Safety and efficacy of damoctocog alfa pegol prophylaxis in patients with severe haemophilia A: Results of an interventional, post-marketing study.

INTRODUCTION: Damoctocog alfa pegol (BAY 94-9027, Jivi® ) is an approved extended half-life factor VIII (FVIII) for treatment of previously treated patients with haemophilia A aged ≥12 years. We report the final results of an interventional, post-marketing study of damoctocog alfa pegol prophylaxis in patients with severe haemophilia A. METHODS: In this open-label, interventional, post-marketing, phase 4 trial (NCT04085458), previously FVIII-treated patients with severe haemophilia A aged ≥18 years received damoctocog alfa pegol for ≥100 exposure days (EDs). Patients initially received 45 IU/kg every 5 days (recommended) or 40 IU/kg twice-weekly. At Visit 3, patients' doses could be increased, or treatment frequency adapted. The primary endpoint was FVIII inhibitor development (titre ≥.6 Bethesda units). Secondary endpoints included anti-polyethylene glycol (PEG) antibody development, treatment-emergent adverse events (AEs) and annualized bleeding rate (ABR). RESULTS: Overall, 36 patients were enrolled; 32 patients received treatment, of whom, 27 completed the study. No patients developed FVIII inhibitors; three tested transiently positive for low-titre anti-PEG antibodies without clinical relevance. Three patients reported study-drug-related AEs of mild or moderate intensity. Two patients discontinued the study due to AEs. No deaths occurred. Most patients (70%) were treated with E5D/E7D regimens. The median (Q1;Q3) total ABR (N = 30) was 3.0 (.0;9.0) pre-study and 1.8 (.7;5.9) during the study. CONCLUSION: Damoctocog alfa pegol individualized prophylaxis regimens were well-tolerated with no immunogenicity concerns. ABRs improved following the switch from pre-study prophylaxis to damoctocog alfa pegol prophylaxis. These results support the favourable safety and efficacy profile of damoctocog alfa pegol prophylaxis.

Health and quality of life of patients with haemophilia: A national study of 124 Danish men.

PURPOSE: In the past decades, haemophilia treatment has greatly improved the health of persons with haemophilia (PWH). This study compares PWH to the general population on social conditions and health. METHODS: In December 2021, all Danes with moderate or severe haemophilia A or B, or von Willebrands disease type 3 were invited to participate in an online self-report survey concerning sociodemographic factors, self-rated health, teeth status, chronic health conditions, symptoms and loneliness. This study compares responses from the 124 adult male PWH with responses from a male general population sample (N = 4849). Analyses used logistic regression, controlling for age and highest completed education. RESULTS: Fewer PWH were in the oldest age group (65-84 years). Controlling for age, no significant differences were found regarding cohabitation status or education. Fewer PWH were employed (OR = .48, [.33-.71])-particularly in the 45-64 age group. PWH were less likely to report good health (OR = .49, [.31-.77]). The odds of joint disease was much higher (OR = 13.00, [8.37-20.28]). Also, hypertension (OR = 2.25, [1.13-5.65]) and previous stroke (OR = 2.51, [1.44-3.50]) were more frequent. PWH were more likely to report pain in the arms/hands/legs/hips (OR = 2.94, [1.92-4.52]), but less likely to report pain in the head/neck/shoulder (OR = .66, [.45-.96]). CONCLUSION: The disease burden of haemophilia has improved so PWH resembles the general population in areas such as marriage and education. However, even for young PWH, the disease still imposes a significant burden from hemophilia arthropathy and pain in extremities and joints. Middle-aged PWH also have poorer levels of employment than same-aged peers.

Platelet function testing: Current practice among clinical centres in Northern Europe.

