Bülent Zülfikar

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

BACKGROUND The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

Anti-Inhibitor Coagulant Complex Prophylaxis in Hemophilia with Inhibitors

BACKGROUND Patients with severe hemophilia A and factor VIII inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Effective strategies to prevent bleeding in such patients have not yet been established. METHODS We enrolled patients with hemophilia A who were older than 2 years of age, had high-titer inhibitors, and used concentrates known as bypassing agents for bleeding in a prospective, randomized, crossover study comparing 6 months of anti-inhibitor coagulant complex (AICC), infused prophylactically at a target dose of 85 U per kilogram of body weight (±15%) on 3 nonconsecutive days per week, with 6 months of on-demand therapy (AICC at a target dose of 85 U per kilogram [±15%] used for bleeding episodes). The two treatment periods were separated by a 3-month washout period, during which patients received on-demand therapy for bleeding. The primary outcome was the number of bleeding episodes during each 6-month treatment period. RESULTS Thirty-four patients underwent randomization; 26 patients completed both treatment periods and could be evaluated per protocol for the efficacy analysis. As compared with on-demand therapy, prophylaxis was associated with a 62% reduction in all bleeding episodes (P<0.001), a 61% reduction in hemarthroses (P<0.001), and a 72% reduction in target-joint bleeding (≥3 hemarthroses in a single joint during a 6-month treatment period) (P<0.001). Thirty-three randomly assigned patients received at least one infusion of the study drug and were evaluated for safety. One patient had an allergic reaction to the study drug. CONCLUSIONS AICC prophylaxis at the dosage evaluated significantly and safely decreased the frequency of joint and other bleeding events in patients with severe hemophilia A and factor VIII inhibitors. (Funded by Baxter BioScience; Pro-FEIBA ClinicalTrials.gov number, NCT00221195.).

Health-related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: results from the Pro-FEIBA study

Patients with haemophilia A and inhibitors are at high risk for severe bleeding, progression of joint disease and deterioration of health‐related quality of life (HRQoL). To determine the impact of prophylaxis with an activated prothrombin complex concentrate (aPCC) on HRQoL, HRQoL was assessed using the Short‐Form (SF)‐36 Health Survey and the EQ‐5D questionnaire in subjects ≥14 years participating in a prospective, randomized, crossover study comparing 6 months of aPCC prophylaxis with 6 months of on‐demand therapy. Eighteen of 19 patients completed the survey or questionnaire before and after the on‐demand therapy and prophylaxis periods. A general trend towards improved HRQoL after prophylaxis was observed for the 18 evaluable patients in all SF‐36 dimensions except for vitality/energy and physical functioning. After prophylaxis, ‘good responders,’ defined as patients experiencing ≥50% reduction in bleeding, exhibited statistically and clinically significant differences in the physical component score (P = 0.021), role – physical (P = 0.042), bodily pain (P = 0.015), and social functioning (P = 0.036). Similarly, the EQ‐5D health profile showed a trend towards improvement after prophylaxis in all evaluable patients. Among the good responders, improvements did not differ from those observed after on‐demand treatment. EQ visual analogue scale values were slightly improved following prophylaxis for all evaluable patients and the EQ‐5D utility index improved in the good responders only. During prophylaxis, patients missed significantly fewer days from school or work because of bleeding than during on‐demand treatment (P = 0.01). In conclusion, by significantly reducing bleeding frequency in good responders, aPCC prophylaxis improved HRQoL compared with on‐demand treatment.

Survival analysis of Y‐90 radiosynovectomy in the treatment of haemophilic synovitis of the knee: a 10‐year retrospective review

