Navigating the challenges: a case report on managing a complicated postpartum course in type 3 von Willebrand disease with alloantibodies.

Background: Von Willebrand disease (VWD) type 3 is characterized by a complete deficiency of von Willebrand factor (VWF), resulting in a severe bleeding phenotype. Treatment often requires administration of VWF concentrates/factor (F)VIII. However, the development of alloantibodies is a rare complication, resulting in ineffective recovery and allergic reactions. Emicizumab, a bispecific antibody mimicking FVIII function, has emerged as a potential alternative, with promising results reported in several case reports. Key Clinical Question: Description of multiple approaches to control highly severe postpartum hemorrhage in type 3 VWD with alloantibodies, including off-label use of emicizumab. Clinical Approach: Here we present a 28-year-old patient with type 3 VWD and alloantibodies, known to have arthropathy of the right elbow. Previous immune tolerance induction was unsuccessful. Despite receiving negative pregnancy advice during preconception counseling, the patient became pregnant. Delivery was induced at 38 4/7 weeks with prostaglandin, and recombinant FVIIa (rFVIIa) was administered every 2 hours. Despite administration of rFVIIa, bleeding persisted, requiring manual placental removal and insertion of a Bakri balloon. Since bleeding persisted, plasma-derived VWF was administered with an initial excellent recovery and successful embolization of the uterine artery. Twelve days postpartum, she developed endometritis and recurrent vaginal bleeding treated with antibiotics, rFVIIa every 2 hours, and multiple erythrocyte transfusions. Plasma-derived VWF was administered but was complicated by anaphylaxis and no recovery. Due to persistent vaginal bleeding, reembolization of uterine arteries was performed and off-label emicizumab was initiated. Twenty-nine days postpartum, she developed septic shock requiring an abdominal hysterectomy, again complicated by severe bleeding necessitating direct intraabdominal packing after rFVIIa. A computed tomography scan 9 days postsurgery revealed thrombosis in the left iliac vein and asymptomatic pulmonary embolisms. rFVIIa was stopped and prophylactic low-molecular-weight heparin was started. The patient was discharged 2 months after delivery on low-dose low-molecular-weight heparin, emicizumab, and antibiotics for an intra-abdominal abscess. During 2.5 years of emicizumab prophylaxis, she has had no rebleeding in her arthropathic right elbow. Conclusion: The current case emphasizes the postpartum clinical challenges of patients with type 3 VWD and alloantibodies. It underscores the potential role of emicizumab in maintaining hemostatic control.

Limited value of testing for factor XIII and α2-antiplasmin deficiency in patients with a bleeding disorder of unknown cause.

INTRODUCTION: In patients with an increased bleeding tendency, extensive diagnostic blood testing is often performed. When results of tier 1 assays of primary haemostasis are normal, protocols recommend additional testing to rule out rare disorders including coagulation factor XIII (FXIII) and α2-antiplasmin (α2AP) deficiency. AIM: To evaluate the added diagnostic value of FXIII and α2AP levels in patients with a bleeding disorder of unknown cause (BDUC). METHODS: A retrospective monocentre cohort study between August 2011 and August 2023 was conducted. In all patients with bleeding tendencies and normal diagnostic tests for von Willebrand disease and platelet function, FXIII and α2AP were measured. RESULTS: We included 158 consecutive patients; mean ISTH-BAT scores were 8.2 (SD ± 3.7) in children, 6.2 (SD ± 2.1) in men and 10.6 (SD ± 3.3) in women. Median age was 37 (range 5-79) years, 88.6% of patients were female. Patients displayed median FXIII activity of 111% (IQR = 97-131) and median α2AP activity of 112% (IQR = 103-119). Three (1.9%) patients had FXIII levels < 50%, respectively 43%, 45% and 46%. Corresponding ISTH-BAT scores were 7, 12 and 14. No α2AP levels < 60% was observed. No significant association was found between FXIII levels and ISTH-BAT scores. CONCLUSION: In our cohort of BDUC patients, no clinical relevant FXIII deficiencies were detected; absolute values were well above the 30% cutoff considered adequate for normal haemostasis. No α2AP deficiencies were detected. These data suggest that in BDUC patients, measuring FXIII or AP activity is of limited value.

