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Prophylaxis is now an established treatment standard in haemophilia in Western Europe and the US with multiple studies demonstrating the clinical benefits of prophylaxis over on-demand treatment. In Western Europe in particular, prophylactic use of factor VIII (FVIII) is high as a result of the findings from the early prophylaxis studies and adherence to national guidelines. Unfortunately, prophylaxis has not yet been implemented on a worldwide basis. The introduction of prophylaxis by haemophilia treatment centres in Bremen, Frankfurt and Munich, as recommended in German guidelines, has significantly improved outcomes for our young haemophilia patients. In the Frankfurt centre, a decreasing rate of inhibitors has been observed since prophylaxis was started early, dosing was individualized, and the importance of treatment continuity was recognized. The centres in Munich and Bremen have explored the possibility of further reducing inhibitor rates using early tolerization - a new prophylaxis regimen that introduces low FVIII doses administered once weekly as soon as a bleeding tendency is observed - with excellent results. All three centres avert the induction of immunological danger signals by avoiding the use of central venous catheters, postponing vaccination wherever possible and not undertaking elective surgery during the early FVIII exposure days. The benefits of using this approach have been confirmed by the remarkably low rates of inhibitors in previously untreated patients reported at these centres. Hopefully, as we and others explore new prophylaxis regimens for our paediatric patients, we can work towards the goal of one day overcoming this serious complication of haemophilia treatment.

Radiological and orthopaedic outcome in severe and moderate haemophilia A and B patients undergoing long-term prophylactic treatment were prospectively investigated focusing on the age of onset of prophylaxis and the number of joint bleedings prior to treatment. We report on 21 patients with severe and moderate haemophilia A and B receiving prophylactic treatment of between 3.1 and 16.1 years duration. Three patient groups were evaluated according to the age at onset of prophylaxis. In group I (n = 8) prophylactic treatment was initiated in the first 2 years of life. Patients of group II (n = 6) received prophylaxis at the age of 3-6 years. Late-onset or secondary prophylactic treatment was started at the age of 6 years and above in 7 patients (group III). All patients received virus-inactivated F VIII or F IX concentrates at dosages of 30-40 IU, in some cases up to 50 IU/kg body weight i. v. three times per week for those with haemophilia A and twice per week for those with haemophilia B. Elbow, knee and ankle joints were investigated at 3-4 yearly intervals according to the radiological and orthopaedic scores recommended by the World Federation of Haemophilia (WFH). The total number of joint bleedings before and after start of prophylaxis were recorded in all patients. In group I 7 out of 8 patients had unaffected joints with constant radiological and orthopaedic scores of zero or 1, after a median of 11.25 years of prophylactic treatment. One patient in this group demonstrated mild radiological alterations (score 4). Patients of group II showed neither radiological nor orthopaedic alterations at study entry. Worsening joint scores could be detected despite ongoing prophylaxis after the 3-year interval (median orthopaedic score 4, median radiological score 8). Treatment group III already showed considerable joint damage at study entry with a median radiological score of 11 (0-33) and a median orthopaedic score of 4 (0-11). Despite prophylactic treatment both, orthopaedic (median 8, range 2-12) and radiological scores (median 19.5, range 2-47) deteriorated after 3 years. Prior to onset of prophylaxis no or only one joint bleeding occurred in treatment group I. In group II, a median of 6 joint bleeds (range 1-8) were reported before prophylaxis was started. Patients of group III usually experienced a median of more than 10 joint haemorrhages (range 6-10 or more). Under prophylactic treatment the number of joint bleedings decreased significantly in groups II and III. However, radiological and orthopaedic scores increased as a sign of progressing osteoarthropathic alterations in patients reporting more than 6 joint haemorrhages before onset of prophylaxis whereas no joint alterations could be assessed in patients with no or only one joint bleeding episode prior to prophylaxis. Even a small number of joint bleedings seems to cause irreversible osteoarthropathic alterations leading to haemophilic arthropathy. Once apparent, further progression of joint damage could not be arrested despite of prophylactic treatment (group II and III). In order to prevent haemophilic arthropathy, effective prophylaxis should be started before or at least after the first joint bleeding in severe haemophilia A and B.

ZusammenfassungAngeborene Thrombozytopathien sind komplexe Erkrankungen. Zur optimalen Blutungsprophylaxe und -behandlung empfehlen wir eine Abklärung und Diagnose der zugrunde liegenden Funktionsstörung. Dazu steht eine interdisziplinäre Leitlinie zur Verfügung (AWMF # 86–003 S2K; Hämostaseologie 2014; 34: 201–212).Die Behandlung ist auf den Defekt, die Thrombozytenzahl, das Lebensalter und die klinischen Umstände abzustimmen. Die Transfusion von Thrombozyten allein kann wegen der damit verbundenen Risiken unangemessen sein. Empfohlen wird ein stufenweiser und individualisierter Behandlungsplan. Antifibrinolytika sind generell anwendbar, besonders bei der Quebec-Erkrankung. Desmopressin ist älteren Kindern vor behalten und vor allem zur Behandlung der Storage- Pool-Erkrankungen und nicht klassifizierter Defekte geeignet. Rekombinanter FVIIa ist zwar nur für die Behandlung der Thrombasthenie Glanzmann mit Alloantikörpern zugelassen, wird jedoch in der klinischen Praxis auch bei Thrombozytendefekten mit schwerer Blutungsneigung eingesetzt. Das Ziel dieser Leitlinie ist die Behandlung von Patienten mit angeborenen Thrombozytenfunktionsstörungen bestmöglich zu unterstützen.

Summary Immune tolerance induction (ITI) has been shown to successfully eliminate factor VIII (FVIII) inhibitors in haemophilia patients with inhibitors. We performed a literature search to identify reports from January 1980 to October 2012 on the use of the plasma-derived, von Willebrand factor (VWF)-containing FVIII concentrate Haemate® P/Humate-P® in the setting of ITI. Six reports were identified that specifically evaluated the use of Haemate® P/Humate-P® including 32 children and 9 adults. Dosing regimens ranged from 20 IU kg−1 every 2–3 days in patients with low-responding (LR; n = 5) inhibitors to 300 IU kg−1 day−1 in patients with high-responding (HR; n = 36) inhibitors. Complete success was achieved in all five LR patients, in all three HR patients with good prognostic factors (age ≤7 years, pre-ITI inhibitor titre

