIII-|Max2| standard curve to obtain individual pharmacokinetics characteristic parameters. The clearance, half-life (t1/2), time to FVIII:C of 1% above baseline (tt1%), and predicted dosage showed no statistically significant differences compared with one-stage assay (p > 0.05). CWA is an economical and practical tool, and its related parameters are associated with the severity of HA. It has promising clinical prospects in predicting FVIII:C levels and individualized treatment when HA patients undergo replacement therapy.

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.

Defining success in haemophilia care - Are we doing it right?

Transformational advances have occurred in the management of haemophilia in the last decade leading to much better outcomes. However, a detailed and critical examination of its assessment and reporting show gaps in many aspects. These are discussed in this review. The relevant literature related to different aspects of management of haemophilia was reviewed to identify gaps which need to be addressed. These include detection and diagnosis of haemophilia, documentation and reporting of joint bleeding, its management and methods of reporting in clinical trials and practice, aspects of personalizing care as well as access to therapeutic products and the need for and organization of comprehensive care. Current diagnostic approaches have more than doubled the identified number of persons with haemophilia (PWH) over the last 25 years but still constitute only ∼30% of the expected number. Joint bleeding is the primary indicator of disease severity and treatment efficacy, but there is lack of consistency and standardization in the way it is recorded and reported. Its continued use as an efficacy measure of modern treatments which maintain steady state factor levels or equivalence of>5% will lack sensitivity. The treatment of acute haemarthrosis has focussed on haemostasis and pain control, ignoring the role of inflammation in joint damage. Phenotypic heterogeneity of severe haemophilia has recognized clinical and laboratory variations based on haemostasis but not differences in local response to blood in the joint. At the organizational level, IU/capita provides a relevant measure of access to therapeutic products when the detection rate is ∼100% but is fallaciously low when detection rates are very low. With highly effective modern therapies for haemophilia and nearly no bleeding, the concept of comprehensive care team will need modifications. As haemophilia care advances, a deeper dive is needed into the details of various aspects its management to ensure consistency and contemporary relevance.

Intrinsic tenase blood biomarker imprinted polymer-aptasensor with carbon nanohorn and gold nano-urchin construct for primitive-phase diagnosis of haemophilia B

The selective biomimetic aptasensor for blood coagulation factor IX protein (FIX) detection was developed using an interdigitated electrode with an Archimedean spiral pattern. In contrast to conventional molecularly imprinted polymer (MIP) techniques, aptamer was employed as a macromonomer to accelerate double binding affinity. To preserve the aptamer profile in its protein-binding orientation, FIX protein and thiol-modified RNA aptamers were complexed prior to MIP fabrication. The immobilized aptamer-FIX complex was surrounded by a polymer generated by the electropolymerization of 3-thiophene acetic acid (3TAA). Subsequent to FIX protein removal, leaves imprinted cavities facilitate selective FIX protein detection in conjunction with the affinity of embedded aptamer affinity. The Archimedean IDE surface was functionalized with carbon nanohorn (CNH) and gold nanourchin (GNU) to increase the imprinting ratios and sensor sensitivity. The developed FIX-aptasensor shows a detection limit of 0.06 fM, which is 660-fold higher than aptamer-embedded MIP nanoparticles. Moreover, the sensor exhibited greater selectivity for FIX, discriminating IgG and thrombin. As a preliminary study for clinical use, the sensor was used to analyze human serum without target spiking and detected FIX-protein with a relative standard deviation of 9.18%. It was ascertained that the sensor maintained 85% sustained performance for a duration of five weeks.