Quantitative MRI assessment of joint effusion using T2-relaxometry at 3 Tesla: a feasibility and reproducibility study.

OBJECTIVE: T2-relaxometry could differentiate between physiological and haemorrhagic joint effusion (≥ 5% blood) in vitro. Are quantitative T2-relaxation time measurements of synovial fluid feasible and reproducible in vivo in clinically bleed-free joints of men with haemophilia? MATERIALS AND METHODS: In this cross-sectional study, we measured T2-relaxation times of synovial fluid in clinically bleed-free ankles, knees or elbows of men with severe haemophilia A using a T2-mapping sequence (duration ≤ 7 min) at 3 Tesla MRI. Manual and circular regions of interest (ROI) were drawn in the synovial fluid of each joint by two independent observers to measure T2-relaxation times. Measurement feasibility was expressed as the success rate of the measurements by both observers. The interobserver and intraobserver reproducibility of the measurements were evaluated by the intraclass correlation coefficient of absolute agreement (ICC) and the limits of agreement (LoA) from Bland Altman analysis. RESULTS: We evaluated 39 clinically bleed-free joints (11 ankles, 12 knees, 16 elbows) of 39 men (median age, 24 years; range 17-33) with severe haemophilia A. The success rate of the T2-measurements was ≥ 90%. Interobserver reliability was good to excellent (manual ROI: ICC = 0.92, 95% CI 0.76-0.97; circular ROI: ICC = 0.82, 95% CI 0.66-0.91) and interobserver agreement was adequate (manual ROI: LoA = 71 ms; circular ROI: LoA = 146 ms). Intraobserver reliability was good to excellent (manual ROI: ICC = 0.78, 95% CI - 0.06-0.94; circular RO: ICC = 0.99, 95% CI 0.98-0.99) and intraobserver agreement was good (manual ROI: LoA = 63 ms; circular ROI: LoA = 41 ms). CONCLUSION: T2-relaxometry of synovial fluid in haemophilia patients is feasible with good interobserver and intraobserver reproducibility.

The spectrum of neutralizing and non-neutralizing anti-FVIII antibodies in a nationwide cohort of 788 persons with hemophilia A.

Objectives: Anti-factor VIII (FVIII) antibodies have been reported to exhibit both neutralizing and non-neutralizing characteristics. This is the first study investigating the full spectrum of FVIII-specific antibodies, including non-neutralizing antibodies, very-low titer inhibitors, and inhibitors, in a large nationwide population of persons with hemophilia A of all severities. Methods: All persons with hemophilia A (mild (FVIII > 5-40 IU/dL)/moderate [FVIII 1-5 IU/dL)/severe (FVIII < 1 IU/dL)] with an available plasma sample who participated in the sixth Hemophilia in the Netherlands study between 2018 and 2019 were included. The presence of anti-FVIII antibodies of the immunoglobulin A, M, and G isotypes and IgG subclasses, along with antibody titer levels, were assessed using direct-binding ELISAs. FVIII specificity was assessed using a competition-based ELISA approach. The inhibitor status was determined using the Nijmegen ultra-sensitive Bethesda assay (NusBA) and the Nijmegen Bethesda assay (NBA). Results: In total, 788 persons with hemophilia A (336 (42.6%) mild, 123 (15.6%) moderate, 329 (41.8%) severe hemophilia) were included. The median age was 45 years (IQR 24-60), and the majority (50.9%) had over 150 exposure days to FVIII concentrates. Within our population, 144 (18.3%) individuals had non-neutralizing FVIII-specific antibodies, 10 (1.3%) had very low-titer inhibitors (NusBA positive; NBA negative), and 13 (1.6%) had inhibitors (both NusBA and NBA positive). IgG1 was the most abundant FVIII-specific antibody subclass, and the highest titer levels were found for IgG4. In individuals without a reported history of inhibitor development, no clear differences were observed in antibody patterns between those who were minimally or highly exposed to FVIII concentrates. IgG4 subclass antibodies were only observed in persons with a reported history of FVIII inhibitor or in those with a currently detected (very low-titer) inhibitor. Conclusion: In this cross-sectional study, we identified non-neutralizing antibodies in a relatively large proportion of persons with hemophilia A. In contrast, in our population, consisting of persons highly exposed to FVIII concentrates, (very low-titer) inhibitors were detected only in a small proportion of persons, reflecting a well-tolerized population. Hence, our findings suggest that only a small subpopulation of non-neutralizing FVIII-specific antibodies is associated with clinically relevant inhibitors.

