We present three pediatric cases of hemophilic arthropathy (HA) of the elbow that had already progressed to advanced stage with osteochondral lesions at the time of diagnosis-Case 1: 13-year-old boy, severe hemophilia A; Case 2: 13-year-old boy, moderate hemophilia A; Case 3: 15-year-old boy, severe hemophilia A. HA results from repeated hemarthrosis. Notably, Cases 2 and 3 had no history of clinically recognized elbow hemarthrosis before HA diagnosis, and Case 1 had only two episodes of hemarthrosis. Cases 2 and 3 did not report elbow extension restriction and pain for 1 or 2 years, as their daily lives were minimally affected. Since full elbow extension or flexion is rarely needed in daily life, and restricted elbow motion can be compensated by other motions, leading to less inconvenience. Consequently, HA of the elbow often remains unnoticed until it progresses to advanced stage; which necessitates careful monitoring from childhood. Canada’s Drug Agency (CDA-AMC) recommends that ALTUVIIIO should be reimbursed for the treatment of hemophilia A (congenital factor VIII [FVIII] deficiency) if certain conditions are met. WHICH PATIENTS ARE ELIGIBLE FOR COVERAGE? ALTUVIIIO should be covered to treat patients living with hemophilia A, provided it is covered for a patient population similar to that of other FVIII replacement therapies currently reimbursed for the treatment of patients with hemophilia A. WHAT ARE THE CONDITIONS FOR REIMBURSEMENT? ALTUVIIIO should only be reimbursed in a similar way as other FVIII replacement therapies that are currently reimbursed for the treatment of patients with hemophilia A. The cost of ALTUVIIIO should be negotiated so that it does not exceed the annual drug program cost of treatment currently reimbursed for prophylactic use in hemophilia A. WHY DID CDA-AMC MAKE THIS RECOMMENDATION? • Evidence from 2 clinical trials demonstrated that ALTUVIIIO given once weekly for 52 weeks reduced bleeding rates in patients with severe hemophilia A, with most patients experiencing no bleeds, and showed potential improvements in joint health, pain, and quality of life, with no major safety concerns reported. • Based on the CDA-AMC assessment of the health economic evidence, ALTUVIIO does not represent good value to the health care system at the public list price. The committee determined that there is not enough evidence to justify a greater cost for ALTUVIIO, for the full indication, compared with other therapies currently reimbursed for the prophylaxis of hemophilia A. • ALTUVIIIO met some of the needs identified by patients, including offering adequate bleed protection at a lower frequency of administration than other FVIII therapies. • Based on public list prices, ALTUVIIO is estimated to provide cost savings of approximately $471 million over the next 3 years. However, the predicted cost savings are highly uncertain and likely overestimated because they were based on evidence from patients with severe disease. This may overstate the clinical efficacy of ALTUVIIIO across all severities and treatment types — particularly for mild and moderate hemophilia A, where evidence is lacking and most of the projected cost savings are expected to originate. WHAT IS HEMOPHILIA A? Hemophilia A is a rare inherited genetic disorder in which the blood fails to clot properly due to defective or low levels of the clotting protein FVIII. As a result, patients living with hemophilia A experience excessive bleeding that can occur internally or externally, and can lead to complications such as joint damage, deep internal bleeding, or neurological problems. It also impacts a patient’s quality of life. Severity of hemophilia A is classified as mild, moderate, or severe based on how much FVIII is present in the blood. In 2023, approximately 3,510 people in Canada were living with hemophilia A, including 1,158 with severe hemophilia A. UNMET NEEDS IN HEMOPHILIA A: Treatments for hemophilia A that offer better bleed protection especially in patients who participate in frequent physical activity, improve joint health, reduce pain, and improve overall quality of life are needed. HOW MUCH DOES ALTUVIIIO COST? Prophylaxis with ALTUVIIO is expected to cost approximately $345,185 (for a patient weighing 40 kg) to $690,371 (for a patient weighing 80 kg) per patient annually. For on-demand use, treatment with ALTUVIIO is expected to cost approximately $6,620 (for a patient weighing 40 kg) to $13,240 (for a patient weighing 80 kg) per bleed.

