Joint Bleeding Research Articles

Analysis of the effects of low/intermediate dose of coagulation factor Ⅷ on 30 adult patients with severe hemophilia A in a single center

Objective: To evaluate the clinical effects of low- and intermediate-dose factor Ⅷ (F Ⅷ) prophylaxis in Chinese adult patients with severe hemophilia A. Methods: Thirty adult patients with severe hemophilia A who received low- (n=20) /intermediate-dose (n=10) F Ⅷ prophylaxis at Nanjing Drum Tower Hospital affiliated with Nanjing University Medical College were included in the study. The annual bleeding rate (ABR), annual joint bleeding rate (AJBR), number of target joints, functional independence score of hemophilia (FISH), quality of life score, and health status score (SF-36) before and after preventive treatment were retrospectively analyzed and compared. Results: The median follow-up was 48 months. Compared with on-demand treatment, low- and intermediate-dose prophylaxis significantly reduced ABR, AJBR, and the number of target joints (P<0.05) ; the improvement in the intermediate-dose prophylaxis group was better than that in the low-dose prophylaxis group (P<0.05). Compared with on-demand treatment, the FISH score, quality of life score, and SF-36 score significantly improved in both groups (P<0.05), but there was no significant difference between the two groups (P>0.05) . Conclusion: In Chinese adults with severe hemophilia A, low- and intermediate-dose prophylaxis can significantly reduce bleeding frequency, delay the progression of joint lesions, and improve the quality of life of patients as compared with on-demand treatment. The improvement in clinical bleeding was better with intermediate-dose prophylaxis than low-dose prophylaxis.

Bleeding phenotype in nonsevere hemophilia by International Society on Thrombosis and Haemostasis bleeding assessment tool, bleeding frequency, and the joint status

BackgroundAlthough the phenotype of severe hemophilia has been well studied, there are still knowledge gaps in nonsevere hemophilia. ObjectivesThe objective of this study was to characterize the clinical bleeding phenotype in nonsevere hemophilia and its association with different factor VIII/IX assessments. MethodsThis was a cross-sectional, multicenter study to investigate the bleeding phenotype in adults with nonsevere hemophilia by the number of bleeding and joint bleeding in the past 5 years, a joint score, and the International Society on Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT). Factor levels were analyzed by 1-stage (lowest in history and at study inclusion) and chromogenic assay (at study inclusion). Patients were enrolled between March 2015 and May 2019. ResultsOf the 111 patients (86 with mild and 25 with moderate hemophilia), 57 patients (54.8%) reported any bleeding and 24 (23.1%) any joint bleeding in the past 5 years. A joint score ≥1 was found in 44 patients (41.9%), an ISTH-BAT ≥4 in 100 patients (90.1%), and an ISTH-BAT joint item ≥1 in 50 patients (45.0%). Within the ISTH-BAT, muscle and joint bleeds showed the largest difference between mild and moderate hemophilia. The lowest factor VIII/IX level in patients’ history was best associated with bleeding outcomes. Factor was inversely associated with joint bleeds (incidence rate ratio 0.88; 95% CI, 0.79-0.98), joint score, and ISTH-BAT (odds ratios from proportional odds ordinal logistic regression 0.92; 95% CI, 0.87-0.97; and 0.89; 95% CI, 0.86-0.93, respectively). ConclusionThe occurrence of joint bleeding differentiated persons with mild and moderate hemophilia. The ISTH-BAT and lowest factor in patients’ history provided valuable information of the bleeding phenotype in nonsevere hemophilia.

Clinical and radiological assessment of joints in people with haemophilia in Assam, Northeast India: a cross-sectional study

