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Introduction: Joint damage in haemophilia often requires surgical correction. However, the surgery effect on bleeding rates and other clinical joint outcomes can be unclear. Aim: To investigate the effects of joint surgery on joint annualized bleeding rates (JABRs) and physical health outcomes in patients with haemophilia A undergoing N8‐GP prophylaxis. Methods: Patients in the pathfinder 2 trial received N8‐GP prophylaxis, enrolling in the pathfinder 3 trial for indicated surgery. Patients returned to pathfinder 2 post‐surgery, continuing N8‐GP prophylaxis until end‐of‐trial. JABRs were calculated from bleeding across all joints for pre‐surgery (immediately before surgery) and post‐surgery (to pathfinder 2 study end) periods. Joint‐health‐related outcomes were derived from patient records. Results: Data (41 joint surgeries; n = 30) were analysed statistically using datamining and descriptively. Pre‐surgery mean JABR was higher in patients who later were operated than in 146 non‐operated patients (p =.004). In operated patients, mean JABR decreased from 1.33 pre‐surgery to.37 post‐surgery (p =.011). In all but three patients, JABR improved or remained the same post‐surgery. In the three patients whose JABR remained at one (all with multiple joint arthropathy), post‐surgery bleeds were mostly at non‐operated sites. Two of the three patients whose JABR increased post‐surgery had undergone surgery for reasons unlikely to improve JABR. Mobility parameters often improved in patients whose JABR remained at zero. Conclusion: Patients with haemophilia treated with N8‐GP prophylaxis benefit from surgeries. However, this analysis could not differentiate the relative contributions of surgical interventions and prophylactic treatment to the improvement of JABR. [ABSTRACT FROM AUTHOR]

Introduction: Challenges with personalised prophylaxis in haemophilia remain, including designing unique dosing schedules that require continual adjustments and monitoring using complex sampling procedures. Aim: To assess long‐term efficacy and pharmacokinetic outcomes with fixed‐dose N8‐GP prophylaxis. Methods: Descriptive analyses were performed on data from the pathfinder 2 and pathfinder 5 trials of patients with severe haemophilia A. Bleed frequency and reoccurrence were assessed in relation to several clinical criteria of interest. Bleed risk relative to time since last dose was assessed using calculated annualised bleeding rate (ABR). Long‐term ABR and mean factor VIII (FVIII) trough levels were assessed in patients who received consistent N8‐GP prophylaxis every 4 days (Q4D). Results: During pathfinder 2, 117/136 patients with study‐drug exposure of ≥600 days experienced bleeding episodes; 8.6% of bleeds were reoccurring bleeds; bleed reoccurrence decreased over time. For patients who received consistent Q4D prophylaxis across the trial (n = 61), mean ABR decreased from 3.5 bleeds/year (Year 1) to 1.6 bleeds/year (Year 6); mean FVIII trough levels stabilised at approximately 5% (Year 6). Across patients who received prophylaxis at some point during pathfinder 2 (n = 177), 125/126 (99%) reoccurring bleeds were joint bleeds. For patients receiving Q4D prophylaxis, bleeding risk generally increased as the time since the last prophylaxis dose increased. A similar reduction in ABR and stabilisation of trough level was observed in pathfinder 5. Conclusion: Long‐term exposure (> 5 years) to fixed‐dose N8‐GP prophylaxis resulted in a protective haemostatic effect, with reduction in bleed frequency and reoccurrence, and stabilisation of FVIII trough level over time. [ABSTRACT FROM AUTHOR]

Background: Life threatening bleeding and emergency procedures in patients on vitamin K antagonists are indications for urgent reversal with prothrombin complex concentrate and vitamin K. Rapid reversal in these situations is emphasized in the literature and guidelines, but only very limited information is available on its real life use, especially on the timing of treatment in relation to presentation., Materials and Methods: We retrospectively audited emergency warfarin reversal in 131 consecutive patients. We studied the indication, use of vitamin K, time between presentation and administration of vitamin K and PCC, effectiveness in INR reduction and clinical outcome., Results: The median PCC dose was 26.8 IU/kg. The median INR was reduced from 3.1 to 1.2. Vitamin K (5 mg) was given in 91.6% of evaluable patients. We found significant delays in administration of PCC and vitamin K. The median time between presentation and administration of vitamin K/PCC was 3.6 and 5.2 hours respectively. The times in intracranial haemorrhage were 2.7 and 3.0 hours and in emergency procedures 17.4 and 15.9 hours respectively. Mortality related to bleeding was 7.6% overall but in patients with intracranial haemorrhage 22.8%. The thrombotic rate within 7 days of reversal was 1.5%., Discussion: The local protocol for reversal with PCC and vitamin K was adhered to well but the delay in pre-procedural patients, suggests that intravenous vitamin K alone may be sufficient in many cases and PCC administration can be avoided by better planning. Intracranial haemorrhage in warfarinised patients carries a high mortality. Treatment delays should be avoided by making PCC stocks available within emergency departments, simple dosing structures independent of INR and administering PCC without waiting for INR and CT scan results in those with strong suspicion of intracranial haemorrhage and clear trauma. Future reports and studies should always include the time from presentation to PCC treatment.

Background: Severe FX deficiency is a rare disorder with a variable bleeding tendency but spontaneous life threatening haemorrhage can occur. Treatment for invasive procedures and spontaneous bleeding is with prothrombin complex concentrates (PCC). When used in large or repetitive doses these are associated with a thrombotic tendency. FX:C levels of 0.15 - 0.30 IU/ mL are thought to be haemostatic during surgery . There is only limited information on the outcome and management of pregnancy in severe FX deficiency. Caesarean section is suggested as delivery mode to reduce the risk of intracranial/abdominal neonatal haemorrhage, but successful vaginal deliveries are also described. The calibrated automated thrombin generation assay (CAT) is a global coagulation test that measures the time course of thrombin generation. It has been reported to correlate with prothrombotic states and the severity of bleeding in rare coagulation disorders. The variability in phenotype, the uncertainty of the minimal haemostatic FX:C concentration and the association of PCC's with thrombosis make thrombin generation of interest in the management of FX deficient patients., Patient: We describe the use of CAT as a possible means to monitor treatment with PCC (Beriplex) in a patient with severe FX deficiency (FX:C < 0.01 IU/mL) during successful vaginal delivery and epidural anaesthesia., Results: Thrombin generation was normal at FX:C 0.80 IU/mL but only borderline normal at FX:C 0.25 IU/mL. Repetitive doses over 3 days increased thrombin generation to the upper limit of normal at FX:C 0.25 IU/mL consistent with a prothrombotic tendency after multiple doses. The increase in thrombin generation was not related to prothrombin levels., Conclusion: The data suggest that CAT may be used to monitor treatment with PCC in FX deficiency. Higher levels than previously thought may be needed to normalize thrombin generation. Further studies into the correlation with bleeding or thrombosis are needed before the approach can be accepted in clinical practice.