Health-related quality of life and its associated factors among hemophilia patients: experience from Ethiopian Hemophilia Treatment Centre

BackgroundHemophilia is a rare genetic condition that is often overlooked and underdiagnosed, particularly in low-income countries. Long-term spontaneous joint bleeding and soft tissues can have a significant negative impact on a patient’s health-related quality of life (HRQoL). The objective of this study was to assess HRQoL and its associated factors in Ethiopian patients with hemophilia.MethodsA cross-sectional survey was conducted among patients with hemophilia at Tikur Anbessa Specialized Hospital (TASH) in Addis Ababa, Ethiopia. Patients were recruited consecutively during follow-up visits. The European Quality of Life Group’s 5-Domain Questionnaires at five levels (EQ-5D-5L) and Euro Quality of Life Group’s Visual Analog Scale (EQ-VAS) instruments were used to assess HRQoL. The EQ-5D-5L utility score was computed using the disutility coefficients. We applied the Krukal-Wallis and Mann–Whitney U tests to determine the differences in EQ-5D-5L and EQ-VAS utility scores between patient groups. A multivariate Tobit regression model was used to identify factors associated with HRQoL. Statistical analyses were performed using STATA version 14 and statistical significance was determined at p < 0.05.ResultsA total of 105 patients with hemophilia participated in the study, with a mean (standard deviation (SD) age of 21.09 (± 7.37] years. The median (IQR) EQ-5D-5L utility and EQ-VAS scores were 0.86 (0.59–0.91) and 75 (60.0–80.0), respectively. Age was significantly negatively associated with the EQ-5D-5L utility index and EQ-VAS (β = -0.020, 95 CI = -0.034, -0.007) and β = -0.974, 95% CI = -1.72, 0.225), respectively. The duration since hemophilia diagnosis (β-0.011, 95% CI, 0.001–0.023) and living out of Addis Ababa (β = -0.128, 95% CI, -0.248-, -0.007) were also significantly negatively associated with the EQ-5D-5L utility index..ConclusionThe median EQ-5D-5L utility and EQ-VAS scores of patients with hemophilia were 0.86 (0.59–0.91) and 75 (60.0–80.0), respectively. Older age, living far from the Hemophilia Treatment Center (HTC), and longer duration since diagnosis were significantly negatively associated with HRQoL. HRQoL may be improved by providing factor concentrates, decentralizing HTCs in different parts of the country, increasing awareness of bleeding disorders among health professionals, and providing psychosocial support to affected patients.

Diagnosis and laboratory monitoring of hemophilia A.

Acquired hemophilia A (AHA) is a rare disorder in which autoantibodies against factor VIII (FVIII) lead to a bleeding phenotype that varies from life-threatening to no bleeding at all. Prolonged activated partial thromboplastin times (APTT) in patients with a bleeding phenotype should be investigated to rule out AHA and should never be ignored in a preprocedure patient. Most inhibitors in AHA are heat and time dependent, so mixing studies performed only on an immediate mix are not useful: both lupus anticoagulants and treatment with direct oral anticoagulants can coexist with AHA and confound the diagnosis. Assays for intrinsic coagulation factors and von Willebrand factor should always be performed, regardless of the results of mixing studies. A Bethesda or modified Bethesda assay should be performed to quantify any inhibitor, and if susoctocog alfa (rpFVIII) is available, then an assay for cross-reacting antibodies should also be performed. At diagnosis and until complete remission, if the FVIII in the patient sample is >5 IU/dL, heat inactivation should be performed before the inhibitor assays are performed. While there are no conventional tests available to measure the effects of FVIII bypassing therapies, newer therapies may require monitoring, or their effects may need to be considered when choosing appropriate assays. Measurement of rpFVIII requires a 1-stage clotting assay, and measurement of patient FVIII while on emicizumab requires a chromogenic assay that does not contain human FX. Close communication is required between the treating clinicians and the laboratory to ensure that the correct tests are performed while patients are receiving treatments.

Multicenter Study of Diagnostic Tool for Patients with Hemophilia: From Bedside to Comprehensive Investigations.

