K. Kavakli

Enhancing the pharmacokinetic properties of recombinant factor VIII: first‐in‐human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A

N8‐GP is a recombinant factor VIII (FVIII) with a site‐directed glycoPEGylation for the purpose of half‐life prolongation.

Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II)

BAY 81‐8973 is a new full‐length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance.

Recombinant factor VIIa analog (vatreptacog alfa [activated]) for treatment of joint bleeds in hemophilia patients with inhibitors: A randomized controlled trial

Summary.  Background: A recombinant factor VIIa analog (NN1731; vatreptacog alfa [activated]) was developed to provide safe, rapid and sustained resolution of bleeds in patients with hemophilia and inhibitors. Patients/Methods: This global, prospective, randomized, double‐blinded, active‐controlled, dose‐escalation trial evaluated and compared one to three doses of vatreptacog alfa at 5, 10, 20, 40, and 80 μg kg−1 with one to three doses of recombinant FVIIa (rFVIIa) at 90 μg kg−1 in the treatment of acute joint bleeds in hemophilia patients with inhibitors. The primary endpoint comprised adverse events; secondary endpoints were evaluations of immunogenicity, pharmacokinetics, and efficacy. Results and Conclusions: Overall, 96 joint bleeds in 51 patients (> 12 years of age) were dosed. Vatreptacog alfa was well tolerated, with a low frequency of adverse events. No immunogenic or thrombotic events related to vatreptacog alfa were reported. A high efficacy rate of vatreptacog alfa in controlling acute joint bleeds was observed; 98% of bleeds were controlled within 9 h of the initial dose in a combined evaluation of 20–80 μg kg−1 vatreptacog alfa. The efficacy rate observed for rFVIIa (90%) is consistent with data from published clinical trials. The trial was not powered to compare efficacy, and further trials are needed to investigate the efficacy of vatreptacog alfa as compared with that of rFVIIa. The trial was registered at ClinicalTrials.gov (Registration Number: NCT00486278).

A single centre experience in circumcision of haemophilia patients: Izmir protocol.

Summary.  Haemophiliacs and their families consider that circumcision is a very important step to become a member of society and it is a social obligation for men in Turkey. Although bleeding risk is high, almost all haemophiliacs would like to be circumcised in Turkish society. The aim of this study was to evaluate our experience in circumcision of haemophilia patients and define efficacy, safety and complication rates of our protocol, called ‘Izmir protocol’. In this study, we retrospectively reviewed medical records of 50 patients with haemophilia who underwent circumcision at our hospital according to Izmir protocol between 1996 and 2009. Oral tranexamic acid and fibrin glue were used in all children. One hour before the operation, first dose of factor concentrate was given. After reaching a plasma factor level of around 90–100%, the prepuce was incised circumferentially and excised using Gomco clamp or open technique under general anaesthesia. Intermittent injections of factor concentrate were given every 12 for 48 h. While the first two doses were given at higher amount to achieve or continue plasma factor level at 90–100%, in the last three doses, the aim was to maintain the plasma factor level at 50–60%. Forty‐eight hours after the circumcision, patients were discharged. Three patients (6%) showed bleeding complication and all were resolved easily. All had at least one excuse from the protocol (Lower doses of factor concentrates was used in 2, tranexamic acid was not used in 2). Izmir protocol is safe, cheap and easy to carry out.

Surgery in patients with haemophilia and high responding inhibitors: Izmir experience

Summary.  This report evaluates the haemostatic efficacy of recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) in patients with haemophilia and high responding inhibitors who underwent major and minor surgery. Data pertaining to surgeries from 2001 to 2009 at a single centre were retrospectively analysed. During this period, 53 surgical procedures were performed in 30 haemophiliacs with high responding inhibitors. Mean age was 16.2 ± 9.4 years. Eleven major surgeries in 4 patients, 41 radioisotope synovectomies (RS) and one circumcision classified as minor surgery in 28 patients were performed. Among the major surgery procedures, four were treated with rFVIIa, five with APCC and two with sequential use of APCC and rFVIIa. We used rFVIIa at the dosage of 80–120 μg kg−1 every 2 h and APCC 100 IU kg−1 every 12 h for the major surgery. When performing RS, we used rFVIIa in 18 patients with 26 target joints and APCC in 9 patients with 15 target joints. Three consecutive doses of rFVIIa (90 μg kg−1) were used at 2‐h intervals followed by additional three doses at 6‐h intervals. The initial dose of APCC was 75 IU kg−1 followed by a second and third dose of 50 IU kg−1 at 12‐h intervals. APCC and rFVIIa demonstrated excellent efficacy in our major and minor surgical interventions [100% (22/22) and 94% (31/33), respectively]. We had only two bleeding complications with rFVIIa. There were no thromboembolic complications. APCC and rFVIIa provide an effective and safe first line haemostatic therapy for inhibitor‐positive haemophiliacs, allowing both major and minor surgery to be successfully performed.

