Haemophilia care in Europe:a survey of 19 countries

In 2009, a questionnaire was circulated to 19 national haemophilia patient organizations in Europe affiliated to the European Haemophilia Consortium (EHC) and the World Federation of Hemophilia (WFH) to seek information about the organization of haemophilia care and treatment available at a national level. The responses received highlighted differences in the level of care despite the recent promulgation of consensus guidelines designed to standardize the care of haemophilia throughout the continent of Europe. There was a wide range in factor VIII consumption with usage ranging from 0.38 IU per capita in Romania to 8.7 IU per capita in Sweden (median: 3.6 IU per capita). Despite the specific inclusion of coagulation factor concentrate in the WHO list of essential medications, cryoprecipitate is still used in some eastern European countrie

Choosing outcome assessment tools in hämophilia care and research: a multidisciplinary perspective

Introduction: The implementation of early long-term, regular clotting factor concentrate (CFC) replacement therapy ('prophylaxis') has made it possible to offer boys with haemophilia a near normal life. Many different regimens have reported favourable results, but the optimum treatment regimens have not been established and the cost of prophylaxis is very high. Both for optimizing treatment and reimbursement issues, there is a need to provide objective evidence of both short-and long-term results and benefits of prophylactic regimens. Aims: This report presents a critical review of outcome measures for use in the assessment of musculoskeletal health in persons with haemophilia according to the International Classification of Functioning, Disability and Health (ICF). This framework considers structural and functional changes, activities and participation in a context of both personal and environmental factors. Methods: Results were generated by a combination of a critical review of available literature plus expert opinion derived from a two day consensus conference between 48 health care experts from different disciplines involved in haemophilia assessment and care. Outcome tools used in haemophilia were reviewed for reliability and validity in different patient groups and for resources required. Results and conclusion: Recommendations for choice of outcome tools were made according to the ICF domains, economic setting, and reason for use (clinical or research). The next step will be to identify a 'core' set of outcome measures for use in clinical care or studies evaluating treatment

Burden of mild haemophilia A: Systematic literature review

Introduction Although the clinical manifestations of severe haemophilia A (HA) are well studied, the challenges, if any, of living with mild HA are not clearly delineated to date. Aim To assess available evidence of clinical risks and societal/economic impacts of disease in adult patients with mild HA using a systematic literature review. Methods Prespecified study selection criteria were applied in a comprehensive literature search. Included studies varied in design and reported outcomes of interest for adults (>= 13 years of age) with mild HA. Results Seventeen studies with a total of 3213 patients met eligibility criteria (published or presented in English, 1966-2017). Most studies were observational, and the outcomes reported were too sparse and dissimilar to support a formal meta-analysis. Mean annual bleeding rates ranged from 0.44 to 4.5 episodes per patient per year. Quality of life (QoL; SF-36 General Health) was impacted compared to healthy controls. Health care costs and productivity were seldom assessed and no robust comparisons to healthy controls were available. Conclusion Quantifying outcomes for adult patients with mild HA remains challenging, with estimates of key QoL and cost data often based on small data sets and without comparison to population norms. Therefore, the clinical impact of mild haemophilia may be under-represented and unmet needs may remain unaddressed. As paradigm-changing therapies for HA emerge, stronger knowledge of mild HA can guide the development of care options that minimize burden and enhance the QoL for this segment of the haemophilia community, and for the haemophilia community in totality

Population pharmacokinetics of the von Willebrand factor-factor VIII interaction in patients with von Willebrand disease

Recent studies have reported that patients with von Willebrand disease treated perioperatively with a von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a ratio of 2.4:1 (Humate P/Haemate P) often present with VWF and/or FVIII levels outside of prespecified target levels necessary to prevent bleeding. Pharmacokinetic (PK)-guided dosing may resolve this problem. As clinical guidelines increasingly recommend aiming for certain target levels of both VWF and FVIII, application of an integrated population PK model describing both VWF activity (VWF:Act) and FVIII levels may improve dosing and quality of care. In total, 695 VWF:Act and 894 FVIII level measurements from 118 patients (174 surgeries) who were treated perioperatively with the VWF/FVIII concentrate were used to develop this population PK model using nonlinear mixed-effects modeling. VWF:Act and FVIII levels were analyzed simultaneously using a turnover model. The protective effect of VWF:Act on FVIII clearance was described with an inhibitory maximum effect function. An average perioperative VWF:Act level of 1.23 IU/mL decreased FVIII clearance from 460 mL/h to 264 mL/h, and increased FVIII half-life from 6.6 to 11.4 hours. Clearly, in the presence of VWF, FVIII clearance decreased with a concomitant increase of FVIII half-life, clarifying the higher FVIII levels observed after repetitive dosing with this concentrate. VWF:Act and FVIII levels during perioperative treatment were described adequately by this newly developed integrated population PK model. Clinical application of this model may facilitate more accurate targeting of VWF:Act and FVIII levels during perioperative treatment with this specific VWF/FVIII concentrate (Humate P/Haemate P).Thrombosis and Hemostasi

