How fit are children and adolescents with haemophilia in Germany? Results of a prospective study assessing the sport-specific motor performance by means of modern test procedures of sports science.

There are a lot of publications on the physical fitness of patients with haemophilia (PWH), however, most studies only reflect individual sport-specific motor capacities or focus on a single fitness ability. They involve small patient populations. In this respect principal objective of this study was to compare the physical fitness in all respects and the body composition of young PWH to healthy peers based on the most valid data we could get. Twenty-one German haemophilia treatment centres were visited from 2002 to 2009. PWH between 8 and 25 years were included. They performed a five-stage fitness test covering the sport-specific motor capacities for coordination, measured by one leg stand, strength, aerobic fitness and mobility as well as body composition. The patients' results were compared with age- and gender-specific reference values of healthy subjects. Two hundred and eighty-five PWH (mean age 13.2 ± 4.5 years, 164 PWH with severe disease) were included prospectively in the study. PWH are significantly below the reference values of healthy subjects in the one-leg stand test, the mobility of the lower extremity, the strength ratio of chest and back muscles and the endurance test. In body composition, the back strength and the mobility of the upper extremity PWH are significantly above the reference values. There are no significant differences in abdominal strength. In conclusion we found specific differences in different fitness abilities between PWH and healthy subjects. Knowing this, we are able to work out exercise programmes to compensate the diminished fitness abilities for our PWH.

New recommendations on cerebral venous and dural sinus thrombosis from the German consensus-based (S2k) guideline.

Over the last years, new evidence has accumulated on multiple aspects of diagnosis and management of cerebral venous and dural sinus thrombosis (CVT) including identification of new risk factors, studies on interventional treatment as well as treatment with direct oral anticoagulants. Based on the GRADE questions of the European Stroke Organization guideline on this topic, the new German guideline on CVT is a consensus between expert representatives of Austria, Germany and Switzerland. New recommendations include:• CVT occurring in the first weeks after SARS-CoV-2 vaccination with vector vaccines may be associated with severe thrombocytopenia, indicating the presence of a prothrombotic immunogenic cause (Vaccine-induced immune thrombotic thrombocytopenia; VITT).• D-dimer testing to rule out CVT cannot be recommended and should therefore not be routinely performed.• Thrombophilia screening is not generally recommended in patients with CVT. It should be considered in young patients, in spontaneous CVT, in recurrent thrombosis and/or in case of a positive family history of venous thromboembolism, and if a change in therapy results from a positive finding.• Patients with CVT should preferably be treated with low molecular weight heparine (LMWH) instead of unfractionated heparine in the acute phase.• On an individual basis, endovascular recanalization in a neurointerventional center may be considered for patients who deteriorate under adequate anticoagulation.• Despite the overall low level of evidence, surgical decompression should be performed in patients with CVT, parenchymal lesions (congestive edema and/or hemorrhage) and impending incarceration to prevent death.• Following the acute phase, oral anticoagulation with direct oral anticoagulants instead of vitamin K antagonists should be given for 3 to 12 months to enhance recanalization and prevent recurrent CVT as well as extracerebral venous thrombosis.• Women with previous CVT in connection with the use of combined hormonal contraceptives or pregnancy shall refrain from continuing or restarting contraception with oestrogen-progestagen combinations due to an increased risk of recurrence if anticoagulation is no longer used.• Women with previous CVT and without contraindications should receive LMWH prophylaxis during pregnancy and for at least 6 weeks post partum.Although the level of evidence supporting these recommendations is mostly low, evidence from deep venous thrombosis as well as current clinical experience can justify the new recommendations.This article is an abridged translation of the German guideline, which is available online.

Results of the WIRK prospective, non-interventional observational study of recombinant activated factor VII (rFVIIa) in patients with congenital haemophilia with inhibitors and other bleeding disorders.