Abstract Background Despite the availability of factor replacement therapy, including prophylaxis, to treat and prevent bleeding, haemophilic arthropathy continues to be the most common complication of haemophilia and significantly impairs the quality of life in people with haemophilia (PwH). Regular periodic assessment of joint status in PwH is essential to identify early arthropathic changes and prevent the development or progression of haemophilic arthropathy. Kinematic and kinetic assessment are preferable and MRI is the gold standard for diagnosing haemophilic arthropathy, but availability is limited in developing countries. HJHS and ultrasound in conjunction with HEAD-US have been shown to effective in assessing changes indicating arthropathy. Aim This study is designed to identify which radiological assessment tool(s) works best when integrated with clinical assessment tools to examine joint health in PwH, with the aim of establishing a cheap, effective, multimodal approach to joint assessment in clinical practice in low resource settings which can then help to guide treatment. Methods A cross-sectional observational study was carried out among PwH attending a clinic in the department of medicine at Assam Medical College and Hospital, Northeast India, over a one-year time period. The elbow, knee and ankle joints of participants were assessed clinically and functionally using HJHS and FISH and radiologically by Pettersson (X-ray) and HEAD-US (ultrasound) scoring. The resulting data was analysed statistically to ascertain correlation between these parameters. Results Sixty-seven PwH were enrolled in the study, with a mean age of 21.69±8.24 years (median 21 years); 38 (57.72%) had severe factor deficiency. The majority (71.70%) presented with joint bleeds; 40 (59.70%) had the knee as a target joint, followed by the elbow (11; 16.41%) and ankle (6; 8.95%). Mean ABR (annual bleed rate), AJBR (annual joint bleed rate) and ATJBR (annual target joint bleed rate) values had a positive correlation with increased severity of factor deficiency (p &lt;0.001). FISH score increased with factor activity level; HJHS, HEAD-US and Pettersson scores decreased with factor activity level. Significant positive correlation was established between Pettersson score, age and ABR. The degree of association was greatest between HJHS and HEAD-US at 60.62%; between HJHS and Pettersson it was 57.74%. Statistically significant negative correlation was established between FISH and HEAD-US. Conclusion A combined multimodal approach using the HJHS, FISH and HEAD-US scoring systems can provide a cheap, quick, more reliable and accurate option for assessing haemophilic joints, with minimal inter and intra observer reliability. This can support the optimisation of management of joint damage in PwH in resource-constrained settings.

Mutation Analysis of F8 Gene and Phenotypic Characterization of Hemophilia A

Background Hemophilia A HA is a congenital bleeding disorder caused due to deficiency of Factor VIII clotting protein in the blood. It follows an X-linked recessive mode of inheritance.Aim In the present study clinical and haematological manifestations have been analysed and their correlation with molecular mutations in patients with haemophilia A has been tested.Methods A total of 90 HA patients were included in the study. Plasma coagulation test PT APTT and correction study factor VIII assay inhibitors screening test and quantification tests were done for all the patients. Mutation analysis was carried out to evaluate the molecular alteration in F8 gene only on exon.Results Among the 90 Hemophilia A patients included 3 3.3 were diagnosed as mild 15 16.6 as moderate and 72 80 were diagnosed as severe hemophilic patients. Positive family history was observed in 62 68.8 patients while 35 38.8 were born to consanguineous couples. Joint bleeding 88.8 was most commonly observed followed by mucocutaneous bleeding 66.6 dental bleeding 48.8 genitourinary bleeding 16.6 gastrointestinal bleeding 15.5 muscle bleeding 14.4 and intracranial bleeding 10. Around 13 14.4 HA patients developed inhibitors among which five were of low titer and eight were of high titer. Mutation analysis of 90 HA patients recorded a total of 21 mutations including 52.4 missense mutations 23.8 nonsense mutations 23.8 frameshift mutations. No novel mutation was noted.Conclusion The present study showed several missense mutations in severe HA patients. This result is a slight deviation from the reports of earlier Indian studies which could be due to difference in geographic population ethnicity and other factors. Hence a detailed genotype and phenotype screening in relation to severity and development of inhibitors is much essential for timely monitoring and appropriate treatment of Hemophilia A.

Acquired hemophilia A that developed after BNT162b2 mRNA COVID-19 vaccination and worsened following re-vaccination

An 86-year-old Japanese male patient visited a nearby hospital with painful swelling in his left upper and lower limbs 35 days after the second dose of the BNT162b2 mRNA coronavirus disease-2019 (COVID-19) vaccine. He was referred to our hematological department due to a prolonged activated partial thromboplastin time and was urgently admitted. He was diagnosed with acquired hemophilia A (AHA) based on factor VIII (FVIII) activity of 1.7%, FVIII inhibitor of 152.3 BU/ml, and FVIII-binding antibodies detected by enzyme-linked immunosorbent assay. Immunosuppressive therapy with prednisolone (PSL) at 0.5 mg/kg/day was started owing to the risk of infection due to old age and poor activities of daily living. Hemostasis treatment with bypass hemostatic preparations (rFVIIa preparation, FVIIa/FX) was administered for each bleeding event, such as intramuscular and knee joint bleeding, resulting in good hemostatic effects. Coagulative complete remission was achieved on day 69 with PSL treatment; however, FVIII activity decreased with PSL tapering. AHA relapse with rectus abdominis muscle hematoma was observed after the third vaccination. This is the first Japanese report of AHA after COVID-19 vaccination and the world's first case, in which the presence of anti-FVIII-binding antibodies were observed.