Towards Personalized Treatment in Haemophilia: The Role of Genetic Factors in Iron and Heme Control to Identify Patients at Risk for Haemophilic Arthropathy.

The treatment landscape for haemophilia is changing rapidly, creating opportunities for personalized treatment. As major morbidity is still caused by haemophilic arthropathy, understanding the factors affecting joint damage and joint damage progression might lead to more individualized treatment regimens. We investigated the association of HFE mutations or HMOX1 polymorphisms affecting iron/heme handling with radiographic joint damage in 252 haemophilia patients (severe and moderate). Although iron levels and transferrin saturation were significantly increased in the 95 patients with an HFE mutation, neither carrying this mutation nor the HMOX1 polymorphism was associated with radiographic joint damage, and the same was true after adjustment for well-known factors associated with arthropathy. In conclusion, this study does not support the hypothesis that HFE mutations or HMOX1 polymorphisms can be used to predict the development of haemophilic arthropathy.

Patients with moderate hemophilia A and B with a severe bleeding phenotype have an increased burden of disease.

BACKGROUND: Patients with moderate hemophilia express varying bleeding phenotypes. OBJECTIVES: To assess the burden of disease in patients with moderate hemophilia and a mild or severe phenotype incorporating the thrombin generation profile. METHODS: This sub-study of the 6th Hemophilia in the Netherlands study, analyzed data of adults with moderate hemophilia A or B. Patient characteristics and information on bleeding tendency, joint status, and quality of life were obtained from electronic patient files and self-reported questionnaires. A severe bleeding phenotype was defined as an annual bleeding rate ≥5, an annual joint bleeding rate ≥3, and/or the use of secondary/tertiary prophylaxis, and a mild phenotype vice versa. TG was measured with the Nijmegen Hemostasis Assay. RESULTS: This study included 116 patients: 21% had a severe phenotype of whom 46% used prophylaxis. Patients with a severe phenotype treated on demand reported a higher median annual bleeding rate (7), annual joint bleeding rate (3), and more frequently an impaired joint (77%) than patients with a severe phenotype on prophylaxis (2; 0; 70%) or patients with a mild phenotype (0; 0; 47%). Furthermore, patients with a severe phenotype treated on demand experienced a more decreased quality of life. Despite similar factor activity levels, patients with a severe phenotype had a lower thrombin peak height and thrombin potential (0.7%; 0.06%) than patients with a mild phenotype (21.3%; 46.8%). CONCLUSION: Patients with moderate hemophilia and a severe phenotype treated on demand displayed a high burden of disease as well as a low thrombin generation profile advocating them toward more intensive prophylactic treatment.

Subclinical synovial proliferation in patients with severe haemophilia A: The value of ultrasound screening and biochemical markers.