Recombinant activated factor VII (rFVIIa) has been available for the treatment of acute bleeding and for prevention of bleeding during surgery and invasive procedures in patients with congenital haemophilia with inhibitors (CHwI) and acquired haemophilia since 1996. The study objective was to assess the efficacy and safety of rFVIIa in patients with CHwI, acquired haemophilia, congenital FVII deficiency and Glanzmann's thrombasthenia, in a real-life clinical setting. There were no specific inclusion or exclusion criteria; participation was offered to all German haemophilia centres known to use rFVIIa to treat patients with the above indications. Data on rFVIIa use and efficacy for the treatment of acute bleeding episodes and invasive procedures were recorded. Adverse drug reactions and recurrent bleeding episodes were also monitored. In total, 64 patients (50.0% women) received rFVIIa treatment. Patients experienced 281 evaluable bleeding episodes and underwent 44 invasive procedures. In 252 of 281 (89.7%) bleeding episodes, a stop (66.5%) or a significant reduction (23.1%) in bleeding was observed. No bleeding complications were reported for 42 of 44 (95.5%) invasive procedures covered with rFVIIa. A clear positive association was observed between early initiation of rFVIIa treatment for acute bleeding and efficacy. The total cumulative dose and number of injections were 468.3 ± 545.8 µg kg(-1) and 3.6 ± 4.6 respectively. No drug-related adverse events were reported. rFVIIa use in Germany provided effective haemostatic cover without associated adverse events in the management of acute bleeds and invasive procedures across a range of bleeding disorders.

Management of bleeding disorders in children.

Haemophilia, if not properly managed, can lead to chronic disease and lifelong disabilities. The challenges and issues in infants/young children are different from those in older children and adults although episodes of bleeding still predominate as the diagnostic trigger. Awareness of clinical manifestations and treatment complications are crucial in instituting appropriate management and implementing preventive strategies. Currently, inhibitor development is a challenging complication of paediatric haemophilia and prophylaxis is emerging as the optimal preventive care strategy. In this section we will review some important aspects of haemophilia in children including early prophylaxis, current evidence relating to inhibitor development, including the aims of the SIPPET study which is already ongoing and involves boys <6 years, and the potential of immune tolerance therapy for eradicating the inhibitor and permitting a resumption of standard dosing schedules.

Homozygous point mutations in platelet glycoprotein ITGA2B gene as cause of Glanzmann thrombasthenia in 2 families.

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by quantitative and/or qualitative defects of the platelet glycoprotein (GP) IIb/IIIa complex. Physiologically, the integrin GPIIb/IIIa binds Von Willebrand factor and fibrinogen on activated platelets. GT is caused by genetic alterations in ITGA2B or ITGB3 (genes encoding GPIIb and GPIIIa).This study describes 2 siblings diagnosed with GT type I associated with homozygous point mutations in ITGA2B. All patients presented with typical bleeding disorder including moderate hematomas, petechiae, and mucocutaneous bleedings.Both siblings showed severely reduced platelet aggregation especially after stimulation with collagen and adenosine diphosphate. Absence of platelet GPIIb/GPIIIa complex was determined using flow cytometry. Molecular genetic analysis revealed 2 distinct homozygous point mutations in exon 18 of ITGA2B. Family 1 was identified with c.1878G>C and family 2 with c.1787T>C substitution. While the c.1787T>C mutation causes a single amino acid substitution p.I565T, the c.1878G>C mutation (p.Q595H) is predicted to induce a mRNA splicing anomaly.These mutations were identified as cause of GT type I in the described patients. Patients with GT should be documented in a prospective register to verify the correlation between the severity of bleeding symptoms and the pathogenic mutation. This can have effects on therapeutic decisions.

Multiplate whole blood impedance point of care aggregometry: preliminary reference values in healthy infants, children and adolescents.

BACKGROUND: The aim of the present study was to evaluate paediatric reference values for platelet function using a point-of-care whole blood impedance aggregometry. METHODS, RESULTS & CONCLUSION: In 265 healthy infants and children aged

Multimodal fetal transesophageal echocardiography for fetal cardiac intervention in sheep.

