Can Balkan

Iliopsoas haemorrhage in patients with haemophilia: results from one centre.

Summary.  Iliopsoas haematoma is a well‐recognized complication of haemophilia, and is considered as potentially life threatening and significantly associated with morbidity. There are only rare reports on the incidence or outcomes of iliopsoas bleeding since the widespread usage of modern therapies for haemophilia. In this study, we present the experience of Ege University Haemophilia Centre with iliopsoas bleeding and its early and late complications. We reviewed 146 haemophiliacs (106 haemophilia A, 40 haemophilia B). Fourteen iliopsoas bleeding episodes were identified in eight haemophiliacs. Three patients (37%) had one episode, four (50%) had two episodes and one (13%) had three episodes. Two patients had a high titre inhibitor against factor VIII and accounted for three bleeding episodes (21%). We did not observe any episodes in six patients receiving prophylaxis. Iliopsoas haematomas were confirmed by ultrasonography in all patients. In physical examination, the most common symptoms were thigh, hip and groin pain, hip flexion contracture, abdominal tenderness and paraesthesia in the distribution of the femoral nerve. The mean duration of therapy with clotting factor concentrate was 7.8 ± 1.6 days. The mean duration of hospitalization was 4.8 ± 2.0 days. All patients started to receive a physical therapy program 6.0 ± 2.4 days after the initiation of haemostatic therapy which lasted 20.0 ± 6.0 days. Ultrasonographic findings related to iliopsoas haematoma disappeared in all patients within 3 months from the initial episodes. Only in one patient with mild haemophilia A, heterotopic bone formation (myositis ossificans) developed as a long‐term complication. In conclusion, pain around the hip joint, femoral neuropathy and hip flexion contracture in a patient with haemophilia should alert the physician to the possibility of an iliopsoas haematoma. Early and effective factor replacement therapy is essential in the prevention of the complications.

Long-term evaluation of radioisotope synovectomy with Yttrium 90 for chronic synovitis in Turkish haemophiliacs: Izmir experience.

Summary.  Since 2001 we have performed 105 radioisotope synovectomy (RS) in 65 children and young adults, age ranging from 3 to 25 years with a average of 15 years in Ege University Hospital, Izmir, Turkey. One fourth of cases were below 10 years of age. All patients had severe haemophilia A and B. Ten patients (17 joints) had high responder inhibitor. We prefer to use Yttrium 90 for all joints (5 mCi for knees; 2 mCi for others). The knees were injected in 56 cases, elbows in 24 cases, ankles in 23 cases and shoulders in two cases. Steroid injections were not preferred as the principle drug of choice. Mean follow‐up period after procedure was 2 years (range: 6 months to 3.5 years). All inhibitor patients had satisfactory results. The best results were obtained in elbows than knees and ankles. Excellent rates (no bleeding) were observed in grade‐II synovitis 84% for knees, 93% for elbows and 50% for ankles. Because of the excellent and good response (bleeding reduction to 75%), rates were 100% for knees and elbows and 92% for ankles. In six cases, repeated injections were given at 6‐month interval and all of them had good results. The grading of synovitis seems to be an important parameter than the age of the patient. Even in patients below 10 years of age, outcomes are not satisfactory in all joints with grade‐III vs. grade‐II synovitis (12% vs. 73%). No serious complications were observed during and after procedure except two cases. A mild and transient inflammatory reaction was observed in the ankle. There was a minimal radioisotope leakage to superficial skin in the elbow. RS seems to be a safe and effective treatment for chronic synovitis causing recurrent joint bleedings.

Radioisotope synovectomy with rhenium186 in haemophilic synovitis for elbows, ankles and shoulders

