New αIIbß3 variants in 28 Turkish Glanzmann patients; structural hypothesis for complex activation by residues variations in I-EGF domains.

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by impaired platelet aggregation due to defects in integrin αIIbß3, a fibrinogen receptor. Platelet phenotypes and allelic variations in 28 Turkish GT patients are reported. Platelets αIIbß3 expression was evaluated by flow cytometry. Sequence analyzes of ITGA2B and ITGB3 genes allowed identifying nine variants. Non-sense variation effect on αIIbß3 expression was studied by using transfected cell lines. 3D molecular dynamics (MDs) simulations allowed characterizing structural alterations. Five new alleles were described. αIIb:p.Gly423Asp, p.Asp560Ala and p.Tyr784Cys substitutions impaired αIIbß3 expression. The αIIb:p.Gly128Val substitution allowed normal expression; however, the corresponding NM_000419.3:c.476G>T variation would create a cryptic donor splicing site altering mRNA processing. The ß3:p.Gly540Asp substitution allowed αIIbß3 expression in HEK-293 cells but induced its constitutive activation likely by impairing αIIb and ß3 legs interaction. The substitution alters the ß3 I-EGF-3 domain flexibility as shown by MDs simulations. GT variations are mostly unique although the NM_000419.3:c.1752 + 2 T > C and NM_000212.2:c.1697 G > A variations identified in 4 and 8 families, respectively, might be a current cause of GT in Turkey. MD simulations suggested how some subtle structural variations in the ß3 I-EGF domains might induce constitutive activation of αIIbß3 without altering the global domain structure.

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

INTRODUCTION: 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. AIM: This paper now seeks to evaluate current knowledge and practice in the use of factor concentrate in the management of VWD patients undergoing invasive procedures. METHODS: A literature search was performed on the use of factor concentrates to cover invasive procedures and a survey of current practice in a number of specialist haematology centres across Europe represented by the European Haemophilia Strategy Board was conducted. RESULTS: Our review of the literature and the results of the survey showed considerable heterogeneity in treatment regimens, and a lack of consistency in reporting of the variables that determine factor concentrate dosing and monitoring. CONCLUSION: By analysing the literature, examining guidelines and using consensus deliberation, this survey allowed the group to develop recommendations for management of VWD patients undergoing invasive procedures.

Benefits of radial head excision in patients with haemophilia: mid-term functional results.

INTRODUCTION: Recurrent haemarthrosis in haemophilic patients result with arthropathy of the radiocapitellar joint and blockage of the forearm rotation. AIM: The aim of this study is to evaluate the mid-term results of radial head excision with partial synovectomy in severe haemophilic patients retrospectively. METHODS: Persistent pain and decreased forearm rotation were the main indications for radial head excision. Between 2002 and 2013, radial head excisions were performed for 14 elbows of 14 patients. Eleven patients were haemophilia A, whereas two patients were haemophilia B patients and the remaining one had von Willebrand (Type 3) disease. The mean age of the patients was 29 at the time of the surgery. The mean follow-up was 51 (12-155) months. VAS (visual analogue score) for pain, forearm rotation, qDASH and MEPS (Mayo Elbow Performance Score) were used as the primary outcome parameters. RESULTS: The mean VAS decreased significantly from 6.5 preoperatively to 2.2 at the final follow-up (P = 0.0003). The mean forearm rotation increased from 40° to 115° respectively (P = 0.0007). In two patients, efficacious rotation increase was not achieved due to distal radioulnar joint problems. The mean qDASH score and MEPS were 18.1 and 87.5 at the latest follow-up, respectively, where four patients had excellent and 10 patients had good results. CONCLUSIONS: Radial head excision is a safe and effective procedure for haemophiliac patients with radiocapitellar arthropathy and decreased forearm rotation. Distal radioulnar joint should be evaluated preoperatively which may impair the results.