Patients with non-severe hemophilia A (PwnSHA) may be at risk for joint damage (JD), yet data remain scarce. Our aim was to evaluate the joint condition in PwnSHA in a real-world setting. A nationwide, multicenter, cross-sectional study was conducted. To mitigate the impact of discrepancies between factor VIII (FVIII) assays, baseline FVIII levels were determined using chromogenic and one-step clotting assays. Mutation in F8 gene, baseline FVIII levels, thrombin generation and age were assessed. The joint condition was described using the HEAD-US score by trained specialists at each participating hospital. One hundred and twenty-four patients were recruited, 84 of them with an available HEAD-US evaluation, who were finally included in our analysis. The median age was 38.4 years (18.3-48.5). Twenty percent (16/84) had moderate hemophilia (MoH) with FVIII levels of 4.0 IU/dL (2.6-4.6), and 80% (68/84) had mild hemophilia (MiH) with FVIII levels of 14.8 IU/dL (10.4-19.9), (p< 0.001). JD (HEAD-US>0) was observed in 50% (8/16) of MoH patients (HEAD-US= 6.5 [5.5-8.5]) and in 40% (27/68) of those with MiH (HEAD-US= 3.0 [2.0-6.5]), p=0.198. In the moderate group, JD was primarily observed in ankles (44%), while in the MiH group, knees were the most affected (31%). MoH patients reported a hypocoagulable thrombin generation profile compared to MiH patients (p<0.05). Near half of PwnSHA had JD. A worse joint health and a lower thrombin generation was observed in MoH population. These patients can benefit from an early prophylaxis and prevent further joint deterioration. Future research should explore additional variables that might influence joint condition.

Objective: This study aimed to analyze pharmacokinetic and clinical parameters (bleeding rates and joint health) before and after switching from standard half-life (SHL) factor VIII (FVIII) to extended half-life (EHL) PEGylated turoctocog alfa pegol in patients with severe/moderate hemophilia A (HA) on prophylaxis, one year prior to and following the switch in a real-world setting. Methods: A single-center, comparative, observational, sequential, retrospective, multidisciplinary study was designed. The population pharmacokinetic parameters were estimated using the WAPPS-Hemo® platform. The annualized bleeding rate (including total and joint bleeds), joint health (Hemophilia Joint Health Score), FVIII consumption, administration frequency, and treatment costs were analyzed. Results: Eight patients with severe (n = 7) or moderate (n = 1) HA on prophylaxis were included after switching to turoctocog alfa pegol. With this regimen, the median FVIII half-life was 16.8 (15.2-19.1) hours, the area under the curve (AUC) was 18,182 (12,879-21,214) IU·h/dL, and the incremental recovery was 2.2 IU/dL per (1.6-2.4) IU/kg. The patients required a median of 2.0 infusions per week (2.0-2.0), corresponding to a weekly consumption of 57.8 (54.2-61.1) IU/kg. Clinically, the prophylactic regimen was associated with fewer infusions per week, stable joint health, and a reduction in overall treatment costs. Conclusions: Prophylaxis with turoctocog alfa pegol provided the expected pharmacokinetic profile of an EHL-FVIII concentrate, enabled a lower infusion frequency, and was linked to a decreased treatment burden and cost while maintaining joint health. Hemophilia A is characterized by deficiency in factor VIII clotting activity that results in prolonged bleeding after injuries, tooth extractions, or surgery, and delayed or recurrent bleeding prior to complete wound healing. The age of diagnosis and frequency of bleeding episodes are related to the level of factor VIII clotting activity. Severe hemophilia A: Individuals are usually diagnosed during the first two years of life following oral or soft tissue bleeding either with procedures or due to a known family history of hemophilia. Without prophylactic treatment, individuals may average up to two to five spontaneous bleeding episodes each month including spontaneous joint bleeds or deep-muscle hematomas, and prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions. Moderate hemophilia A: Less frequent spontaneous bleeding, although it varies between individuals. Affected individuals have prolonged or delayed bleeding after relatively minor trauma and are usually diagnosed before age five to six years; the frequency of bleeding episodes varies, usually from once a month to once a year. Mild hemophilia A: Individuals generally do not have spontaneous bleeding episodes; however, without pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions. The frequency of bleeding episodes varies widely, typically from once a year to once every ten years. Individuals