Risk of Bleeding and Inhibitor Development After Circumcision of Previously Untreated or Minimally Treated Severe Hemophilia A Children

Background: Surgery and intensive factor VIII (FVIII) replacement may be risk factors for development of inhibitors. Objective: To evaluate time and rate of inhibitor development postcircumcision over 12-month period, and to assess bleeding of children with severe hemophilia A after low-dose FVIII replacement and local hemostasis. Patients and Methods: Sixty-one previously untreated patients (PUPs) or minimally treated patients (MTPs) with severe hemophilia A less than 36 months were enrolled; 25 underwent circumcision during the 18-month enrollment period, and 36 matched patients were not circumcised. All patients were treated on demand with plasma-derived FVIII, and all were inhibitor negative at the time of enrollment. Intron 22 inversion was analyzed. A potent hemostatic agent (gelatin sponge) was applied on the site of surgery, and then dressed with gauze. Two doses of FVIII concentrate (25 U/kg) were given, 1 hour before circumcision and 1 hour before removal of dressing. The inhibitor was determined every 8 exposure days (EDs). Results: None of the patients had bleeding or infection, except one who had minimal transient bleeding 8 days after surgery, and was treated easily by a single dose of FVIII (50 U/kg). After a median of 16 EDs, high-titer inhibitors developed in seven patients: three patients in the circumcised group (12%) in contrast to four patients (11.1%) in the noncircumcised group. Conclusion: Two doses factor concentrate and gelatin sponge application were generally enough to prevent bleeding after circumcision of severe hemophilia A. Circumcision and low-dose FVIII protocol were not an additional risk for development of high-titer inhibitor.     

Pitfalls in the diagnosis of hemophilia severity: What to do?

Measurements of factor VIII coagulation activity (FVIII:C) may vary and result in misclassification of hemophilia A with delay in initiation of prophylactic treatment. We describe two young brothers who were diagnosed as moderate hemophilia patients and therefore not prophylactically treated with factor VIII concentrate despite frequent bleeding events. These findings emphasize the importance of (i) multiple measurements of FVIII:C by certified laboratories, (ii) adjustment of treatment when test results do not correspond to clinical symptoms, (iii) relevance of additional DNA mutation analysis in patients with hemophilia A, and (iv) treatment in centers with expertise.     

Should hemophiliac patients be circumcised?

Social and cultural integration of hemophilic boys into society is one of the most important cornerstones of modern hemophilia therapy. Circumcision, a traditional procedure, is an important ritual for Muslims and Jews and an important social problem for the hemophiliac patient and his family. The aim of this study was to evaluate the psychosocial dimension of circumcision and the opinions of parents and children. A total of 105 hemophiliac patients and parents were interviewed and surveyed. Of these, 94% of the parents of uncircumcised patients wanted circumcision for their children. Most parents saw circumcision as a mandatory procedure. Hemophilic boys (60%) and their parents (82%) have an inferiority complex because the boys are unable to be circumcised. Bleeding risk is the primary reason of anxiety (70%). The parents of all the circumcised patients were happy after circumcision. In conclusion, circumcision is an important social problem of hemophilic patients that needs to be solved.     

KLUVER-BUCY SYNDROME IN A BOY WITH NON-HODGKIN LYMPHOMA

Social and cultural integration of hemophilic boys into society is one of the most important cornerstones of modern hemophilia therapy. Circumcision, a traditional procedure, is an important ritual for Muslims and Jews and an important social problem for the hemophiliac patient and his family. The aim of this study was to evaluate the psychosocial dimension of circumcision and the opinions of parents and children. A total of 105 hemophiliac patients and parents were interviewed and surveyed. Of these, 94% of the parents of uncircumcised patients wanted circumcision for their children. Most parents saw circumcision as a mandatory procedure. Hemophilic boys (60%) and their parents (82%) have an inferiority complex because the boys are unable to be circumcised. Bleeding risk is the primary reason of anxiety (70%). The parents of all the circumcised patients were happy after circumcision. In conclusion, circumcision is an important social problem of hemophilic patients that needs to be solved.     