AIM: Subclinical bleeding and inflammation play a role in progression of haemophilic arthropathy. Synovial proliferation is predictive of joint bleeding and its early detection may guide treatment changes and prevent arthropathy progression. This study evaluated the prevalence of active and inactive subclinical synovial proliferation and investigated potential biochemical blood/urine markers to identify patients with active subclinical synovial proliferation. METHODS: This cross-sectional study included patients with severe haemophilia A born 1970-2006 who were evaluated during routine clinic visits. Patients with (a history of) inhibitors or recent joint bleeding were excluded. Elbows, knees and ankles were examined for subclinical synovial proliferation by ultrasound and physical examination. Active synovial proliferation was distinguished from inactive synovial proliferation using predefined criteria. Blood/urine biochemical markers (serum osteopontin, sVCAM-1, Coll2-1, COMP, CS846, TIMP, and urinary CTX-II) were compared individually and as combined indexes between patients with and without active synovial proliferation. RESULTS: This cohort consisted of 79 patients with a median age of 31 years (range 16.5-50.8 years) with 62/79 (78%) of the patients using continuous prophylaxis. The annualized joint bleeding rate over the last 5 years was .6 (.2-1.1). Active (17/79, 22%) and inactive subclinical synovial proliferation (17/79, 22%) were both prevalent in this cohort. Biochemical markers were not correlated with active subclinical synovial proliferation. CONCLUSION: Subclinical synovial proliferation, both active and inactive, was prevalent in patients with severe haemophilia A with access to prophylaxis and would be overlooked without routinely performed ultrasounds. Biochemical markers were unable to identify patients with active subclinical synovial proliferation.

Pre-operative synovial hyperaemia in haemophilia patients undergoing total knee replacement and the effects of genicular artery embolization: A retrospective cohort study.

AIM: Haemophilia is characterized by recurrent joint bleeding caused by a lack of clotting factor VIII or IX. Due to repeated joint bleeding, end-stage arthropathy occurs in relatively young patients. A total knee replacement (TKR) can be a solution. However, TKR may be complicated by perioperative and postoperative bleeds despite clotting factor therapy. The aim of this study was to evaluate the prevalence of pre-operative synovial hyperaemia and the effects of Genicular Artery Embolization on synovial hyperaemia and 3-month postoperative joint bleeding. METHODS: In this retrospective cohort study, all patients with haemophilia who underwent periarticular catheter angiography between 2009 and 2020 were evaluated after written informed consent. Synovial hyperaemia on angiography was scored by an interventional radiologist. RESULTS: Thirty-three angiography procedures in 24 patients were evaluated. Median age was 54.4 years (IQR 48.4-65.9). Preoperative synovial hyperaemia was observed in 21/33 joints (64%). Moderate and severe synovial hyperaemia was observed in 10/33 joints (30%). Synovial hyperaemia decreased in 13/15 (87%) joints after embolization. Three-month postoperative joint bleeding occurred in 5/32 joints: in 2/18 joints (11%) without synovial hyperaemia and in 3/14 joints (21%) with mild synovial hypertrophy. Non-embolized and embolized joints did not differ regarding 3-month postoperative bleeding (P = .425). No complications were observed after embolization. CONCLUSION: One-third of patients with haemophilia requiring a TKR had moderate or severe synovial hyperaemia which can be reduced safely by Genicular Artery Embolization prior to TKR. Three-month postoperative bleeding appears to occur independently of the presence of residual mild synovial hyperaemia.

Desmopressin in nonsevere hemophilia A: patient perspectives on use and efficacy.

Background: Desmopressin increases plasma factor VIII and von Willebrand factor levels in persons with nonsevere hemophilia A. Patients' perspectives on desmopressin are relevant to increase and optimize its suboptimal use. However, patients' views on desmopressin are not reported. Objectives: To evaluate the perspectives of persons with nonsevere hemophilia A on desmopressin use, barriers for its use, side effects, and their knowledge about desmopressin's efficacy and side effects. Methods: Persons with nonsevere hemophilia A were included in a cross-sectional, national, multicenter study. Questionnaires were filled out by adult patients and children aged ≥12 years themselves. Caretakers filled out questionnaires for children aged <12 years. Results: In total, 706 persons with nonsevere hemophilia A were included (544 mild, 162 moderate, [age range, 0-88 years]). Of 508 patients, 234 (50%) patients reported previous desmopressin use. Desmopressin was considered as at least moderately effective in 171 of 187 (90%) patients. Intranasal administration was the modality of choice for 138 of 182 (76%) patients. Flushing was the most reported side effect in 54 of 206 (26%) adults and 7 of 22 (32%) children. The most frequently reported advantage and disadvantage were the convenience of intranasal, out-of-hospital administration by 56% (126/227) and side effects in 18% (41/227), respectively. Patients' self-perceived knowledge was unsatisfactory or unknown in 28% (63/225). Conclusion: Overall, desmopressin was most often used intranasally and considered effective, with flushing as the most common side effect. The most mentioned advantage was the convenience of intranasal administration and disadvantage was side effects. More information and education on desmopressin could answer unmet needs in patients with current or future desmopressin treatment.