Background Hereditary angioedema (HAE), caused by deficiency in C1-inhibitor (C1-INH), leads to unpredictable edema of subcutaneous tissues with potentially fatal complications. As surgery can be a trigger for edema episodes, current guidelines recommend preoperative prophylaxis with C1-INH or attenuated androgens in patients with HAE undergoing surgery. However, the risk of an HAE attack in patients without prophylaxis has not been quantified. Objectives This analysis examined rates of perioperative edema in patients with HAE not receiving prophylaxis. Methods This was a retrospective analysis of records of randomly selected patients with HAE type I or II treated at the Frankfurt Comprehensive Care Centre. These were examined for information about surgical procedures and the presence of perioperative angioedema. Results A total of 331 patients were included; 247 underwent 700 invasive procedures. Of these procedures, 335 were conducted in 144 patients who had not received prophylaxis at the time of surgery. Categories representing significant numbers of procedures were abdominal (n = 113), ENT (n = 71), and gynecological (n = 58) procedures. The rate of documented angioedema without prophylaxis across all procedures was 5.7%; in 24.8% of procedures, the presence of perioperative angioedema could not be excluded, leading to a maximum potential risk of 30.5%. Predictors of perioperative angioedema could not be identified. Conclusion The risk of perioperative angioedema in patients with HAE type I or II without prophylaxis undergoing surgical procedures ranged from 5.7% to 30.5% (CI 3.5–35.7%). The unpredictability of HAE episodes supports current international treatment recommendations to consider short-term prophylaxis for all HAE patients undergoing surgery.

Das hereditare Angioodem (HAE) aufgrund eines Mangels an funktionellem C1-Inhibitor (HAE-C1-INH) ist eine seltene Erkrankung, die oft bereits im Kindesalter zu unregelmasig auftretenden Episoden potenziell lebensbedrohlicher Odeme fuhrt. Eine fruhe Diagnose ist wichtig, um unwirksame Therapiemasnahmen zu vermeiden und Odeme richtig zu behandeln. Auf einem Konsenstreffen im Juni 2011 diskutierten Kinderarzte und Dermatologen aus Deutschland, Osterreich und der Schweiz die Literatur einschlieslich der internationalen Konsensempfehlungen zur HAE-Therapie fur alle Altersgruppen. Aufgrund des derzeitigen Zulassungsstatus konnen diese Empfehlungen nicht ohne Vorbehalt fur die Padiatrie in deutschsprachigen Landern ubernommen werden. Dieser Artikel gibt einen Uberblick und diskutiert die zur HAE-Therapie erhaltlichen Medikamente, den Zulassungsstatus und Studien mit Erwachsenen und padiatrischen Patienten. Empfehlungen fur adaquate Behandlungsstrategien fur Kinder und Jugendliche im deutschsprachigen Raum werden gegeben. Die derzeit beste zugelassene Option fur die Behandlung akuter HAE-C1-INH-Attacken und fur die Kurz- und Langzeitprophylaxe bei padiatrischen Patienten im deutschsprachigen Raum ist aus Plasma gewonnenes C1-Inhibitor-Konzentrat.

BACKGROUND: C1-esterase inhibitor (C1-INH) replacement therapy is the treatment of choice for acute edema attacks in patients with hereditary angioedema (HAE). STUDY DESIGN AND METHODS: Our retrospective, observational study assessed the efficacy and safety of home therapy with a human plasma-derived C1-INH concentrate (pC1-INH) in 20 pediatric patients with HAE who had previously been treated with physician-based therapy. While on home therapy, 15 patients received on-demand treatment and five received individual replacement treatment (IRT). RESULTS: The switch to home therapy did not involve a significant increase in the dose of pC1-INH administered, but there was a significant increase in dosing frequency. Although only two patients were affected, the frequency of laryngeal attacks appeared to decrease on home therapy. All attacks, including laryngeal edema, were treated successfully during home therapy with pC1-INH. The mean annual number of days hospitalized was reduced from 3.8 during physician-based therapy to 0.11 during home therapy. No side effects or injection site complications were reported. The median time from onset of attack to administration of pC1-INH was reduced from 67.5 minutes during physician-based therapy to 15 minutes after switching to home therapy. The corresponding median time to initial symptom relief for all types of attack was reduced from 60 to 40 minutes. CONCLUSION: As in adults, home therapy with pC1-INH is effective and safe in the treatment of HAE attacks in pediatric patients; a larger, randomized study should ideally confirm our findings before this approach can be considered the standard of care for pediatric patients.

BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P

BACKGROUND: The modulation of Factor (F)VIII activity (FVIII : C), von Willebrand factor antigen (VWF : Ag), and von Willebrand factor ristocetin cofactor (VWF : RCo) by the ABO(H) blood group is well established in adults. Expression of ABH antigens on N-linked glycans of VWF protects plasma VWF from proteolysis and clearance. Protection by H antigens is less effective than by AB antigens, resulting in approximately 25% lower VWF plasma levels in adults with blood group O compared to non-O. Given the reduced branching of ABO(H) bearing structures (I blood group system) with lower numbers of H, A, and B antigen sites during the first 18 months of life, we reasoned that if the relationship between ABO(H) blood group and VWF levels were causal, the difference of ABO(H) blood group–dependent VWF levels should be marginal or not be observed in the first months of life. STUDY DESIGN AND METHODS: We undertook quantification of FVIII : C and VWF in 574 presumably healthy children aged 1 to 210 months and correlated the values with ABO(H) blood type. Moreover, we establish reference intervals for common coagulation variables for several pediatric age groups. RESULTS: Significant differences between blood group O versus non-O values of FVIII : C, VWF : Ag, and VWF : RCo were not observed in the first months of life, started to develop during childhood, and in adolescence reached adult values. CONCLUSION: In comparison to the levels for adults and adolescents, we report fundamental differences of VWF levels in the first year of life, which may be associated with the physiologic development of the ABO(H) and I blood group system.