长期小剂量凝血因子Ⅷ预防重度血友病A患儿关节出血的疗效与相关因素分析

目的探讨重组人凝血因子Ⅷ(FⅧ)长期小剂量次级预防重度血友病A患儿关节出血的疗效与相关因素。方法对2010年4月1日～2011年4月1日我院16位2～16岁重度血友病A患儿进行FⅧ预防性静脉输注(每次5～15 U/kg,间隔3 d),记录治疗前1年与治疗后1年的关节出血次数,同一关节反复出血的情况,治疗前后FⅧ抑制物产生情况,梅毒、艾滋病、乙肝、丙肝、丁肝、戊肝感染情况及肝功能变化。结果治疗前1年关节出血次数为(29.69±4.48),治疗后1年关节出血次数为(10.94±3.30)次,治疗前后比较差异有显著性(P<0.01)。治疗前靶关节出血发生率为45.2%,治疗后靶关节出血发生率为14.6%,治疗前后比较差异有显著性(P<0.01)。治疗后FⅧ抑制物产生率为12.5%,产生率低及抗体滴度低,治疗前后梅毒、艾滋病、乙肝、丙肝、丁肝、戊肝均阴性,肝功能正常。结论 FⅧ长期小剂量次级预防输注可有效减少中重度血友病A患儿关节出血次数,同时可有效减少靶关节出血发生率,从而在一定程度上保护关节的功能,且FⅧ抑制物产生率及滴度低,无相关疾病传播,安全可靠。     

Haemophilia A in two premature infants

The incidence of prematurity in Germany is about 10% and premature infants with haemophilia A (OMIM 306700) are in fact very rare. We report two new cases, one born in the 28th gestational week, weighing 1200 g with a factor VIII (FVIII) level of 0.03 IU/ml treated with bolus injections of plasma derived FVIII concentrate (pdFVIII), and one born at week 30, weighing only 710 g with a factor level of <0.01 IU/ml and treated with recombinant FVIII concentrate (rFVIII). Recovery of FVIII was 96% in case 1 and 120% in case 2, FVIII half-life was 6 h and 8 h, respectively. During FVIII substitution, neither bleeding, thrombosis nor inhibitor development were noted in both infants. Conclusion:Immediate and frequent factor VIII substitution appears to be safe and effective for prophylaxis and treatment in premature haemophilic neonates.     

Reduction of Factor VIII Inhibitor Titers During Immune Tolerance Induction With Recombinant Factor VIII‐Fc Fusion Protein

The development of inhibitors toward factor VIII (FVIII) is a common and serious complication of hemophilia A (HA) therapy. Patients with hemophilia who develop inhibitors often undergo time‐ and resource‐intensive immune tolerance induction (ITI) protocols. We report a 15‐month‐old male with severe HA and a high‐titer inhibitor that occurred while receiving prophylactic treatment with recombinant FVIII (rFVIII), in whom significant inhibitor titer reduction was achieved with thrice weekly infusions of a new, prolonged half‐life rFVIII‐Fc fusion protein product (trade name Eloctate). Further studies are warranted to explore the potential of Eloctate in ITI protocols.     

Inflammatory and immune response genes: A genetic analysis of inhibitor development in Iranian hemophilia A patients

A major problem of hemophilia A (HA) treatment is the development of factor VIII (FVIII) inhibitor, which usually occurs shortly after initiating replacement therapy. Several studies showed the correlation between inhibitor development and polymorphisms in inflammatory and immune response genes of HA patients; however, literature data are not available to prove this association in Iranian population. The aim of this study was to investigate a possible association between FVIII inhibitor formation and the polymorphisms of 16 inflammatory and immune response genes in Iranian severe HA patients (FVIII activity < 1%). This case-control study was performed on 55 patients with severe HA inhibitors and 45 samples without inhibitors from Iranian Comprehensive Hemophilia Care center. After extraction of whole genomic DNA from blood samples and design of primers for 16 genes, the genotyping was performed by Tetra primer ARMS PCR, and the validation of single nucleotide polymorphisms was determined by DNA sequencing. The data indicated that there was a significant association between inhibitor development, and F13A1 (TT), DOCK2 (CC& CT), and MAPK9 (TT) genotypes. Moreover, a considerably increased inhibitor risk carrying T, C, and T allele for F13A1, DOCK2, and MAPK9 genes was observed in patients with inhibitors, respectively. In contrast, there was no statistically significant difference between the genotypic and allelic frequencies for other genes in patients with inhibitors compared to patients without inhibitors. These results demonstrate that only polymorphisms in F13A1, DOCK2, and MAPK9 genes are associated with the risk of developing FVIII inhibitors in Iranian HA patients.     

