Predictive performance of pharmacokinetic-guided prophylactic dosing of factor concentrates in hemophilia A and B.

Background: Pharmacokinetic (PK)-guided dosing is used to individualize factor (F)VIII and FIX replacement therapy. Objectives: This study investigates the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B. Methods: In this multicenter, prospective cohort study, people of all ages with hemophilia received prophylactic treatment with factor concentrates based on individual PK parameters. During follow-up, at least 4 measured FVIII/FIX levels per patient were compared with corresponding predicted levels obtained by Bayesian forecasting. Predictive performance was defined as adequate when ≥80% of measured FVIII/FIX levels were within ±25% of prediction (relative error). Additionally, mean absolute error and mean error were calculated. In post hoc analyses, predictive performance was assessed allowing maximum absolute errors of 1 (trough), 5 (mid), and 15 (peak) IU/dL. Five-point scale questionnaires addressed feasibility of PK guidance. Results: We included 50 patients (median age, 19 years; range: 2-72 years). Median follow-up was 36 weeks. Seventy-one percent of levels (58% trough, 83% mid, and 80% peak) were within ±25% of prediction. Mean absolute errors were 0.8 (trough), 2.0 (mid), and 8.6 (peak) IU/dL. In post hoc analyses, 81% (trough), 96% (mid), and 82% (peak) of levels were within set limits. Patients reported low burden and high satisfaction. Conclusion: PK-guided dosing was reliable according to post hoc analyses, based on low absolute errors that were regarded as clinically irrelevant in most cases. The predefined predictive performance was achieved in mid and peak factor levels but not in trough factor levels due to measurement inaccuracy. PK guidance also seemed feasible.

Poor correlation between biomarkers and MRI-detected joint damage in a cross-sectional study of persons with nonsevere hemophilia A (DYNAMO study).

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.

Little discrepancy between one-stage and chromogenic factor VIII (FVIII)/IX assays in a large international cohort of persons with nonsevere hemophilia A and B.

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.

Desmopressin for bleeding in non-severe hemophilia A: Suboptimal use in a real-world setting.

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.

The bleeding phenotype in people with nonsevere hemophilia.

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.

Joint status of patients with nonsevere hemophilia A.

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.

A semiquantitative color Doppler ultrasound scoring system for evaluation of synovitis in joints of patients with blood-induced arthropathy.

BACKGROUND: Intra-articular bleeds in patients with inherited bleeding disorders lead to active synovitis which may progress to a chronic state over time. We explored the diagnostic value of color Doppler ultrasound in detecting synovitis in boys with bleeding disorders. RESULTS: Sixty boys with hemophilia and 3 boys with type 3 von Willebrand disease aged 5 to 18 years (median 12.3 years) were imaged by gray-scale and color Doppler ultrasound (US) in three centers (Beijing, China [n = 22], Guangzhou, China [n = 12] and Toronto, Canada [n = 29])) in this observational study. Images were independently reviewed by two radiologists blinded to clinical data using a subjective semi-quantitative scoring system and objective measurements of synovial thickness and vascularity. Inter-reader reliability for using subjective versus objective color Doppler US methods for assessing synovial vascularity was excellent for the subjective method and moderate/lower range of substantial for the objective method. Agreement between degree of vascularity on color Doppler and extent of synovial hypertrophy on gray-scale US was overall poor for Canada data and moderate for China data. Correlations between degree of vascularity on color Doppler and synovial hypertrophy on gray-scale US, and clinical constructs (total and itemized HJHS scores and total Pettersson X-ray scores) for assessment of blood-induced arthropathy were all poor. CONCLUSION: Color Doppler US is a valuable scoring method for evaluating reactive synovitis in joints of subjects with inherited bleeding disorders and holds potential for assessing post-bleed reactive synovitis once further information on its association with timing of the joint bleed becomes available in the literature.

Incidence and mortality rates of intracranial hemorrhage in hemophilia: a systematic review and meta-analysis.

Intracranial hemorrhage (ICH) is a severe complication that is relatively common among patients with hemophilia. This systematic review aimed to obtain more precise estimates of ICH incidence and mortality in hemophilia, which may be important for patients, caregivers, researchers, and health policy makers. PubMed and EMBASE were systematically searched using terms related to "hemophilia" and "intracranial hemorrhage" or "mortality." Studies that allowed calculation of ICH incidence or mortality rates in a hemophilia population ≥50 patients were included. We summarized evidence on ICH incidence and calculated pooled ICH incidence and mortality in 3 age groups: persons of all ages with hemophilia, children and young adults younger than age 25 years with hemophilia, and neonates with hemophilia. Incidence and mortality were pooled with a Poisson-Normal model or a Binomial-Normal model. We included 45 studies that represented 54 470 patients, 809 151 person-years, and 5326 live births of patients with hemophilia. In persons of all ages, the pooled ICH incidence and mortality rates were 2.3 (95% confidence interval [CI], 1.2-4.8) and 0.8 (95% CI 0.5-1.2) per 1000 person-years, respectively. In children and young adults, the pooled ICH incidence and mortality rates were 7.4 (95% CI, 4.9-11.1) and 0.5 (95% CI, 0.3-0.9) per 1000 person-years, respectively. In neonates, the pooled cumulative ICH incidence was 2.1% (95% CI, 1.5-2.8) per 100 live births. ICH was classified as spontaneous in 35% to 58% of cases. Our findings suggest that ICH is an important problem in hemophilia that occurs among all ages, requiring adequate preventive strategies.

Hemophilia management: Huge impact of a tiny difference.

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.