Transition readiness among adolescents and young adults with haemophilia in the Netherlands: Nationwide questionnaire study.

INTRODUCTION: Care for adolescents with haemophilia is transferred from paediatric to adult care around the age of 18 years. Transition programs help to prepare adolescents for this transfer and prevent declining treatment adherence. Evaluating transition readiness may identify areas for improvement. OBJECTIVE: Assess transition readiness among Dutch adolescents and young adults with haemophilia, determine factors associated with transition readiness, and identify areas of improvement in transition programs. METHODS: All Dutch adolescents and young adults aged 12-25 years with haemophilia were invited to participate in a nationwide questionnaire study. Transition readiness was assessed using multiple-choice questions and was defined as being ready or almost ready for transition. Potential factors associated with transition readiness were investigated, including: socio-demographic and disease-related factors, treatment adherence, health-related quality of life, and self-efficacy. RESULTS: Data of 45 adolescents and 84 young adults with haemophilia (47% with severe haemophilia) were analyzed. Transition readiness increased with age, from 39% in 12-14 year-olds to 63% in 15-17 year-olds. Nearly all post-transition young adults (92%, 77/84) reported they were ready for transition. Transition readiness was associated with treatment adherence, as median VERITAS-Pro treatment adherence scores were worse in patients who were not ready (17, IQR 9-29), compared to those ready for transition (11, IQR 9-16). Potential improvements were identified: getting better acquainted with the adult treatment team prior to transition and information on managing healthcare costs. CONCLUSIONS: Nearly all post-transition young adults reported they were ready for transition. Improvements were identified regarding team acquaintance and preparation for managing healthcare costs.

Clotting factor activity levels and bleeding risk in people with haemophilia playing sports.

BACKGROUND: Improved treatment options for people with haemophilia (PWH) have increased the possibilities for sports participation, but the risk of sports-induced bleeding (SIB) is still considered considerable by many. AIM: To assess sports associated injury- and bleeding risk in PWH and to assess clotting levels associated with safe sports participation. METHODS: Sports injuries and SIBs were prospectively collected for 12 months in PWH aged 6-49 without inhibitors playing sports at least once weekly. Injuries were compared according to factor levels, severity, joint health, sports risk category and sports intensity. Factor activity at the time of injury was estimated using a pharmacokinetic model. RESULTS: 125 participants aged 6-49 (41 children, 90% haemophilia A; 48% severe, 95% severe on prophylaxis) were included. Sports injuries were reported by 51 participants (41%). Most participants (62%) reported no bleeds at all and only 16% reported SIBs. SIBs were associated with factor levels at time of injury (OR: 0.93/%factor level (CI 0.88-0.99); p = .02), but not with haemophilia severity (OR: 0.62 (CI 0.20-1.89); p = .40), joint health, sports risk category or sports intensity. PWH with factor levels <10% during sports injury had a bleeding risk of 41% versus 20% in those with higher (>10%) factor levels. CONCLUSION: The results of this study emphasize the importance of clotting factor levels in prevention of bleeds. This information is vital for patient counselling and tailoring prophylactic treatment with clotting factors and non-replacement therapy.

Structural changes after ankle joint distraction in haemophilic arthropathy: an explorative study investigating biochemical markers and 3D joint space width.