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

INTRODUCTION: 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. AIM: The European Haemophilia Therapy Strategy Board (EHTSB) wished to investigate published information and clinical use of DDAVP in VWD patients. METHODS: We conducted a literature survey on management of VWD during surgical interventions and undertook a survey of specialist haematologist centres across Europe to assess current management of VWD patients. RESULTS: DDAVP is ineffective in type 3 VWD and its use in type 2B remains controversial due to the possibility of thrombocytopenia. It can, however, be used effectively to cover minor surgery and dental procedures in most other VWD patients. For major surgery there is wider use of factor concentrate in preference to DDAVP depending on the subtype of VWD. We give consensus recommendations on the use of DDAVP for surgical interventions in VWD including laboratory parameters that denote an adequate response and contraindications to its use. CONCLUSIONS: DDAVP can be recommended to cover invasive procedure in selected patients with VWD, however, we need more information and systematic recording of adverse events associated with DDAVP use in VWD. A companion paper will be published covering the use of factor concentrates in VWD patients.

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.

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.

Long-term outcomes in haemophilic synovitis after radiosynovectomy using rhenium-186: a single-centre experience.

Radiosynovectomy has been performed successfully for more than 10 years in our hospital. This study investigated the long-term outcome in the context of time to progression (TTP) analysis and the factors influencing TTP following radiosynovectomy with Re-186 in patients with haemophilic synovitis. Radiosynovectomy performed in 165 joints (81 elbows, 74 ankles, 8 shoulder and 2 hip joints) of 106 patients (median age was 18.0 ± 7.5 years; 91 haemophilia A, 13 haemophilia B and 2 von Willebrand's disease between June 2001 and July 2011. The mean follow-up was 48 months (range: 9-120 months). This study revealed that patients' mean TTP after primary radiosynovectomy was satisfactory for both the ankle and elbow joints. There was no TTP differences between the ankle and elbow joint groups (67 vs. 72 months respectively; P = 0.22). 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 (ROM) status of joints and the pretreatment bleeding frequency. In this study, 18-20% of the treated joints had improved ROM and 82-79% of the treated joints had unchanged ROM after treatment both the ankle and elbow joints respectively. In this report including TTP analysis in the largest series with long-term follow-up, we demonstrated long-term effectiveness of Re-186 radiosynovectomy in haemophilic synovitis. In our experience, the main predictor of outcome following radiosynovectomy is the number of joint bleeding within 6 months after therapy.

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

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.

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

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.

Monitoring the genotoxic effects of radiosynovectomy with Re-186 in paediatric age group undergoing therapy for haemophilic synovitis.

PURPOSE: The aim of this study was to investigate the genotoxic effect on the peripheral blood lymphocytes potentially induced by Re-186 in paediatric age group undergoing radiosynovectomy for haemophilic synovitis, by using chromosomal aberration analysis (CA) and the micronuclei (MN) assay for detecting chromosomal aberrations, as well as the sister chromatid exchanges (SCE) technique for assessing DNA damage. METHODS: Cytogenetic analyses were evaluated in 20 boys (mean age: 13.8 +/- 2.7 years) before, and 2 and 90 days after radiosynovectomy from the peripheral lymphocytes of the patients. Joint retention and extra-articular spread of the radionuclides were evaluated by using quantitative gamma camera imaging. RESULTS: Imaging after radiosynovectomy revealed local lymph node visualization in 8 (40%) patients and hepatosplenic visualization in 3 (15%) patients due to extra-articular leakage of radioactive material. The mean frequency of chromosome aberrations (0.2 +/- 0.4/1000 cells) determined prior to the onset of therapy was not significantly increased in comparison with control values obtained 2 days (0.4 +/- 0.5/1000 cells) and 90 days (0.2 +/- 0.4/1000 cells) after therapy (P = 0.754 and P = 1.0). In the analysis of MN and SCE, when we compare the baseline levels, the mean MN and SCE frequencies were slightly higher in the control analyses performed 2 and 90 days after radiosynovectomy but there were no significant differences between baseline and control levels (chi(2) = 2.621, P = 0.270 and F = 0.573, P = 0.569, respectively). CONCLUSION: The major finding of this study with relatively small sample is that, radiosynovectomy with Re-186 does not seem to induce early genotoxic effects on the peripheral blood lymphocytes in paediatric age group.

Two patients with haemophilia and acute leukaemia.

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 case involved 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 chemotherapy and this report 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 Children's 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.

Leukemic children: clinical and histopathological gingival lesions.

The relation between leukemia and gingiva was investigated in the present study. An extensive tumor infiltration in the gingiva was established in 1 of 2 patients with acute leukemia (AML). An inflammatory cell infiltration in various degrees was noticed in total 28 patients with leukemia (L). Various degrees of epithelium hyperplasia in all patients existing in 14 patients with medium intensity and occurring in 14 patients with light intensity of hyperplasia were observed. An increase in the keratinization of epithelium, in 3 patients with medium intensity and 1 patient with light intensity was found. It was also seen that there were fungal infections in 3 patients with medium intensity, in 6 patients with light intensity and existing in a total 26 patients with acute lymphoblastic leukemia (ALL).