BACKGROUND: Hereditary angioedema (HAE) caused by functional deficiency of C1-inhibitor (C1-INH) is a rare disease that manifests with recurrent spontaneous nonallergic edema of the subcutaneous tissues and mucous membranes. In cases of laryngeal edema that are not treated immediately, HAE is associated with high mortality rates. Attenuated androgens (e.g., danazol) are usually administered for prophylaxis, but associated side effects may limit their use. This study investigated the efficacy, safety, and quality of life (QoL)

SummaryThe development of neutralizing alloanti-bodies (inhibitors) to factor VIII (FVIII) is one of the most serious complications in the treatment of haemophiliacs. Inhibitors occur in approximately 20 to 30% of previously untreated patients (PUPs), predominantly children, with severe haemophilia A within the first 50 exposure days (ED). Immune tolerance induction (ITI) leads to complete elimination of the inhibitor in up to 80% of the patients and offers the possibility to restore regular FVIII prophylaxis. However, patients with high titre inhibitors, in whom standard ITI fails, usually impose with high morbidity and mortality and therefore prompting physicians to alternate therapy regimens. Rituximab, an anti-CD 20 monoclonal antibody has been successfully used in children and adults for the management of B-cell mediated disorders. We report on the use of a new protocol including rituximab in two adolescents with severe haemophilia A and high titre inhibitors, severe bleeding tendency and high clotting factor consumption after failing standard ITI. Both patients received a concomitant treatment with FVIII according to the Bonn protocol, cyclosporine A and immunoglobulin. Treatment with rituximab resulted in a temporary B-cell depletion leading to the disappearance of the inhibitor. FVIII recovery and half-life turned towards normal ranges. In patient 1 the inhibitor reappeared 14 months after the last rituximab administration. In patient 2 complete immune tolerance could be achieved for 60 months. Bleeding frequency diminished significantly and clinical joint status improved in both patients. In patient 1 the treatment course was complicated by aspergillosis and hepatitis B infection. Conclusion: Rituximab may be favourable for patients with congenital haemophilia, high-titre inhibitors and a severe clinical course in whom standard ITI has failed. Prospective studies are required to determine safety, efficacy and predictors of success.

The neurological findings in 41 HIV-seropositive children are described. 23 children were symptomatic, eight seropositive but without symptoms and 10 seropositive children less than 15 months of age had no other evidence of immunodeficiency. Acquired microcephaly, developmental regression and progressive motor deterioration indicated HIV encephalopathy, as did developmental delay, mental retardation, cerebellar symptoms and behavioural changes. Three children with progressive encephalopathy improved after treatment with azidothymidine (AZT). In eight children treated with prophylactic intravenous immunoglobulin therapy (IVIG) and seven treated with both IVIG and AZT, no mental deterioration has been observed since the beginning of therapy. One child with advanced encephalopathy and severe pyramidal tract involvement did not improve.

BACKGROUND AND OBJECTIVE Resistance against activated protein C (APC), caused by factor V R506Q mutation (factor V Leiden mutation), is among the most important hereditary clotting defects that are associated with an increased risk of venous thrombosis. As there are hardly any data for Germany regarding APC resistance that have been validated by genetic analysis, this study was undertaken to determine the prevalence of factor V Leiden (fVL) mutations in a sizeable group of patients in Germany with venous thromboembolism (VTE) and a control group of healthy persons. PATIENTS AND METHODS 1200 consecutive patients (689 females, 511 males) from various regions of Germany were examined who, at an age between 0.1 and 45 years, had developed primary deep vein thrombosis (DVT) and/or pulmonary embolism (PE), as confirmed by imaging tests. The control group consisted of 740 healthy persons (332 females and 408 males; median age 33 years) for whom there was no evidence in their personal or family history of TE. Analysis of the fV-1691 genotype was by Mnll-restriction analysis of genomic fV DNA fragments, amplified by polymerase chain reaction. RESULTS The prevalence in the control group was 7.5% the for heterozygotic fV:Q506 mutant (25 females, 30 males). For the patients the prevalence of the fV R506Q mutation was 27.2% (32.1% heterozygotes [165 females, 112 males]; 4.1% homozygotes [33 females, 16 males], i.e. significantly higher than in the healthy controls (P < 0.0001). In 81.3% of the patients with fV:Q506 DVT in the leg-pelvic vein region was found as the first manifestation, thrombosis in an atypical site in 14.4% and isolated PE in 4.3%. The first manifestation had occurred spontaneously in 36% of patients with the fV:Q506 mutant (44 females, 75 males), in 53.1% of homozygotes and in 33.5% of heterozygotic carriers of the mutation. CONCLUSION The fV Leiden mutation due to APC resistance is the most common cause of venous thrombosis and apparently one of the most common inherited diseases.

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent episodes of potentially life-threatening angioedema. The most widespread underlying genetic deficiency is a heterozygous deficiency of the serine protease inhibitor Cl esterase inhibitor (C1-Inh). In addition to low C4 levels, the most important laboratory parameter for correct diagnosis of HAE or angioedema due to acquired C1-Inh deficiency is reduced C1-Inh function (fC1-Inh). No direct recommendations about the assays for fC1-Inh or sample handling conditions are available, although this would prove especially useful when a laboratory first starts to offer assays on fC1-Inh for HAE diagnosis. In the present study we evaluated the performance of fC1-Inh assays in the 15 different laboratories that are specialised in HAE diagnostics and assessed inter-laboratory variation with each laboratory using their own assays and standards. A double-blind survey was conducted using plasma/serum samples from healthy donors and HAE patients and the uniformity of HAE diagnosis was evaluated. It can be concluded that the diagnosis of fC1-Inh deficiency was made correctly inmost cases in this survey. We can recommend the chromogenic assay for the determination of fC1-Inh, while the complex ELISA needs further investigation. (C) 2008 Elsevier B.V. All rights reserved

Hereditary angioedema (HAE) is an autosomal dominant disease that manifests as intermittent acute swellings of the skin and mucosal surfaces, which, in the gastrointestinal tract and larynx, may even be fatal. HAE results from functional deficiency of the C1 inhibitor (C1INH) protein, which plays a key role in the classical pathway of complement activation. C1INH is the sole inhibitor of the activated proteases C1r and C1s, and is the major regulator of activated coagulation Factor XII and plasma kallikrein, which limits the generation of the vasoactive peptide bradykinin. In this paper, we report on the genetic analysis of 173 families (including 326 members) with a clinical diagnosis of HAE. Direct sequencing, Southern blotting and quantitative PCR by the MLPA method were used to screen for mutations in C1INH (SERPING1). In 142 families (82.1%), a causative C1INH gene mutation could be identified. A total of 80 novel point mutations of C1INH not published previously were detected in 96 pedigrees (including 172 members). Our results corroborate C1INH (SERPING1) deficiency as a disease of extreme allelic heterogeneity with almost each individual family carrying their own mutation. Routine molecular genetic analysis is an effective way of confirming the clinical diagnosis and identifying mutation carriers early on before any clinical manifestation becomes apparent. It is, therefore, a valuable tool in prevention and adequate treatment of acute and life-threatening oedema.