BACKGROUND: The overall performance of available mechanical intravascular ultrasound catheters for fetal transesophageal echocardiography during fetoscopic fetal cardiac interventions in sheep has been limited by radioelectronic interference, low system frame rates, and low acoustic outputs. Therefore, a more reliable device is desired for human fetoscopic surgical procedures. METHODS AND RESULTS: We assessed the potential of a newly available 10-French phased-array intravascular ultrasound catheter for multimodal fetal transesophageal echocardiography in 5 fetal sheep between 78 and 98 days of gestation (term, 145 to 150 d). The intravascular ultrasound catheter was easily inserted through the mouth into the esophagus in all 5 sheep fetuses (mean weight, 600 g), and it permitted high-quality 2D imaging of the fetal heart in vertical imaging planes that were validated by MRI. Color Doppler and pulsed Doppler imaging permitted clear assessment of fetal cardiovascular flows and recording of velocity-time integral tracings of the fetal heart and great vessels. The vertical imaging planes were particularly useful to demonstrate interventional material inside the fetal heart and great vessels. CONCLUSIONS: Our early experience with the phased-array intravascular ultrasound catheter indicates that multimodal fetal transesophageal echocardiography has now become possible in these smallest of patients.

Infant methylenetetrahydrofolate reductase 677TT genotype is a risk factor for congenital heart disease.

OBJECTIVE: Recently, an association between the homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in infants with congenital neural tube defects or congenital oral clefts has been shown. However, no data are available so far with respect to the MTHFR 677TT genotype in children with underlying structural congenital heart disease (CHD). METHODS: We investigated the MTHFR genotype in 114 Caucasian CHD patients aged newborn to 16 years (median 0.6 years; 53% male) and in 228 age- and sex-matched healthy controls. RESULTS: In childhood patients with CHD the homozygous MTHFR 677TT genotype was found in 21 out of 114 subjects (18.4%) compared with 21 out of 228 controls (9.2%; odds ratio (OR) 2.2, 95%-confidence interval (CI) 1.2-4.3; P=0.027). In patients with pulmonary valve stenosis, hypoplastic left heart syndrome, coarctation of the aorta, aortic valve stenosis or subaortic stenosis the frequency of the TT genotype varied between 38 and 67% with corresponding ORs from 6.1 (CI, 1.4-27.5; P=0.034) to 20.4 (CI, 1.8-235.0; P=0.025), whereas in other structural CHD the frequency of this genotype was not significantly different from the controls. CONCLUSIONS: With the present study we can show for the first time that the embryonal MTHFR 677TT genotype is significantly associated with the development of structural congenital heart malformations during early pregnancy. It remains to be clarified, whether this genotype is at least a risk marker or a risk factor for structural congenital heart malformations.

Thrombolysis in newborns and infants.

This review analyses literature reports from 1970 to 1998 assessing the use of streptokinase (SK), urokinase (UK) or recombinant tissue-type plasminogen activator (rt-PA) for thrombolytic therapy in neonates and infants. From 1970 to 1998 182 infants were reported to have received SK (n = 54; 29.5%), UK (n = 41; 22.5%) or rt-PA (n = 87; 48%). During thrombolytic therapy no concomitant heparin administration or low dose heparin therapy (5 U/kg/h) were recorded. To perform reocclusion prophylactics heparin was reinitiated at the end of thrombolytic therapy usually in the recommended dosage of 20 U/ kg/h. The overall thrombolytic patency rate in neonates varied from 39% to 86%. Besides bleeding from local puncture sites or recent catheterisation sites (10.4%), pulmonary embolism was reported in 1.1% of the 182 infants. Major bleeding complications, i.e. pulmonary bleeding (0.6%), gastrointestinal bleeding (0.6%) or intraventricular haemorrhage (IVH 2.7%) are rarely reported side effects and only 2 thrombolysis related deaths due to haemorrhage were mentioned. Bleedings reported in the central nervous system (n = 4) mainly occurred in preterm infants (n = 3). In conclusion, data of this preliminary analysis suggest that there is no big difference (p = 0.09; chi2-test) in the efficacy rate between the 3 thrombolytic agents used in the first year of life. In each case an assessment must be made with respect to the relative benefit conferred by thrombolytic therapy in preventing organ or limb damage versus the potential side effects, costs and inconvenience for the childhood patient. Controlled prospective multicentre studies on thrombolytic therapy in neonates and infants are recommended to evaluate patency rates and adverse effects for the different thrombolytic agents used.

Symptomatic onset of severe hemophilia A in childhood is dependent on the presence of prothrombotic risk factors.