INTRODUCTION: Ankle joint distraction (AJD) is a promising treatment for patients with severe haemophilic ankle arthropathy (HAA). However, some patients showed no clinical improvement after AJD and these differences may be related to structural differences. AIM: Primarily to quantify the structural changes after AJD in patients with HAA by the use of 3D joint space width (JSW) measurements and biochemical markers and secondarily to correlate these findings with clinical pain/function. METHODS: Patients with haemophilia A/B who underwent AJD were included for this study. Bone contours on MRI (performed before and 12 and 36 months after AJD) were drawn manually and percentage change in JSW was calculated. Blood/urine (before and 6, 12, 24 and 36 months after AJD) was collected for biomarker measurement (COMP, CS846, C10C, CALC2, PRO-C2, CTX-II) and combined indexes of markers were calculated. Mixed effects models were used for analyses on group level. Structural changes were compared with clinical parameters. RESULTS: Eight patients were evaluated. On group level, percentage changes in JSW showed a slight decrease after 12 months followed by a non-statistically significant increase in JSW after 36 months compared to baseline. Biochemical marker collagen/cartilage formation also showed an initial decrease, followed by a trend towards net formation 12, 24 and 36 months after AJD. On individual patient level, no clear correlations between structural changes and clinical parameters were observed. CONCLUSION: Cartilage restoration activity on group level in patients with HAA after AJD was in concordance with clinical improvements. Correlating structural modifications with clinical parameters in the individual patient remains difficult.

Monitoring recovery of joints after bleeding: Physical examination and ultrasound are complementary.

AIM: Traditionally, recovery after a joint bleed in people with bleeding disorders is evaluated by clinical symptoms. Following a bleed, however, asymptomatic joints may still show synovial hypertrophy and effusion on ultrasound. We evaluated the duration of full recovery from a joint bleed. Additionally, we determined how recovery differed when assessed by physical examination and ultrasound. METHODS: In this retrospective cohort study, we investigated joint bleeds in elbows, knees and ankles of people with haemophilia or Von Willebrand disease who attended the Van Creveldkliniek between 2016 and 2021. Physical examination (warmth, swelling, range of motion and gait) and ultrasound (effusion and synovial hypertrophy) were performed within 7 days after the onset of the bleed, 1 week after the first examination and monthly thereafter until patients had recovered fully. Joint bleeds were treated in line with the current international treatment guidelines. RESULTS: We evaluated 30 joint bleeds in 26 patients. The median recovery time was 1 month (range 0.3-5 months). In 47% of the joint bleeds, the recovery took longer than 1 month. The moment of recovery based on physical examination and ultrasound differed in 27% of bleeds. Both persistent abnormalities at physical examination in joints with normalized ultrasounds and persistent ultrasound findings in clinically recovered joints occurred. CONCLUSION: Joint bleed recovery can take long and recovery times differed per bleed. Recovery differed when assessed by physical examination or ultrasound. Therefore, both should be used to closely monitor recovery of joint bleeds and offer personalized care.

In patients with hemophilia, a decreased thrombin generation profile is associated with a severe bleeding phenotype.

Background: Heterogeneity in clinical bleeding phenotype has been observed in hemophilia patients with similar FVIII or FIX activity levels. Thrombin generation and plasmin generation, as a global hemostasis assay, may contribute to a better prediction of which patients are at an increased risk of bleeding. Objectives: The objective of this study was to describe the association between clinical bleeding phenotype and thrombin generation and plasmin generation profiles in patients with hemophilia. Methods: The Nijmegen Hemostasis Assay, which simultaneously measures thrombin and plasmin generation, was performed in plasma samples of patients with hemophilia participating in the sixth Hemophilia in the Netherlands study (HiN6). Patients receiving prophylaxis underwent a washout period. A severe clinical bleeding phenotype was defined as a self-reported annual bleeding rate of ≥5, a self-reported annual joint bleeding rate of ≥3, or the use of secondary/tertiary prophylaxis. Results: In total, 446 patients, with a median age of 44 years, were included in this substudy. Thrombin generation and plasmin generation parameters differed between patients with hemophilia and healthy individuals. The median thrombin peak height was 1.0 nM, 25.9 nM, 47.1 nM, and 143.9 nM in patients with severe, moderate, and mild hemophilia and healthy individuals, respectively. A severe bleeding phenotype was observed in patients with a thrombin peak height of <49% and a thrombin potential of <72% compared to healthy individuals, and was independent of the hemophilia severity. The median thrombin peak height was 0.70% in patients with a severe clinical bleeding phenotype and 30.3% in patients with a mild clinical bleeding phenotype. The median thrombin potentials for these patients were 0.06% and 59.3%, respectively. Conclusion: A decreased thrombin generation profile is associated with a severe clinical bleeding phenotype in patients with hemophilia. Thrombin generation in combination with bleeding severity may be a better tool to personalize prophylactic replacement therapy irrespective of hemophilia severity.