Summary. Immune tolerance induction (ITI) in haemophilia B patients with inhibitor should be carefully considered because of the relatively poor (25%) overall success rate and the high risk of complications. ITI in combination with an immunosuppressive treatment was started in two children with haemophilia B with factor IX (FIX) inhibitor. To avoid anaphylactic reactions and inhibitor boost, the FIX replacement therapy was stopped and patients received a treatment with recombinant activated factor VII (rFVIIa). After disappearance of FIX inhibitor, a combination of mycophenolate-mofetil (MMF), dexamethasone (DEXA) and intravenous immunoglobulin (IVIG) and a high dose FIX replacement therapy was started. Immune tolerance could be induced in patient 2, whereas eradication of FIX inhibitor was incomplete in patient 1. Both patients benefited from the immune suppressive treatment and FIX replacement therapy was tolerated without any allergic complications. Neither development of a nephrotic syndrome nor a severe bleeding episode was observed. Strategies to induce tolerance in haemophilia B patients with inhibitors need to be explored in a systematic way. Given the low frequency of disease and even lower incidence of inhibitors, prospective randomized studies may not be possible. International registry-based retrospective and prospective data collection could play the key role in the study of the outcome variables in ITI for haemophilia B.

CCR5 is a chemokine receptor that mediates entry of human immunodeficiency virus-1 (HIV-1). Two monoclonal antibodies (mAbs) that block HIV-1 entry, 3A9 and 5C7, were used to select peptide mimotopes of sequences on CCR5 from phage displayed peptide libraries. The selected mimotofpes comprised motifs at the N-terminus and on the first and third extracellular loops (ECL1 and ECL3) of CCR5. Amino acids in these motifs were exchanged for alanines by site-directed mutagenesis (sdm) in the cDNA for human CCR5. Ensuing effects on antibody binding to CCR5, cellular entry of HIV-1 and chemokine-induced signalling were analysed by transfection of mutant cDNAs into HEK293.CD4 cells. For both mAbs, fluorescence-activated cell sorting analysis was used to define overlapping conformational epitopes on CCR5 at the N-terminus, on ECL1 and ECL3. Mutation of the N-terminal motif 10YD11 prevented HIV-1 entry into transfected cells as judged by single round infection assays with R5 and R5X4 HIV-1 isolates, as did mutation of the motif 96FG97 in ECL1, whereas mutation of the motif 274RLD276 in ECL3 had only a minor effect. None of the motifs in CCR5 relevant to HIV-1 entry disrupted chemokine-induced signalling. Thus, peptide mimotopes of conformational contact sites of CCR5 with the paratope of mAbs 3A9 and 5C7 represent sites on CCR5 that are essential for HIV-1 entry. Structural knowledge of these mimotopes could help elucidate the nature of the interaction between CCR5 and HIV-1, and thus the derivation of specific inhibitors of entry of HIV-1 into susceptible cells without interference with chemokine signalling.

Background In hereditary angioedema, bradykinin is assumed to be the most important mediator of edema formation. Objective To assess whether the selective bradykinin receptor-2 antagonist Icatibant is effective in acute edema attacks of hereditary angioedema. Methods In this uncontrolled pilot study, 15 patients with 20 attacks were treated with Icatibant. The attacks were analyzed by using a standardized and validated visual analog scale measurement and compared with historical data of untreated attacks. Plasma bradykinin concentration was measured before and 4 hours after intravenous Icatibant treatment. Results Symptom intensity decreased within 4 hours after administration of Icatibant; the median time to onset of symptom relief was 1.50, 1.42, and 1.13 hours in the intravenous groups and 0.58 and 0.45 hours in the subcutaneous groups, respectively. The median difference in the 10-cm visual analog scale 4 hours after start of treatment was 4.11 cm (95% CI, 1.72-6.07). Compared with untreated attacks, Icatibant treatment reduced the mean (SD) time to onset of symptom relief by 97% from 42 ± 14 to 1.16 ± 0.95 hours (all groups combined). Median bradykinin concentration was 7-fold above the norm during acute attacks at 48.5 pmol/L and decreased to 18.0 pmol/L 4 hours after Icatibant infusion or injection. Conclusion Icatibant was effective in treating acute attacks of hereditary angioedema. Clinical implications This is the first report demonstrating the clinical usefulness of antagonizing bradykinin binding to bradykinin receptor-2 in hereditary angioedema.

Without treatment, pregnancies in patients with congenital afibrinogenemia terminate in miscarriage at 5-6 weeks of gestation. Animal model studies have suggested that implantation site bleeding contributes to miscarriage in afibrinogenemia; however, retrochorionic hematoma in human congenital afibrinogenemia has not been previously observed. A patient with congenital afibrinogenemia receiving fibrinogen prophylaxis developed a retrochorionic hematoma in the first trimester. With continuous intensified fibrinogen concentrate replacement the hematoma resolved over 6 weeks, and the patient delivered a healthy infant. Median fibrinogen levels in the first trimester were 48 mg/dL and in second and third trimester 44 mg/dL. Median fibrinogen levels under 60 mg/dL may be adequate to maintain pregnancy in patients with congenital afibrinogenemia, although it is possible that higher levels might reduce the risk of hemorrhagic events.

Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder.

Hintergrund. In einer prospektiven Studie wurden Viruslastsenkung, CD4-Zellanstieg, Compliance und Resistenzentwicklung bei 16 therapienaiven padiatrischen Patienten uber einen Zeitraum von 24 Monaten unter einer initialen 3fach-Therapie untersucht. Die Auswertung erfolgte als Intention-totreat-Analyse.

Twenty-four joints (10 knees and 14 ankles), with at least one manifestation of bleeding (proven by sonographic assessment), of 15 patients with haemophilia were investigated prospectively. For magnetic resonance imaging (MRI) evaluation, the MRI scale of Nuss et al. was modified to a MRI score (max. 13 points/joint) to allow a comparison with the physical examination score (max. 12 points) and the radiological score (Pettersson score; max. 13 points). The number of joint bleeds correlated well with the degree of arthropathy P < 0.01). In all 16 joints with a maximum of two bleeds, no alterations were found by physical examination, or radiological and MRI assessment. Joints with three bleeds had physical examination scores between 0 and 2, Pettersson scores from 0 to 3 and MRI scores of 2. Joints with four or more bleeds had physical examination scores ranging between 3 and 7, radiological scores between 7 and 12 and MRI scores between 3 and 8. The MRI score describes initial joint alterations more precisely and earlier than other assessments, allowing a discerning estimation of the degree of arthropathy, as well as a follow-up of haemophilic arthropathy and an improvement after change of treatment. In addition, the modified MRI score seems to differentiate better between early and advanced signs of arthropathy than the MRI scale of Nuss et al.