It has been recently suggested that the clinical phenotype of severe hemophilia A (HA) is influenced by co-inheritance with the factor V G1691A mutation. We therefore investigated 124 pediatric PUP patients with hemophilia (A: n = 111) consecutively admitted to German pediatric hemophilia treatment centers. In addition to factor VIII activity, the factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, antithrombin, protein C, protein S and antithrombin were investigated. 92 out of 111 HA patients (F VIII activity < 1%) were suffering from severe HA. The prevalence of prothrombotic risk factors in children with severe HA was no different from previously reported data: FV G1691A 6.5%, PT G20201A 3.2%, and protein C type I deficiency 1.1%. No deficiency states of antithrombin or protein S were found in this cohort of hemophilic patients. The first symptomatic bleeding leading to diagnosis of severe hemophilia (< 1%) occurred with a median (range) age of 1.6 years (0.5-7.1) in children carrying defects within the protein C pathway or the PT gene mutation compared with non-carriers of prothrombotic risk factors (0.9 years (0.1-4.0; p = 0.01). The cumulative event-free bleeding survival was significantly prolonged in children carrying additionally prothrombotic defects (log-rank/Mantel-Cox: p = 0.0098). In conclusion, data of this multicenter cohort study clearly demonstrate that the first symptomatic bleeding onset in children with severe HA carrying prothrombotic risk factors is significantly later in life than in non-carriers.

Pharmacokinetics of recombinant factor XIII at steady state in patients with congenital factor XIII A-subunit deficiency.

BACKGROUND: The use of monthly recombinant factor XIII (rFXIII) recently demonstrated favorable safety and efficacy for congenital FXIII A-subunit deficiency patients aged ≥ 6 years (mentor(™) 1 trial), although the pharmacokinetics (PK) were not fully evaluated. OBJECTIVES: To comprehensively evaluate the steady-state PK of rFXIII in patients aged ≥ 6 years with congenital FXIII A-subunit deficiency. PATIENTS/METHODS: mentor(™) 2 is an ongoing, multinational safety and efficacy trial in which patients are receiving monthly rFXIII (35 IU kg(-1) ) for ≥ 52 weeks. For this 28-day PK analysis, blood samples were collected immediately predosing, and 1 h, 2 h, 3, 7, 14, 21, and 28 days postdosing. FXIII activity was measured and PK parameters were calculated using non-compartmental analysis, without prior baseline adjustment. Information regarding adverse events and bleeding was collected at each visit. Antibody assessments were performed predosing and at day 28. RESULTS: PK analysis in 23 patients revealed first-order elimination of rFXIII with a geometric mean half-life of 13.6 days. Mean FXIII activity was > 0.1 IU mL(-1) throughout the 28-day period, with a geometric mean peak activity of 0.87 IU mL(-1) and trough of 0.16 IU mL(-1) . The geometric mean clearance was 0.15 mL h(-1) kg(-1) . No bleeding episodes occurred during the PK session, and no anti-rFXIII antibodies were detected. Peak and trough FXIII activities were constant over time, compared with previous activities (≥ 10 rFXIII doses) in the same patients. CONCLUSIONS: Clearance of rFXIII is unaffected over time, and monthly prophylaxis with 35 IU kg(-1) rFXIII provides FXIII activity > 0.1 IU mL(-1) throughout the dosing interval in patients with congenital FXIII A-subunit deficiency.

Clinical and laboratory characteristics of paediatric and adolescent index cases with venous thromboembolism and antithrombin deficiency. An observational multicentre cohort study.

Venous thromboembolism [TE] is a multifactorial disease and antithrombin deficiency [ATD] constitutes a major risk factor. In the present study the prevalence of ATD and the clinical presentation at TE onset in a cohort of paediatric index cases are reported. In 319 unselected paediatric patients (0.1-18 years) from 313 families, recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. 21 of 319 paediatric patients (6.6%), corresponding to 16 of 313 families (5.1%), were AT-deficient with confirmed underlying AT gene mutations. Mean age at first TE onset was 14 years (range 0.1 to 17). Thrombotic locations were renal veins (n=2), cerebral veins (n=5), deep veins (DVT) of the leg (n=9), DVT & pulmonary embolism (n=4) and pelvic veins (n=1). ATD co-occurred with the factor-V-Leiden mutation in one and the prothrombin G20210A mutation in two children. In 57.2% of patients a concomitant risk factor for TE was identified, whereas 42.8% of patients developed TE spontaneously. A second TE event within primarily healthy siblings occurred in three of 313 families and a third event among siblings was observed in one family. In an unselected cohort of paediatric patients with symptomatic TE, the prevalence of ATD adjusted for family status was 5.1%. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high risk population.