Summary.  We have performed 221 radioisotope synovectomy (RS) in more than 150 children and young adults with haemophilia, age ranging 3–30 years (mean 15) in Ege Hemophilia Center, Izmir, Turkey for last 7 years. We always preferred to use Yttrium 90 (Y90) for knees; however, since 2005, we started using rhenium 186 (Re186) for medium‐sized joints with respect to safety. In this article, we have evaluated long‐term experience ranging from 6 months to 3 years (mean 18 months) with Re186 for elbows (n = 35), ankles (n = 26) and shoulders (n = 2) in total of 63 RS procedures for 49 patients. Their age range was 3–30 years and mean age was 15.5. Two mCi of Re186 intra‐articularly injected for treating target joints and chronical synovitis. After RS, joint bleedings were decreased for all patients. The best results were obtained for all joints in patients with grade‐II synovitis as like earlier experience with Y90. Excellent rates (no bleeding) were observed in grade‐II synovitis in 81% and 46% for elbows vs. 86% and 57% for ankles after 6 months and after 1 year follow‐up of patients, respectively. In grade‐III synovitis, excellent rates were 53% and 25% for elbows and 44% and 29% for ankles, respectively. In five joints for five patients, repeated injections were needed for better outcome. No adverse events such as radioisotope leakage, local inflamatory reactions or malignancy development were observed during and after RS. For medium‐sized joints, RS with Re186 seems to be either effective or safe treatment method. Our results confirm those previously published by others on the value of Re186 synoviorthesis in medium‐sized joints in haemophilia patients. After this experience, we changed our protocol and we use Re186 for all medium‐sized joints for treating chronical synovitis.

SINGLE-CENTER EXPERIENCE: Use of Recombinant Factor VIIa for Acute Life-Threatening Bleeding in Children without Congenital Hemorrhagic Disorder

Coagulopathy is an important cause of mortality in critically ill children. Traditional therapies to correct coagulopathy lead to great time delays and cause fluid overload in patients. The authors report the effectiveness and safety of the activated recombinant factor VII (rFVIIa) administration in a series of 13 nonhemophiliac children with acute, life-threatening bleeding. In this retrospective study, the records of the patients who were not diagnosed with congenital hemorrhagic disorder and were administered rFVIIa due to any other reason in Ege University Faculty of Medicine, Department of Pediatrics, between February 2002 and February 2007 were reviewed retrospectively. Thirteen nonhemophiliac patients with acute life-threatening bleeding and ages ranging from 2 days to 15 years received rFVIIa over a 5-year period. Three patients were diagnosed with hemaphagocytic lymphohistiocytosis, 4 with prematurity, sepsis, and disseminated intravascular coagulation (DIC), 5 with sepsis, multiple organ dysfunction syndrome, and DIC, and 1 with acute liver failure. Severe bleeding resulted from pulmonary (n = 3), lower gastrointestinal system (n = 2), esophagus varices (n = 1), pulmonary and gastrointestinal system (n = 4), pulmonary, gastrointestinal system, and intracranial hemorrhage (n = 1), and gastrointestinal system and intracranial hemorrhage (n = 2). Median frequency of rFVIIa administration was 3 per patient (range 2–15) and median dose of rFVIIa was 90 μg/kg, ranging from 60 to 135 μg/kg each administration. All of the patients were given fresh frozen plasma and if necessary platelet transfusion (n = 10) or fibrinogen concentrate (n = 3) before administration of rFVIIa. In 6 patients, lack of success to control bleeding by conventional methods was the only cause to start rFVIIa. In 7 patients, the need for volume restriction was also a significant contributing factor in deciding to start rFVIIa. Median PT was 32.9 s (range: 19–65) before rFVIIa administration and it was decreased to 11.6 s (range: 10.7–12.8), 2–3 h after rFVIIa infusion. Bleeding was stopped completely in 10 patients at least for 24 h and decreased in 3 patients 30–45 min after rFVIIa administration. Two patients had thrombotic complications attributed to rFVIIa administration. No other complication was observed in the other patients. In this retrospective study, rFVIIa was found to be effective at controlling severe hemorrhagic symptoms of different etiologies in children without congenital hemorrhagic disorder. In addition to the rapid control of bleeding, administration of this agent improved fluid balance and led to a reduction in blood product requirements in critically ill children. However, survival was still poor (23%), and 2/13 (15.4%) patients developed venous and arterial thrombosis within 3 h of treatment. The authors emphasize that in acquired, acute life-threatening bleeding, simultaneous administration of rFVIIa with conventional treatment may contribute to patient survival. However, the risk of thromboembolism should be considered before this treatment is given.

Spinal epidural haematoma in a patient with haemophilia B

Summary.  Spinal epidural haematoma (SEH) is a rare complication in haemophiliacs. We report the case of a 17‐year‐old boy with severe haemophilia B who presented with acute onset of neck/back pain, walking impairment and urinary retention because of an extensive SEH. The haematoma was identified by magnetic resonance imaging of the spinal column. Prompt and aggressive treatment with factor IX concentrate led to complete recovery at 3 weeks. This case calls attention to the clinical manifestation, radiological features and management options of the rarely reported SEH in haemophiliacs. Despite evidence of extensive SEH, factor replacement therapy and a multidisciplinary team approach result in complete neurological recovery without the need for surgical decompression.