Various associations of human parvovirus B19 infection.

A variety of diseases encountered in association with human parvovirus B19 infection seen at Paediatric clinic during 6 months is presented and their relation to parvovirus B19 is discussed. We conclude that investigation of parvovirus B19 in variable diseases by using the newly developed methods of molecular biology will enlighten many etiopathogenetic mechanisms.

Circumcision ceremonies at the Ottoman palace.

Circumcision is widely practiced in all Islamic countries. Festivities pertaining to circumcision vary according to the regions and civilizations. In this report, circumcision festivities at the Ottoman Palace and the socioeconomic importance of the tradition are presented. The Ottoman circumcision technique is discussed, as are the miniature paintings, in manuscript, written on the occasion of the circumcision of the sons of the Sultans. Because these festivities involved the participation of all classes of the society and all professions they contributed to social and technical progress and led to developments in art, music, sports, and ideas.

Monosomy 7 myeloproliferative disease associated with neurofibromatosis type I: a case report.

A 7-year-old girl with neurofibromatosis type I (NF1) was diagnosed to have monosomy 7 myeloproliferative disease (Mo 7-MPD). Of the benign and malignant tumors that are encountered with increased incidence in NF1, those originating from the neural crest are frequent. However, tumors that do not originate from the neural crest may also be seen and among these, myeloid leukemias are prominent. Studies on NF1 patients with Mo 7-MPD and juvenile chronic myeloid leukemia (JCML) have suggested the role of the NF1 gene in the leukemogenesis. The relationship between monosomy 7 and hematological malignancies is already known. These findings are in agreement with the multi-step development theory of cancer. In addition, our case is one of the very rare NF1 cases having father to daughter inheritance with a myeloid malignancy. We believe that cytogenetic and molecular genetic studies will contribute to further understanding of leukemogenesis.

Ewing's sarcoma: experience with 12 cases.

Twelve patients with localized Ewing's sarcoma were treated between 1980-1990 at the Istanbul School of Medicine, Department of Pediatric Oncology-Hematology, Oncology Research and Treatment Center and Our Children Leukemia Foundation. There were 8 boys and 4 girls, with a mean age of 8.1 (range 3-17) years. The tumors were in the femur in 3 patients, in the humerus and rib in 2 patients each and in the tibia, radius, vertebra, clavicula and pelvis in 1 patient each. Chemotherapy alone was applied in 2 patients, 1 patient had chemotherapy and radiotherapy. The remaining 9 cases were treated with Chemotherapy and radiotherapy (during the chemotherapy). The chemotherapy protocols were: VAC (n = 5), VACA (n = 3), IVAD (n = 3) and T.9 (n = 1). One patient died from the disease itself. Remissions were achieved in the other 11 patients. After 5 to 95 months (mean: 22 months) 7 patients had relapsed (4 had local and 3 had distant metastases). Three patients were not able to be followed, 3 died due to additional problems (infection, cardiotoxicity). The best prognosis was achieved when Ewing's sarcoma initiated in the long bones, with less than 100 ml tumor volumes and patients were under 5 years old. There were no significant differences among chemotherapy protocols.

The efficacy of mezlocillin-amikacin combination in febrile neutropenic children with oncologic disease.

The efficacy of mexlocillin-amikacin combination as empirical therapy for febrile neutropenic patients was studied in 30 children (21 males, 9 females) with various oncologic diseases aged 1-15 years (mean age 7.3 +/- 4.4) in the Istanbul Medical School, Oncologic Disease Research and Treatment Center, and Department of Pediatric Hematology-Oncology between January 1 and May 31, 1988. The response rate was 76.6%. Profound persistent granulocytopenia (fewer than 100 ml) was present in 70% of the patients. In 63.3% of patients, the infections were microbiologically documented (60%) Gram(+) and 40% Gram(-). The combination was well tolerated with hepatic and/or renal disturbances in 8 cases (26.6%). We conclude that mezlocillin-amikacin is an effective empirical combination in the initial treatment of infections in febrile neutropenic children with various oncologic diseases.