Prophylaxis is the new standard of care in patients with haemophilia

Randomised controlled clinical trial evidence on prophylaxis as optimal care for patients with haemophilia was generated more than a decade ago. However, this knowledge has not translated into clinical practice in South Africa (SA) owing to many barriers to prophylaxis. These include the high treatment burden imposed by prophylaxis (frequent injections two to four times a week), the need for intravenous access to administer replacement clotting factor therapies, and the higher volume of clotting factor required compared with episodic treatment. The recently introduced non-factor therapies in haemophilia care have addressed many of these barriers. For example, emicizumab, which is currently the only globally approved non-factor therapy, can be administered subcutaneously less frequently (weekly, fortnightly or every 4 weeks) and has led to global adoption of prophylaxis as the standard of care in haemophilia by the bleeding disorders community. Haemophilia A is the most prevalent clotting factor deficiency in SA, with >2 000 people diagnosed to date. However, only a few of these patients are currently on prophylaxis. In this ‘In Practice’ article, we review the rationale for prophylaxis, outline its goals and benefits, and provide evidence-based guidance on which haemophilia patients should be prioritised for emicizumab prophylaxis. This consensus guidance facilitates the adoption of prophylaxis as a national policy and the new standard of care in haemophilia in SA.http://www.samj.org.zadm2022HaematologyPaediatrics and Child Healt

Effect of haemodilution, acidosis, and hypothermia on the activity of recombinant factor VIIa (NovoSeven®)

Background. A range of plasma volume expanders is used clinically, often in settings where haemostasis may already be impaired. The haemostatic agent, recombinant activated factor VII (rFVIIa, NovoSevenw), may be used to improve haemostasis but potential interactions with different volume expanders are poorly understood. Methods. Clot formation was measured by thromboelastography (TEG) using blood from healthy volunteers. In vitro effects of rFVIIa with haemodilution, acidosis, and hypothermia were examined. Conditions were induced by dilution with NaCl (0.9%), lactated Ringer’s solution, albumin 5%, or hydroxyethyl starch (HES) solutions [MW (molecular weight) 130–670 kDa]; by adjusting pH to 6.8 with 1 M HEPES (N-2-hydroxyethylpiperazine-N0-2-ethanesulphonic acid) buffer; or by reducing temperature to 328C. We also studied the effect of low vs high MW HES (MW 200 vs 600 kDa) and rFVIIa on in vivo bleeding time (BT) in rabbits. Results. Haemodilution progressively altered TEG parameters. rFVIIa improved TEG par-ameters in the presence of acidosis, hypothermia or 20 % haemodilution (P,0.05). At 40 % hae-modilution, the rFVIIa effect was diminished particularly with high MW HES. In vivo, rFVIIa shortened the BT (P,0.05) with low but not high MW HES. Conclusions. Efficacy of rFVIIa was affected by the degree of haemodilution and type of volume expander, but not by acidosis or hypothermia

SYMPHONY consortium:Orchestrating personalized treatment for patients with bleeding disorders

Background Treatment choices for individual patients with an inborn bleeding disorder are increasingly challenging due to increasing options and rising costs for society. We have initiated an integrated interdisciplinary national research program. Objectives The SYMPHONY consortium strives to orchestrate personalized treatment in patients with an inborn bleeding disorder, by unraveling the mechanisms behind interindividual variations of bleeding phenotype. Patients The SYMPHONY consortium will investigate patients with an inborn bleeding disorder, both diagnosed and not yet diagnosed. Results Research questions are categorized under the themes: (1) diagnosis, (2) treatment, and (3) fundamental research, and consist of work packages addressing specific domains. Importantly, collaborations between patients and talented researchers from different areas of expertise promise to augment the impact of the SYMPHONY consortium, leading to unique interactions and intellectual property. Conclusions SYMPHONY will perform research on all aspects of care, treatment individualization in patients with inborn bleeding disorders, as well as diagnostic innovations and results of molecular genetics and cellular model technology with regard to the hemostatic process. We believe that these research investments will lead to health-care innovations with long-term clinical and societal impact. This consortium has been made possible by a governmental, competitive grant from the Netherlands Organization for Scientific Research (NWO) within the framework of the NWA-ORC Call grant agreement NWA.1160.18.038

Fibrinogen Replacement Therapy for Traumatic Coagulopathy : Does the Fibrinogen Source Matter?

Funding: This work was supported by an NIHR programme grant for applied research; PGfAR01590; “Traumatic coagulopathy and massive transfusion: improving outcomes and saving blood”.Peer reviewedPublisher PD