Despite recent advances including new therapeutic options and availability of primary prophylaxis in haemophiliacs, haemophilic synovitis is still the major clinical problem in significant patient population worldwide. We retrospectively reviewed our 10‐year experience with Y‐90 radiosynovectomy to determine the outcome in the knee joints of patients with haemophilic synovitis. Between 2002 and 2012, 82 knee joints of 67 patients with haemophilic synovitis were treated with Y‐90 radiosynovectomy. The mean age was 16.8 ± 7.8 years (range: 5–39 years). The mean follow‐up period was 39.6 ± 25.6 months (range: 12–95 months). Failure of therapy represented re‐bleeding after a radiosynovectomy was used as an end point in patient time to progression (TTP) analysis. The median TTP was calculated as 72.0 ± 3.6 months (95% CI 64.8–79.1 months) in Kaplan–Meier analysis. The 1, 3 and 5‐year survival rates were 89%, 73% and 63% respectively. Longer TTP (hazard ratio for progression, 2.5; P = 0.00) was evident in patients who have greater reduction in bleeding frequency within 6 months after radiosynovectomy. We did not find a relationship between the TTP and the following variables: age, type and severity of haemophilia, the presence or absence of inhibitor, the radiological score, range of motion status of joints and the pretreatment bleeding frequency. We concluded that Y‐90 radiosynovectomy in knee joint represents an important resource for the treatment of haemophilic synovitis, markedly reducing joint bleeding and long‐term durability, irrespective of the radiographic stage and inhibitor status.

Oral and general health-related quality of life among young patients with haemophilia

Summary.  The clinical diagnosis of dental diseases may indicate their cause and prognosis, however it gives little information about resulting levels of impairment from the patients’ perspective. In this study, we aimed to investigate oral and general health‐related quality of life (OHRQoL‐HRQoL) in patients with haemophilia; and to test whether haemophiliacs would have worse or better OHRQoL compared with the general population. Data were collected from haemophiliacs (age range 14–35; mean 23 ± 6.58, n = 71) and age/sex‐matched controls (age range 14–35; mean 21.00 ± 6.45, n = 60) through face‐to‐face interviews including nine questions and using oral health impact profile (OHIP)‐14, oral health‐related quality of life‐UK (OHQoL‐UK), short‐form general measure of health (SF)‐36 to measure self‐rating oral health status, perceived dental treatment needs, tooth brushing frequencies, OHRQoL‐HRQoL. In the field of self‐rating oral health status, perceived dental treatment needs, tooth brushing frequencies and OHIP, OHQoL‐UK, SF‐36 scores – except the subscales including vitality, role emotional and mental health – the control group is in better conditions compared with the haemophilia group. At the same time, both the two groups are in good conditions in dental attendance, vitality, role emotional and mental health. Life quality is related with the perceived discrepancy between the reality of what a person has and the concept of what that person wants, needs or expects. In order to eliminate the dilemma in the field of health, we should facilitate the haemophiliacs’ lives by serving the health care in a multidisciplinary view.

Efficacy of FEIBA for acute bleeding and surgical haemostasis in haemophilia A patients with inhibitors: a multicentre registry in Turkey

Summary.  Long used in established industrialized nations to treat patients with haemophilia and inhibitors, factor eight inhibitor bypassing activity (FEIBA) has, in recent years, been introduced into more geographically diverse settings. Data are needed on how successfully FEIBA therapy has been implemented in new regions. To determine the efficacy and safety of FEIBA for the treatment of acute bleeding and surgical haemostasis in a newly industrialized country. A multicentre registry of haemophilia A patients with inhibitors receiving FEIBA treatment was established in Turkey. With a standardized case report form, data were collected retrospectively on: patient demographics; characteristics of acute bleeding episodes and surgical interventions; FEIBA regimen; and treatment outcomes. Thirty‐seven patients received a total of 112 FEIBA treatment courses, 90 for acute bleeding and 22 for surgical haemostasis. The median FEIBA dose per infusion for acute bleeding was 50 IU kg−1, and for surgery was 100 IU kg−1. For both acute joint and muscle/soft tissue bleeding and in surgery, haemostasis was attained in a median of two FEIBA infusions. FEIBA was judged effective in 92% of treatment courses for acute bleeding, with a 95% confidence interval (CI) of 85–97%. Rates of haemostatic efficacy did not differ significantly between anatomical sites of acute bleeding. The haemostatic efficacy rate of FEIBA in surgery was 86% (CI, 65–97%). No thromboembolic complications or other adverse events occurred during any treatment course. FEIBA has been successfully integrated into clinical practice in Turkey, with rates of haemostatic efficacy comparable to those reported in countries with a longer history of FEIBA usage.