INTRODUCTION: Platelet function tests are used to screen and diagnose patients with possible inherited platelet function defects (IPFD). Some acquired platelet dysfunction may be caused by certain drugs or comorbidities, which need to be excluded before testing. AIMS: To identify current practice among centres performing platelet function tests in Northern Europe. METHODS: A total of 14 clinical centres from Sweden (six), Finland (two), Denmark (two), Norway (one), Estonia (two) and Iceland (one) completed the survey questionnaire, the population capture area of about 29.5 million. RESULTS: Six of the 14 (42.8%) centres providing platelet function assessment represent comprehensive treatment centres (EUHANET status). A Bleeding score (BS) or ISTH bleeding assessment tool (ISTH BAT score) is evaluated in 11/14 (78.6%) centres and family history in all. Five/14 centres (35.7%) use structured preanalytical patient instructions, and 10/14 (71.4%) recorded questionnaire on the preassessment of avoidance of any drugs or natural products affecting platelet functions. Preliminary investigations of screening tests of coagulation are performed in 10/14 (71.4%), while in 4/14 (28.6%), the diagnostic work-up of IPFD and von Willebrand disease (VWD) is performed simultaneously. The work-up of IPFD includes peripheral blood smear in 10/14 (71.4%), platelet aggregometry in all, flow cytometry in 10/14 (71.4%) and Platelet Function Analysis (PFA) in 3/11 (28.6%). Molecular genetic diagnosis is available in 7/14 (50%) centres. CONCLUSIONS: The considerable variability in the current practice illustrates the need for harmonization between the Northern European centres according to the international registers (i.e. EUHASS) and IPFD guidelines (ISTH, EHA).

Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results.

Results from the main parts (24 weeks) of 2 concizumab phase 2 trials are presented: explorer4 in hemophilia A (HA) or B (HB) with inhibitors (HAwI/HBwI) and explorer5 in HA. The trials aimed to evaluate the efficacy of daily subcutaneous concizumab prophylaxis (evaluated as annualized bleeding rate [ABR] at last dose level), with secondary objectives being safety and immunogenicity (assessed as number of adverse events [AEs] and antidrug antibodies [ADAs]). Patients received 0.15 mg/kg concizumab, with potential dose escalation to 0.20 and 0.25 mg/kg (if ≥3 spontaneous bleeding episodes within 12 weeks of concizumab treatment). Relevant pharmacokinetic/pharmacodynamic (PK/PD) parameters were assessed. Thirty-six HA, 9 HAwI, and 8 HBwI patients were exposed to concizumab. Most inhibitor patients (15 of 17; 88.2%) did not escalate the dose; all patients chose to continue to the extension phase of the trials. Clinical proof of concept for prevention of bleeding episodes was demonstrated in both trials. Estimated ABRs in HAwI and HBwI were lower vs HA: 3.0 (95% confidence interval [CI], 1.7; 5.3) and 5.9 (95% CI, 4.2; 8.5) vs 7.0 (95% CI, 4.6; 10.7), respectively. PK/PD results were as expected, with no difference between hemophilia subtypes for concizumab exposure, free tissue factor pathway inhibitor, thrombin generation, prothrombin fragment 1+2, and d-dimers. Concizumab was safe and well tolerated (no severe AEs, AE-related withdrawals, or thromboembolic events). Three patients had (very low to medium titer) ADA+ tests in each trial, with no observed clinical effect. These results support further development of concizumab as a daily prophylactic treatment in all hemophilia patients. These trials were registered at www.clinicaltrials.gov as #NCT03196284 and #NCT03196297.

Incidence of von Willebrand disease in Denmark, 1995-2016: A cohort study.

INTRODUCTION: Information about temporal development of von Willebrand disease (VWD) incidence at a population level is scarce. To our knowledge, no study has described the incidence of VWD at a population level. AIM: To estimate overall and annual incidence rates of hospital diagnosed VWD in Denmark between 1995 and 2016 as well as the frequency of hospital treated bleeding episodes before and after VWD diagnosis. METHODS: A registry-based cohort study that included all Danish patients with a first diagnosis of VWD in Denmark, identified in the Danish National Patient Registry through 1995-2016. RESULTS: We identified 1,035 patients with a diagnosis of VWD. The overall incidence rate of VWD in 1995-2016 was 8.6 (95% CI: 8.1-9.2). The annual age-standardized incidence rate per 100 000 person-years varied between 4.1 (95% CI: 2.4-5.9) in 1998 and 16.7 (95% CI: 13.1-20.3) in 2005. A prominent peak in rates appeared from 2002 to 2008. One and five years before VWD diagnosis, 6% and 11.5% of the patients had at least one hospital treated bleeding episode. One and five years after diagnosis, the corresponding percentages were 7.9% and 13.4%. CONCLUSION: These results are the first population-based estimates of VWD incidence. The incidence may be underestimated because asymptomatic individuals may not be diagnosed. The observed peak in incidence from 2002-2008 may be explained by increased medical attention, leading to more patients being diagnosed, rather than an actual increase in VWD incidence. However, overall, we observed no systematic changes in VWD incidence over the study period.

Joint Mobility and Physical Function of Danish Hemophilia Patients: A Three-Wave Panel Study Spanning 24 Years.