with mild hemophilia A are often not diagnosed until later in life. Heterozygous females: Approximately 30% of heterozygous females have factor VIII clotting activity below 40% and are at risk for bleeding (even if males in the family are only mildly affected). After major trauma or invasive procedures, prolonged or excessive bleeding usually occurs, regardless of severity. In addition, 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency. The diagnosis of hemophilia A is established in an individual with low factor VIII clotting activity in the presence of a normal, functional von Willebrand factor level. Identification of a hemizygous F8 pathogenic variant by molecular genetic testing in a male proband confirms the diagnosis. Identification of a heterozygous F8 pathogenic variant by molecular genetic testing in a symptomatic female confirms the diagnosis. Targeted therapies: For those with severe hemophilia A and those with moderate or mild hemophilia A and frequent bleeding, prophylactic treatment with factor VIII concentrate infusions or subcutaneous administration of emicizumab; other non-factor prophylactic therapies (marstacimab, concizumab, and fitusiran) are approved in those age 12 years and older. Desmopressin acetate in those with mild hemophilia A and documented response to this therapy. Immune tolerance therapy in those with inhibitors. Adeno-associated viral (AAV)-mediated gene therapy for hemophilia A (valoctocogene roxaparvovec) was approved by the FDA for adults with severe disease in 2023. Supportive care: Referral to a hemophilia treatment center (HTC) for assessment, education, genetic counseling, and treatment. Training to facilitate home infusions administered by parents or affected individuals should be provided for individuals affected by moderate and severe hemophilia; physical therapy for evaluation and treatment of musculoskeletal disease; standard treatments for pain with help from a pain specialist as needed; standard treatments for transfusion-related infections contracted prior to virucidal treatment of plasma-derived concentrates. Surveillance: For individuals with severe or moderate hemophilia A, assessments including inhibitor screen every six to 12 months at an HTC; for individuals with mild hemophilia A, assessment at an HTC every one to two years. Children and individuals with comorbidities may require more frequent visits. The assessment should include a review of bleeding episodes, adjustment of treatment plans as needed, a joint and muscle evaluation, an inhibitor screen, viral testing if indicated, and a discussion of any other issues related to the individual's hemophilia A as well as family and community support. Screening for alloimmune inhibitors is performed during initial ten to 20 treatment days in children with severe hemophilia then on recommended schedule or in individuals with a suboptimal clinical response to treatment. Agents/circumstances to avoid: Circumcision of at-risk males until hemophilia A is either excluded or treated with factor VIII concentrate regardless of severity; activities with a high risk of trauma, particularly head injury; cautious, if any, use of medications and herbal remedies that affect platelet function, including aspirin; use precaution with intramuscular injections (apply pressure; intramuscular injection may be scheduled after factor VIII treatment or while on emicizumab therapy). Evaluation of relatives at risk: It is appropriate to evaluate asymptomatic male and female at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment, preventive measures, and surveillance. It is recommended that the genetic status of at-risk females be established prior to pregnancy or as early in a pregnancy as possible. Pregnancy management: Monitor affected females during pregnancy and for delayed bleeding post partum unless it is known that their baseline factor VIII clotting activity is normal prior to pregnancy and there are no symptoms of bleeding. Hemophilia A is inherited in an X-linked manner. The risk to sibs of a male proband depends on the genetic status of the mother. The risk to sibs of a female proband depends on the genetic status of the mother and father. If the mother of the proband has an F8 pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. If the father of the proband has an F8 pathogenic variant, he will transmit it to all his daughters and none of his sons. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant are heterozygotes and may be at risk for bleeding. Once the F8 pathogenic variant has been identified in an affected family member, genetic testing for at-risk family members and prenatal/preimplantation genetic testing are possible.