Practical aspects of DDAVP use in patients with von Willebrand Disease undergoing invasive procedures: a European survey.

Desamino D‐arginine vasopressin (DDAVP or desmopressin) is a useful and effective haemostatic treatment for patients with von Willebrand Disease (VWD). However, there are still issues regarding in which subtypes of VWD DDAVP is appropriate and little consensus on its use in different surgical settings. We also lack information concerning the appropriate laboratory parameters that should be monitored.

Two patients with haemophilia and acute leukaemia

Summary.  Acute leukaemia is the commonest form of malignancy in childhood. The coincidental development of leukaemia in children or adults with haemophilia is extremely rare, although cases of leukaemia and other malignancies have been reported previously in HIV‐positive subjects. Of a total of 440 people with haemophilia registered with our society, two were diagnosed with acute leukaemia last year. The development of leukaemia in a subject with haemophilia has previously been reported from our country in 1985, but the negative HIV status of these recent cases is very interesting. The first caseinvolved a 14‐year‐old boy with moderate haemophilia A, who developed acute lymphoblastic leukaemia (ALL) [French–American–British (FAB) classification L2]. The second subject was a 16‐year‐old boy who had moderately severe haemophilia A with no previous family history, and developed acute nonlymphocytic (myelomonocytic) leukaemia (FAB‐M4). Both patients received conventional chemotherapyand thisreport discusses the potential problems in management of such cases, including diagnosis and administration of chemotherapy in subjects with a pre‐existing haemorrhagic disorder. Extensive cutaneous and mucosal bleeding, as well as bleeds in joints previously affected by haemarthrosis and alterations of haematological values were all initially suggestive of the development of inhibitors against factor VIII, but the appearance of blasts in the peripheral blood and bone marrow led to the definitive diagnosis. The risk of bleeding, due to the combination of both leukaemia and the consequences of the chemotherapy, was overcome by the administration of coagulation factor concentrates (daily initially followed by prophylactic doses after successful induction of remission in both patients). The young patient with ALL is now receiving the maintenance phase of the Childrens Cancer Study Group 1961 protocol and is in the 15th month of follow‐up, without any complications. The other case relapsed in the seventh month, developing enterobacter sepsis, and died. An important lesson to be learnt from these cases is that the possible diagnosis of leukaemia should not be overlooked in a patient with haemophilia and severe haemorrhagic problems, if the first‐line differential diagnosis of inhibitor development against factor VIII (or IX) has been excluded.

The Effectiveness of a New Hemostatic Agent (Ankaferd Blood Stopper) for the Control of Bleeding following Tooth Extraction in Hemophilia: A Controlled Clinical Trial

Objective: To assess the hemostatic efficacy of a new local hemostatic agent, Ankaferd Blood Stopper (ABS), for the control of bleeding following tooth extraction in hemophiliacs. Materials and Methods: Simple tooth extractions were performed in 27 hemophilia A patients. In the treatment group (n=17) local hemostasis was achieved via application of ABS to the extraction sockets, whereas in the control group (n=10) local hemostasis was achieved via direct packing with gauze. Results: In all, 57 (21 primary and 36 permanent) teeth extractions were performed in 27 hemophilia A patients. There were no significant differences in age or factor VIII level distribution between the 2 groups (p>0.05). The most significant clinical difference between the groups was associated with the use of ABS; those in the treatment group had significantly shorter duration of bleeding (p=0.002). Conclusion: This is the first study to evaluate the efficacy of ABS for the control of bleeding following tooth extraction in hemophiliacs. ABS can be considered an alternative local hemostatic agent for reducing clotting factor concentrates in hemophilia patients. Conflict of interest:None declared.

Practical aspects of factor concentrate use in patients with von Willebrand disease undergoing invasive procedures: a European survey.

The bleeding propensity in von Willebrand disease (VWD) is usually moderate or mild and patients with VWD do not need continuous treatment, but do require extra increased haemostatic cover when undergoing dental or surgical procedures. Desmopressin can be effective in certain patient groups and this has been considered in a previous publication.