Treatment of refractory hemorrhage with factor XIII in a patient with hemophilia A with inhibitor

An 11‐year‐old male with hemophilia A and a known high‐titer Factor VIII inhibitor was admitted with retroperitoneal hemorrhage. The patient was receiving infusions of recombinant activated Factor VII (rFVIIa) for a recent elbow hemorrhage when retroperitoneal bleeding commenced. Despite increased dosing of rFVIIa and a dose of activated prothrombin complex concentrate (aPCC), he continued to hemorrhage and required several blood transfusions. Factor XIII was administered 1 hour after rFVIIa and the patient demonstrated cessation of bleeding and normalization of clot strength. Factor XIII may act as an adjuvant in effective clot stabilization in patients with hemophilia and inhibitory antibodies. Pediatr Blood Cancer 2013; 60: E23–E25. © 2013 Wiley Periodicals, Inc.     

Efficacy of standard prophylaxis versus on-demand treatment with bayer's sucrose-formulated recombinant FVIII (rFVIII-FS) in Chinese children with severe hemophilia A

In China, care of patients with severe hemophilia primarily involves insufficient dosing of on-demand treatment and secondary low-dose prophylaxis (10 IU/kg 2× /wk). We sought to evaluate 3× /wk, standard-dose prophylaxis with sucrose-formulated recombinant factor VIII (rFVIII-FS; Bayer) compared with on-demand treatment in Chinese children with severe hemophilia A. Children and adolescents aged 2–16 years with severe hemophilia A, no inhibitors, and no prophylaxis for >6 consecutive months before study entry were eligible for this 24-week, interventional, sequential-treatment study. Patients received rFVIII-FS on demand for 12 weeks followed by a 12-week prophylaxis period (25 IU/kg 3× /wk). The primary efficacy endpoint was comparison of the annualized bleeding rate (ABR) of all bleeds in the prophylaxis versus on-demand phase. Additional variables included ABR of joint bleeds, school attendance/activity, daily activity, and hemophilia Joint Health Score (HJHS). Thirty patients (median age, 12 years) were treated and analyzed. Compared with on-demand treatment, prophylaxis reduced median (quartile [Q1; Q3]) ABR of all bleeds (57.5 [44.5; 73.9] vs 0 [0; 4.0]) and joint bleeds (34.5 [26.1; 56.5] vs 0 [0; 4.0]). Median (range) total HJHS improved after both the prophylaxis and on-demand phases (8.0 [0–48.0] and 11.0 [0–55.0], respectively) compared with baseline (16.0 [0–56.0]). School attendance/activity and daily activity improved with prophylaxis versus on demand. No inhibitors or treatment-related adverse events were reported. In this first prospective, standard-dose, secondary prophylaxis study in China, rFVIII-FS prophylaxis reduced bleeding and improved health outcomes versus on-demand treatment in children with severe hemophilia A.     

Therapeutic consequences for misdiagnosis of type 2N von Willebrand disease

Patients presenting with a low FVIII:C and with normal VWF levels are usually presumed to have hemophilia (males) or be carriers for hemophilia (females). Some of these patients may instead have VWD:2N. Such patients if misdiagnosed are likely to suffer from insufficiently treated bleeds. We report 2 males and 1 female who presented with a low FVIII:C (1-21%) and minimally reduced/normal VWF and were assumed to have, or be a carrier for, hemophilia A. Eventually all were found to have VWD:2N. Prior to the correct diagnosis the males had been treated with rFVIII with poor responses and ultimately adverse clinical consequences.     

Combined analgesia and local anesthesia to minimize pain during circumcision

BACKGROUND: Pain of circumcision is only partially relieved by single modalities, such as penile nerve block, lidocaine-prilocaine cream, and sucrose pacifiers. OBJECTIVE: To assess the effectiveness of a combination of interventions on the pain response of infants undergoing circumcision. METHODS: Cohort study. Group 1 included infants circumcised using the Mogen clamp and combined analgesics (lidocaine dorsal penile nerve block, lidocaine-prilocaine, acetaminophen, and sugar-coated gauze dipped in grape juice). Group 2 included infants circumcised using the Gomco clamp and lidocaine-prilocaine. Infants were videotaped during circumcision, and pain was assessed using facial activity scores and percentage of time spent crying. RESULTS: There were 57 infants in group 1 and 29 infants in group 2. Birth characteristics did not differ between groups. Infants in group 1 were older than infants in group 2 (17 days vs 2 days) (P < .001). The mean duration of the procedure was 55 seconds and 577 seconds for infants in group 1 and 2, respectively (P < .001). Facial action scores and percentage of time spent crying were significantly lower during circumcision for infants in group 1 (P < .001). The percentage of time spent crying was 18% and 40% for infants in groups 1 and 2, respectively. No adverse effects were observed in infants in group 1; 1 infant in group 2 had a local skin infection. CONCLUSIONS: Infants circumcised with the Mogen clamp and combined analgesia have substantially less pain than those circumcised with the Gomco clamp and lidocaine-prilocaine cream. Because of the immense pain during circumcision, combined local anesthesia and analgesia using the Mogen clamp should be considered.     