Magnetic resonance imaging evidence for subclinical joint bleeding in a Dutch population of people with severe hemophilia on prophylaxis.

BACKGROUND: Previous studies suggest that subclinical bleeding occurs in persons with hemophilia. OBJECTIVES: The aim of this study was to investigate whether patients with lifelong access to prophylaxis showed signs of previous subclinical bleeding on magnetic resonance imaging (MRI) in joints without a history of joint bleeding. METHODS: This single-center cross-sectional study included persons with severe hemophilia A on prophylaxis, aged 16 to 33 years, with lifetime bleeding records available. Per participant, 1 index joint without a history of joint bleeding was evaluated with 3-Tesla MRI, including hemosiderin sensitive sequences. MRI scans were reviewed according to the International Prophylaxis Study Group (IPSG) additive MRI scale (range, 0-17/joint). Hemosiderin deposits with/without synovial hypertrophy were considered signs of previous subclinical bleeding. Additionally, physical examination was performed, followed by ultrasound examination according to the Hemophilia Early Arthropathy Detection with Ultrasound protocol. RESULTS: In 43 patients with a median age of 23.5 years, 43 joints (16 elbows, 13 knees, 14 ankles) without reported bleeds were evaluated with MRI. The median IPSG MRI score was 1 (range, 0-9). Signs of previous subclinical bleeding were observed in 7 of 43 joints (16%; 95% CI, 7-30): 7 of 7 joints showed hemosiderin deposits, with concomitant synovial hypertrophy in 2 of 7 joints. MRI changes were accompanied by swelling and ultrasound-detected synovial hypertrophy in 1 ankle only. None of the other joints showed abnormalities at physical examination and ultrasound. CONCLUSION: In this study, 16% of the joints without reported bleeds showed signs of previous subclinical bleeding, providing evidence for subclinical bleeding in people with severe hemophilia with lifelong access to prophylaxis.

Colorectal cancer screening in patients with inherited bleeding disorders: high cancer detection rate in hemophilia patients.

BACKGROUND: The population-based colorectal cancer (CRC) screening program in individuals aged 55 to 75 years in the Netherlands uses fecal immunochemical testing (FIT), to detect hemoglobin in feces, followed by colonoscopy in individuals with a positive FIT. OBJECTIVES: The objectives of this study are to assess the false-positive rate, detection rate, and positive predictive value of FIT for CRC and advanced adenoma (AA) in patients with Von Willebrand disease (VWD) or hemophilia. METHODS: We performed a multicenter, nationwide cross-sectional study embedded in 2 nationwide studies on VWD and hemophilia in the Netherlands. RESULTS: In total, 493 patients with hemophilia (n = 329) or VWD (n = 164) were included, of whom 351 patients participated in the CRC screening program (71.2%). FIT positivity and false-positive rate in patients with hemophilia and VWD were significantly higher than those in the general population (14.8% vs. 4.3%, p < .001 and 10.3% vs. 2.3%, p <.001, respectively). In patients with hemophilia, the detection rate of CRC/AA was significantly higher than that in the general male population (4.5% vs. 1.8%, p = .02), and the positive predictive value of FIT for CRC/AA was comparable (32.3% vs. 39.7%, n.s.). In patients with VWD, the detection rate was similar to that of the general population (0.8% vs. 1.4%, n.s.), whereas the positive predictive value was significantly lower than that in the general population (6.3% vs. 36.8%, p = .02). CONCLUSION: This study indicates that despite a high false-positive rate of FIT in patients with inherited bleeding disorders, the detection rate of CRC and/or AA in hemophilia patients is high. FIT performs different in patients with hemophilia or VWD compared with the general population.

