BACKGROUND:Persons with nonsevere hemophilia A (NSHA) experience less frequent joint bleeding than persons with severe hemophilia A, but may still develop joint damage. Biomarkers of cartilage and synovial remodeling can reflect ongoing pathologic processes that may precede or coincide with damage on joint imaging. If so, biomarkers may be an important diagnostic tool for joint damage in NSHA.OBJECTIVE:To assess the correlation between biomarkers and MRI-detected joint damage in persons with NSHA.METHODS:In a cross-sectional study, men with NSHA (factor VIII [FVIII], 2-35 IU/dL) were included. Participants underwent magnetic resonance imaging of elbows, knees, and ankles and blood and urine sampling for biomarker analysis on a single visit. The following biomarker(s) were analyzed in urine: CTX-II or serum: cartilage oligomeric matrix protein, chondroitin sulfate 846, vascular cell adhesion molecule 1, osteopontin (OPN), neo-epitope of MMP -mediated degradation of type II collagen, N-terminal propeptide of type II collagen, collagen type IV M, and propetide of type IV collagen. Spearman's rank correlations were calculated between these biomarkers and the total International Prophylaxis Study group (IPSG) score, soft-tissue subscore, and osteochondral subscore.RESULTS:In total, 48 persons with NSHA were included. Median age was 43 years (range, 24-55 years) and median FVIII was 10 IU/dL (IQR, 4-16 IU/dL). The median IPSG score was 4 (IQR, 2-9). Median IPSG soft-tissue subscores were 3 (IQR, 2-4) and osteochondral subscores were 0 (IQR, 0-4). No strong correlations were found between the studied biomarkers, total IPSG score, subsequent soft-tissue, and osteochondral subscores.CONCLUSIONS:In this study, selected biomarkers indicative of different aspects of hemophilic arthropathy showed no consistent correlation with IPSG scores. This suggests that systemically measured biomarkers are currently not suitable for identifying milder joint damage in NSHA, as observed on magnetic resonance imaging.

Background: Bone diseases, such as low bone mineral density (BMD) and osteoporosis are emerging concerns in people with hemophilia (PWH).As a consequence, PWH might experience fractures more frequently than the general population.Aims: Our primary aim was to compare the incidence of bone fractures in PWH and people with no bleeding disorders.The secondary aim was to identify the risk factors associated with bone fractures in PWH.Methods: This was a retrospective, case-control, study based on data from the Canadian Bleeding Disorders Registry and administrative data from the Institute for Clinical Evaluative Sciences (ICES).PWH were eligible if born before Jan 1, 2017, and alive on April 1, 1993.They were followed up to March 31, 2018.Age-and sex-matched controls with no bleeding disorders were randomly selected with a 20:1 case:control ratio.We analyzed the data using multivariate regression models, adjusting for age, severity, and inhibitor status, and comorbidities (Charlson Comorbidity index).

Background Accurate measurements of coagulation factor activity form an essential part of hemophilia management and are performed by the one-stage or chromogenic assay. Current literature suggests that approximately one-third of persons with nonsevere hemophilia A exhibit assay discrepancy, albeit with a high variability between studies. Such data are scarce in nonsevere hemophilia B. Objectives To investigate the extent of factor VIII/IX one-stage and chromogenic assay discrepancy in moderate and mild hemophilia A and B. Methods Persons with previously diagnosed nonsevere hemophilia A and B with a factor level of 2 to 35 IU/dL were included from the international DYNAMO cohort study. Central measurements of the factor VIII and IX activity levels were performed by the one-stage and chromogenic assay. Relative and absolute discrepancy definitions were used, with the International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee proposed ratio of >2.0 or <0.5 being the primary outcome. Discrepancy was also evaluated in a subgroup of 13 persons with mutations previously associated with discrepancy (≥3 cases reported in literature). Results A total of 220 persons were included, of whom 3 (1%) showed assay discrepancy: 2/175 hemophilia A and 1/45 hemophilia B. Six persons (3%) exhibited an absolute difference >10 IU/dL between the assay results. In addition, with more lenient definitions, over 90% of participants (n = 197) had no discrepant results. Only 1 out of 13 persons with a mutation previously associated with discrepancy had significant assay discrepancy. Conclusion Little assay discrepancy was observed despite the presence of mutations previously associated with discrepancy, suggesting that the presence and magnitude of assay discrepancy are largely determined by laboratory variables.