Acquired factor VIII deficiency associated with a novel primary immunodeficiency suggestive of autosomal recessive hyper IgE syndrome

Primary immunodeficiency diseases (PID) are associated with various autoimmune complications and several manifestations of autoimmunity can be seen in the disorders of T cells, B cells, phagocytes, and complement components. Acquired hemophilia is a rare entity in childhood. Although autoantibodies may develop in various forms of PID, Factor VIII (FVIII) inhibitors have not been described before. Herein, we present a case of acquired hemophilia resulting from FVIII inhibitors who had underlying undefined PID features suggestive of autosomal recessive hyper IgE syndrome. Our patient responded to corticosteroid treatment rather well and quickly, with an increased FVIII level and decreased FVIII inhibitors. However, FVIII inhibitor reappeared 7 months later, and disappeared spontaneously 4 months ago. Long-term and close follow-up is needed to observe the long-term prognosis in this child.     

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??Objective??To evaluate the number of annual bleeding and annual joint bleeding and safety of third-generation full length recombinant human coagulation factor ????ADVATE?? in the prophylactic treatment of childhood patients with moderate-to-severe hemophilia A. Methods??Fifteen children aged from 5 to 18 years with moderate-to-severe hemophilia A were enrolled in the one center??prospective??nonrandom??self-control study from Nov.01??2014 to Nov.30??2016. Children were treated with one-year long-course infusion of ADVATE with a dose of 20??40 U/kg twice-weekly or three times weekly. The numbers of annual bleeding and annual joint bleeding after the prophylaxis treatment were compared with that on-demand. Moreover??any adverse effect and serious adverse reaction related to ADVATE usage were documented during the study. The F?? inhibitor titer were measured with modified Nijmegen method before and after the prophylaxis every 3 to 6 months. Results??The F????C for these 15 boys??median age 15??was less than 2.2%??with 8 patient severe type. The number of annual bleeding was reduced from??27.60±13.67?? on-demand treatment to??2.57±1.36?? after the prophylaxis treatment??P??0.001????and the number of annual joint bleeding was also reduced from??11.13±8.81?? to??0.93±1.10????P??0.001??. Seven patients had zero annual joint bleeding the mean annual bleeding for mild??moderate and severe degree was decreased significantly with zero times for severe degree bleeding after the prophylactic treatment. No adverse effect or serious adverse reaction related to ADVATE was recorded during one-year period treatment and F?? inhibitor detection was negative. Conclusion??Prophylactic treatment with ADVATE can effectively decrease the annual bleeding and annual joint bleeding in children with moderate-to-severe hemophilia A. This therapy is safe with F?? inhibitor test negative.     

Induction of tolerance to factor VIII in a child with a high-titer inhibitor: in vitro and in vivo observations

High dose factor VIII concentrate was infused over 12 months in a 3-year-old child with hemophilia A and a high-titer inhibitor. This regimen was successful in producing clinical tolerance to the factor VIII and was associated with a fall of inhibitor titer from 85 BU to less than 1 BU. Subsequently, a rise in inhibitor to peak at 3.5 BU correlated with a decrease in infusion dose. In vitro studies using a microdroplet assay for immunoglobulin synthesis in the presence of varying concentrations of factor VIII was carried out prior to the clinical trial. This system indicated that the patient's peripheral blood mononuclear cells were stimulated to release IgG by 0.01 U/ml factor VIII coagulant activity and inhibited at 0.9 U/ml FVIIIc. Lymphocyte subsets were monitored during the course of therapy. The ratio of Leu-3a+/Leu-2a+ (helper/suppressor) varied considerably, fluctuating between a peak of 4.4 and low point of 0.6, with the initial pretrial ratio being 1.2.     

Attitudes and decision making about neonatal male circumcision in a Hispanic population in new york city

Objective. To understand attitudes and decision making regarding neonatal male circumcision. Methods. Parents (n = 150) with a son 3 years old were interviewed regarding demographics, communication with a medical provider, attitudes, and process by which the neonatal circumcision decision was made. Results. Thirty-three percent of sons were circumcised. In univariate analyses, choosing male circumcision was associated with parents being interviewed in English, the father being circumcised, positive attitudes, being informed of the advantages of circumcision, making a decision before birth, and being offered a choice. In the final model, parents who came from a culture and family that believed in circumcision and who believed that it was not too risky were more likely to circumcise their sons. Conclusions. Decisions regarding circumcision appear to be influenced by values, risk perceptions, and medical providers. Future research should address ways of ensuring that families have the opportunity to make an informed decision.     