Conservative management for spontaneous lumbar facet joint hemarthrosis in severe hemophilia a: A rare case report

Spontaneous lumbar facet joint bleeding is rarely observed in patients with hemophilia. Since it is categorized as a spinal epidural hematoma, surgery is the main treatment. Conservative treatment was successful in patients with minor or absent neurological deficits. We aimed to present the case of a patient with severe hemophilia who suffered from acute sciatica caused by lumbar facet joint hematoma. Nonsurgical treatment using a multidimensional approach was provided. The hemarthrosis is completely resolved. The patient recovered from clinical neurological symptoms without recurrence throughout the 4-year follow-up period. Spontaneous lumbar facet joint hemarthrosis in patients with severe hemophilia who present with mild neurological symptoms can be conservatively treated if the hemarthrosis is recognized early. Moreover, a multidisciplinary team approach is paramount in achieving good patient outcomes.

Real-world data in patients with congenital hemophilia and inhibitors: final data from the FEIBA Global Outcome (FEIBA GO) study.

The bypassing agent, activated prothrombin complex concentrate [aPCC, FEIBA (factor VIII inhibitor bypass activity); Baxalta US Inc, a Takeda company, Lexington, MA, USA], is indicated for the treatment of bleeding episodes, perioperative management, and routine prophylaxis in patients with hemophilia A or B with inhibitors. In certain countries, aPCC is also indicated for the treatment of bleeding episodes and perioperative management in patients with acquired hemophilia A. To describe long-term, real-world effectiveness, safety, and quality-of-life outcomes for patients with congenital hemophilia A or B and high-responding inhibitors receiving aPCC treatment in routine clinical practice. FEIBA Global Outcome (FEIBA GO; EUPAS6691) was a prospective, observational study. Investigators determined the treatment regimen and clinical monitoring frequency. The planned patient observation period was 4 years. Data are from the safety analysis set (patients who received ⩾1 aPCC infusion). Overall, 50 patients received either aPCC prophylaxis (n = 37) or on-demand therapy (n = 13) at screening [hemophilia A, n = 49; hemophilia B, n = 1; median (range) age, 16.5 [2-71] years). Mean ± standard deviation overall annualized bleeding rate and annualized joint bleeding rate for patients receiving prophylaxis were 6.82 ± 11.52 and 3.77 ± 5.71, respectively, and for patients receiving on-demand therapy were 10.94 ± 11.27 and 6.94 ± 7.39, respectively. Overall, 177 and 31 adverse events (AEs) were reported in 28 of 40 and 10 of 13 patients receiving prophylaxis or on-demand therapy, respectively. Two serious AEs were considered possibly related to aPCC: acute myocardial infarction due to coronary artery embolism in one patient receiving prophylaxis. No thrombotic microangiopathy was reported. No AEs resulted in death. This study demonstrated the long-term, real-world effectiveness and consistent safety profile of aPCC as on-demand therapy and prophylactic treatment in patients with hemophilia and high-responding inhibitors. FEIBA Global Outcome Study; EUPAS6691 https://www.encepp.eu/encepp/viewResource.htm?id=32774.

Long-term impact of primary prophylaxis on joint status in patients with severe hemophilia A

BackgroundPrimary prophylaxis with factor VIII concentrates is the therapeutic gold standard for severe hemophilia A. Although this approach will change substantially with the use of nonsubstitutive therapies, the long-term effects of primary prophylaxis remain unclear. We present information on joint health with tailored primary prophylaxis in a consecutive series at a single center. MethodsWe retrospectively analyzed 60 patients who did not develop early inhibitors. The annual bleeding rate and annual joint bleeding rate, prophylaxis characteristics, physical activity, adherence, and development of inhibitors were compared between those with and without joint involvement at the end of follow-up. Joint involvement was defined as a Hemophilia Joint Health Score or Hemophilia Early Arthropathy Detection with an ultrasound score ≥1. ResultsAmong 60 patients with median follow-up of 113 ± 6 months after starting prophylaxis, 76.7% had no joint involvement at the end of the follow-up. Those without joint involvement started prophylaxis at a younger median age (1 [IQR 1-1] year vs 3 [IQR 2-4.3] years). They also had lower annual joint bleeding rate (0.0 [IQR 0-0.2] vs 0.2 [IQR 0.1-0.5]), were more often physically active (70% vs 50%), and had lower trough factor VIII levels. Adherence to treatment was not significantly different between groups. ConclusionInitiation of primary prophylaxis at a younger age was the main factor associated with long-term preservation of joint status in patients with severe hemophilia A.