Inhibitor development is the most problematic and costly complication of haemophilia treatment. Inhibitor development depends on a complex multifactorial immune response that is influenced by patient- and treatment-related factors. Considerable research is focussed on inhibitor development as well as the mechanism of eradication through immune tolerance induction (ITI). Once an inhibitor develops, two general treatment options are available: to treat acute bleeds through bypassing agents, and to eradicate the inhibitor permanently through ITI. Previously untreated haemophilia A patients (PUPs) are at greatest risk of inhibitor development within the first 20 exposure days to factor VIII (FVIII). Inhibitor incidence in PUP studies ranges from 0% to as high as 52%. Plasma-derived FVIII concentrates have repeatedly been shown in cohort studies to be associated with a decreased inhibitor risk compared with recombinant FVIII concentrates, but results from randomized clinical trials are lacking; although one such trial is ongoing (SIPPET study). The occurrence of an inhibitor represents a major hardship for the patient and his family, and can result in high morbidity and a significant reduction in quality of life. Inhibitor eradication often requires the need for demanding and expensive treatment strategies aimed at inducing immune tolerance or bypassing the inhibitor. The role of von Willebrand factor (VWF) in immunoprotection is currently under review. The high-purity, pasteurized, plasma-derived FVIII concentrate, Beriate(®), contains sufficient amounts of VWF to not only bind all FVIII molecules but also provide additional FVIII binding sites, and may have additional beneficial effects that reduce the general immunogenicity of FVIII.

After a first episode of spontaneous venous thromboembolism (VTE), the risk of recurrence persists for many years. However, comprehensive data about the risk of recurrence in pediatric patients have hitherto not been reported. Thus, this study evaluated the risk of recurrent VTE among children in relation to the presence of single or combined-inherited and/or acquired causes of thrombophilia. A total of 301 patients aged neonate to 18 years (median, 6 years) who were referred for an objectively confirmed first episode of spontaneous VTE were followed prospectively for a median time of 7 years (range, 6 months to 15 years) after withdrawal of anticoagulation. All patients were studied for established acquired and inherited causes of thromboembolism. With reference to all 301 patients, one single prothrombotic risk factor was found in 176 subjects (58.5%), whereas combined defects were found in 20.6% (n = 62). Recurrent VTE occurred in 64 patients (21.3%) within a median time of 3.5 years (range, 7 weeks to 15 years) after withdrawal of anticoagulation, with a significantly shorter cumulative thrombosis-free survival in children carrying combined defects (P.0001; chi-square, 42.2). The factor V G1691A mutation was present in the majority of patients with recurrent VTE. Including genetic defects, gender, and acquired risk factors, multivariate analysis showed that only the presence of prothrombotic defects increases the risk of recurrent VTE (single defect: odds ratio [OR], 4.6; 95% confidence interval [CI], 2.3-9.0; P.0001; combined defect: OR, 24.0; 95% CI: 5.3-108.7; P.0001). As a consequence of the data presented here, it is suggested that screening for genetic risk factors be done among pediatric patients with VTE.

The factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, the methylenetetrahydrofolate reductase (MTHFR) T677T genotype, together with fasting homocysteine (HCY) concentration, lipoprotein (Lp)(a), anti-thrombin (AT), protein C (PC), protein S (PS) and anti-cardiolipin antibodies were investigated in 65 consecutively recruited infants (neonate to < 12 months) with renal venous thrombosis (RVT; n = 31), portal vein thrombosis (PVT; n = 24) or hepatic vein thrombosis (HVT n = 10), and 100 age- and sex-matched healthy controls. FV G1691A was found in 14 babies (heterozygous: RVT n = 9, PVT n = 4; homozygous HVT n = 1) and five controls, the MTHFR TT677 genotype together with increased HCY in four infants with thrombosis (RVT n = 2; PVT n = 1; HVT n = 1) compared with one control, and the PT G20210A variant was present in one control only. PC type I deficiency was diagnosed in three patients (RVT n = 2; PVT n = 1) and AT deficiency in two patients (RVT n = 1; PVT n = 1). Three neonates with spontaneous thrombosis showed FV G1691A combined with Lp(a) and the FV G1691A was combined with the PT G20210A genotype in two infants. Additional triggering factors were reported in 27 patients (41.5%). The overall odds ratios (ORs) and 95% confidence intervals (CIs) with respect to the different thrombosis locations were: RVT (OR/CI: 10.9/3.85-31.1; P < 0.0001), PVT (5.47/1.7-17.6; P < 0.0007) and HVT (3.3/0.58-18.7; P = 0.18). The data presented here suggest that genetic prothrombotic risk factors also play an important role in abdominal venous thrombosis during infancy.

Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder. Mutations and polymorphisms of the FVII gene were characterized in more than 40 unrelated patients with FVII deficiency. Among the 29 different mutations, the most frequent were Ala294 Val, Ala294Val;404delC, IVS7+7, and Val281 Phe. Four novel mutations (IVS2+1G>C, Arg247 Cys, Glu265 Lys, Asp343 His) were detected. The relationships between genotypes of mutations and polymorphisms of the FVII gene, FVII deficiency, and clinical phenotype were investigated. Homozygosity of the Phe4 Leu, IVS4+1G>A, Cys135 Arg, Ala244 Val, and Ala294 Val;404delC and the double heterozygosity of Tyr68 Cys / IVS3-1G>A, Val252 Met / IVS2+5G>T, Val281 Phe / Cys135 Arg, Ala294 Val / Val281 Phe, Ala294 Val;404delC / Val281Phe, Ala294 Val;404delC / Arg152 stop, Ala294Val;404delC / Gln(-35) stop, Ala294 Val / Val252 Met, Ala294 Val / Gly156 Asp, and Thr359 Met / Asp242 His were related to clinical symptoms. Double heterozygotes for Arg247 Cys / IVS2+1G>C, Ala206 Thr / Pro303 Arg, Leu(-20) Pro / Val252 Met as well as IVS7+7 /Ala294 Val, IVS7+7 /Ala206 Thr, and IVS7+7 / Met298 Ile were asymptomatic. The clinical symptomatology is rather poor in correlation with the FVII activity. Concerning the clinical phanotype, a correlation seems to exist between specific mutations and clinical symptoms.