Circumcised hypospadias

Purpose  Patients with circumcised hypospadias have been of significant concern over many decades due to the belief that prior circumcision might negatively affect the results of hypospadias’ repair. We evaluated outcomes in consecutive males with anterior, distal penile, and the megameatus with intact prepuce variant of hypospadias (MIP). Methods  After IRB approval a retrospective of 48 consecutive males with circumcised hypospadias was reviewed. In all cases the urethroplasty was accomplished with either urethral plate tubularization or a MAGPI procedure. No skin flaps were used. Results  A total of 48 patients with circumcised hypospadias (anterior, MIP variant, and distal penile) underwent operative reconstruction by one of us (RVP). All patients were followed for at least 8 months. Conclusions  Prior circumcision did not negatively affect the results of subsequent urethroplasty in patients with anterior, distal penile, and the MIP variant of hypospadias. The use of the tubularized incised plate urethroplasty (TIP) has virtually eliminated the need for skin flaps in anterior hypospadias repair.     

Late complications of circumcision in Iran

Today, circumcision is the most commonly performed surgical procedure worldwide. Early and late complications may occur due to circumcision. To find the prevalence of late complications of circumcision, we studied 3,205 elementary-school boys aged 6–12 years in 2002. All of them were Iranian and Muslim. Nearly 3,125 of the boys have been circumcised. Most of the boys (2,214 boys) had been circumcised after 2 years of age. Moreover, most of them were operated by traditional circumcisers (43.49%). Late complications (7.39%) were reported in 231 boys. Excessive residual foreskin was seen in 113 children (3.6%). Excessive removal of skin was detected in 42 boys (1.3%), meatal stenosis in 29 boys (0.9%), granoloma in 22 boys (0.7%), penile rotation in 17 boys (0.5%), and 8 boys had secondary chordee (0.2%). The complication rate was not different between the neonatal circumcision and older groups. We suggested that circumcision should only be performed in medical institutions by suitably trained specialists.     

Health-related quality of life in Egyptian children and adolescents with hemophilia A

Quality of life (QoL) in hemophilia is an important area in hemophilia outcome assessment. The Haemo-QoL instrument is a set of questionnaires to measure QoL in those children. The objectives of this study was to assess health-related quality of life (HRQoL) in Egyptian hemophilic children and adolescents using an Arabic version of the Haemo-QoL questionnaire. Sixty patients with severe hemophilia A were recruited from 2 hemophilia treating centers in Egypt. Assessment of quality of life was done using the Haemo-QoL questionnaire. The scores of HRQoL were found to be for all dimensions widely above 50. It was highly significant in the 3 dimensions (physical health-family-treatment) in different age groups, but it was impaired in the dimension of "physical health" for 2 groups, and in the dimension of "family" for the oldest group, whereas the youngest group had highly impaired scores concerning the "treatment." The HRQoL in this study was not affected by the presence of factor VIII (FVIII) inhibitors. The QoL in hemophilic patients in Egypt needs strenuous efforts from hemophilia care-integrated teams of pediatric hematologists and psychiatrists in order to properly assess and improve QoL.     

What factors influence the age at diagnosis of hemophilia? Results of the French hemophilia cohort

OBJECTIVE: The diagnosis of hemophilia was reported as delayed in historic studies. We therefore investigated this issue to provide current epidemiologic data in a large series of patients. STUDY DESIGN: The French cohort provided the opportunity to investigate the age at diagnosis and the circumstances of diagnosis in 599 individuals with hemophilia born between 1980 and 1994. The type and the severity of hemophilia, the family history, and the period of birth were analyzed as potential modifying factors. RESULTS: The median age at diagnosis was 7.7 months, with significant differences among subgroups: 5.8 months in severe hemophilia, 9.0 months in moderate forms, 28.6 months in mild forms, 0.4 months in the case of hemophilic brothers, and 10.1 months in de novo hemophilia, which accounted for 55.3% of cases. In severe forms we observed a trend for earlier diagnosis throughout 3 consecutive periods from 1980 to 1994. Of bleeding episode, testing due to family history, or routine testing, bleeding was the main circumstance of diagnosis (59.9%). CONCLUSIONS: Diagnosis was made earlier than in historic series, but it remained somewhat delayed. Early diagnosis will require efforts in the fields of genetic counseling and specific diagnosis of early bleeding, even without family history, because of the high incidence of de novo hemophilia.