Bülent Antmen

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.

The value of early treatment in patients with haemophilia and inhibitors

Summary.  Development of inhibitors to infused factor concentrates represents a major clinical and economic challenge in the treatment of haemophilic patients. It has been shown that a delay in initiation of treatment leads to requirement of a larger number of injections to stop the bleeding but this has never been formally linked to costs associated with the bleeding. The objectives of this study were to assess the relationship between time to initiation of NovoSeven® and total costs, number of doses administered and time to bleeding resolution in mild to moderate bleeding episodes. Data on time to treatment initiation, time to bleeding resolution and on all resource use related to the bleeding were extracted from medical records in Turkey for 129 bleeding episodes. Regression analysis was used to assess the impact of time to treatment on outcomes. Longer time to treatment initiation increased both total costs associated with the bleeding, the number of doses needed and the time to bleeding resolution. Treatment in hospital was associated with significantly longer time to treatment, higher costs and longer time to bleeding resolution as compared with home treatment or outpatient treatment. When controlling for other bleeding characteristics, the cost of bleedings treated in hospital was more than 150% higher. This study shows that treatment with NovoSeven® should be initiated as soon as possible after the onset of bleeding in order to minimize costs and optimize outcomes. Home treatment reduces time to treatment initiation and also reduces costs related to the bleeding.

The immunohistochemical analysis of vascular endothelial growth factors A and C and microvessel density in gingival tissues of systemic sclerosis patients: their possible effects on gingival inflammation

OBJECTIVE In systemic sclerosis (SSC), certain abnormalities can occur in fibroblasts, endothelial cells, and immune system cells. Severe pathological changes such as visceral fibrosis and obliteration of the lumen of arteries may develop due to functional alterations of these cells. Because the vascular abnormality is a central mechanism of sclerosis, the aim of this study was to further investigate the impaired vascularity in the gingival tissues of SSC patients by means of immunohistochemistry using vascular endothelial growth factor A (VEGF-A), VEGF-C, and CD34 staining. STUDY DESIGN Thirteen SSC patients and 11 systemically healthy controls who had moderate gingivitis were included in the study. Gingival biopsies were obtained from the interdental papilla, and VEGF-A, VEGF-C, and CD34 analyses were done by using immunohistochemical methods. RESULTS Patients with scleroderma had higher levels of inflammatory infiltrate (P = .041) and microvessel density (P = .003) in their gingival biopsy samples. In contrast, when compared with the controls, the expressions of VEGF-A and VEGF-C were significantly lower in scleroderma patients (P = .033 and P = .015, respectively). CONCLUSION These findings may reflect the defective vascularity and the pronounced histological inflammation of the gingival tissues in systemic scleroderma and may provide a novel target for treatment methods for the gingival involvement in these patients.

Circumcision and complications in patients with haemophilia in southern part of Turkey: Çukurova experience

Summary.  Circumcision is the oldest and most frequent surgical procedure in the world and especially in Turkey as is seen in the other Islamic countries because of religious and traditional pressures. In this study, we aim to report the experience of circumcision at Çukurova University in a total of 76 patients with haemophilia between 1990 and 2011. We retrospectively reviewed medical records of 69 haemophilia patients without inhibitors and seven haemophilia patients with inhibitors who had been circumcised. Before the year 2000, factor concentrates were given before and after circumcision for 6–7 days. After 2000, we used fibrin glue together with factor concentrates for only 3 days. By‐passing agents were used for circumcision in haemophilia patients with inhibitors. Twelve of 69 patients without inhibitors were referred to our centre with bleeding after the circumcision before diagnosis of haemophilia. Nine of these twelve patients had severe life threatening bleeding and three of them had moderate bleeding. Sixty‐four patients with haemophilia were circumcised in our centre under general anaesthesia except for three patients who were given local anaesthesia. Thirteen of 57 haemophilia patients (22.8%) without inhibitors had seven mild and six moderate bleeding complications. A few patients had significant bleeding, despite adequate factor replacement. Five of seven haemophilia patients with inhibitors had two moderate and three mild bleeding complications. Our experience showed that circumcision for patients with haemophilia should be carefully performed by surgeons together with paediatric haematologist, under appropriate conditions in haemophilia centres which has comprehensive coagulation lab.

The effect of hemolysis on plasma oxidation and nitration in patients with sickle cell disease.

Abstract This study aimed to determine the effect of haemolysis on plasma oxidation and nitration in sickle cell disease (SCD) patients. Blood was collected from haemoglobin (Hb)A volunteers and homozygous HbSS patients who had not received blood transfusions in the last 3 months. Haemolysis was characterised by low levels of haemoglobin and haptoglobin and high levels of reticulocyte, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), plasma cell-free haemoglobin, bilirubin, total lactate dehydrogenase (LDH) and dominance of LDH-1 isoenzyme. Plasma 8-isoprostane, protein carbonyl and nitrotyrosine levels were measured to evaluate oxidised lipids, oxidised and nitrated proteins, respectively. Plasma nitrite–nitrate levels were also determined to assess nitric oxide (NO) production in both SCD patients and controls. Markers of haemolysis were significantly evident in SCD patients compared to controls. Plasma 8-isoprostane, protein carbonyl and nitrotyrosine levels were markedly elevated in SCD patients compared to controls. Linear regression analysis revealed a significant inverse correlation between haemoglobin and reticulocyte counts and a significant positive correlation of plasma cell-free haemoglobin with protein carbonyl and nitrotyrosine levels. The obtained data shows that increased haemolysis in SCD increases plasma protein oxidation and nitration.

Influence of smoke exposure on serum IgE levels of atopic patients.

The effect of environmental tobacco smoke on serum total immunogobulin E (IgE) of respiratory allergic patients was evaluated in this study. A total of 558 patients with respiratory allergies (311 boys and 248 girls) aged between 1 and 17 years (mean 6.92 ± 3.81 years) were included. None of the subjects were active smokers. IgE levels were significantly higher in children with smoking parents compared with non‐smokers (P < 0.05). Children with smoking mothers were found to have higher levels of IgE than children with smoking fathers. The highest level of IgE was found in children when both parents were smokers (P < 0.005).

Cardiac mucormycosis in a child with severe aplastic anemia: a case report.

Mucormycosis is an uncommon, severe, life-threatening fungal infection in the immunocompromised host. Mucormycosis with aplastic anemia is seen rarely. Only a few cases of cardiac mucormycosis with aplastic anemia have been reported in the literature. The authors present a case with severe aplastic anemia that did not respond to classic and immunosuppressive treatment for disease and developing invasive cardiac mucormycosis despite empiric treatment for febrile neutropenia.

Fatal encephalitis associated with novel influenza A (H1N1) virus infection in a child.

A 4-year-old girl presented with fever, coughing, and vomiting; followed by unconsciousness. Magnetic resonance imaging showed hyperintense changes in the thalami bilaterally, brain stem, cerebellum, and subcortical cortex. Novel influenza A (H1N1) virus was identified by polymerase chain reaction in patient’s nasopharyngeal swab specimen. We reported a rare case of clinically severe, novel influenza A-associated encephalitis. Novel influenza A should be considered in the differential diagnosis in patients with seizures and mental status changes, especially during an influenza outbreak.