Hemophilia cannot be diagnosed in most laboratories of economically less-developed countries leading to high mortality and morbidity rates. A diagnostic tool was established ranging from bleeding assessment and a simple bedside test of mixing venous clotting time (VCT) to comprehensive DNA analysis for patients with hemophilia. Patients with known (n=80) and suspected hemophilia (n=14) were included. Their bleeding symptoms were initially evaluated using verified translated-Thai ISTH bleeding assessment tool. Then, blood samples were drawn using a two-syringe technique, 2 mL each was placed in three tubes, for the mixing VCT and citrate blood was kept for coagulogram and coagulation factor assay. Finally, DNA analysis was determined. A total of 94 patients with hemophilia (A68, B26) defined as severe (A 57, B 17), moderate (A 7, B 5), and mild degrees (A 4, B 4) with the mean (SD) age of 14.0 (11.7) years and 24 normal controls aged 25.5 (4.5), were enrolled in the study. The mean (SD) bleeding score of patients with hemophilia was 13.5 (5.5), which did not significantly differ between patients with hemophilia A and B. The mixing venous clotting time offered the presumptive diagnosis of hemophilia A and B, which were subsequently confirmed by the prolonged APTT, low FVIII:C and FIX:C and mutations on the factor VIII and IX genes. A diagnostic tool for bleeding assessment, mixing venous clotting time, coagulogram, coagulation factor assay, and DNA analysis for patients with hemophilia has been established in the existing health-care system.

Understanding Treatment Burden in Pediatric Hemophilia: Development of the Child Hemophilia Treatment Experience Measure (Child Hemo-TEM)

Background: Currently available hemophilia treatments have resulted in significant improvements in quality of life. However, children with hemophilia (CwH) may still experience considerable treatment burden due to technical, physical, logistical, and emotional aspects of treatment administration. Aims: The objective of the current study was to examine the treatment experiences of CwH with the aim of developing a patient-centered measure of hemophilia to assess treatment burden in CwH, in accordance with the United States Food and Drug Administration guidelines for patient-reported outcome (PRO) measure development. Methods: Concept elicitation (CE) data included a review of the current hemophilia literature and 1-1.5-hour interviews with 4 clinical experts, 25 CwH, and 25 caregivers of CwH. A clinical expert was defined as a hematologist or nurse who currently had at least a 50% patient load in hemophilia and had been providing care to CwH for ≥ 5 years. CwH had to: be male; be between the ages of 8 to &amp;lt; 12 years; have a diagnosis of hemophilia A or B, with or without an inhibitor, and a factor level of &amp;lt; 2%; and currently be receiving, by caregiver administering or self-administering (with or without assistance), either on-demand or prophylactic treatment for hemophilia via factor replacement therapy or a bypassing agent. For caregivers to be eligible, their CwH had similar eligibility criteria except that they had to be &amp;lt; 12 years of age. The child, caregiver, and clinician CE interview transcripts were analyzed using Dedoose software. The information was synthesized and coded based on grounded theory principles. Based on this analysis, a theoretical model of the treatment experiences of CwH was developed and items reflecting the major and minor aspects of, distal consequences, and modifiers to the experience were included. Items reflecting the major concepts were generated and cognitive debriefing (CD) was conducted with 12 children and 15 caregivers. Results: For the CE, the average age of the child participants was 9.6 years (median 10, range 8-11). Sixty-four percent ( n=16) of the sample was White/Caucasian, all had severe hemophilia, the majority ( n=23, 92%) had hemophilia A, and had been treated with factor for an average of 8.9 years (median 9, range 7-11). The average age of caregivers' CwH was 6.3 years (median 6, range 2-11). Forty-four percent of children ( n=11) were White/Caucasian, all had severe hemophilia, the majority ( n=22, 88%) had hemophilia A, and had been receiving treatment for an average of 6.0 years (median 5.5, range 2-11.5). The treatment experience issues most frequently reported by 50% or more by either or both child participants or caregivers of CwH were: Ease of Use: inserting the needle; Adherence: missing or delaying treatments and difficulty keeping track of schedule/remembering to do treatment; Emotional Impacts and Treatment Concerns: feeling nervous, anxious or scared; proud/good about oneself; emotionally resolved/used to treatment; and stress; Physical Impacts: pain and scarring/scar tissue; and Interference with Daily Life: needing to stop activities to do treatment (see Table 1 for list of issues reported by ≥ 10% of either one or both child or caregiver and percent endorsements). Based on the theoretical model (see Figure 1), a preliminary measure was generated, and the CD was completed. As a result of the CD, a decision was made to develop only a caregiver observer-reported outcome (ObsRO) measure to capture the experiences of children aged &amp;lt; 12 years. The decision to not develop a PRO was based on the interviews with children aged 10 to &amp;lt; 12 years, which resulted in 10 out of the 12 respondents using an incorrect timeframe when answering one or more items, about one-third answered one or more items related to the impact of a bleed and not their treatment, and over half of the children had issues with comprehension with one or more items and/or trouble navigating layout/skip pattern. Following CD, the validation-ready version of the measure, the Child Hemo-TEM, was finalized. Conclusion: This study has identified key aspects of the treatment experience of CwH, which support thecontent validity of the Child Hemo-TEM ObsRO. Compared to generic measures, condition- and age-specific instruments, should have greater face validity, be more responsive to change over time, and may be more useful to both clinicians and researchers to assess the hemophilia treatment burden of CwH.