Many studies have shown a high percentage of venous thromboses in children to be associated with haematological disorders. However, studies assessing the influence of haemostaseological disorders on paediatric stroke are rare. We compared 26 children with cerebral infarction (median age 2 months, range 0-16.2 years) and 17 with venous thrombosis (median age 4.5 years, range 0-17 years) with regard to prothrombotic risk factors. Prothrombotic disorders were found in 8 out of 26 patients with cerebral infarction (FV Leiden mutation: n = 4; protein C deficiency: n = 1; FV Leiden mutation + protein C deficiency: n = 2; prothrombin mutation G20210A: n = 1) and in 13 out of 17 with venous thrombosis (FV Leiden mutation n = 3; protein C deficiency n = 5; elevated HRGP + PAI: n = 1, combined deficiency of AT, protein C and plasminogen: n = 1; F XII deficiency: n = 1; lupus anticoagulans n = 1; FV Leiden + F XII deficiency + lupus anticoagulans + PAI: n = 1). Comparison of these prevalences with those of 150 healthy paediatric controls showed in children with FV Leiden mutation and/or protein C deficiency an increased risk of cerebral infarction (patients vs. controls: 26.9% vs. 6%; OR 5.77; 95%-CI 1.92-17.3; P = 0.0031) as well as of venous thrombosis (53% vs. 5.3% 19.9; 95%-CI 6-65.6; P0.0001). This result is in contrast with reports on thrombophilia in cerebral infarction in adult patients.Our results indicate that FV Leiden mutation and protein C deficiency may contribute to the multifactorial aetiology of stroke in early childhood.

To evaluate the role of multiple established and potential causes of childhood thrombophilia, 285 children with a history of thrombosis aged neonate to 18 years (first thrombotic onset) were investigated and compared with 185 healthy peers. APC- resistance (FV:Q506), protein C, protein S, antithrombin, heparin cofactor II (HCII), histidine-rich glycoprotein (HRGP), and prothrombin (F.II), factor XII (F.XII), plasminogen, homocysteine and lipoprotein (a) (Lp(a)) were investigated. In 59% of patients investigated one thrombotic defect was diagnosed, 19.6% showed two thrombotic risk factors, while in 21.4% of children investigated no risk factor could be identified. Single defects comprised established causes of inherited thrombophilia: FV:Q506 (homozygous n = 10, heterozygous n = 69), protein C (homozygous n = 1; heterozygous n = 31), heterozygous type I deficiency states of protein S (n = 7), antithrombin (n = 7) and homocystinuria (n = 6); potentially inherited clotting abnormalities which may be associated with thrombophilia: F.XII (n = 3), plasminogen (n = 2), HCII (n = 1), increased HRGP (n = 4); new candidate risk factors for thrombophilia: elevated plasma levels of Lp(a) (n = 26), F.II (n = 1). Heterozygous FV:Q506 was found in combination with heterozygous type I deficiency states of protein C (n = 2), protein S (n = 13), antithrombin (n = 8) and HCII (n = 1), increased Lp(a) (n = 13), and once each with elevated levels of F.II, moderate hyperhomocysteinemia, fibrinogen concentrations >700 mg/dl and increased HRGP. In addition to the association with FV:Q506, heterozygous protein C type I deficiency was combined with deficiencies of protein S (n = 2), antithrombin (n = 1), and increased Lp(a) (n = 3). One patient showed protein C deficiency along with familially increased von Willebrand factor >250%. Besides coexistence with FV:Q506 and protein C deficiency, protein S deficiency was combined with decreased F.XII and increased Lp(a) in one subject each. Furthermore, we found combinations of antithrombin deficiency/elevated Lp(a), hyperhomocysteinemia/Lp(a), deficiency of HCII/plasminogen, and plasminogen deficiency along with increased Lp(a) each in one. Increased prothrombin levels were associated with fibrinogen concentrations >700 mg/dl and with HCII deficiency in one child each. Carrier frequencies of single and combined defects were significantly higher in patients compared with the controls. Conclusion In conclusion, data of this multicentre evaluation indicate that paediatric thromboembolism should be viewed as a multifactorial disorder.

A survey among centres of the paediatric group of the GTH was performed to evaluate the prevalence and outcome of haemophiliacs with intracerebral haemorrhage. A questionnaire sent to the centres covered the following points: number of patients with severe, moderate and mild haemophilia A and B; for each patient with ICH: birth date, age at bleeding, aetiology and neurological sequelae. Overall, 30 ICH in 744 haemophiliacs (4.0%) were reported by 17/40 centres (42.5%). There was no significant difference between the prevalence of patients with haemophilia A and B (3.5% vs. 6.3%) and among the age groups. Bleeding was diagnosed within 1 week of birth in 11/27 patients (41%). For 3 patients, no age-related information was given. The most important factor was trauma (17/30 = 57%), either during birth (9/30 = 30%) or later in life (8/30 = 27%). Seizures were common, occurring in 19/30 patients (63%). As 1 patient died after posttraumatic ICH, the neurological outcome of 29 patients could be evaluated. Psychomotor and statomotor retardation and cerebral palsy were reported in 17/29 (59%), 15/29 (51%) and 13/29 (45%) patients respectively. Only 7/29 (24%) showed no neurological sequelae. Severity of deficits was not correlated with birth date but to age at bleeding. Older children showed a better neurological outcome than neonates.The frequency and outcome of ICH in haemophiliacs have not changed in our cohort over the past 20 years. Trauma at birth is an important risk factor for ICH in patients with haemophilia A or B. Intracranial haemorrhages in older children are rare, and a better outcome may be expected.

Objective: In an intent-to-treat study increase in CD4 cell count, reduction of viral load, clinical benefit and adverse reactions were examined in HlV-infected previously treatment-naive children taking triple therapy. Methods: sixteen HlV-infected children in category A or B on antiretroviral triple therapy were followed-up for a period of 12 months. In group I eight patients received zidovudine, lamivudine and nelfinavir; in group II eight patients received stavudine, didanosine and nelfinavir. Viral load and CD4 cell count were measured every 4-8 weeks. Plasma nelfinavir levels were assessed once in all patients at baseline and monitored in patients with increasing viral load. Results: No significant differences were observed between treatment groups in terms of CD4 cell counts and viral load. A median viral load reduction of 2.8 log 10 (range, 1.4-4.2 log 10 ) was achieved over a period of 12 months in both groups. Viral load < 500 copies/m was found in 69% of patients and viral load < 50 copies/ml in 44% of patients after 12 months. Median CD4 cell count increased from 656 × 10 6 to 850 × 10 6 cells/l after 3 months and was maintained at 813 × 10 6 cells/l after 12 months of treatment. Main side-effects were diarrhoea, rash and hyperlipidaemia. Except for application problems, both regimens were well tolerated. Appropriate formula and individual counselling must be performed during the first weeks of treatment in order to achieve good compliance in paediatric patients. Conclusion: Triple antiretroviral therapy shows a stronger and more sustained reduction of viral load in HlV-infected children compared with studies combining two nucleoside analogues.

SummaryThis review analyses literature reports from 1970 to 1998 assessing the use of streptokinase (SK), urokinase (UK) or recombinant tissuetype 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; χ2-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.

