R. Klamroth

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

Safety and pharmacokinetics of anti‐TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial

Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia.

Replacement therapy for invasive procedures in patients with haemophilia: literature review, European survey and recommendations.

Summary.  Although most surgical and invasive procedures can be performed safely in patients with haemophilia, the optimal level and duration of replacement therapy required to prevent bleeding complications have not been established conclusively. For providing more insight into optimal therapy during invasive procedures, a literature review of surgical procedures in patients with haemophilia was conducted. Concomitantly, current practice was surveyed in 26 European Haemophilia Comprehensive Care Centres, representing 15 different countries. The review identified 110 original papers published between 1965 and 2007. Of these, only two studies were randomized controlled trials. Target levels and the duration of replacement therapy in the published studies were as follows. For major orthopaedic surgery: preoperative targets were 80–90%; postoperative targets showed a high degree of variation, with trough levels ranging from 20% to 80%, duration 10–14 days; for liver biopsy, 70–100%, 1–7 days; tonsillectomy: 90–100%, 5–11 days; indwelling venous access device insertion: 100%, 3–10 days; circumcision: 50–60%, 2–4 days; dental surgery: 30–50%, single treatment. With the exception of dental surgery, current practice in Europe, as assessed by the survey, was largely in agreement with published data. In conclusion, this study provides both a comprehensive review and a large survey of replacement therapy in patients with haemophilia undergoing invasive procedures; these data have informed the consensus practical treatment recommendations made in this paper. This study highlights the need for better‐designed studies in order to better define minimal haemostatic levels of replacement therapy and optimal treatment duration.

Should prophylaxis be used in adolescent and adult patients with severe haemophilia? An European survey of practice and outcome data

Summary.  A survey of 21 haemophilia doctors, throughout Europe, who care for a total of approximately 5000 patients with bleeding disorders addressing practice and opinions regarding prophylaxis in patients aged 16–24 years and adults aged over 50 years, is presented. The outcome of adolescent patients who reduced or stopped prophylaxis was recorded. Eighteen of 19 respondents would consider modification of established prophylaxis in the adolescent age group, principal considerations being avoidance of risks of further concentrate exposure, predicted poor compliance and treatment costs. The preferred age for modification was 16–20 years, but there was very little consensus on the particular prophylactic regime recommended. Approximately, half of a cohort of 218 patients with severe haemophilia successfully reduced or stopped prophylaxis when they reached adolescence. Only 26 of 92 (28%) of the patient cohort who stopped prophylaxis, required reintroduction of a prophylactic regime and 12 of 59 (20%) of those who reduced the intensity of prophylaxis had to reintroduce a more intensive regime. A majority of respondents would consider starting prophylaxis in those over 50 years. There was no consensus as to indications for this practice or the nature of the prophylaxis protocol. We conclude that there is an absence of consensus on the management of patients with severe haemophilia, as they pass through adolescence and young adulthood, and reach the age of 50. Aggregate outcome data suggest a significant proportion of patients in the 18–22 years age range may be able to reduce or stop prophylaxis. A substantial number of older patients are on prophylaxis.

Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial.

Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.

Deficiencies of antithrombin, protein C and protein S – Practical experience in genetic analysis of a large patient cohort

Deficiencies of natural anticoagulant proteins including antithrombin (AT), protein C (PC) and protein S (PS) are important causes of inherited thrombophilia. This study aimed to report on the practical experience gained in performing genetic analyses of a large cohort of patients with AT, PC and PS deficiencies and to relate this knowledge to clinical application. We genotyped a large cohort of 709 unrelated patients with AT (231), PC (234) and PS (244) deficiencies referred to us by physicians throughout Germany. Mutations were detected by direct sequencing and multiplex ligation-dependent probe amplification (MLPA). The highest mutation detection rate (MDR) was found for the SERPINC1 gene (83.5%), followed by the PROC (69%) and PROS1 (43%) genes. Even at AT activities close to the normal range (75%), the MDR was 70%. Contrastingly, for PC and PS deficiencies, the MDR dropped significantly and mildly lowered to subnormal values. At PS activities >55% for PS no mutations were detected. Mutation profiles of all three genes were similar with the highest prevalence for missense mutations (63-78%), followed by nonsense (7-11%), splice-site mutations (7-13%), small deletions (1-8%), small insertions/duplications (1-4%) and large deletions (3-6%). In conclusion, genetic testing is a useful diagnostic tool for diagnosing thrombophilia. Based on our data, genetic analysis for patients with AT deficiency is indicated for all subnormal activities. In contrast, genotyping is not advisable for PC activities >70% and for PS activities >55%.

Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study

Acquired hemophilia A (AHA) is caused by autoantibodies against factor VIII (FVIII). Immunosuppressive treatment (IST) results in remission of disease in 60% to 80% of patients over a period of days to months. IST is associated with frequent adverse events, including infections as a leading cause of death. Predictors of time to remission could help guide IST intensity but have not been established. We analyzed prognostic factors in 102 prospectively enrolled patients treated with a uniform IST protocol. Partial remission (PR; defined as no active bleeding, FVIII restored >50 IU/dL, hemostatic treatment stopped >24 hours) was achieved by 83% of patients after a median of 31 days (range 7-362). Patients with baseline FVIII <1 IU/dL achieved PR less often and later (77%, 43 days) than patients with ≥1 IU/dL (89%, 24 days). After adjustment for other baseline characteristics, low FVIII remained associated with a lower rate of PR (hazard ratio 0.52, 95% confidence interval 0.33-0.81, P < .01). In contrast, PR achieved on steroids alone within ≤21 days was more common in patients with FVIII ≥1 IU/dL and inhibitor concentration <20 BU/mL (odds ratio 11.2, P < .0001). Low FVIII was also associated with a lower rate of complete remission and decreased survival. In conclusion, presenting FVIII and inhibitor concentration are potentially useful to tailor IST in AHA.

Pain management in patients with haemophilia: a European survey

Summary.  There are no evidence‐based guidelines on pain management in people with haemophilia (PWH), who may suffer acute, disabling pain from haemarthroses and chronic arthropathic pain. To review evidence and to investigate current clinical practice in pain assessment and management in PWH the European Haemophilia Therapy Standardisation Board undertook a literature review and a survey in 22 Haemophilia Treatment Centres (HTC), using a questionnaire and seven clinical scenarios. Consensus was sought on pain assessment and management in PWH. Few clinical studies on pain management in PWH were identified. The HTCs care for 1678 children (47% severe haemophilia, 84% on prophylaxis, 17% with arthropathy and 8% with chronic pain) and 5103 adults (44% severe haemophilia, 40% on prophylaxis, 67% with arthropathy and 35% with chronic pain). Analgesics are prescribed by HTCs in 80% of cases (median; range 0–100%) and in 10% (median; range 0–80%) are bought over the counter. Pain and analgesic use are assessed when reported by patients and at check‐ups. Only eight centres use a specific pain scale and/or have specific pain guidelines. Two HTCs arrange regular consultations with pain specialists. For acute pain, the preferred first‐line drug is paracetamol for children, and paracetamol or non‐steroidal anti‐inflammatory drugs (NSAIDs) for adults. Children with chronic pain are treated with paracetamol or NSAIDs, whereas adults usually receive Cox‐2 inhibitors. Second‐line therapy is heterogeneous. There is little published evidence to guide pain assessment and management in PWH, and clinical practice varies considerably across Europe. General and specific recommendations are needed.

Sequential combined bypassing therapy is safe and effective in the treatment of unresponsive bleeding in adults and children with haemophilia and inhibitors

Summary.  Some 10–20% of bleeding events in haemophilia patients with high‐responding inhibitors cannot be controlled with bypassing agents. However, sequential combined bypassing therapy (SCBT) has been reported to be successful in five children. To extend this observation, a survey was undertaken by the European Haemophilia Treatment Standardisation Board (EHTSB) in children and adults. Data were collected from all centres belonging to the EHTSB network by a retrospective medical record review. SCBT courses were defined as the administration of both recombinant activated factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) within 12 h. A web‐based database was prepared to collect data on SCBT courses in a standardized and anonymous manner from patients’ files. Eleven inhibitor patients underwent SCBT (nine haemophilia A; two haemophilia B). Two children had refractory knee haemarthrosis and one, an unresponsive calf haematoma. Five adults had significant bleeds following major surgery, one had lower limb compartmental syndrome and one a post‐traumatic upper limb haematoma and haemarthrosis. SCBT administration alternated one APCC dose to 1–3 rFVIIa doses: dosing intervals ranged between 3 and 6 h; APCC (20–80 U kg−1) was given every 8–12 h; rFVIIa (90–270 μg kg−1) was given every 3–12 h. Bleeding control was achieved in 12–24 h in all patients. SCBT was discontinued after 1–15 days. No clinical adverse events were observed, but a significant increase in D‐dimer levels was seen in three/five patients who were assessed. SCBT was efficacious without adverse events; nevertheless, due to potential risks, it remains a salvage treatment. A prospective clinical trial is needed to provide further evidence.

Management of acute haemarthrosis in haemophilia A without inhibitors: literature review, European survey and recommendations

Summary.  Acute haemarthrosis is a frequent type of bleeding in individuals with haemophilia. Delayed and/or inadequate treatment can trigger a series of pathological changes within the joint, leading to a painful and disabling arthropathy. The early management of intra‐articular bleeding has the potential to prevent chronic joint disease and may include a combination of factor replacement, rest, ice, rehabilitation and, in certain cases, joint aspiration. Little data are, however, available regarding the optimal management of acute haemarthrosis, especially with respect to replacement therapy and the use of adjunctive therapies (aspiration, avoidance of weight bearing and immobilization, as well as the use of anti‐inflammatory medication and embolization). To provide more insight into the management of acute haemarthrosis in patients with haemophilia, a literature review was conducted. Concomitantly, current management was surveyed in 26 European haemophilia comprehensive care centres representing 15 different countries. The review highlights the need for future robust studies to better define the appropriate replacement therapy and the role of adjunctive therapies such as aspiration. The survey reveals much heterogeneity in the management of acute haemarthrosis across the EU. Within the constraints discussed, treatment recommendations are presented that reflect the literature, current practice and the clinical experience of the European Haemophilia Therapy Standardisation Board (EHTSB).