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.

Complete clinical recovery of a central pontine and extrapontine myelinolysis delayed onset in a child with acute myeloblastic leukemia.

Central pontine myelinolysis (CPM) is a demyelinating disease of the pons often associated with the demyelination of extrapontine areas of the central nervous system. It typically occurs 0.5-7 days after a rapid increment in serum Na level in hyponatremic patients and may lead to death. A 2.5-year-old child with a diagnosis of acute myeloblastic leukemia developed febril neutropenia, diarrhea, gastrointestinal hemorrhage followed by pulmonary aspergillosis. He could not tolerate enteral nutrition. He was given broad spectrum antibiotics and antifungal treatment. Laboratory tests showed electrolyte abnormalities including hyponatremia, hypokalemia and hypophosphatemia in a chronic course. Twenty three days after a rapid correction of hyponatremia (16 mEq/L/24 h) he revealed flask quadriparesis, disphagia, mutism, irregular respiratory pattern and loss of cough and gag reflex. Cranial magnetic resonance showed central pontine and extrapontine myelinolysis. He required mechanical ventilation and then he regained his neurologic functions. He completed chemotherapy protocol and underwent hematopoietic stem cell transplantation. After 2.5 years of the occurrence of CPM he is in completely normal physical and neurological status. CPM is a very severe but rare disorder in children with underlying disease. In the presence of multiple etiologic factors it may reveal a delayed onset and optimum outcome can be seen even in the severe clinical presentation with adequate intensive support.

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

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.

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

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.

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

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 Yttrium(90) (Y(90)) and Rhenium(186) (Re(186)) in children with haemophilia undergone RS. Forty haemophilia patients were enrolled. The mean age was 16.4 +/- 6.2 years (range: 8-40). Y(90) was used for knees, Re(186) 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 Y(90) and Re(186) 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.

The value of early treatment in patients with haemophilia and inhibitors.

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.

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

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 (Y(90)) for knees; however, since 2005, we started using rhenium 186 (Re(186)) 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 Re(186) 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 Re(186) 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 Y(90). 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 Re(186) seems to be either effective or safe treatment method. Our results confirm those previously published by others on the value of Re(186) synoviorthesis in medium-sized joints in haemophilia patients. After this experience, we changed our protocol and we use Re(186) for all medium-sized joints for treating chronical synovitis.

Spinal epidural haematoma in a patient with haemophilia B.

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.

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

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.

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

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.

The effect of clotting factor concentrates on the immune system in HIV-negative haemophilics.

Immune abnormalities have been reported in patients with haemophilia. Although infections with HIV and hepatitis viruses contribute to these abnormalities, chronic exposure to extraneous proteins in clotting factor concentrates (CFC) may also play a role. A number of studies suggest that the degree of immunological abnormalities correlates with the amount of intermediate purity CFC administered over time. The purpose of this study was to investigate whether there were cellular and humoral immunological abnormalities in haemophilics receiving intensive factor replacement therapy with intermediate purity CFC. For this purpose 48 severe haemophilics and 33 healthy controls were enrolled in this study. T and B lymphocytes, CD4+ and CD8+ cell counts, CD4/CD8 ratio, natural killer cells, active T cells were studied in prophylaxis group, on-demand therapy group and healthy controls. In the percentages and absolute counts of lymphocyte subgroups, no significant difference was found between three groups. We also investigated serum antitetanus IgG levels in these 48 haemophilics and the controls to evaluate the specific antibody response. Antitetanus IgG levels were significantly lower in haemophilics compared to healthy controls (P < 0.001). Additionally we evaluated the response to tuberculin skin test in 45 of 48 haemophilics vaccinated with BCG. The response to PPD test was significantly lower in haemophilics compared to the controls (P = 0.037). There was no response to tuberculin test, which is the best marker of delayed type hypersensitivity (DTH) reactions in 24% of haemophilics. In conclusion, although there was no significant change in the ratio of CD4/CD8 and lymphocyte subgroups, specific antibody responses and DTH tests were partially impaired in haemophilic patients receiving intermediate purity CFC.

Myelofibrosis associated with severe vitamin D deficiency rickets.

Myelofibrosis is a rare disorder in childhood. In this report, we present the case of a 6-month-old infant with myelofibrosis due to severe vitamin D deficiency rickets. The characteristic clinical and laboratory findings of myelofibrosis improved rapidly after vitamin D therapy. In developing countries, nutritional rickets is still an important health problem. Rickets is not only a skeletal system-related disorder, it is also a systemic disorder. Rickets should be considered, therefore, as one of the conditions that can lead to severe haematological disorders in infants.

The factors affecting the relation between the menarcheal age of mother and daughter.