18 F-FDG PET/CT imaging for haemophilic arthropathy compared with clinical, radiological and power Doppler sonographic characteristics of 20 haemophilia patients.

Repeated joint bleeding in haemophilia patients may lead to haemophilic arthropathy with marked inflammation and synovitis. This study investigated the potential of 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (18 F-FDG PET/CT) as a novel diagnostic method for haemophilic arthropathy. We recruited 20 adult haemophilia patients who reported history of hemarthroses in the shoulder, elbow, hip, knee, or ankle joints. All joints were assessed by power Doppler ultrasonography and radiography, and graded by hyperaemia score and Pettersson score, respectively. Joint pain was evaluated by visual analogue score (VAS). Range of motion (ROM), Haemophilia Joint Health Score (HJHS) and annual joint bleeding rate (AJBR) were recorded. Finally, all participants had whole-body 18 F-FDG PET/CT, and maximum standardized uptake value (SUVmax) of the joints being studied was measured. Thirteen patients had severe haemophilia, and seven had moderate haemophilia. The mean age was 36 years. PET SUVmax showed significant correlations with VAS, ROM, Pettersson score, hyperaemia score, HJHS score and AJBR in all large joints except hip. Joints with pain, hyperaemia and radiographic changes were found to have higher SUVmax than those without these features. Using Youden's index, the optimal cut-off value for early radiographical arthropathy was found to be between 1.9 and 2.0. Our study indicates that 18 F-FDG PET/CT imaging correlated well with various conventional diagnostic techniques. It also demonstrated high sensitivity and specificity for early radiographic arthropathy. 18 F-FDG PET/CT imaging may quantitatively evaluate disease activity of most large joints in a single examination and help detect early haemophilic arthropathy.

Nonreplacement therapy for hemophilia in low-income countries: experience from a prospective study in Ivory Coast

BackgroundHemophilia management has fundamentally evolved over the last decades with the development of ground-breaking therapies. Because of their mode of action and biochemical properties, these innovative therapies that are available in developed countries could be readily implemented among people from low-income countries who are either not or inadequately treated with clotting factor concentrates (CFCs). ObjectivesWe aimed at evaluating the impact of prophylaxis with emicizumab, a bispecific monoclonal antibody mimicking the FVIII activity administered subcutaneously, among boys with severe hemophilia A (HA) from the Ivory Coast, where access to CFCs is limited to humanitarian aid. MethodsWe prospectively collected data on the implementation and outcomes of prophylaxis with emicizumab, in 33 Ivorian boys aged 2 to 13 years with severe HA (with and without inhibitors). Bleeds, CFC consumption, quality of life and satisfaction of the patients and their parents were assessed. ResultsOverall, 12 months after initiating emicizumab, a 99% reduction in bleeding rates was observed, with a raise from 18% to 100% of boys having zero spontaneous joint bleeds. Three boys required a single FVIII infusion following a traumatic bleed. Health-related quality of life measures significantly improved, and perception of treatment efficacy was positively rated in children and parents. Acceptance, tolerance, and adherence were excellent. Emicizumab was instrumental in successfully implementing uninterrupted, highly efficacious, and well-tolerated prophylaxis in 72% of the Ivorian children aged ≤ 13 years identified with severe hemophilia A. ConclusionThese data illustrate how innovative and disruptive nonreplacement therapies that are already accessible in developed countries could potentially provide equity in care by profoundly and rapidly modifying hemophilia burden with a magnified impact in low-income countries.

