Sacral Osteoneogenesis after Complete Sacrectomy in a Patient with Ewing Sarcoma.

Ewing sarcomas are the second most common primary malignant bone tumors in childhood and adolescence which rapidly metastasize. Due to improvement of treatment options in recent years, the survival rate has significantly increased. Nevertheless, lethality is still high, and neurologic symptoms are frequent. To the best of our knowledge, this is the first reported case of a sacral osteoneogenesis after complete sacrectomy in a patient with Ewing sarcoma.

Pain therapy in haemophilia in Germany. Patient survey (BESTH study).

UNLABELLED: One of many challenges in the treatment of persons with haemophilia is the selection and application of appropriate pain-relieving therapies. The current situation of pain management for persons with haemophilia in Germany was evaluated using a survey with the intention of identifying potential areas for improvement. Results of 685 respondents showed that 86% experienced episodes of pain and that pain was already present in 66% of children and adolescents. Joint pain was the most common type of pain (92%), remarkably so even in 80% of young patients. Half of the patients received pharmacological therapy for the pain and 46% of the patients received physiotherapy. Priority and sequence of the contacted physicians and therapists for diagnosis and therapy is described. Satisfaction with pain therapy was expressed by 56% of participants and 18% felt their pain not treated sufficiently. CONCLUSION: The results of the survey will be used to develop measures for improvement of long-term care of haemophilia patients regarding pain therapy.

[Therapy of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)]. / Therapie hereditärer Thrombozytopathien. Interdisziplinäre S2K-Leitlinie der Ständigen Kommission Pädiatrie der Gesellschaft für Thrombose- und Hämostaseforschung e. V.

Inherited disorders of platelet function are a heterogeneous group. For optimal prevention and management of bleeding, classification and diagnosis of the underlying defect are highly recommended. An interdisciplinary guideline for a diagnostic approach has been published (AWMF # 086-003 S2K; Hämostaseologie 2014; 34: 201-212). Underlying platelet disorder, platelet count, age and clinical situation modify treatment. Exclusive transfusion of platelet concentrates may be inappropriate as potentially adverse effects can outweigh its benefit. A stepwise and individually adjusted approach for restitution and maintenance of haemostasis is recommended. Administration of antifibrinolytics is generally endorsed, but is of particular use in Quebec disease. Restricted to older children, desmopressin is favourable in storage pool disease and unclassified platelet disorders. Although licensed only for patients with Glanzmann thrombasthenia and alloantibodies, in clinical practice rFVIIa is widely used in inherited platelet disorders with severe bleeding tendency. This guideline aims at presenting the best available advice for the management of patients with inherited platelet function disorders.

[Diagnosis of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)]. / Diagnose angeborener Störungen der Thrombozytenfunktion. Interdisziplinäre S2K-Leitlinie der Ständigen Kommission Pädiatrie der Gesellschaft für Thrombose- und Hämostaseforschung e. V.

Congenital disorders of platelet function are a heterogeneous group of disorders that are often not detected until bleeding occurs. In clinical settings only a few methods have proven to be useful for identification and classification of inherited platelet disorders. For a rational diagnostic approach, a stepwise algorithm is recommended. Patient history and clinical investigation are mandatory. Von Willebrand disease and other coagulation disorders should always be ruled out prior to specific platelet testing. Platelet count, size, volume (MPV) and morphology may guide further investigations. The PFA-100® CT is suited for screening for severe platelet defects. Platelet aggregometry allows assessment of multiple aspects of platelet function. Flow cytometry enables diagnosis of thrombasthenia Glanzmann, Bernard-Soulier syndrome and storage pool defects. Molecular genetics may confirm a putative diagnosis or pave the way for identifying new defects. We present an unabridged version of the interdisciplinary guideline.

High sensitivity and specificity of a new functional flow cytometry assay for clinically significant heparin-induced thrombocytopenia antibodies.