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.

SAFETY PROFILES OF Fe2+ AND Fe3+ ORAL PREPARATIONS IN THE TREATMENT OF IRON DEFICIENCY ANEMIA IN CHILDREN

The major purpose of this study was to compare the oxidant-related toxicities of the different oral iron preparations in children with iron deficiency anemia (IDA); the second aim was to investigate the side effects of iron preparations. Seventy-two children with IDA were randomly included in the Fe2+ group (= 39) or the Fe3+ group (= 33). Some oxidizable substrates (erythrocytes malondialdehyde (MDA), urine 8-isoprostane, and basal and Cu-stimulated-oxidized LDL and antioxidant enzyme (superoxide dismutase (SOD), catalase and glutathione peroxidase) activities were evaluated at the beginning and at the 1st, 3rd, and 6th months of therapy. Side effects due to medication were recorded. While at the end of the 1st month SOD levels were significantly increased in Fe3+ group, at the 6th month evaluation, basal-oxidized LDL levels were significantly increased in the Fe3+ group, as was urine 8-isoprostane in the Fe2+ group. No other difference was found between two groups. In conclusion, there were minimal differences between children treated with ferric or ferrous iron in antioxidant system activities, the status of oxidizable substrates, and clinical toxicities.

A rescue therapy with a combination of caspofungin and liposomal amphotericin B or voriconazole in children with haematological malignancy and refractory invasive fungal infections.

Combination treatment of paediatric invasive fungal infections (IFIs) has rarely been reported. A total of 17 children with 19 IFI episodes were enrolled in the study. The median age of the patients was 5.3 (range 0.5–17) years. IFI was classified as proven in 4, probable in 12 and possible in 3 episodes. These patients received empiric antifungal treatment, which consisted of liposomal amphotericin B (LAmB) monotherapy for a median duration of 12 days (range 3–69 days). All patients were refractory to LAmB; therefore, caspofungin was added to the therapy in 11 patients. In the remaining six patients, LAmB was ceased and a combination of caspofungin and voriconazole was started. Among the patients who received caspofungin + LAmB, four did not show favourable response and the combination was switched to caspofungin + voriconazole. The median (range) and total duration of the therapy were 7 (3–14) days and 91 patient days for LAmB + caspofungin combination and 49 (7–126) days and 516 patient days for caspofungin + voriconazole combination. We found a favourable response rate of 68.4% in 16 proven or probable IFI episodes. Twelve‐week survival rate of these patients was 75%. No serious side effect was observed among the patients. Our data suggest that combination antifungal therapy is safe and effective in children with haematological malignancies.

Long-term evaluation of chromosomal breakages after radioisotope synovectomy for treatment of target joints in patients with haemophilia

Summary.  Radioisotope synovectomy (RS) is defined as the intra‐articular injection of radioisotopic agents with the aim of fibrosis on hypertrophic synovium in the target joint. The aim of this study was to investigate genotoxic effects on lymphocytes and malign transformation induced by Yttrium90 (Y90) and Rhenium186 (Re186) in children with haemophilia undergone RS. Forty haemophilia patients were enrolled. The mean age was 16.4 ± 6.2 years (range: 8–40). Y90 was used for knees, Re186 was used for other joints. For safety, cytogenetic analysis was performed to determine potential chromosomal changes after RS procedure at three different time points as prior to procedure, 3rd day and 90th day. For the stimulation of chromosomal breakages, diepoxybutane was used (DEB test). Chromosomal breakages (CBs) were found in 23 patients (67.6%) prior to RS. We have found CBs additionally in nine of 11 patients who had no CBs prior to RS after 3 days of radioisotope exposure. At that time, the patients who had CBs were 29 (85.2%). At day 90, only 21 patients revealed (61.7%) CBs. The mean frequency of CBs slightly but not significantly increased in the 3rd day. However, there was a significant decreasing trend between 3rd and 90th days. Radioisotope synovectomy with Y90 and Re186 does not seem to induce the genotoxic effects significantly on peripheral blood lymphocytes. However, CBs even after one year in the re‐evaluation of four patients, significant decrease in the number of CBs between the 3rd and 90th days and de novo CBs after exposure may be accepted as warning signals for young population. It should also be pointed out that families and patients be informed properly related with historical and potential dangers of radioisotopic agents.