Therapeutic options for hemarthrosis in severe hemophilic patients

the coagulation factors VIII (FVIII) or IX (FIX), respectively. The primary therapeutic approach is to replace the deficient coagulation factor, which can be achieved with factors derived from human plasma or recombinants. However, despite having a therapeutic approach, most severe cases are symptomatic and may have complications, mainly in the muscles and joints. One example of such disorder is hemarthrosis. This manifestation tends to affect mainly the knee, ankle, or elbow joints in about 80% of cases. Objective: to describe the primary forms of treatment for joint bleeding in patients with severe hemophilia. Methods: This is a qualitative research of the integrative review type meant to identify productions on topics associated with hemarthrosis and severe hemophilia. The articles were searched through the databases PubMed, Scientific Electronic Library Online (Scielo) and Virtual Health Library (BVS) with the following search descriptors: “hemarthrosis andhemophilia”; “joint diseases and Hemophilia” and corresponding terms in Portuguese. The inclusion criteria were as follows:a) scientific articles b) available in full-text c) studies available in Portuguese, English, or Spanish d) randomized clinical trials e) articles published between 2016 and 2021 f) articles containing hemarthrosis caused by severe hemophilia. As exclusion criteria, texts that had no relation to the theme, did not answer the guiding question, other types of articles that did not include randomized clinical trials and/or presented duplicates were discarded. Results: In total, 42 articles were found in the selected databases; eight were duplicated, and 25 were excluded for not being randomized clinical trials or because they did not contemplate the theme. After careful reading, nine articles that met the inclusion and exclusion criteria were identified. Of the eligible studies, one reported factor replacement, and eight reported physiotherapeutic treatment. Conclusion: Factor replacement for hemophilic patients is essential and, based on the information obtained, early replacement is beneficial for the patient to avoid joint complications. Prophylaxis is indicated in severe hemophilia and its main objective is to prevent recurrent hemarthrosis, which can cause permanent functional deformities. Some physiotherapeutic interventions are indicated to prevent joint damage in severe hemophilic patients. The findings show diversity in the physical therapy modalities employed. The complete prevention of joint damage is still a challenge. A combination of treatments and a multidisciplinary team follow-up is necessary to ensure health and quality of life of patients.

Primary prophylaxis in children with severe haemophilia A and B-Implementation over the last 20 years as illustrated in real-world data in the PedNet cohorts.

The prophylactic regimen in children with severe haemophilia is suggested in various publications and guidelines. Few data exist on its implementation in clinical practice. To investigate the implementation of primary prophylaxis based on real-life data from PedNet during the last 20 years. All children from the PedNet cohort (n=1260) with severe haemophilia A (SHA) or severe haemophilia B (SHB), FVIII/IX<.01 IU/mL, born between 2000 and 2009 (Cohort I; SHA n=662; SHB n=88) and 2010-2019 (Cohort II; SHA n=598; SHB n=94) were included. In SHA, the median age at start of prophylaxis was 17.3 months (IQR; 12.5-26.1) in Cohort I which decreased to 13.1 months (IQR; 10.4-19.1) in Cohort II (p<.000). "Once-a-week" prophylaxis at start increased from 49% to 68% (SHA) and 38% to 70% (SHB). FVIII doses were reduced from median 43.5 (IQR; 34.6-49.0) to 30.9IU/kg (IQR; 26.3-46.3), while dosing with FIX did not change. After 2010 approximately 60% of the patients with SHA and SHB started prophylaxis before any joint bleed. The number of CVADs needed in both cohorts was around 30%. Incidences of inhibitors were unchanged: SHA (∼31%) and SHB (∼10%). Sporadic cases were diagnosed significantly later (median 8.3 months; IQR; 3.7-11.9) and they had more joint bleeds before start of prophylaxis. Primary prophylaxis nowadays starts at an earlier age: before any joint bleed (60% of patients with SHA and SHB). Approximately 70% started on a once-weekly schedule with significantly reduced doses in SHA but unchanged in SHB.

Thromboembolic Disease in Haemophilic Patients Undergoing Major Orthopaedic Surgery: Is Thromboprophylaxis Mandatory?

Haemophilia is a rare genetic disorder, that results from various degrees of deficiency of coagulation factor VIII (haemophilia A), or factor IX (haemophilia B), with an X-linked transmission. The patients affected are in the majority of cases males (who inherit the affected X-chromosome from the maternal side), with rare cases of females with haemophilia (FVIII or FIX &lt; 40 IU/dL), situations in which both X-chromosomes are affected, or one is affected, and the other one is inactive (known as carrier). The hypocoagulable state due to the deficiency of clotting factors, manifests as an excessive, recurrent tendency to bleeding, which positively correlates with plasmatic levels. Severe haemophilia results in hemarthrosis, although recent data have shown that moderate or even mild disease can lead to joint bleeding. Recurrent episodes of haemorrhages, usually affecting large joints such as knees, elbows, or ankles, lead to joint remodelling and subsequent haemophilic arthropathy, which may require arthroplasty as a last therapeutic option. Orthopaedic patients have the highest risk among all for deep vein thrombosis (DVT) and venous thromboembolism (VTE) with morbid and potentially fatal consequences. While for the rest of the population thromboprophylaxis in orthopaedic surgery is efficient, relatively safe, and widely used, for patients with haemophilia who are considered to have a low thromboembolic risk, there is great controversy. The great heterogeneity of this particular population, and the lack of clinical trials, with only case reports or observational studies, makes thromboprophylaxis in major orthopaedic surgery a tool to be used by every clinician based on experience and case particularities. This review aims to briefly summarise the latest clinical data and to offer an insight into the current recommendations that readers would find useful in daily practice.