Some patients with nonsevere hemophilia A (HA) are diagnosed with reduced factor (F)VIII activity (FVIII:C) relative to FVIII antigen (FVIII:Ag) and are classified as cross-reactive material-positive. We previously found a novel FVIII-Lys1693Asn (K1693N) natural mutation in a patient with HA with moderate phenotype (FVIII:C/FVIII:Ag = 1.9 IU/dL/124 IU/dL). To examine the mechanism(s) involving the P4' site on thrombin cleavage site at Arg1689 in a cross-reactive material-positive phenotype. FVIII-K1693N and its comparison variant K1693A were analyzed for t thrombin-mediated activation. FVIII-K376N, listed in the HA database due to a similar Lys-to-Asn substitution, was examined with K376A as its comparison. All mutants were expressed in BHK cells. FVIII-K1693N showed delayed cleavage at Arg1689 and low peak FVIII:C, while FVIII-K1693A showed mildly reduced FVIII:C after thrombin activation. Mildly reduced peak FVIII:C and similar cleavage to wild-type was illustrated, however, with the FVIII-K1693A mutation after thrombin activation. These findings indicated that the conversion to Asn at P4' site mediated thrombin resistance. FVIII specific activities of FVIII-K376N and FVIII-K376A were 6.1%/3.1% (one-stage assay) of wild-type, respectively. Thrombin-catalyzed cleavage at Arg372 was comparable to wild-type with both mutants, but thrombin-catalyzed FVIII activation was severely-depressed. Spontaneous decay rates of FVIIIa activity with FVIII-K376N (k = 0.53) and FVIII-K376A (k = 0.99) were greater compared to wild-type (k = 0.32), suggesting that cleavage of P4' site following cleavage at Arg372contributed to A1-A2 domainal interaction. Lys1693 and Lys376, both located at P4' sites, are suggested to influence FVIII function via distinct mechanisms, indicating that patient-derived mutations can reveal functional aspects of FVIII activation.

The prevalence of arthropathy in people with moderate hemophilia A (mHA) is highly variable. People with mHA are often undertreated, and this may lead to joint damage and worsen their quality of life. The aim of the present study was to evaluate joint status in mHA by means of point-of-care ultrasound (PoCUS) and clinical examination. Consecutive people with mHA receiving on-demand replacement treatment underwent a clinical examination of joint status according to the Hemophilia Joint Health Score (HJHS) protocol. On the same day, all patients underwent a PoCUS assessment according to the Hemophilia Early Detection by UltraSound (HEAD-US) protocol. A total of 51 subjects were included. The median HJHS score was 2.0 (IQR, 0-3.0). A 0 to 1 HJHS score was found in 23 people with mHA (45.1%), between 2 and 3 in 17 (33.3%) and >3 in 11 (21.6%). The median HEAD-US score was 2.0 (IQR, 1-7), and a statistically significant correlation between HJHS and HEAD-US was found (rho = 0.732; P < .001). Osteochondral damage was found in 21.6% of patients, and hypertrophic synovium (HS) was found in 29.4%. Among those reporting a 0 to 1 HJHS score, 13.0% showed HS. Analysis at the joint level showed that the most commonly affected joint was the ankle, both for osteochondral damage and the presence of HS. Our study suggests that the prevalence of arthropathy changes in people with mHA receiving on-demand treatment is not negligible and that PoCUS is able to detect osteochondral damage as well as HS in this clinical setting. A more extensive screening of the joint status could be useful to tailor treatment and improve outcomes in mHA.