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is a life-threatening condition, in which the anticoagulant heparin, platelet factor 4 (PF4), and platelet-activating antibodies form complexes with prothrombotic properties. Laboratory tests to support clinical diagnosis are subdivided into functional, platelet activation assays, which lack standardization, or immunological assays, which have moderate specificity toward HIT. In this study, clinical performance of HITAlert, a novel in vitro diagnostic (IVD) registered platelet activation assay, was tested in a large cohort of HIT-suspected patients and compared with immunological assays. METHODS: From 346 HIT-suspected patients (single center), clinical data including 4T pretest probability results, citrated platelet-poor plasmas, and sera were collected, allowing direct comparison of clinical observations with HITAlert results. HITAlert performance was compared with PF4 IgG ELISA (246 patients, three centers) and PF4 PaGIA (298 patients, single center). RESULTS: HITAlert showed high sensitivity (88.2%) and specificity (99.1%) when compared with clinical diagnosis. Agreement of HITAlert with PF4 ELISA- and PF4 PaGIA-positive patients is low (52.7 and 23.2%, respectively), while agreement with PF4 IgG ELISA- and PF4 PaGIA-negative patients is very high (98.1 and 99.1%, respectively). CONCLUSION: HITAlert performance is excellent when compared with clinical HIT diagnosis, making it a suitable assay for rapid testing of platelet activation due to anticoagulant therapy.

X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis.

X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.

Hereditary angioedema (HAE) in children and adolescents--a consensus on therapeutic strategies.

Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short-term and long-term prophylaxis.

Newly diagnosed immune thrombozytopenia--German guideline concerning initial diagnosis and therapy.

Newly diagnosed immune thrombocytopenia occurs in 3-5/100 000 children < 14 y per year. Bleeding symptoms do not correlate with platelet count. Diagnostic approach includes history, clinical examination and analysis of blood count with blood smear by experienced hematologist. Additional investigations are only necessary in atypical cases and cases with additional symptoms or inadequate response to therapy. The decision to treat ITP should be made cautiously and not entirely be based on the platelet count. Decisions based on clinical symptoms and progress of the illness are more reasonable. There is no evidence, that therapy at the time of diagnosis influences the further course and can avoid intracerebral hemorrhage.

Inhibitor-immunology-study. Evaluation of inhibitor development in haemophilia B.

UNLABELLED: The development of inhibitors in haemophilia B is one of the most important complications of replacement therapy, affecting mortality and morbidity. Inhibitor development is based on complex immunological factors, and to date, only little is known about its underlying mechanisms. Here, we present first results of the haemophilia B group of our Inhibitor-Immunology study. PATIENTS, METHODS: So far we have analysed 15 patients with haemophilia B. Four of them developed a high titre inhibitor; the remaining 11 had no inhibitor. We evaluated 9 SNPs in 8 genes (CD40, CTLA-4 , IL-1ß, IL-10, TLR2 , TLR4, TLR9, TNF-α). We compared the distribution of these alleles between inhibitor and non-inhibitor haemophilia B patients and between haemophilia B patients and a normal male control population. HLA typing was performed in all patients. Results, discussion: There appears to be a trend towards a skewed distribution of TLR 9, IL-10 and CTLA4 alleles in haemophilia B patients. Due to the limited number these differences are, however, not statistically significant. The t-test of all patients with inhibitor versus without inhibitor was significant for HLA-A*03 and DPB1*0401 and borderline for DRB1*0201.

Postoperative bleeding in paediatric ENT surgery. First results of the German ESPED trial.

Bleeding after ear-nose-and throat surgery in children is a serious complication. With the help of the German Surveillance Unit for Rare Paediatric Disorders (Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland; ESPED) a two year survey was performed to record the incidence, severity, reasons and treatment of haemorrhages. During the study period, 1069 bleeds were reported from 720 paediatric hospitals and departments of otorhinolaryngology after adenoidectomy and tonsillectomy. 713 reports could be analyzed. Two deaths occurred after adenoidectomy. Although laboratory screening was performed in more than 70% of all cases, bleeding complications were neither foreseeable nor preventable. Inherited coagulopathies were rare and in most cases not detected, neither by laboratory screening nor by taking a history. Since preoperative measures cannot help much to improve the situation, all efforts have to be taken to improve the postoperative period, especially since more than 20% of the hemorrhages occurred during weekends. Guidelines on postoperative care and behaviour should therefore be implemented and parents and patients must be informed on bleeding risks and on what to do in case of emergency. If bleeding occurs, extensive coagulation testing is mandatory.

Inherited disorders of platelet function in pediatric clinical practice: a diagnostic challenge.