Chinese guidelines on the diagnosis and management of hemophilia with inhibitors (2023)

Chinese guidelines on the diagnosis and management of hemophilia with inhibitors (2023)

Trends in Invasive Orthopedic Interventions in Patients with Hemophilia Enrolled in the Community Counts Program (2015-2021)

Background Recurrent joint bleeding due to hemophilia often leads to the development of chronic joint disease resulting in chronic pain, decreased joint function and a significant decline in quality of life. Invasive orthopedic interventions (IOI) such as arthroplasty and arthrodesis for end stage joint disease have historically been pursued to decrease pain and improve joint function especially in patients with severe hemophilia and joint disease. Using data collected on patients receiving care in a large network of hemophilia treatment centers in the United States (USHTCN), Tobase et al have previously reported a 5.6% decline in all IOI in patients with hemophilia during the period 2000-2010 (1). Aims The primary objective of the current analysis was to extend those findings using similar data collected during the period 2015-2021 with a focus on IOI indicative of end stage joint disease such as arthrodesis and arthroplasty. Data on IOI were collected annually during the period 2015-2021 from patients who participated in the Community Counts (CC) surveillance project at the 147 member USHTCN using standardized data collection tools. The proportion of patients having IOI in each year was calculated by dividing the total number of patients who reported an IOI by the total number of patients who had a CC visit in that year. Trends in proportions were plotted over time and assessed for statistical significance using the Cochran-Armitage trend test. Results In total, 8,378 CC patients with a diagnosis of hemophilia A or B, over the age of 2 years who completed a subsequent CC visit within last 12 months of last surveillance visit during the years 2015-2021 were included in this study. Enrollees reported a total of 28 arthrodesis and 168 arthroplasty procedures during a total of 21,082 clinic visits over the entire study period. We found that arthroplasty represented 42.6 %, 68.8%, 17.9%, 26.3%, and 7.4% of all procedures reported in the knee, hip, ankle, shoulder, and elbow, respectively (Figure 1). The rate of IOI during the study timeframe remained very low, with only 2.4% of all participants reporting an IOI. During 2015-2021 there was a statistically significant decline in IOI among all patients &amp;gt;=60 years of age (0.59% in 2015 vs. 0.27% in 2021) (p=0.0325) (Figure 2). Similarly, patients with severe hemophilia regardless of age experienced a significant decline in invasive procedures during the study period (1.69% in 2015 vs. 0.88% in 2021) (p=0.021). Conclusions The rates of IOI reported during the years 2015-2021 remained very low (~2.4%). This suggests less joint morbidity and a continued decline in the rates of end stage joint disease during the study period, likely due, at least in part, to improved therapy and early adoption of preventative factor replacement protocols.