BACKGROUND: Menarche is one of the most important biologic signals in the life of a woman. Menarche is a biological variable which has a significant genotypic component in girls. In recent years, many studies reporting the earlier onset of menarche owing to the improvement of socio-economic conditions have been published. DESIGN: We asked some questions about menarche to 1017 female students studying in the high schools of Manisa region in order to determine the menarcheal age and the correlation of menarcheal age between the mothers and daughters in our region. RESULTS: The mean age at menarche for the girls was 12.82+/-1.07 years and for the mothers was 13.6+/-1.39 years. The mean menarcheal age of the mothers was higher than the mean menarcheal age of the girls (P<0.001). This difference persisted independent of the socio-economic status, nutritional state and physical activity of the girls. There was a significant correlation between the menarcheal age of the girls and their mothers (r=0.262, P<0.001). This correlation existed in all the girls with different socio-economic status, nutritional state and physical activity. However, this correlation disappeared in girls with body mass index (BMI)>25 (r=0.04, P=0.813). In girls with BMI<25, there was a correlation between the menarcheal age of the girls and mothers (r=0.282, P<0.001). CONCLUSION: These results suggest that the menarche occurs earlier in the daughters than their mothers. The correlation between the menarcheal age of the girls and their mothers persists under all circumstances except in obesity. The mother's menarcheal age is a good predictor of the daughter's menarcheal age in non-obese girls and the BMI is an important factor.

Effects of different socioeconomic conditions on menarche in Turkish female students.

PURPOSE: The aim of this study was to determine the age at menarche, the menarcheal features, and the association between menarcheal age and socioeconomic status in an urban area in Turkey. In addition, we tried to assess whether there is a relationship between age at menarche and body composition. METHODS: We asked some questions about menarche of 1017 female adolescent students in the high schools of Manisa region. Height and weight were measured. The body mass index (BMI; kg/m2) was used as an index of relative weight. Adolescent girls were grouped into three socioeconomic status according to the educational and occupational levels of their parents. The age at menarche and the menarcheal pattern were evaluated according to the socioeconomic status. RESULTS: The ages of girls involved in the study ranged between 14 and 18 years, with a mean of 15.7+/-1.1 years. Although the menarcheal age was found to be lower in girls with higher socioeconomic status, there was no significant difference between the three different socioeconomic status. In all of the three groups, menarche was more common in summer and fall than in spring and winter. Although the mother was an important source of knowledge in all groups, it was significantly more important in the group with high socioeconomic status. Adolescent girls with low socioeconomic status had fewer premenstrual complaints. However, there was no significant difference between the groups. We found an inverse correlation between menarcheal age and postmenarcheal weight and the BMI (r=-0.14, p=0.000). However, there was no correlation between menarcheal age and postmenarcheal height. CONCLUSION: These results indicate that as the social status differences decrease, the difference observed in menarcheal age and pattern disappears in urban areas of developing countries. Menarcheal age may be an indicator of socioeconomic development. It does not influence postmenarcheal height; however, as menarcheal age decreases, BMI increases.

The pelvi-femoral incomplete bone bridge in a patient with mild haemophilia.

A 15-year-old boy with mild haemophilia who regularly participates in contact sports presented with right hip pain radiating to the groin and buttock areas and difficulty in walking. Conventional radiography disclosed a heterotopic new bone formation in the adductor region. The reformatted and three-dimensional reconstructed images of computerized tomography (CT) scans detailed an incomplete pelvi-femoral bone bridge formation in the quadratus femoris muscle, which was located very close to the sciatic nerve but did not cause any clinical symptoms. Postural exercises and clinical survey were selected as the primary treatment.

Analysis of meatal location in 300 boys.

The high incidence of anterior hypospadias and the consideration of some of the parents that this location is a normal variation and the resistance to the surgical treatment led us to investigate the normal meatal location in boys. The location of external meatus was analyzed in 300 boys. The meatal location was classified as type A (anterior third/tip of the glans) type B (middle third) and type C (posterior third/glandular hypospadias). Of the 300 boys taken into study, in 282 (94%) meatus was located at the tip of the glans in 14 patients (4.6%) on the middle third, 'type B' and in 2 patients (0.6%) on the posterior third, 'type C'. The present study clearly demonstrated that the true location of urethral meatus should be at the tip of the glans. Type B is an acceptable location, which requires no operation and is seen in a very small percentage. Type C is a true glandular hypospadias and should certainly be corrected by glanuloplasty and meatal advancement. We are of the opinion that after surgery for anterior hypospadias meatal position presenting elsewhere than at the tip of the glans should not be considered a successful intervention.

Hypernatriuria and kaliuresis in enuretic children and the diurnal variation.

PURPOSE: We investigate the underlying pathophysiological cause of primary nocturnal enuresis by comparing electrolyte alterations in urine samples of enuretics during the daytime and nighttime compared with those of nonenuretic subjects. MATERIALS AND METHODS: Urine output, urine specific gravity and urinary electrolytes in 15 enuretic and 12 nonenuretic children were measured. We collected daytime serum and urine samples of children fed a similar diet between 7 a.m. and 7 p.m., and nighttime between samples 7 p.m. and 7 a.m. Urinary calcium/creatinine ratio, tubular reabsorption of phosphorus and excretions of fractional sodium and potassium were calculated. RESULTS: There was no significant difference between the calcium/creatinine ratio ratios. There was a significant increase in fractional sodium and fractional potassium values in enuretics compared to nonenuretics during the day and at night. Daytime and nighttime fractional sodium and fractional potassium values in enuretics were similar. In contrast to nonenuretics, enuretic patients had no diurnal variation of fractional sodium. There was significant positive correlation between bedwetting status, and fractional sodium and fractional potassium. CONCLUSIONS: Since sodium and potassium excretions were higher in enuretic patients than nonenuretic children, and no significant diurnal variation in urinary excretion of these ions there might be a difference in the mechanism of reabsorption of sodium and potassium between enuretic and nonenuretic children.