FVIII inhibitor surveillance in children with hemophilia A in Indonesia: a report from the Indonesian Pediatric Hematology-Oncology Working Group.

Factor VIII (FVIII) inhibitor diagnosis and surveillance in Indonesia are challenging owing to geographic conditions and the lack of laboratory facilities nationwide for inhibitor assays. This study aimed to determine the prevalence of FVIII inhibitors in children diagnosed with hemophilia A (HA) in Indonesia. A cross-sectional study was conducted in 12 hospitals in eight provinces of Indonesia between 2020 and 2021. Factor VIII inhibitor screening was performed in a central hemostasis laboratory for all children with HA (≤18 yr) who had received a minimum of 10 exposure days to clotting factor concentrates. The FVIII inhibitor titer was determined using the Bethesda assay. Children (388) were enrolled in this study, including 219 (56.4%), 131 (33.8%), and 38 (9.4%) with severe, moderate, and mild HA, respectively. The prevalence of children who developed FVIII inhibitors was 37 out of 388 (9.6%). Factor VIII inhibitors were found in 25/219 (11.4%) severe, 11/131 (8.3%) moderate, and 1/38 (2.6%) children with mild HA. Thirteen children had low-titer inhibitors and 24 had high-titer inhibitors, with a median of 9.44 (1.48‒412.0) Bethesda Units. Among 13 children with low-titer inhibitors, eight underwent a confirmation test, of which five tested negative and were classified as transient. A significant difference in annual joint bleeding rate was found between patients with low and high inhibitor titers and those without inhibitors (P＜0.001). Factor VIII inhibitor prevalence in Indonesia was relatively low. However, the risk factors that may contribute to FVIII inhibitor development among Indonesian patients require further study.

Value of 3.0T MRI T2 mapping combined with SWI for the assessment of early lesions in hemophilic arthropathy

ABSTRACT Purpose To explore the value of magnetic resonance imaging (MRI) T2 mapping combined with susceptibility-weighted imaging (SWI) in detecting early cartilage damage and joint bleeding in the hemophilic arthropathy (HA). Methods 147 patients and 56 healthy controls were prospectively recruited. The knees were divided into groups A and B according to the criteria of the International Cartilage Repair Society (ICRS). The Regions of Interest (ROIs) of T2 mapping were drawn for the patella, lateral and medial femoral condyle, and lateral and medial tibial condyle. The T2 values were compared between the patients and control group using one-way ANOVA. The joint count data of International Prophylaxis Study Group (IPSG) scores of conventional and SWI sequences were statistically described using the composition ratio, and the rank sum test was used for the difference analysis. Results Finally, there were 99 joints in the control group, 135 knees in group A, and 94 knees in group B. There was a significant difference between the T2 value in each subgroup. Comparison of T2 value groups in each cartilage partition, except for group A and group B of the patella, revealed significant differences (all P<0.05). SWI was likely more sensitive than conventional sequences in detecting hemosiderin deposits in hemophilic joints. In addition, the IPSG scores detected by the SWI were generally higher than those of conventional sequences. Conclusions MR T2 mapping combined with SWI has great potential to be used for detecting early cartilage damage and micro-hemosiderin deposition in hemophiliac arthropathies and developing preventative treatment plans.

Occurrence of familial Mediterranean fever in haemophilia patients.

This is the first study of simultaneous occurrences of Familial Mediterranean Fever (FMF) in patients with haemophilia. The aim was to investigate the frequency and clinical characteristics of FMF in patients with severe haemophilia. Our study included 30 patients with severe haemophilia (26 haemophilia A and four haemophilia B). All 30 patients are screened for MEFV genotypes in FMF according to the new Eurofever/PRINTO diagnostic criteria. All cohorts were genetically tested for FMF and thrombophilia. Eight (26%) of 30 haemophilic patients were diagnosed with FMF. Six different heterozygous FMF mutations including M694V (n=2), E148Q (n=2), V726A(n=1), P369S (n=1), E148Q/K695R (n=1) and E148Q/M694I (n=1) were identified. Seven had haemophilia A and only one had haemophilia B. Four (50%) patients had a positive family history and three of them had extraarticular findings specific to FMF. Only one haemophilia B patient received colchicine. Target joints in the knee, ankle, and elbow were identified in three FMF patients. The number of target joints in eight patients with FMF was significantly lower than in twenty-two patients without FMF (p<.05). The annual number of suspected joint bleedings in FMF patients admitted to the hospital was 40; however, 15 (37.5%) were documented bleedings in ultrasounds. Hereditary thrombophilia was detected in seven of eight patients. Our data indicate that screening for FMF may be useful in patients with haemophilia who develop arthritis without prominent bleeding and have a positive family history in many Mediterranean countries, including Turkey.