Risk factors for coagulation inhibitor development in children with severe hemophilia A

Aim of the study: to examine the role of potential risk factors in inhibitor development in previously untreated patients (PUPs) (or minimally treated patients) with severe hemophilia A. The study was approved by the Independent Ethics Committee and the Scientific Council of the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus). The study included 89 boys who underwent regular follow-up for severe hemophilia A at the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus) from 1998 to 2022. The median age (10th–90th percentile) at diagnosis of hemophilia was 8.0 (1.0–21.0) months, the baseline factor VIII activity was 0.7% (0.4–0.95%). Age at first exposure to factor VIII concentrate was 11.0 (1.0–31.0) months. Out of 89 patients, 23 children had severe hemophilia A with inhibitors. The cumulative incidence of inhibitors in the whole group of PUPs was 31.0 ± 5.6%. The cumulative incidence of hemophilia A with inhibitors was higher in the patients with null mutations (37.0 ± 6.9%) than in the patients with non-null mutations (6.5 ± 6.0%) (the log-rank test, p = 0.041). The use of plasma-derived FVIII concentrate (approved for use in neonates and for prophylaxis) from one manufacturer was associated (c2 = 8.53; p = 0.004) with a lower incidence of factor VIII inhibitors (up to 21.3 ± 8.5%) compared with the incidence in the group of patients treated with FVIII concentrates from different manufacturers (45.2 ± 7.8%). Age (&gt; 1 year old or &lt; 1 year old) at first exposure to FVIII had no effect on the formation of inhibitors (the log-rank test, p = 0.746). Such factors as age at diagnosis of hemophilia (odds ratio (OR) 0.99; 95% confidence interval (CI) 0.93–1.024; p = 0.991) and baseline factor VIII activity (OR 0.99; 95% CI 0.8–1.06; p = 0.09) were not associated with inhibitor development. The first measurements of activated partial thromboplastin time (APTT) ratio (patient APTT value over the APTT reference value) (OR 1.89; 95% CI 0.72–5.09; p = 0.21) and FVIII recovery in vivo (OR 0.74; 95% CI 0.27–2.01; p = 0.55) were not associated with inhibitor development either. We have confirmed that one of the main risk factors for FVIII inhibitor development is F8 gene mutations. The incidence of inhibitors among the patients who received plasma-derived FVIII concentrates (recommended for use in PUPs in the neonatal period) from one manufacturer was lower than among those who received FVIII from different manufacturers.

A portable point-of-care testing device for forward blood typing with hemophilia diagnosis.

This paper presents a portable point-of-care testing (POCT) device to conduct simultaneous and on-site tests of ABO and Rh(D) forward blood typing and hemophilia diagnosis using only a small amount of human whole blood sample. The POCT device consisted of a spinning module, a measuring circuit, an interdigitated electrode (IDE) for hemophilia diagnosis, and three disposable microfluidic chips for bioassays with anti-A, anti-B, and anti-D, respectively, and measurement of the concentration of factor VIII. Agglutination will occur if red blood cells (RBCs) are exposed to the corresponding antibody. To evaluate the degree of RBC agglutination, a linear sweep voltage, ranging from - 0.5 to + 0.5V, was applied to the electrodes of the microfluidic chip and the resulting current was measured. For different levels of agglutination, the measured I-V curves were explicitly discriminated, providing five clinical levels from non-agglutination (level 0) to strong agglutination (level 4). The quantitative norm obtained from cubic fitting function of each I-V curve served as the criterion to represent this agglutination level. The ABO blood type was determined by both agglutination levels of the blood sample reacting with anti-A and anti-B. The degree of agglutination with anti-D gave the Rh(D) type. Moreover, the concentration of factor VIII was detected for the determination of hemophilia. Without requiring expensive equipment, this POCT device is especially suitable for usage in emergency or natural disasters to provide quantitative testing in rescue and relief operations.