Hereditary disorders of platelet function are a heterogeneous group of diseases that are often complex and tend to go undetected until clinically relevant bleeding occurs. Hallmarks are epistaxis, easy bruising, mucous membrane bleeding, perioperative bleeding and menorrhagia. Bleeding may be intermittent and unpredictable. After decades of successful research on platelet biology and genetics, research findings have not been satisfactorily translated to clinical practice. The lack of robust and well- standardized test systems continues to make the diagnosis of platelet defects cumbersome for the practising clinician. Patient history and description of clinical bleeding symptoms are essential. Exclusion of von Willebrand disease, platelet count and investigation of blood smears may provide a tentative diagnosis. Light transmission aggregometry is still considered the gold standard for assessing platelet function. Due to the wide range of possible genetic defects molecular biological analyses can complement but do not substitute for other tests. The true incidence of inherited disorders of platelet function is unknown. A survey in Germany revealed that receptor-defects including Glanzmann's thrombasthenia and Bernard-Soulier syndrome and aspirin-like defects were the most frequently diagnosed platelet disorders. Of affected children 60% presented with mild and 40% with moderate to severe bleeding tendency. Epistaxis, cutaneous and mucous membrane bleeding were the most frequent symptoms. The paediatric competence network of the GTH e.V. comprises 44 collaborating centres that are caregivers to over 150 children with well-defined inherited platelet defects. A major goal of this network is to promote diagnosis of children with inherited disorders of platelet function.

Haemostatic testing prior to elective surgery in children? Not always!

In Germany, preoperative coagulation tests are commonly used, based on the belief that these tests should identify patients with an increased bleeding risk. However, published evidence does not longer support this approach for both traditional screening tests and novel techniques of global assessment of haemostasis. Unselected screening yields many false positive results and detects irrelevant disorders. It leads to postponement of surgery, anxiety in parents and patients, and is not cost effective. Even worse, it does not reliably detect relevant bleeding disorders such as the most common coagulopathy, von Willebrand disease. The bleeding history of patients and their relatives is a more effective tool to detect patients at risk. According to international guidelines and a joint statement of different German medical societies, a standardized questionnaire should be mandatory in preoperative screening. A diagnostic pathway should be employed to identify patients in whom specific tests are helpful. Because neither laboratory tests nor questionnaires can infallibly predict or exclude perioperative bleeding, guidelines for the management of these unexpected situations have to be established.

[First results of the THROMKID study: a quality project for the registration of children und adolescents with hereditary platelet function defects in Germany, Austria, and Switzerland]. / Erste Ergebnisse der THROMKID-Studie: Qualitätsprojekt zur Erfassung von Kindern und Jugendlichen mit angeborenen Thrombozytenfunktionsstörungen in Deutschland, Osterreich und der Schweiz.

THROMKID is a quality project of the Paediatric Group of German Thrombosis and Haemostasis Research Society (GTH). Data from paediatric patients with hereditary thrombocytopathies (HT) treated in Germany, Austria, and Switzerland were obtained between May 2005 and August 2006. By evaluation of results of platelet function tests criteria were determined to assess the diagnosis in each patient into most likely, likely or unlikely. A total of 215 patients treated in 31 centers were identified. In 95 patients (44%) the diagnosis of HT was most likely, in 28 (13%) likely and in 92 (43%) unlikely. Taken the first two groups together (n = 123) the diagnoses were as follows: Glanzmann thrombasthenia (n = 39, 32%), Aspirin-like defect (n = 26, 21%), thrombocyte receptor defects (n = 21, 17%), storage pool disorders (n = 18, 15%), Bernard-Soulier syndrome (n = 10, 8%), Hermansky-Pudlak syndrome (n = 6, 5%) and MYH9-related hereditary makrothrombocytopenia (n = 3, 2%). The low prevalence of these diseases and the high percentage of patients with unclassified HT stresses the necessity for the establishment of a competence network for comprehensive care of these patients in the three German-speaking countries.

[Preoperative coagulation screening prior to adenoidectomy and tonsillectomy]. / Präoperatives Screening auf Gerinnungsstörungen vor Adenotomie und Tonsillektomie.