Clinical outcomes of low-dose pharmacokinetic-guided extended half-life versus low-dose standard half-life factor VIII concentrate prophylaxis in haemophilia A patients.

Despite receiving standard half-life (SHL) factor VIII (FVIII) concentrates prophylaxis, some severe haemophiliaA (HA) patients still encounter spontaneous breakthrough bleeding. Individualized pharmacokinetic (PK)-guided dosing of extended half-life (EHL) FVIII concentrates may reduce their bleeding events. To compare clinical outcomes before and after switching low-dose prophylaxis using weight-based SHL FVIII to PK-guided EHL FVIII concentrates, taking into consideration of a trough FVIII activity at 1IU/dl above natural baseline. In this single-centre prospective cohort, Thai severe or moderate HA (FVIII activity ≤3IU/dl) patients receiving low-dose weight-based SHL FVIII prophylaxis were enrolled. After a 3-day wash-out period, participants underwent low-dose EHL FVIII prophylaxis with PK-based adjustment (myPKFiT® ) for 6 months. The annualized bleeding rates (ABR), the annualized joint bleeding rates (AJBR), the haemophilia-specific quality-of-life (Haemo-QoL or Haemo-QoL-A) scores, the Hemophilia Joint Health Scores (HJHS) and the annualized FVIII consumption were compared between the two prophylactic periods. Of 15 eligible subjects (mean age 18.7±6.7 years), ABR, AJBR and HJHS were significantly reduced (mean differences of -11.1±4.9 bleeds/year, -10.4±5.2 joint bleeds/year and -5.1±1.5 marks, respectively; P<.001 for all comparisons) after switching regimen. The quality-of-life scores had also improved (P=.001). Nonetheless, FVIII consumption tended to increase despite no statistical significance (means of 1240.9±531.3 SHL FVIII IU/kg/year versus 1591.7±438.9 EHL FVIII IU/kg/year; P=.05). This is the first low-dose, PK-guided, EHL FVIII prophylaxis clinical study in Thailand. Benefits and practicability of this personalized regimen may support the implementation of regular FVIII prophylaxis in developing countries with budget constraints. gov NCT05281185.

Desferoxamine protects against hemophilic arthropathy through the upregulation of HIF-1α-BNIP3 mediated mitophagy

AimsHemophilic arthropathy (HA) is a typically iron overload induced joint disease secondary to continuous joint bleeding, however, the exact role of iron chelators in HA has not been fully elucidated. In the present study, we investigated whether desferoxamine (DFO), an iron chelator, could limit the development of HA and the underlying mechanisms. Materials and methodsA HA mice model was established by needle puncture in the left knees of FVIII-deficient hemophilic mice. HA progression was evaluated at 8 weeks after DFO administration. Moreover, chondrocytes were treated with ferric ammonium citrate (FAC) to mimic iron overload in vitro. Modulating effect of DFO on iron overload induced oxidative stress, chondrocytes apoptosis and extracellular matrix (ECM) degradation and the role of HIF-1α-BNIP3 mediated mitophagy were examined. Key findingsWe found that DFO limited the development of HA and protected iron overload induced ECM degradation, chondrocytes apoptosis and oxidative stress. Besides chelating Fe2+, we found that HIF-1α-BNIP3 mediated mitophagy played important roles in the protective effect of DFO. HIF-1α inhibition suppressed chondrocytes mitophagy process and partly diminished the protective effect of DFO on chondrocytes iron overload. SignificanceIn conclusion, DFO could protect against HA development via HIF-1α-BNIP3 mediated mitophagy, suggesting DFO might be a potential therapeutic supplement for HA treatment.

Real-World Use of Octocog Alfa and Damoctocog Alfa Pegol in Women with Hemophilia a from the ATHNdataset