Treatment-related outcome from patient report outcome (PRO) of children with severe and moderate hemophilia A in China: An analysis report of registration data from patient organization "hemophilia home care center".

To assess current treatment-related outcomes for children with severe and moderate haemophilia A (cHA) in China. This cross-section Patient Report Outcome (PRO) report collected PRO data of severe and moderate cHAs registered in the 'Hemophilia Home Care Center' database (http://web.bjxueyou.cn) between January 2021 and November 2022. Data included records of bleeding, activities, and concentrates consumption. All patients had a confirmed diagnosis of moderate or severe haemophilia A (FVIII: C ≤ 5%) and were<18 years old. Among 1038 analysable cases, 9.6% of children with inhibitors had a higher rate of intracranial haemorrhage, dropout school rate, and higher FVIII consumption than children without inhibitors. Among 100 children with inhibitors, 36 patients were treated without immune tolerance induction (ITI), 14 patients with irregular treatment and 50 patients received ITI. Children with ITI had a lower ABR (2.4 (0,6.6) vs. 13.4 (9.5, 26.6), p<.001) and AJBR (0 (0, 3.1) vs. 8.9 (1.6, 19.3), p<.001) compared to those without ITI. Among 938 children without inhibitors, 28.5% received on-demand treatment and 71.5% received prophylaxis. Of 528 children with 1343.8 (1050.4, 2922.9)IU/kg/year median FVIII consumption, 43.0% received low-dose, 43.2% received intermediate-dose, and 13.8% received high-dose regimen; these children with prophylaxis had a lower ABR (3.1 (0, 10.7) vs. 12.8 (2.4, 45.5), p<.001), AJBR (0.5 (0, 3.9) vs. 3.0 (0, 12.0), p<.001) and disability rate (9.0% vs.18.5%, p=.032) compared to children who received on-demand treatment. The high rate of drop-out of school and disability still present a huge gap to meet the needs in China. It is necessary to improve the level of medical accessibility and medicine affordability and strengthen the patient/parent's education in China.

Molecular Diagnosis of Hemophilia A and Pathogenesis of Novel F8 Variants in Shanxi, China.

The aim of this study was to perform a molecular diagnosis of hemophilia A (HA) among patients in the Shanxi Province of China. Fifty-two HA patients were tested, including IVS22 (31 samples), IVS1 (3 samples), missense (11 samples), nonsense (3 samples), and 4 cases of frameshift (2 cases of deletion, 1 case of insertion, 1 case of single-base duplication). With the exception of the single-base G duplication variant (p.Ile1213Asnfs*28), this was the hotspot variant reported by research groups at an early stage. The remaining variants were found, for the first time, in the region. The missense variants p.Cys172Ser, p.Tyr404Ser, p.Asp1903Gly, and p.Ser2284Asn, the deletion variant p.Leu2249fs*9, and the insertion variant p.Pro2319fs*97 were novel variants. The application of next-generation sequencing (NGS) molecular diagnosis enriched the variant spectrum of HA, which is greatly significant for individualized genetic counseling, clinical diagnosis, and treatment. NGS and a variety of bioinformatics prediction methods can further analyze the impact of genetic variation on protein structure or function and lay the foundation to reveal the molecular pathogenic mechanism of novel variants.

Prevalence of temporomandibular disorders (TMD) in bleeding disorders: A systematic review with meta-analysis.

