How do we optimally utilize factor concentrates in persons with hemophilia?

The current mainstay of therapy for hemophilia is to replace the deficient clotting factor with the intravenous administration of exogenous clotting factor concentrates. Prophylaxis factor replacement therapy is now considered the standard of care in both pediatric and adult patients with hemophilia with a severe phenotype to protect musculoskeletal health and improve quality of life. Heterogeneity in bleeding presentation among patients with hemophilia due to genetic, environmental, and treatment-related factors has been well described. Accordingly, the World Federation of Hemophilia recommends an individualized prophylaxis regimen that considers the factors mentioned above to meet the clinical needs of the patient, which can vary over time. This review focuses on the practical points of choosing the type of factor concentrate, dose, and interval while evaluating appropriate target trough factor levels and bleeding triggers such as level of physical activity and joint status. We also discuss the use of a pharmacokinetics assessment and its incorporation in the clinic for a tailored approach toward individualized management. Overall, adopting an individualized prophylaxis regimen leads to an optimal utilization of factor concentrates with maximum efficacy and minimum waste.

Reduced cardiovascular morbidity in patients with hemophilia: results of a 5-year multinational prospective study

Hemophilia is a congenital bleeding disorder caused by low clotting factor VIII or IX levels. Life expectancy of people with hemophilia (PWH) has increased with the availability of clotting factor concentrates. At the same time, the incidence of cardiovascular disease (CVD) has increased. In retrospective studies there are conflicting data if, despite this increase, the incidence is still lower than in the general population. We prospectively compared the incidence of CVD in PWH with the predicted incidence. This prospective, multicenter, observational study included adult PWH (>30y) from the Netherlands and United Kingdom (UK). They were followed for a 5-year period and CVD incidence was compared with a predicted event rate based on the QRISK2-2011 CVD risk model. The primary endpoint was the observed fatal and nonfatal CVD incidence after 5 years compared to the estimated events and in relation to severity of hemophilia. The study included 709 patients, of whom 687 (96.9%) completed 5 years follow up or reached an endpoint. For 108 patients the QRISK score could not be calculated at inclusion. For the remaining 579 fewer CVD events were observed than predicted: 9 versus 24 (RR 0.38; 95% CI: 0.18 - 0.80 p=0.01), corresponding with an absolute risk reduction of 2.4%. Severe hemophilia treated on demand had the highest risk reduction. There was no statistical significant relation between severity of hemophilia and incidence of CVD. In hemophilia a lower than predicted CVD incidence was found, supporting the theory that hemophilia protects against CVD. The study is registered at www.clinicaltrials.gov (identification number NCT01303900).

Experience in Surgical Management for Persons with Hemophilia a and with Inhibitors in Western Kenya