BACKGROUND:Joint bleeding in hemophilia may eventually lead to joint damage. In nonsevere hemophilia, joint bleeds occur infrequently. Currently, knowledge on the joint status of patients with nonsevere hemophilia using objective imaging is limited.OBJECTIVE:To investigate the joint status in patients with nonsevere hemophilia A.METHODS:This cross-sectional study included patients with nonsevere hemophilia A aged 24-55 years. Joint status was assessed by magnetic resonance imaging (MRI) of the elbows, knees, and ankles and International Prophylaxis Study Group (IPSG) scores were calculated. Lifetime joint bleeding history was collected from medical files. The contribution of factors to joint outcome was explored using multivariable linear regression analysis.RESULTS:In total, 51 patients were included, of whom 19 (37%) had moderate and 32 (63%) had mild hemophilia. Patients had a median age of 43 years (interquartile range [IQR] 32-50), a median factor VIII activity of 10 IU/dl (IQR 4-16) and a median annual joint bleeding rate (AJBR) of 0.0 (IQR 0.0-0.2). Soft-tissue changes (IPSG subscore > 0) in the elbows, knees, and ankles were present in 19%, 71%, and 71% of patients, respectively. Osteochondral changes (IPSG subscore > 0) in the elbows, knees, and ankles were present in 0%, 20%, and 35% of patients, respectively. In 14% of bleed-free joints, hemosiderin depositions were observed. Age and AJBRs were most strongly associated with the IPSG score.CONCLUSION:This study demonstrates that a substantial proportion of adults with nonsevere hemophilia has joint changes on MRI despite low joint bleeding rates.

Background:Desmopressin is an important treatment option in nonsevere hemophilia A because it has several benefits compared with factor (F) concentrates, including no inhibitor risk and much lower costs. Despite these advantages, data are limited on the real-world use of desmopressin in the treatment of bleeds. Objective:To describe the clinical use of desmopressin in relation to other therapeutic modalities in the treatment of bleeding episodes in patients with nonsevere hemophilia A. Methods:Patients with nonsevere hemophilia A aged 12-55 years were included from the DYNAMO cohort study. Data on the desmopressin test response and treated bleeding events in the period January 2009 to July 2020 were retrospectively collected from medical files. An adequate desmopressin test response was defined based on a peak FVIII level of ≥30 IU/dl. Results:A total of 248 patients with a median age of 38 years (interquartile range 25-49) were included. An adequate desmopressin test response was documented in 25% and 73% of patients with moderate and mild hemophilia, respectively. In adequate responders, 51% of bleeds were exclusively treated with FVIII concentrates, 24% exclusively with desmopressin, 21% with a combination of both and 4% with other treatments. In 54% of bleeds treated with a single dose of factor concentrates, the expected FVIII level after desmopressin exceeded the level targeted. Conclusion:Most bleeds in patients with an adequate response to desmopressin are treated with factor concentrates. These findings may indicate a suboptimal use of desmopressin and that barriers to the use of desmopressin should be explored.

Detailed information on the onset, frequency, and severity of bleeding in nonsevere hemophilia is limited. We aimed to assess the bleeding phenotype of persons with nonsevere hemophilia and to analyze the association between baseline factor VIII/IX (FVIII/IX) levels and the joint bleeding rate. In the DYNAMO (Dynamic Interplay Between Bleeding Phenotype and Baseline Factor Level in Moderate and Mild Hemophilia A and B) study, an international multicenter cohort, we included males with nonsevere hemophilia (FVIII/IX, 0.02-0.35 IU/mL) aged 12 to 55 years. Information on age at first treated (joint) bleed, annual bleeding rates (ABRs), and annual joint bleeding rates (AJBRs) was collected from the medical files. The association between baseline FVIII/IX levels and the joint bleeding rate was assessed by using a frailty model for recurrent events. In total, 304 persons (70 with moderate hemophilia and 234 with mild hemophilia) were included. The median age was 38 years (interquartile range [IQR], 25-49 years), and the median baseline FVIII/IX level was 0.12 IU/mL (IQR, 0.05-0.21 IU/mL). In total, 245 (81%) persons had experienced at least 1 bleed, and 156 (51%) had experienced at least 1 joint bleed. The median age at first bleed and first joint bleed was 8 and 10 years, respectively. The median ABR and AJBR was 0.2 (IQR, 0.1-0.5) and 0.0 (IQR, 0.0-0.2). From baseline FVIII/IX levels 0.02 to 0.05 IU/mL to >0.25 IU/mL, the median ABR decreased from 0.6 (IQR, 0.2-1.4) to 0.1 (IQR, 0.0-0.2) and the AJBR from 0.2 (IQR, 0.0-0.4) to 0.0 (IQR, 0.0-0.0). Baseline FVIII/IX was inversely associated with the joint bleeding rate (P < .001). Low bleeding rates were observed in persons with nonsevere hemophilia. However, one-half of all adolescents and adults had experienced a joint bleed.