BACKGROUND: The positive effects of factor treatment of hemophilia are well established, but the long-term outcomes are not well documented. This panel study evaluated changes in bleeding frequency, joint mobility, physical function, and symptoms in Danish patients with moderate to severe hemophilia A or B over 24 years. METHODS: Three anonymous surveys were conducted in 1988, 2001, and 2012 targeting Danish patients with moderate to severe hemophilia, and the study participants, respectively, were 128, 156, and 164 male patients with hemophilia (PWH). The number of bleeding episodes, the use of factor concentrate, comorbidities, joint mobility, physical function, and symptoms were evaluated by means of self-reporting. Trends over time were analyzed using ordinal and multinomial logistic-regression models controlling for age group. RESULTS: The proportion of PWH in the oldest age group (55-88 years) increased from 4% in 1988 to 18% in 2012. In 1988, a high risk of bleeding episodes was primarily found in the age group of 16-34 years. In 2012, a high risk was primarily found in the age group of 35-54 years. Joint mobility and physical function increased significantly from 1988 to 2012 but showed a noticeable decrement in the older age groups, even in 2012. Pain in the extremities, anxiety, and depression decreased significantly, but back pain increased. No significant changes were found for 7 other symptoms. CONCLUSIONS: Significant improvements in joint mobility and physical function have occurred over the last 24 years, but PWH > 35 years still experience a decline in these areas with age. This decline underscores the importance of life-long treatment and continuous rehabilitation of PWH.

Left atrial appendage occlusion in haemophilia patients with atrial fibrillation.

PURPOSE: Advanced targeted therapy has resulted in increasing life expectancy and incidence of age-related cardiovascular diseases like atrial fibrillation in patients with haemophilia. Oral anticoagulation constitutes a significant dilemma in this patient category as the risks of stroke and bleeding are difficult to balance. We sought to demonstrate the feasibility of left atrial appendage occlusion (LAAO) in patients with haemophilia and atrial fibrillation. METHODS: All patients with haemophilia treated with LAAO at Aarhus University Hospital, Denmark, were identified from a local prospective database comprising all consecutive LAAO procedures from 2010 up to November 2020. Based on review of the medical records, a retrospective descriptive analysis was performed. RESULTS: Seven patients with haemophilia A and atrial fibrillation underwent LAAO after multidisciplinary conference. Peri-procedural coagulation management was guided by factor VIII activity and treated with repeated bolus administrations of recombinant factor VIII targeting an activity of 100%. The implantation was successful in all patients with only minor bleeding complications post-procedurally. Based on these experiences, a suggested regime has been formulated. CONCLUSIONS: LAAO is feasible in haemophilia patients with concurrent atrial fibrillation. However, special care including intravenous substitution with coagulation factors must be given in the periprocedural management.

Safety and effectiveness of recombinant factor XIII-A2 in congenital factor XIII deficiency: Real-world evidence.

BACKGROUND: Regular factor XIII (FXIII) prophylaxis is standard treatment for congenital FXIII A-subunit deficiency (FXIII-A CD). Recombinant factor XIII-A2 (rFXIII-A2) was extensively evaluated in the mentor trials. OBJECTIVE: To assess real-world safety and treatment effectiveness of rFXIII-A2 prophylaxis from the mentor 6 trial. PATIENTS/METHODS: mentor 6 was a noninterventional, postauthorization safety study investigating rFXIII-A2 prophylaxis in FXIII-A CD. rFXIII-A2 treatment was observed for 2 to 6 years per patient. The primary end point was documentation of adverse drug reactions (including anti-FXIII antibody development). Secondary end points were serious adverse events (SAEs), medical events of special interest (MESIs), and annualized bleeding rate (ABR). RESULTS: Among 30 patients (mean age, 25.5 years), there were 44 adverse events (AEs) (30 mild, 13 moderate, 1 severe). Eleven AEs were possibly/probably related to rFXIII-A2. Of four MESIs, two were unlikely related to rFXIII-A2 (accidental overdose, deep vein thrombosis), and two were possibly/probably related (nonneutralizing anti-FXIII antibody, decreased therapeutic response). All 10 SAEs were unlikely related to rFXIII-A2. Over a follow-up of 75.4 patient-years, there were six treatment-requiring bleeds (all trauma-related with no spontaneous bleeds), giving a treatment-requiring ABR of 0.066; five bleeds were treated successfully with rFXIII-A2. Eight of nine minor surgeries performed during rFXIII-A2 prophylaxis reported successful hemostatic outcomes (one missing evaluation). CONCLUSIONS: These data confirm that rFXIII-A2 prophylaxis is well tolerated as long-term care. There were no spontaneous bleeds, ABR was low, and rFXIII-A2 successfully treated bleeds in patients receiving rFXIII-A2 prophylaxis.