Introduction: Persons with hemophilia (PWH) who develop need for surgery usually require a huge amount of clotting factor concentrate (CFC) infusion to manage their bleeding during the procedure and up to a few days or weeks afterwards until they achieve tissue healing. Managing such patients in a resource limited setting (RLS) is challenging endeavor due to limited availability of clotting factor concentrates to replace their specific deficient clotting factor. The peri-operative treatment for PWH who have antibodies against CFC is even more complicated because by-passing agents (BPA) remain largely unavailable and require more frequent administration. Health care institutions in most RLS depend on limited donations of these products and therefore surgical procedures performed require intricate planning to enable the use of the minimum required CFC or BPA to achieve optimal hemostasis. We sought to highlight our experience in managing patients with Hemophilia A who have antibodies against CFC who presented with need for surgery at Moi Teaching and Referral Hospital in western Kenya. Methods: We reviewed patients charts of PWH A who presented at MTRH for surgery between 2020 and 2021 and documented their factor levels, blood counts and inhibitor levels. Three PWH A had high responding inhibitor levels. The clotting factor concentrates (CFC) used were a combination of activated Prothrombin Complex Concentrates (aPCC) and recombinant Activated Factor VII (rFVIIa) with Antifibrinolytics to achieve hemostasis. Hemostasis was monitored by the patients' hemoglobin levels (Hb) in grams per deciliter (g/dl), clinical examinations of the surgical sites and patients reported symptoms. Results: Case 1: 42-year-old with severe hemophilia A and inhibitor of 143BU, presented with femur fracture needed fixation with platting. Surgery was done one year after the injury because of unavailability of adequate bypassing agents during the time of injury. Day 1-7 of surgery, patient was given rFVIIa 270mcg/kg 6hourly with Tranexamic acid, then reduced at 180mcg/kg 6hourly on days 8-9 post surgery. He was then switched to aPCC 100IU/kg first dose then at 75IU/kg 12hourly on days 10-14, then at 75IU/kg 24hourly days 15-17. Tranexamic acid was stopped before infusion of aPCC. Just after the surgery, was transfused two units of blood. He was started physiotherapy day 14 post-operation. Patient pre-operative Hb was at 17.6g/dl, the Hb post-operation remained stable between 15g/dl and 12g/dl. There was some blood oozing noted during the first change of dressing but site remained clean and dry with reduction of limb swellings by 3cm. Case 2 : 8-year-old with severe hemophilia A and inhibitor of 6BU, had bilateral undescended testis needed bilateral orchidopexy and circumcision. The surgery proceeded after 2 months of the schedule. He was given rFVIIa at 180mcg/kg 6hourly on Day 1 and 2 of surgery with Tranexamic Acid 8 hourly. On the evening of day 2 post surgery, he was switched to aPCC at 100IU/kg 24hourly to day 4 post surgery. He continued with Tranexamic acid 6 hourly, given 6 hours after aPCC infusions. Patients Hb remained stable at 13g/dl pre and postoperatively with no noted bleeding at the surgical sites. Case 3: 3year old with moderate hemophilia A, presented with extensive subdural hematoma causing midline shift and loss of speech, needed emergency surgery. Burr hole was done with factor replacement then noted to have inhibitor of 6BU a days after the surgery. He was immediately given aPCC at 100IU/kg 12hourly for 10 days. His Hb remained stable at 10-9g/dl pre- and post-operatively with dry surgical site. Revaluation head Computerized tomography (CT) scan showed resolving hematoma with no midline shift. Conclusion: All the patient had adequate hemostasis during the surgery period with only the first case needing blood transfusion. There were no reported bleeding complications or thrombosis seen post-surgery and on follow up reviews. Despite the challenges faced it was possible to achieve adequate hemostasis needed for the surgical interventions using moderate doses of BPA, attesting to the potential that RLS are capable in managing hemophilia patients with inhibitors. We recommend further studies on the minimal dosing recommendations of BPA needed to achieve adequate hemostasis in surgical management of hemophilia patients with inhibitors in resources constrained environments. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Portuguese Consensus and Recommendations for Acquired Coagulopathic Bleeding Management (CCBM)

We aimed to determine how Portuguese physicians handle major bleeding. We also aim to establish global diagnostic and therapeutic recommendations to be followed in clinical practice by using a step-wise approach of evidence generation. This study followed a three-step process: a steering committee desk review, a Delphi technique, an expert panel meeting. A modified 3-round Delphi including 31 statements was performed. Questions were answered in a five-point Likert-type scale. Consensus threshold was established as a percentage of agreement among participants ≥90% in the first round, and ≥85% in the second and third rounds. The level of consensus achieved by panelists was discussed with the scientific committee (January-2020). Fifty-one physicians participated in the study (compliance rate >90%). Analyzing the three rounds, consensus was reached on 20 items (64.5%) in the first, 4/11 items (36.4%) in the second and 6/7 items (85.7%) in the third. One statement about administration of clotting factor concentrates for bleeding control did not reach consensus. A high level of consensus was reached toward the need for implementing Patient Blood Management strategies in Portuguese hospitals, reduce exposure to allogeneic blood components, to use goal directed therapies for acquired bleeding management, and the need for evaluating blood transfusion indirect costs. A final version with 12 recommendations was built, according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Our results provide critically appraised and updated evidence on bleeding coagulopathies management in Portugal. Additional studies, mainly about indirect costs of blood transfusion, are needed.