We read with great interest the letter of Álvarez Román et al.,1.Álvarez Román MT, De la Corte RH, Bonanad S, Mingot‐Castellano M & Fernández N The factor VIII treatment history of non‐severe hemophilia A: COMMENT. Joint damage in adult patients with mild or moderate hemophilia A evaluated with the HEAD‐US system; 2021.Google Scholar reporting an alarming incidence of joint damage in 28 adults with non‐severe hemophilia A (14 moderate and 14 mild hemophilia) in Spain as measured by the HEAD‐US protocol. We thank Álvarez Román et al. for sharing these previously unpublished data. The study group found joint abnormalities in the majority of patients, with only 29% (8 of 28 patients) reporting zero scores for all joints as measured by HEAD‐US. In the total cohort, varying degrees of synovial or articular changes were seen in the joints. Percentage of patients who reported synovial hypertrophy ranged from 17.9% to 39.3%. In general, the ankles were the most affected joint, with HEAD‐US scores ≥3 reported in 25% and 39.3% of patients in the left and right ankle, respectively. Patients with moderate hemophilia had a total score of 0 less frequently than patients with mild hemophilia (21% vs. 35%). Moreover, in nearly all joints higher proportions of positive scores were seen in the moderate patient group.1.Álvarez Román MT, De la Corte RH, Bonanad S, Mingot‐Castellano M & Fernández N The factor VIII treatment history of non‐severe hemophilia A: COMMENT. Joint damage in adult patients with mild or moderate hemophilia A evaluated with the HEAD‐US system; 2021.Google Scholar In non‐severe hemophilia, research on the joint status by imaging is limited and previous research has mainly focused on patients with severe hemophilia. Recently, the results from a multicenter study in the Nordic countries, the MoHem study, were published on the joint health in 118 patients with moderate hemophilia A and B.2.Måseide R.J. Berntorp E. Astermark J. et al.Joint health and treatment modalities in Nordic patients with moderate haemophilia A and B ‐ the MoHem study.Haemophilia. 2020; 26: 891-897Crossref PubMed Scopus (13) Google Scholar Joint status evaluation was performed by the HEAD‐US protocol. In comparison to the study results by Álvarez Román et al., lower positive HEAD‐US scores were seen for both the total scores and individual joint scores. In the MoHem study, 52% of the study population had a total HEAD‐US score of 0 for all joints. Positive scores (≥1) on joint level were seen in 19% of the elbows, 20% of the knees, and 23% of the ankles, with corresponding median scores of 0 (IQR 0, 0) for the elbows, 0 (IQR 0, 0) for the knees, and 0 (IQR 0, 1) for the ankles.3.Måseide R.J. Berntorp E. Astermark J. et al.Haemophilia early arthropathy detection with ultrasound and haemophilia joint health score in the moderate haemophilia (MoHem) study.Haemophilia. 2021; 27: e253-e259Crossref PubMed Scopus (6) Google Scholar The difference in observed proportions of joint abnormalities between the patients with moderate hemophilia in the MoHem study and the Spanish cohort may be explained by the difference in age because the patients in the MoHem study were younger than in the Spanish cohort (median age 28 years vs. 51 years, respectively). In the MoHem and the Spanish study, the percentage of patients on prophylaxis was 38% and 27%. It is not possible, however, to analyze the effect of prophylaxis on joint abnormalities as the age at start of prophylaxis is an important factor in the prevention of bleeds. Explorations in the MoHem study showed no difference in scores between the modes of treatment. Nevertheless, joint abnormalities were still observed in a substantial proportion of this Nordic population, where it is to be noted that the annual joint bleeding rate (AJBR) was low (median AJBR 0, IQR 0, 1). Because no joint bleeding rates were reported in the letter of Álvarez Román et al, this cannot be compared between the two studies. If the joint bleeding rates in the population of Álvarez Román et al are comparable to ours and the MoHem study, the degree of synovial hypertrophy and articular damage raise concern. Apart from the joint bleeding rate, factors such as the severity of a joint bleed, time required for initiation of treatment, accessibility of the hemophilia treatment center, and availability of home treatment are important factors that may affect the sequelae of a joint bleed and ensuing joint abnormalities. In both the MoHem study and the Spanish cohort, ultrasound was used as the diagnostic imaging technique. Ultrasound has many advantages: it is cheap, easily accessible, and fast. It is an accurate tool in the assessment of synovial hypertrophy and the peripheral areas of the cartilage and bone. However, it is limited in the assessment of the central joint areas and therefore cannot rule out any cartilage and bone defects located in the central location. Magnetic resonance imaging (MRI) is the golden standard for joint evaluation because it is the most sensitive imaging technique in evaluating soft‐tissue and cartilage changes.4.Foppen W. Fischer K. van der Schaaf I.C. Imaging of haemophilic arthropathy: awareness of pitfalls and need for standardization.Haemophilia. 