BACKGROUND: Laboratory tests are widely used to screen children with planned surgery to detect unknown coagulation defects. This study investigates the predictive value of commonly used coagulation tests (thromboplastin time, partial thromboplastin time and thrombocyte count) compared with a standardized bleeding history. PATIENTS: In 702 patients 500 adenoidectomies and 500 tonsillectomies were done, results of laboratory evaluation and individual bleeding history were evaluated. RESULTS: 9.4 % of all laboratory tests showed abnormal results. 30.5 % of the children awaiting adenoidectomy had a suspicious bleeding history as had 22 % of patients undergoing tonsillectomy. In the clinical course of adenoidectomy no bleeding occurred. After tonsillectomy 15 children (3 %) showed moderate, 12 patients (2.4 %) severe postoperative bleeding. The positive predictive value of coagulation screening reached 6.8 % whereas history alone predicted 9.2 % of observed post tonsillectomy bleeding. CONCLUSIONS: The results of this study demonstrate the lacking effect of laboratory tests to predict postoperative bleeding complications. Taking a careful history of bleeding risks and testing only patients with suspicious history reduces the risk of bleeding more effective. Counseling about bleeding symptoms and postoperative survey of patients are additional measures which may protect the children.

An approach to study the viral safety of plasma-derived products in previously treated, non-infected patients.

Using the polymerase chain reaction (PCR), we designed a study concept to evaluate the safety of plasma derivatives in previously treated patients who are non-infected by the specific viruses studied. Several product lots can be studied in a single patient, with a study period for each lot of 3 months. In the present study 19 patients were included for treatment with Baxter Hyland Immuno's PCR-screened factor VIII concentrate Immunate (n=7), factor IX concentrate Immunine (n=10), the by-passing agent FEIBA plus Immunine (n=1), and the protein C concentrate Ceprotin (n=1). PCR testing for hepatitis B, C or HIV genomic material in patient samples was done as well as serological testing. All patients remained negative for the tested markers. All seven Immunate patients completed three treatment periods with three different lots of the study drug. The median study period was 282 days and the median dose 115 000 units, with a median of 115 exposure days. Five of the 10 Immunine patients completed three treatment periods and four patients, two treatment periods. One Immunine patient was discontinued from the study for reasons unrelated to the study drug administration. The median study period was 305 days and the median total dose 82 200 units, with a median of 88 exposure days. Our study presents a new design to approach the evaluation of viral safety of new plasma derivatives in previously treated, non-infected patients (NIPs) and offers several advantages over the currently recommended studies using testing for serological markers of infection in previously untreated patients (PUPs).

Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex.

Hereditary combined deficiency of the vitamin K dependent coagulation factors is a rare bleeding disorder. To date, only eleven families have been reported in the literature. The phenotype varies considerably with respect to bleeding tendency, response to vitamin K substitution and the presence of skeletal abnormalities, suggesting genetic heterogeneity. In only two of the reported families the cause of the disease has been elucidated as either a defect in the gamma-carboxylase enzyme (1) or in a protein of the vitamin K 2,3-epoxide reductase (VKOR) complex (2). Here we present a detailed phenotypic description of two new families with an autosomal recessive deficiency of all vitamin K dependent coagulation factors. In both families offspring had experienced severe or even fatal perinatal intracerebral haemorrhage. The affected children exhibit a mild deficiency of the vitamin K dependent coagulation factors that could be completely corrected by oral substitution of vitamin K. Sequencing and haplotype analysis excluded a defect within the gamma-carboxylase gene. The finding of highly increased amounts of vitamin K epoxide in all affected members of both families indicated a defect in a protein of the VKOR-multienzyme-complex. Further genetic analysis of such families will provide the basis for a more detailed understanding of the structure-function relation of the enzymes involved in vitamin K metabolism.

Blood transfusion. Iron load and retinopathy of prematurity.