Hereditary angioedema (HAE), caused by functional deficiency of C1-esterase inhibitor1 (C1-INH), is a rare disease characterized by recurrent, spontaneous, nonallergic edema in subcutaneous (SC) tissues and mucous membranes. In case of laryngeal edema, HAE is associated with high mortality rates when there is a delay in treating the attacks.2,3 HAE is a debilitating disease that can have a severe effect on quality of life. C1-INH is a serine protease inhibitor that controls vascular permeability by acting on the initial activation phase of the complement, coagulation, contact, and fibrinolytic systems. The functional deficiency of C1-INH leads to increased activation of plasma kallikrein and Factor (F)XIIa with a subsequent release of bradykinin, which is a key mediator of vascular permeability.4 Additionally, C1-INH is the main inhibitor of FXIa, which plays an important role in the generation of thrombin, a positive modulator of vasopermeability.5-8 HAE Type I results from a quantitative deficiency in functional C1-INH, whereas the less common HAE Type II, affecting 15% of patients, results from a dysfunctional form of C1-INH circulating at normal or elevated plasma concentrations.4 Both defects are inherited as an autosomal dominant trait. HAE Type III is extremely rare, with mainly women being clinically affected; it is not associated with C1-INH deficiency and its pathophysiology is uncertain.9 Common anti-inflammatory treatments, such as corticosteroids, antihistamines, or epinephrine, are usually inappropriate for treating acute attacks caused by HAE.10 Clinical studies,11-13 as well as more than 30 years of clinical use,14,15 have shown that intravenous (IV) C1-INH replacement therapy with human C1-INH concentrate is an effective and safe treatment for acute edema attacks in patients with HAE. Therefore, C1-INH concentrate is recommended as first-line therapy in this indication.16 In patients with HAE requiring frequent IV treatment with C1-INH concentrate, either for acute edema attacks or for prophylaxis, venous access may become difficult over time. The SC administration of C1-INH concentrate is therefore being investigated as a potential alternative therapeutic approach, specifically for the prophylactic treatment of HAE. In support of this approach, a preclinical study with CSL Behring's human pasteurized C1-INH concentrate (Berinert, CSL Behring, Marburg, Germany) revealed a relative bioavailability of approximately 70% after SC administration in rabbits, compared with IV administration (Ingo Pragst, CSL Behring, May 2013). Building on this preclinical experience, the primary objective of our study was to compare the pharmacokinetics of the same preparation of C1-INH concentrate after IV and SC administration in subjects with mild or moderate HAE during an attack-free interval, evaluating the relative bioavailability of SC administration based on plasma levels of C1-INH activity. In addition to assessing the safety and tolerability of C1-INH concentrate when administered via both these routes, we also assessed plasma levels of C1-INH antigen and cleaved high-molecular-weight kininogen (clHK), serum levels of C4 antigen, and the presence of C1-INH antibodies after treatment. These additional endpoints were assessed to provide insight into the pharmacokinetic and pharmacodynamic effects of the C1-INH concentrate administered.

ZusammenfassungDie steigende Anzahl von thrombotischen Ereignissen im Kindesalter, auch bedingt durch die zunehmenden Katheterisierungen in Neonatologie, Kardiologie und Onkologie, zeigen die Bedeutung und Notwendigkeit thrombolytischer Therapien im Kindesalter. Die Indikationsstellung zu einer thrombolytischen Therapie hängt ab von der Lokalisation des Verschlusses sowie den Zielen und möglichen Folgen einer Thrombolyse. Für die Anwendung der Thrombolytika Streptokinase und Urokinase bei Erwachsenen liegen Richtlinien vor, aus denen die Indikationen eindeutig hervorgehen. Im Kindesalter existieren inzwischen zahlreiche Erfahrungen mit der Lysetherapie, jedoch gibt es keine offiziell erstellten Indikationen für diese Therapie. Daher muß bei Kindern auf bisher publizierte Erfahrungen bei der Indikationsstellung zurückgegriffen werden und der zu erwartende Nutzen einer thrombolytischen Therapie gegenüber möglichen Folgeschäden abgewogen werden.Durch die Entwicklung des Thrombolytikums rt-PA haben sich neue Aspekte für die Lysetherapie bei Kindern ergeben. Eine fibrinolytische Behandlung mit rt-PA bietet den großen Vorteil einer weitgehend fibrinspezifischen Wirkung im Gegensatz zu Streptokinase und Urokinase. Ein weiterer Vorteil liegt in der guten Steuerbarkeit der fibrinolytischen Therapie mit rt-PA aufgrund der kurzen Halbwertszeit.Generell sollte die Indikation zur Thrombolyse im Kindesalter gestellt werden, wenn von dem thrombotischen Verschluß unmittelbar eine Lebensbedrohung ausgeht oder wenn eine lebensbedrohliche Krankheitsprogredienz durch eine erfolgreiche Lyse abgewendet werden kann. Außerdem ist die Indikation zur Lyse dann gegeben, wenn ein sicherer oder möglicher Dauerschaden aus dem Thromboseereignis erwächst. Eine Lyse kann auch indiziert sein, wenn dadurch Beschwerden des Patienten bekämpft werden oder ein thromboembolisches Ereignis beziehungsweise ein Thromboserezidiv verhindert werden kann. Vor jeder Indikationsstellung müssen eventuelle Kontraindikationen beachtet werden. Eine Relativierung der Kontraindikationen ist bei vitaler Indikation beziehungsweise bei zu erwartenden schweren Folgeschäden zu erwägen.

In 34 perinatally HIV infected children time of manifestation, type and treatability of neurologic disorders were investigated for a period of 7 years (1987-1994). Neurological investigations were done every 6 months; EEG and MRI/CT were examined initially in the asymptomatic stage and were repeated when neurologic Symptoms occurred. Zidovudine therapy was started after onset of symptoms, dosage was raised, when treatment with Zidovudine had already begun (600-720 mg/m2/day). Various neurological manifestations were seen in 4 of 12 patients in stage B (33%) and in 11 of 14 children in AIDS (80%). 7 of the 14 AIDS-patients (50%) developed a subacute progressive course or progressive plateau course and 4 of 14 (30%) a static course of encephalopathy. Pathological changes in EEG were seen in 54% of investigated patients with neurological deficits. Neuroimaging revealed pathological findings in all symptomatic subjects, 6 of 11 patients in AIDS (55%) has a severe general cerebral atrophy and multifocal white matter lesions. Zidovudine had a positive temporary effect from 6 to 12 months in 5 of 11 treated patients (45%). At present a thorough neurological examination is the most sensitive method to detect neurological impairment in HIV infected children. In most cases CT/MRI scan provides information about the course of the encephalopathy. Antiretroviral therapy has a limited benefit, if neurologic symptoms start after the second year of life.