Real-world outcomes with recombinant factor VIIa treatment of acute bleeds in haemophilia patients with inhibitors: results from the international ONE registry

The ONE Registry (OR) was an international prospective observational study of on‐demand recombinant factor VIIa (rFVIIa) treatment for mild to moderate bleeds in haemophilia A/B patients with inhibitors. To describe real‐world use of single and multi dose rFVIIa and to compare outcomes, including effectiveness, safety, quality of life and treatment satisfaction associated with treatment. Baseline data included demographics, treatment, medical and bleed history and patient/caregiver‐reported outcomes regarding bleeds. rFVIIa was prescribed according to routine practice; regimens varied and initial dose was categorized as low (LD, ≤120 μg kg−1), intermediate (ID, >120 and <250 μg kg−1) or high (HD, ≥250 μg kg−1). OR included 102 patients and 85 (83%) reported 494 bleeds overall. Mean age was 23 years (SD 16.4), with 52% ≥18 years. Majority of bleeds (n = 350, 71%) involved ≥1 joints; 46% involved a target joint. Median initial dose was 90 μg kg−1 in LD (range 87–120, n = 156), 174 μg kg−1 in ID, (range 121–249, n = 127) and 270 μg kg−1 in HD, (range 250–375, n = 211). For spontaneous bleeds, effective haemostasis rate at 9 h was 63% LD, 60% ID and 56% HD. Rates of combined partially effective/effective haemostasis was 85% LD, 96% ID and 86% HD. Median number of doses in HD was one (range 1–7), compared with two in LD (range 1–17) and ID (range 1–23). No thromboembolic events were reported in 1145 doses given. These observational data in real life are consistent with previous studies which have shown similar overall effectiveness of rFVIIa and similar effectiveness and safety across different patterns of standard initial dosing.

Once‐weekly prophylactic treatment vs. on‐demand treatment with nonacog alfa in patients with moderately severe to severe haemophilia B

Limited data are available on optimal prophylaxis regimens of factor IX (FIX) replacements for patients with haemophilia B.

Feasibility of using thrombin generation assay (TGA) for monitoring of haemostasis during supplementation therapy in haemophilic patients without inhibitors.

Monitoring factor replacement treatment and observing concordance with clinical haemostasis is crucial in vital haemorrhages and major surgeries in haemophilic patients. We aimed to investigate the value of the thrombin generation assay (TGA) and thromboelastography (TEG) for monitoring haemostasis in haemophilic patients during factor replacement treatment. The study group consisted of 29 patients (21 haemophilia A, 8 haemophilia B). All the patients FVIII‐inhibitor were negative. A total of 35 bleeding episodes and/or surgical interventions were evaluated. aPTT, FVIII/FIX activity, TEG and TGA tests were conducted before and after factor therapy during the bleeding episode or surgical prophylaxis of haemophilic patients. Correlations among these tests were evaluated and compared with clinical responses. No correlation was found among aPTT, factor activities and clinical outcome. There were also no correlation found between TEG parameters and clinical outcome. The only significant correlation found between TGA parameters and clinical outcome was the correlation between peak thrombin. In conclusion, we found superiority of TGA‐peak thrombin over other traditional tests for monitoring haemostasis in haemophilic patients in this study.

Feasibility of Using Thrombin Generation Assay (TGA) for Monitoring Bypassing Agent Therapy in Patients With Hemophilia Having Inhibitors

Background: Monitoring bypassing agent therapy and observing concordance with clinical hemostasis is crucial in vital hemorrhages and major surgeries in patients with hemophilia having inhibitor. Objective: We aimed to investigate the value of the thrombin generation assay (TGA) and thromboelastography (TEG) for monitoring hemostasis in patients with hemophilia having inhibitor, during supplementation therapy with bypassing agents. Patients and Methods: The study group consisted of 7 patients with hemophilia having factor VIII inhibitor. All patients were male. The median age of the participants was 10 years. Age range was 6 to 32 years. The median inhibitor level was 10 Bethesda units (BU), with a range of 5 to 32 BU. A total of 17 bleeding episodes were evaluated. Both TEG and TGA tests were assessed in addition to clinical responses. Assessments were made prior to bypass agent therapy such as recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrate (aPCC) for bleeding episodes, during the first hour and 24 hours after either intervention in patients. Results: No relation between clinical response and TGA or TEG parameters was found in patients. There was no difference between clinical responses after rFVIIa and aPCC treatments. However, after aPCC treatment, endogenous thrombin potential and peak thrombin levels and also TEG R, K, and alpha angle degrees were significantly higher. Conclusions: In conclusion, we found that the clinical effectiveness of bypass therapy in hemophilia cannot be assessed by TGA and TEG.

Intracranial haemorrhage in children and adolescents with severe haemophilia A or B - the impact of prophylactic treatment

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on‐demand‐group, 8% (2/24) children with ICH died and 33% had long‐term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non‐frequent or no prophylaxis.