2017; 23: 645-647Crossref PubMed Scopus (8) Google Scholar Previous studies who have evaluated joint status by MRI have included patients with severe and moderate hemophilia, but to our knowledge no studies have purely focused on male patients with non‐severe hemophilia. Within the DYNAMO study group, which aims to explain phenotypic heterogeneity among patients with non‐severe hemophilia, we are presently analyzing MRI data that we obtained of all six joints in 51 patients with non‐severe hemophilia A, to assess the extent of joint damage in this patient group. We expect the manuscript to be submitted by the end of the year. As stated, current data from the literature and from Álvarez Román et al report the occurrence of joint abnormalities in patients with non‐severe hemophilia despite low joint bleeding rates. Further research into the joint bleeding rates and onset of joint damage in non‐severe hemophilia is important. It has been postulated that, in absence of evident joint bleeds, subclinical joint bleeds occur and may initiate the process of inflammation leading to synovitis and osteochondral damage.5.Gualtierotti R. Solimeno L.P. Peyvandi F. Hemophilic arthropathy: current knowledge and future perspectives.J Thromb Haemost. 2021; 00: 1-10https://doi.org/10.1111/jth.15444Google Scholar A few studies have explored the burden of arthropathy in patients with non‐severe hemophilia. One of these studies was a register‐based study in Sweden that compared arthropathy between patients with mild hemophilia and control group from the general population, matched for age and sex. Osooli and colleagues found an impressive 9‐fold and 16‐fold increase in the incidence of arthropathy‐related hospital admissions and arthropathy diagnosis in participants born between 1984 and 2008. In older patients, born before 1984, a 2‐fold and 5‐fold increase was seen in arthropathy diagnosis and surgery of index joints (elbows, knees, and ankles).6.Osooli M. Lovdahl S. Steen Carlsson K. et al.Comparative burden of arthropathy in mild haemophilia: a register‐based study in Sweden.Haemophilia. 2017; 23: e79-e86http://dx.doi.org/10.1111/hae.13166Crossref PubMed Scopus (15) Google Scholar A recently published national study in the Netherlands, reported joint impairment and orthopedic surgery in 25% and 24% of the patients with non‐severe hemophilia who were aged 50 years or older. Additionally, this population had lower scores on the RAND‐36, a questionnaire of general health status.7.Hassan S. van Balen E.C. Smit C. et al.Health and treatment outcomes of patients with hemophilia in the Netherlands, 1972–2019.J Thromb Haemost. 2021; 00: 1-13https://doi.org/10.1111/jth.15424Google Scholar These results indicate that in addition to the abnormalities seen on imaging, a higher burden of disease is also observed. Future studies exploring the extent of joint damage in non‐severe hemophilia are needed to confirm whether the results from these imaging studies are generalizable for the total group of patients with non‐severe hemophilia. Moreover, data on the joint status in non‐severe hemophilia could also be relevant for patients with severe hemophilia who are treated with non‐replacement treatments (NRTs). By use of NRT, the phenotype of these patients converts from severe to non‐severe hemophilia because they achieve a steady‐state therapeutic protection estimated to correspond to 10% of plasma factor level or higher, with concurrently reported low joint bleeding rates close to zero bleeding rates.8.Kizilocak H. Marquez‐Casas E. Malvar J. Carmona R. Young G. Determining the approximate factor VIII level of patients with severe haemophilia A on emicizumab using in vivo global haemostasis assays.Haemophilia. 2021; : 1-6https://doi.org/10.1111/hae.14359Google Scholar, 9.Barg A.A. Budnik I. Avishai E. et al.Emicizumab prophylaxis: prospective longitudinal real‐world follow‐up and monitoring.Haemophilia. 2021; 27: 383-391Crossref PubMed Scopus (16) Google Scholar Because joint damage develops over decades, rather than years, current data on joint health in non‐severe hemophilia, especially mild hemophilia, could shed light on what we can expect in patients with severe hemophilia who are long‐term users of NRT. In our opinion, it is of urgent importance to address the present knowledge gaps on the extent and the development of joint damage in patients with non‐severe hemophilia. The most robust design to study this would be a longitudinal setting cohort study that follows patients from birth. Research on factors contributing to the development of joint abnormalities is key in identifying which patients are at risk for the development of joint damage. These