Haemophilia A, B and von Willebrand disease are the most common bleeding disorders. There is an increased tendency of spontaneous bleeding into joints resulting in intra-articular infection. It is believed that Temporomandibular Joint (TMJ) can be affected in a similar manner which can further lead to limited mouth opening and ankylosis. The association between bleeding disorders (BD) and development of temporomandibular disorders (TMD) is poorly understood. This systematic review intends to evaluate the association of TMD in individuals with inherited bleeding disorders as compared to healthy controls. PubMed, Ovid SP and Google Scholar were searched for articles published between the times of inception to 1 May 2023. All the articles were subjected to Population, Exposure, Comparison and Outcome model (PECO) based on which inclusion and exclusion criteria were applied. Participants (P) is children, adults or adolescents; Exposure (E) is children, adults or adolescents with a diagnosis of Haemophilia or bleeding disorder (BD); Comparator (C) is age and gender-matched healthy controls who do not have Haemophilia or bleeding disorder; Outcome (O) is prevalence of any signs or symptoms (clinical, radiographic) that is suggestive of temporomandibular disorder (TMD). Studies showing the prevalence of TMD are included for qualitative analysis. Only the studies which provided data of the prevalence of TMD in both the groups (BD and healthy controls) were included in the quantitative analysis. TMD diagnosis can be by clinical signs and symptoms, radiographic criteria, Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) or any other imaging criteria (MRI). We have set the exclusion criteria as articles without a control group, diagnostic sensitivity studies, case reports and systematic reviews and narrative reviews. The software Review Manager version 5.4 (Cochrane Collaboration) was used to perform the pooled analysis. We measured the risk ratio (RR) between the two groups (BD and healthy controls) for the outcome TMD. A total of seven studies are included for qualitative analysis of data. The age of the population (BD and control) in the included studies ranged between 2 and 57 years. The prevalence of TMD in individual studies varied from 2% to 77%, and controls in the individual studies varied from 2% to 14%. Among the included studies, only clinical signs, symptoms and history were taken into consideration in four studies. Four studies were included for meta-analysis, the pooled result of the four studies suggests there is no significant difference in the prevalence of TMD in BD and control group (p value = .11, RR 2.19; 95% CI [0.84, 5.73]). This systematic review and meta-analysis elicits no association between bleeding disorders and increased prevalence of TMD.

Four Decades of Carrier Detection and Prenatal Diagnosis in Hemophilia A: Historical Overview, State of the Art and Future Directions.

Hemophilia A (HA), a rare recessive X-linked bleeding disorder, is caused by either deficiency or dysfunction of coagulation factor VIII (FVIII) resulting from deleterious mutations in the F8 gene encoding FVIII. Over the last 4 decades, the methods aimed at determining the HA carrier status in female relatives of HA patients have evolved from phenotypic studies based on coagulation tests providing merely probabilistic results, via genetic linkage studies based on polymorphic markers providing more accurate results, to next generation sequencing studies enabling highly precise identification of the causative F8 mutation. In parallel, the options for prenatal diagnosis of HA have progressed from examination of FVIII levels in fetal blood samples at weeks 20-22 of pregnancy to genetic analysis of fetal DNA extracted from chorionic villus tissue at weeks 11-14 of pregnancy. In some countries, in vitro fertilization (IVF) combined with preimplantation genetic diagnosis (PGD) has gradually become the procedure of choice for HA carriers who wish to prevent further transmission of HA without the need to undergo termination of pregnancies diagnosed with affected fetuses. In rare cases, genetic analysis of a HA carrier might be complicated by skewed X chromosome inactivation (XCI) of her non-hemophilic X chromosome, thus leading to the phenotypic manifestation of moderate to severe HA. Such skewed XCI may be associated with deleterious mutations in X-linked genes located on the non-hemophilic X chromosome, which should be considered in the process of genetic counseling and PGD planning for the symptomatic HA carrier. Therefore, whole exome sequencing, combined with X-chromosome targeted bioinformatic analysis, is highly recommended for symptomatic HA carriers diagnosed with skewed XCI in order to identify additional deleterious mutations potentially involved in XCI skewing. Identification of such mutations, which may profoundly impact the reproductive choices of HA carriers with skewed XCI, is extremely important.