One of the most serious complications of the treatment of haemophilia A is the development of inhibitors. Former studies mostly considered the prevalence of inhibitor development, thus underestimating its true risk. Prevalences ranged widely (7-18%) probably due to the populations studied and the study design. Recent prospective previously untreated patients (PUP) studies were more comparable because of similar study designs. Eight PUP studies regarding the incidence of factor VIII inhibitors were analyzed: The inhibitor incidences (Independent of severity of haemophilia) ranged from 18.4 to 28%. Evaluating only severe haemophiliacs (factor VIII < 2%) significantly higher incidences were found. After 9-36 exposure days (as medians inhibitor development occurred at 0.8-3.3 years of age (as medians).

Among the proposed predictors for immune tolerance induction (ITI) outcome, the therapeutic regimen - specifically the dose and frequency of administered factor VIII (FVIII) as well as FVIII product type - is intensely debated. Are there any advantages for low-dose regimens (50 IU FVIII kg(-1) three times a week) over high-dose regimens (200 IU FVIII kg day(-1)) or vice versa? Are von Willebrand factor (VWF)-containing plasma-derived concentrates superior to recombinant FVIII concentrates for tolerance induction? A review of the available literature indicates that patients with good prognostic factors can achieve success with either low-dose or high-dose ITI regimens. Retrospective data suggest that patient characteristics such as maximum historical inhibitor titres and pre-ITI inhibitor titres are better predictors of treatment success than dose. Results of the prospective International ITI Study have recently become available. In inhibitor patients with good prognosis, success rates were similar between low-dose (50 IU FVIII kg(-1) three times a week) and high-dose (200 IU FVIII kg(-1) daily) regimens. However, patients receiving low-dose ITI took longer to achieve various ITI milestones and had a significantly higher bleed rate per month compared with the high-dose group (0.62 vs. 0.28; P = 0.00024), findings with important clinical implications. Inhibitor patients with poor prognostic features should be treated with a high-dose protocol. This conclusion is supported by a meta-analysis of the International Immune Tolerance Registry and North American Immune Tolerance Registry and by data from Germany showing good success rates with the high-dose, high-frequency Bonn protocol in poor prognosis patients. Type of concentrate also appears to have an influence on ITI success rates in this patient subgroup, with evidence suggesting an advantage for VWF-containing plasma-derived FVIII concentrates over recombinant or VWF-free concentrates. The ongoing prospective studies REScue Immunotolerance STudy and Observational Immune Tolerance Induction are evaluating ITI outcome with respect to product type and are expected to answer this important clinical question as well as provide greater insight into patient- and therapy-related variables in inhibitor patients with poor prognostic features.

Summary. We report our clinical experience in the first inhibitor detection and onset of IT therapy and to immune tolerance (IT) therapy of 21 paediatric haemo- interruption of IT therapy. For a rapid elimination of philiacs with FVIII inhibitor: high responders (16 HR) FVIII inhibitors it is important to start continuous received initially FVIII twice daily at a dosage of 50- administration of high-dose FVIII (2100 FVIII U/kg/ 300U/kg/day, 11/16 received a concomitant treatment day) before repeated exposure to FVIII, in order to with activated prothrombin complex concentrate (100- prevent rebooster effects, prolongation of elimination 200 U/kg/day). Low responders (five LR) received 20- time, and to reduce expense. 100 FVllI U/kg every second or third day. Inhibitor elimination was achieved in 19/21 patients in a median time of 4 months in HR and 1.5 months in LR. The outcome and length of time needed to induce IT was Keywords: factor VIII inhibitors, children with haemo- philia A, immune tolerance therapy, requirements for successful FVIII inhibitor elimination. significantly correlated with FVIII exposure between the Antibody formation against substituted factor VIII (FVIII) represents the most severe complication

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.

In our center, 289 children with von Willebrand’s disease (vWD) have been diagnosed since 1982. The majority of cases (n = 198) were congenital vWD whereas 91 patients suffered from vWD induced by valproate (VPA). We overview bleeding episodes in 45 children and 64 operative procedures requiring therapeutic intervention. The aim of therapeutic and prophylactic procedures in vWD is correcting the hemostatic disorder and normalization of bleeding time. This can be achieved by application of Haemate P leading to an elevation of plasma levels of von Willebrand parameters together with normalization of bleeding time. In patients with vWD type I, DDAVP will be preferred if contraindications can be excluded and efficacy has been shown. Severe bleeding complications could be prevented in a total of 50 surgical procedures in children with vWD type I by prophylactic treatment with DDAVP or Haemate P. Two children initially treated with DDAVP had to be substituted with Haemate P in the follow-up because of continuous bleeding. In type IIa and type III vWD as well as in VPA-induced vWD, the use of Haemate P was essential for sufficient hemostasis in all bleeding and operations. We conclude that Haemate P provides effective bleeding prophylaxis and treatment in all types of vWD except platelet-type.

C1-esterase inhibitor (C1-INH) replacement therapy is the treatment of choice for acute edema attacks in patients with hereditary angioedema (HAE).Our retrospective, observational study assessed the efficacy and safety of home therapy with a human plasma-derived C1-INH concentrate (pC1-INH) in 20 pediatric patients with HAE who had previously been treated with physician-based therapy. While on home therapy, 15 patients received on-demand treatment and five received individual replacement treatment (IRT).The switch to home therapy did not involve a significant increase in the dose of pC1-INH administered, but there was a significant increase in dosing frequency. Although only two patients were affected, the frequency of laryngeal attacks appeared to decrease on home therapy. All attacks, including laryngeal edema, were treated successfully during home therapy with pC1-INH. The mean annual number of days hospitalized was reduced from 3.8 during physician-based therapy to 0.11 during home therapy. No side effects or injection site complications were reported. The median time from onset of attack to administration of pC1-INH was reduced from 67.5 minutes during physician-based therapy to 15 minutes after switching to home therapy. The corresponding median time to initial symptom relief for all types of attack was reduced from 60 to 40 minutes.As in adults, home therapy with pC1-INH is effective and safe in the treatment of HAE attacks in pediatric patients; a larger, randomized study should ideally confirm our findings before this approach can be considered the standard of care for pediatric patients.

From 1988 to 1991 the long-term efficacy of a combined therapy with a polyvalent immunoglobulin/cytomegalovirus (CMV) hyperimmunoglobulin, oral low dose zidovudine, oral cotrimoxazole or inhaled pentamidine was investigated in three groups of human immunodeficiency virus (HIV)-infected children. Group 1A consisted of three perinatally infected children with a CD4 cell decrease of >400, cells/μl per year. Group 1B were 17 perinatally infected children with a CD4 cell decrease of