Background and rationale Women and girls with one or two abnormal alleles of clotting factor genes can experience hemophilia symptoms, but a lack of data exists on the treatment of women with hemophilia. We used the ATHNdataset to identify female patients who received octocog alfa (BAY 81-8973/Kovaltry®) or damoctocog alfa pegol (BAY 94-9027/Jivi®) between January 1, 2010 and April 30, 2022. Baseline demographics, treatment history and medical history of patients aged ≥12 years with hemophilia A for damoctocog alfa pegol and all ages for octocog alfa were collected. The HIPAA-compliant, de-identified database, ATHNdataset, is a national database sponsored by the American Thrombosis and Hemostasis Network. This repository contains patient data, including of those with hemophilia A, gathered from ATHN-affiliated hemophilia treatment centers across the United States. Results: A total of 354 and 205 patients receiving octocog alfa and damoctocog alfa pegol, respectively, were in the ATHNdataset at the time of data cutoff. Of these, 13 patients receiving octocog alfa and four receiving damoctocog alfa pegol were female. Of the patients receiving octocog alfa, there was one pediatric patient (<12 years), two adolescent patients (12-18 years), and ten adult patients (>20 years) of whom seven were older than 30 years. For damoctocog alfa pegol, there were two adolescent patients (12-18 years) and two adults (>50 years). These patients were treated as listed in Table 1. For the octocog alfa patients, out of 11 patients, only one was treated with octocog alfa for <1 year, and six patients were treated for >3 years. Data regarding length of treatment were missing for two patients. Two patients were treated with damoctocog alfa pegol for <1 year, and two for >1 year with one of them for >3 years (Table 2). Of the octocog alfa patients, there was one patient who had four bleeds; all bleeds were traumatic, including three joint bleeds. One patient receiving damoctocog alfa pegol had one traumatic bleed with no joint bleeds. All other patients had zero bleeds. Eight patients on octocog alfa with known data were previously treated with another product. Five of these eight patients were on a previous standard half-life product. Three of the eight had bleeding episodes, including spontaneous and joint bleeds, on their previous product; one patient with five bleeds had two traumatic bleeds and three joint bleeds. None of these patients had bleeds while using octocog alfa. All these patients were classified as having mild hemophilia; there was also one patient with moderate and two with severe hemophilia. Two patients on damoctocog alfa pegol with known data were previously treated with another product, one episodically with desmopressin and the other prophylactically with an extended half-life product. Neither had any bleed data listed in the dataset. Previous product usage of the patient with one traumatic bleed on damoctocog alfa pegol was unknown. Three patients receiving damoctocog alfa pegol had mild hemophilia and one severe. Conclusions: The real-world data obtained from the ATHNdataset confirm that some women and girls in all age groups are being treated with octocog alfa or damoctocog alfa pegol, and indicate the effectiveness of these treatments in this real-world setting. The majority have mild hemophilia A. Approximately 1/3 of the female patients were treated on some form of prophylaxis with 2/3 of these being classified as mild. Only traumatic bleeds, including traumatic joint bleeds, were noted. Three patients treated with different products before using octocog alfa had spontaneous, joint and traumatic bleeds on their previous therapies. More data are needed on the diagnosis and treatment of women with hemophilia A. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Joint Status and Bleeding Phenotype Characterization in Severe and Non-Severe Hemophilia a and B

Introduction: Persons with hemophilia (PwH) A and B are known to have variable bleeding phenotypes and may have joint bleeding that is less clinically apparent. In recent years, musculoskeletal ultrasound (MSKUS) has become an established modality useful for evaluating joint status. Further, determination of individual bleeding phenotype can be challenging, but clinical tools including the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT), self-BAT, and the Beighton Hypermobility Score (BHS) have been developed. Methods: We hypothesize that presence and degree of joint disease, evaluated with MSKUS and physical assessment scoring, will correlate with severity of bleeding phenotype as characterized through clinical history, BAT assessment, and presence of joint hypermobility in PwH A and B. This will be accomplished through assessing baseline joint status and disease progression over time with MSKUS, as well as through use of the ISTH-BAT, self-BAT, and assessment of hypermobility with the BHS. Up to 100 individual subjects with severe, moderate, or mild hemophilia A or B will be enrolled and assessed at baseline and annually during the study period at our institution. Correlation of joint status with BHS and BAT scores will be analyzed with the generalized estimating equation (GEE) and other statistical methods. Results: Thus far, 15 male patients have been enrolled (Table 1). All moderate and severe hemophilia patients are on prophylactic therapies for bleed prevention, and 3 patients have history of inhibitors. Target joints were reported only in severe PwH. MSKUS measurements were completed using the JADE protocol1. Patient enrollment remains ongoing. Discussion: Knowledge pertaining to joint status and bleeding phenotype is PwH A and B is limited. This pilot study will assess the presence and degree of joint disease, evaluated with MSKUS and physical assessment scoring, and its correlation with severity of bleeding phenotype as characterized through clinical history, BAT assessment, and presence of joint hypermobility in PwH hemophilia A and B. The results will be used to justify a larger, multicenter study to expand understanding of joint status and bleeding phenotype in PwH.