Liver-related complications before and after successful treatment of chronic hepatitis C virus infection in people with inherited bleeding disorders.

INTRODUCTION: With availability of direct-acting antivirals (DAA), most persons with inherited bleeding disorders are currently cured of hepatitis C virus (HCV) infection. The risk of liver-related complications following HCV cure has not been reported for this population. AIM: Reporting liver-related complications during long-term chronic HCV infection and following sustained virological response (SVR) in this population. METHODS: Retrospective follow-up of a prospective single-centre cohort of HCV antibody-positive persons with inherited bleeding disorders. Primary endpoint was liver-related complications [hepatocellular carcinoma (HCC), decompensated cirrhosis, bleeding gastroesophageal varices]. Liver-related complications were reported separately during chronic HCV and following SVR, stratified for interferon-based and DAA-based SVR. RESULTS: In total 309/381 (81%) HCV antibody-positive individuals developed chronic HCV infection. Median follow-up was 44 years [interquartile range (IQR): 34-50]. Liver-related complications occurred in 36/309 (12%) of individuals with chronic HCV infection after median 31 years of chronic infection. Of 199 individuals with SVR, 97 were cured with interferon-based regimens and 102 with DAA after median infection durations of 29 and 45 years, respectively. At end of follow-up, respectively, 21% and 42% had advanced fibrosis or cirrhosis. Post-SVR, seven (4%) individuals had a liver-related complication, mainly HCC (n = 4). Incidence of liver-related complications per 100 patient-years post-SVR follow-up was .2 for interferon-cured and 1.0 for DAA-cured individuals (p = .01). CONCLUSION: Successful HCV treatment does not eliminate the risk of liver-related complications in persons with inherited bleeding disorders. Due to higher baseline risk, incidence was higher after DAA than interferon-based SVR. We advise continuing HCC surveillance post-SVR in all with advanced fibrosis or cirrhosis.

Socioeconomic participation of persons with hemophilia: Results from the sixth hemophilia in the Netherlands study.

Background and objectives: Treatment availability and comprehensive care have resulted in improved clinical outcomes for persons with hemophilia. Recent data on socioeconomic participation in the Netherlands are lacking. This study assessed participation in education, in the labor market, and social participation for persons with hemophilia compared with the general male population. Methods: Dutch adults and children (5-75 years) of all hemophilia severities (n = 1009) participated in a questionnaire study that included sociodemographic, occupational, and educational variables. Clinical characteristics were extracted from electronic medical records. General population data were extracted from Statistics Netherlands. Social participation was assessed with the PROMIS Ability to Participate in Social Roles and Activities short form, with a minimal important difference set at 1.0. Results: Data from 906 adults and children were analyzed. Participation in education of 20 to 24 year olds was 68% (general male population: 53%). Educational attainment was higher compared with Dutch males, especially for severe hemophilia. Absenteeism from school was more common than in the general population. The employment-to-population ratio and occupational disability were worse for severe hemophilia than in the general population (64.3% vs. 73.2% and 14.7% vs. 4.8%, respectively), but similar for nonsevere hemophilia. Unemployment was 5.4% (general male population: 3.4%). Absenteeism from work was less common (38% vs. 45.2%). Mean PROMIS score was similar to or higher than in the general population (54.2; SD 8.9 vs. 50; SD 10). Conclusion: Socioeconomic participation of persons with nonsevere hemophilia was similar to the general male population. Some participation outcomes for persons with severe hemophilia were reduced.