UNLABELLED: To study the relationship between blood transfusion, iron load and retinopathy of prematurity (ROP), we performed a prospective observational cohort study in a level III neonatal intensive care unit. During a 24-month period, data on the volume of blood transfused during the first 6 weeks of life and on the incidence of ROP were collected in all surviving very low birth weight infants (n = 114; median birth weight 1130 g. range 520-1500 g). Associations between these data and values for serum iron, transferrin and ferritin measured at weekly intervals were analysed in a nested case-control design by logistic regression. There was a significant association between the volume of blood transfused and the incidence of ROP. After adjustment for gestational age at birth, duration of oxygen therapy (FiO2 > 0.3) and duration of mechanical ventilation, the relative risk of developing ROP was 6.4 (95% CI 1.2-33.4) for infants who had received 16-45 ml/kg, and 12.3 (1.6-92.5) for those who had received more than 45 ml/kg of blood (reference, 0-15 ml/kg). In contrast, there was no independent relationship between ROP and any of the parameters on iron metabolism analysed. CONCLUSION: This study confirms the role of blood transfusions as an independent risk factor for ROP. This relationship, however, does not appear to be mediated via an increased iron load.

Prevalence of factor V Leiden in children with thrombo-embolism.

UNLABELLED: Hereditary resistance to the anticoagulatory action of activated protein C (APC resistance, APCR) was identified as a possible new thrombophilic factor in a high percentage (17%-60%) of young adults with thrombotic events. A single missense mutation (R506Q) due to a G/A transition (G1691A) in exon 10 of the factor V gene is regarded as the causative molecular defect, resulting in factor V Leiden which is correlated with APCR. Identification of this mutation by polymerase chain reaction-based methods is easy to perform and prevents pre-analytical and analytical errors in the coagulometric assay for APCR. Since the impact of this mutation in children with thrombo-embolic disease has not been determined to date, we initiated a multi centre prevalence study in two paediatric populations, with and without thrombo-embolic events. We compared 125 paediatric patients with thrombosis, divided into three different age groups (0 to < 0.5 years; > 0.5 to < 10 years; > 10 to < 18 years) with a normal population of 159 children. Although the mutation G1691A was found with an unexpectedly high prevalence of 12% in our normal controls, the prevalence was significantly higher in the age groups; 0 to < 0.5 years (26%) and > 10 to < 18 years (30%). In patients between > 0.5 and < 10 years the overall prevalence was similar to that of the control group (13%). However, in patients of this age with spontaneous thrombosis, G1691A was also a significant risk factor (5/17 approximately equal to 29%). Homozygosity for G1691A was detected in three patients but not in the control group. Including deficiencies of protein C, protein S, antithrombin, and the presence of anti-phospholipid antibodies, thrombosis was correlated with endogenous thrombophilic factors in 38/125 patients (30.4%). CONCLUSION: Our results emphasize the impact of factor V Leiden on thrombogenesis in children. However, the significance is age-dependent and may reflect the different physiology of haemostasis in the three age groups. The diagnostic workup of children with thrombosis should include tests for factor V Leiden. The correlation of factor V Leiden with the clinical course of thrombo-embolism in children is essential to establish rational guidelines for therapy and prophylaxis of APCR-related thrombosis which are not yet available.

[Imaging methods in diagnosis of cerebrovascular complications with L-asparaginase therapy]. / Bildgebende Verfahren in der Diagnostik zerebrovaskulärer Komplikationen unter L-Asparaginase-Therapie.

During or immediately following L-asparaginase (L-asp) therapy especially intracranial thromboembolic or hemorrhagic complications due to hemostatic imbalance have been observed. We report about 6 children who had intracranial thrombosis or hemorrhage after 3 to 8 doses of L-asp. Initial symptoms of the cerebral events were similar--seizure, coma, hemiparesis and disorientation. All patients were examined by cerebral computerized tomography (CT) or/and magnetic resonance imaging (MRI). Three patients had a dural sinus thrombosis, one had an intracranial hemorrhage and two a hemorrhagic infarction with typical findings in the cerebral CT or MRI. Two other patients were interpreted as having peripheral thrombosis. They showed nontypical hypodense cortical and subcortical areas without any contrast medium enhancement in CT and hyperintense areas in T2-weighted MRI scan. All patients recovered from neurological symptoms, and showed obvious regression of CT and MRI findings which correlate with the good prognosis of these complications. Both CT and MRI are useful in diagnosis and follow-up of cerebrovascular complications of L-asp therapy. The CT and MRI findings of the reported cases seem to reflect different appearances of the same entity, i.e. thrombosis of venous vessels of different size with or without congestive edema and hemorrhagic complication.