[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.

[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.

Menorrhagia and bleeding disorders in adolescent females.

In women, von Willebrand disease (VWD) is the most common inherited bleeding disorder. Since VWD and other inherited bleeding disorders are autosomal disorders, they affect women and men. Menorrhagia, or heavy menstrual bleeding (HMB), is the most common symptom of women with bleeding disorder experience. Objectively, it is defined as bleeding that lasts for more than seven days or results in the loss of more than 80 ml of blood per menstrual cycle. The prevalence of menorrhagia in a woman with a bleeding disorder ranges from 32 to 100% in patients with VWD, from 5 to 98% in patients with a platelet dysfunction and from 35 to 70% in women with a rare factor deficiency. A detailed history and a careful physical exam are the first steps towards a diagnosis in adolescents, adding a PBAC>100 increased the sensitivity of the screening tool further to 95%. Laboratory testing should be made at the time of menstrual bleeding in an effort to capture the lowest level of VWF:Ag and FVIII:C. Treatment options for menorrhagia in VWD: (1) antifibrinolytic therapy with tranexamic acid, (2) the non-transfusional agent desmopressin (DDAVP), (3) purified blood products that contain factor VIII and VWF concentrated from plasma and (4) hormonal preparations.

[Treatment of haemophilia with an integrated therapeutical concept--Duisburg model]. / Hämophiliebehandlung als ganzheitliches Konzept der Patientenversorgung. Das Duisburger Modell.

A top quality, effective treatment of haemophilia requires an integrated therapeutical concept and an excellent cooperation of an interdisciplinary team. Since years different models are discussed in Germany in order to enlarge the offers for a suitable care of patients with hard to treat diseases. The health-political targets are expressed in the changes of the Code of Social Law number V (SGB V) and in innovations in the statutory health insurance. This new legal basis provides opportunities to implement innovative treatment concepts outside university hospitals and paves the way for ambulant haemophilia centres to offer an integral care, all legally saved by a contract. The Coagulation Centre Rhine-Ruhr reveals as an example how haemophilia treatment in accordance with guidelines and with the latest results of international research can be realise in an ambulatory network.

Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders.

BACKGROUND: The European Network of Rare Bleeding Disorders (EN-RBD) was established to bridge the gap between knowledge and practise in the care of patients with RBDs. OBJECTIVES: To explore the relationship between coagulation factor activity level and bleeding severity in patients with RBDs. PATIENTS/METHODS: Cross-sectional study using data from 489 patients registered in the EN-RBD. Coagulation factor activity levels were retrieved. Clinical bleeding episodes were classified into four categories according to severity. RESULTS: The mean age of patients at data collection was 31 years (range, 7 months to 95 years), with an equal sex distribution. On linear regression analysis, there was a strong association between coagulation factor activity level and clinical bleeding severity for fibrinogen, factor (F) X, FXIII, and combined FV and FVIII deficiencies. A weaker association was present for FV and FVII deficiencies. There was no association between coagulation factor activity level and clinical bleeding severity for FXI. The coagulation factor activity levels that were necessary for patients to remain asymptomatic were: fibrinogen, > 100 mg dL(-1); FV, 12 U dL(-1); combined FV + VIII, 43 U dL(-1); FVII, 25 U dL(-1); FX, 56 U dL(-1) ; FXI, 26 U dL(-1); FXIII, 31 U dL(-1). Moreover, coagulation factor activity levels that corresponded with Grade III bleeding were: undetectable levels for fibrinogen, FV and FXIII, < 15 U dL(-1) for combined FV + VIII; < 8 U dL(-1) for FVI; < 10 U dL(-1) for FX; and < 25 U dL(-1) for FXI. CONCLUSIONS: There is a heterogeneous association between coagulation factor activity level and clinical bleeding severity in different RBDs. A strong association is only observed in fibrinogen, FX and FXIII deficiencies.