Long-term efficacy and safety of subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors.

Despite current therapies, there remains an unmet need for treatment for patients with hemophilia. The main parts of two phase 2 trials established clinical proof-of-concept for once-daily, subcutaneous concizumab prophylaxis in patients with hemophilia A/B with inhibitors (HAwI/HBwI; explorer4) and severe hemophilia A without inhibitors (HA; explorer5). Here, we present results from extension parts of these trials, included to evaluate longer term safety and efficacy. Both trials included main (≥24 weeks) and extension (52-102 weeks) parts, with patients receiving concizumab 0.15 mg/kg with potential dose escalation to concizumab 0.20 or 0.25 mg/kg if they experienced ≥3 treated spontaneous bleeding episodes within 12 weeks. Endpoints included annualized bleeding rate (ABR), adverse events (AEs), and occurrence of antidrug antibodies. Thromboembolic events were AEs of special interest. Thirty-six patients with HA, 15 with HAwI, and 10 with HBwI were exposed to concizumab. Estimated ABRs during the main + extension parts at last dose level were 4.8 (95% confidence interval [CI], 3.2-7.2) and 6.4 (95% CI, 4.1-9.9) in explorer4 and explorer5, respectively (spontaneous ABRs were 1.8 [95% CI, 1.2-2.6] and 2.1 [95% CI, 1.3-3.3]). Most AEs were mild, with no deaths, events leading to withdrawal, or thromboembolic events. Anti-drug antibodies developed in 25% of patients and were low titer and transient, with no observed clinical effect in most cases. Results of the main + extension parts of these trials were consistent with results of the main parts. Ongoing phase 3 trials will further evaluate concizumab as a once-daily, subcutaneous treatment across hemophilia subtypes. These trials were registered at www.clinicaltrials.gov as #NCT03196284 and #NCT03196297.

Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia A.

Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.

Recombinant activated factor VIIa in uncontrolled bleeding: a haemostasis laboratory study in non-haemophilia patients.

Extensive surgery and massive tissue trauma are often associated with severe bleeding. We present retrospective data on the use of recombinant factor VIIa in haemostatic emergencies in13 non-hemophilia patients with uncontrolled bleeding. Recombinant factor VIIa was administered in doses ranging from 16 mug/kg bodyweight to 60 microg/kg bodyweight. Blood loss during 24 h before and after the infusion was registered, showing that 10 out of 13 patients (77%) had a 70% or greater reduction in transfusion requirement decreasing significantly in mean from 28.1 to 9.9 red blood cell units. Coagulation parameters were studied in blood samples collected 10 min before and 10-15 min after the injection of recombinant factor VIIa. Factors VII:C, II:C, and X:C increased significantly while the activated partial thromboplastin time, platelet numbers, and concentration of fibrinogen and D-dimers were unchanged. The dose of rFVIIa correlated significantly with the rise in factor X:C and inversely with transfusion requirements. Dynamic clot velocity of whole blood was recorded before and after rFVIIa infusion in four patients. Judged from red blood cell usage no improvement in haemostasis was seen in one patient suffering thrombocytopenia and low fibrinogen. This patient died 6 h after recombinant factor VIIa infusion, and three other patients died before 1 month. None of the fatalities appeared to be related to recombinant factor VIIa usage. No thromboembolic complications were seen. In conclusion, 12 out of 13 patients survived the first 24 h after treatment with relatively low doses of recombinant factor VIIa for large-scale bleeding. Recombinant factor VIIa was well tolerated and safe in these non-hemophilia patients. With quite low doses of recombinant factor VIIa (

[Large venous malformations increase the risk of thromboembolic complications]. / Store venøse malformationer øger risikoen for tromboemboliske komplikationer.

Venous malformations (VM) represent vascular developmental errors. They are low-flow lesions composed of ectatic vessels that histologically and morphologically are similar to veins. Episodic thromboses commonly occur in VM. Moreover, pulmonary emboli, sudden death and chronic thromboembolic pulmonary hypertension have been described in children and adults with extensive VM. This article discusses the management and treatment of patients with extensive VM.