patients could benefit from intensification of treatment to mitigate the detrimental effect of further (subclinical) joint bleeds. This would be facilitated by identification of biomarkers that predict the development of joint damage before it has already occurred. Thus, the identification of such biomarkers should be high on the research agenda. Pending the answers to the questions raised above, the results of the ARTIHA study group by Álvarez Román indicate that increased awareness and closer monitoring of joints may be warranted in patients with non‐severe hemophilia. Increased education of both staff and persons living with hemophilia about the potential for joint complications and evaluation of more subtle joint symptoms in patients with non‐severe hemophilia could allow for early identification of joint bleeds and subsequently early initiation of treatment interventions, whether clotting factor or ideally DDAVP in absence of contraindication. Early identification of joint changes likely attributable to hemophilic complication, rather than non‐hemophilia cause, could be reason to intensify treatment strategies, as was considered by the investigator for seven of the patients in the study by Álvarez Román et al. F.K., A.A., and S.G. have nothing to disclose. The institution of K. Fijnvandraat has received unrestricted research grants from CSL Behring, Novo Nordisk, and received consultancy fees from Grifols, Takeda, and Novo Nordisk. D.P.H. has received research grant awards from Bayer, Octapharma, and Takeda; he and/or his institution have received advisory or lecturing honoraria from Bayer, Biomarin, Biotest, CSL Behring, Grifols, Octapharma, Pfizer, Roche, Sanofi, Sobi, Spark, Takeda, and UniQure. Fabienne R. Kloosterman wrote the manuscript, Amal Abdi, Samantha C. Gouw, and Daniel P. Hart reviewed the manuscript and Karin Fijnvandraat reviewed and approved the final version of this manuscript.

Background In patients with non-severe hemophilia A, we lack detailed knowledge on the timing of treatment with factor VIII (FVIII) concentrates. This knowledge could provide information about the expected treatment timing in patients with severe hemophilia A treated with non-replacement therapies. Objective To assess the FVIII treatment history in patients with non-severe hemophilia A. Methods Patients with non-severe hemophilia (baseline FVIII activity [FVIII:C] 2-40 IU/dL) were included from the INSIGHT study. The primary outcome was median age at first FVIII exposure (ED1). In a subgroup of patients for whom more detailed information was available, we analyzed the secondary outcomes: median age at first 20 EDs, annualized bleeding rate for all bleeds (ABR), joint bleeds (AJBR), and major spontaneous bleeds (ASmBR). Results In the total cohort (n = 1013), median baseline FVIII activity was 8 IU/dL (interquartile range [IQR] 4-15) and the median age at ED1 was 3.7 years (IQR 1.4-7.7). Median age at ED1 rose from 2.5 years (IQR 1.2-5.7) in patients with FVIII:C 2-5 IU/dL to 9.7 years (IQR 4.8-16.0) in patients with FVIII:C 25-40 IU/dL. In the subgroup (n = 104), median age at ED1, ED5, ED10, and ED20 was 4.0 years (IQR 1.4-7.6), 5.6 years (IQR 2.9-9.3), 7.5 years (IQR 4.4-11.3), and 10.2 years (IQR 6.5-14.2), respectively. Median ABR, AJBR, and ASmBR were 1.1 (IQR 0.5-2.6), 0.3 (IQR 0.1-0.7), and 0 (IQR 0-0), respectively. Conclusion This study demonstrates that in non-severe hemophilia A, the age at first FVIII exposure increases with baseline FVIII:C and that major spontaneous bleeds rarely occur.

Hemophilia A and B are inherited X-linked disorders of hemostasis, associated with an increased bleeding tendency. Patients with severe hemophilia have undetectable clotting factor levels and experience spontaneous bleeds. In patients with nonsevere hemophilia, the clotting factor levels are 2% to 40% of normal and bleeds predominantly occur after provocative events such as trauma and surgery. Despite this milder phenotype, patients with nonsevere hemophilia may suffer from considerable morbidity and have an increased mortality risk. However, many aspects of the course of disease and treatment remain unclear. Information on the factors influencing interindividual differences in bleeding phenotype is lacking, and misdiagnosis may occur due to assay discrepancies in the diagnostic workup. Desmopressin is the preferred treatment modality, but some patients and indications require treatment with clotting factor concentrates. This may elicit inhibitor formation, which is associated with an increased burden of disease and a higher mortality rate. It has been found that patients with nonsevere hemophilia A carry a lifelong risk for this serious complication. In this review, we provide an overview of the current knowledge of the diagnosis and management of nonsevere hemophilia. A report of science presented at the International Society on Thrombosis and Haemostasis 2019 Annual Congress is also provided.