C. Escuriola Ettingshausen

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.

Recombinant vs. plasma-derived products, especially those with intact VWF, regarding inhibitor development.

Summary.  The development of inhibitors in previously untreated patients (PUPs) with haemophilia A is correlated with a variety of endogenous and exogenous risk factors. It is still controversial whether recombinant factor VIII (rFVIII) products pose a higher risk for inhibitor development than plasma‐derived (pd) FVIII concentrates, particularly with intact von Willebrand factor (VWF). A systematic review on the epidemiology of inhibitors in haemophilia A investigated the influence of different FVIII products on inhibitor formation. Patients treated with a single pd product had a lower cumulative incidence (0–12.4%) than those treated with a single recombinant concentrate (36.0–38.7%) independent of disease severity, study size, or inhibitor testing frequency. However, this analysis does not take into account the heterogeneity of the study populations. A study investigating the effects of different variables on inhibitor development in PUPs was started 13 years ago by the Paediatric Committee of the German, Austrian and Swiss Society on Thrombosis and Haemostasis Research. This prospectively conducted study revealed a slight difference (P = 0.08) in terms of type of concentrate. In the group of severe haemophiliacs treated with pdFVIII concentrate (n = 57), 12 patients developed an inhibitor (21%), whereas 17 of 47 patients receiving rFVIII (36%) were affected by this complication. This observation was substantiated by retrospective Italian and French analyses. These results, as well as hypothetical considerations, indicate that there is a body of evidence that FVIII products with VWF may be less immunogenic in PUPs. However, in order to provide more evidence a well‐designed randomized study is needed.

Early long‐term FEIBA prophylaxis in haemophilia A patients with inhibitor after failing immune tolerance induction: A prospective clinical case series

Summary.  Persistent high‐titre inhibitors after immune tolerance induction (ITI) increase the risks of haemorrhage and arthropathy, resulting in high morbidity and mortality. Long‐term prophylaxis with bypassing agents may avert these risks. This study was performed to assess the effectiveness and safety of early prophylaxis with FEIBA in preventing bleeding and joint damage after failed ITI. Seven paediatric patients proceeded immediately after failed ITI to long‐term FEIBA prophylaxis at 60–100 IU kg−1 dosages and various dosing intervals depending upon bleeding tendency. Bleeding episodes and joint status were assessed. Thrombin generation assays (TGA) were also used to gauge treatment response. FEIBA prophylaxis was commenced at a median age of 6.0 years (range, 1.5–11.8 years) and continued for a median duration of 6.9 years (range, 0.8–17.1 years). The mean annual incidence of joint bleeding was 1.5 episodes per year with a 95% CI of 0.7–3.0 episodes per year. Muscle bleeding incidence was 0.9 episodes per year (CI, 0.6–1.2 episodes per year). No patient experienced major joint damage during prophylaxis. Median Pettersson and orthopaedic joint scores at the last follow‐up evaluation were 4 (range, 0–12) and 2 (range, 0–4) respectively. Endogenous thrombin potential (ETP) measured by TGA exceeded 80% of normal after FEIBA infusion in the majority of the patients. Between regular prophylactic infusions, mean trough ETP equalled 2.6 fold of the inhibitor plasma control mean. FEIBA prophylaxis was well‐tolerated without serious thrombotic or other complications. The only adverse event involved venous access. Therefore early long‐term FEIBA prophylaxis is valuable in controlling bleeding and preserving joint integrity in young patients failing ITI.

Type and intensity of FVIII exposure on inhibitor development in PUPs with haemophilia A. A patient-level meta-analysis

The impact of treatment-related factors on inhibitor development in previously untreated patients (PUPs) with haemophilia A is still debated. We present the results of a collaborative, individual patient data meta-analytic project. Eligible data sources were published cohorts of PUPs for which patient-level data were available. The exposures of interest were factor (F)VIII type (recombinant [rFVIII] vs plasma-derived [pdFVIII]) and treatment intensity (≥ vs < 150 IU/kg/week) at first treatment. Family history of inhibitors, F8 mutations, age, treatment regimen (on-demand vs prophylaxis), secular trend and surgery were analysed as putative confounders using different statistical approaches (multivariable Cox regression, propensity score analyses, CART). Analyses accounted for the multi-centre origin of the data. We included 761 consecutive, unselected PUPs with moderate to severe haemophilia A from 10 centres in Egypt, Germany, Israel and Italy. A total of 27 % of patients developed inhibitors; 40 % and 22 % of patients treated with rFVIII and pdFVIII (unadjusted HR 2.2, 95 % CI 1.6-2.9), respectively; 51 % and 24 % of patients receiving high- and low-intensity treatment (unadjusted HR 2.9, 95 % CI 2.0-4.2), respectively. In adjusted analyses, only treatment intensity remained an independent predictor; the effect of FVIII type was largely due to confounding, but with a significant interaction between FVIII type and treatment intensity. This patient-level meta-analysis confirms, across different statistical approaches, that high-intensity treatment is a strong risk factor for inhibitor development. The possible role of FVIII type in subgroups is suggested by the test for interactions but could not be proven because of the limited subgroups sample sizes.

Portal vein thrombosis in a patient with severe haemophilia A and F V G1691A mutation during continuous infusion of F VIII after intramural jejunal bleeding--successful thrombolysis under heparin therapy.

Abstract We report on a 14-year-old boy with severe haemophilia A who developed a portal vein thrombosis during continuous infusion of F VIII. For treatment of a posttraumatic intramural jejunal haematoma with extension into the mesenterium the patient received continuous infusion (CI) of a high purity F VIII concentrate, starting with an initial bolus injection of 100 IU F VIII/kg bw and followed by 4–5 IU F VIII/kg bw/h i.v. F VIII plasma activity ranged between 47 and 88%. Resorption of the haematoma was proven by abdominal ultrasonic follow-ups. After 3 weeks of CI a thrombus formation in the portal vein was detected by ultrasound and confirmed by duplex ultrasound. Subsequent to diagnosis the patient was heparinised with unfractionated heparin (UFH 300–450 IU/kg/d i.v.). In order to induce further resorption of the haematoma, F VIII concentrate was given concomitantly (50 IU/kg bw twice daily) during the initial phase of treatment. After 14 days of anticoagulant therapy with UFH, the regimen was changed to low molecular weight heparin (LMWH; Fraxiparin 0.3™; 2850 IU anti-X activity/d s.c.; bw 60 kg). F VIII dosage was gradually reduced with advanced resorption of the haematoma and thereafter switched to prophylaxis (40 IU/kg bw 3 times weekly). Complete lysis of the thrombus was observed after 6 months of treatment with UFH and LMWH respectively without any further complications. Thereafter LMWH was discontinued. Thrombophilic screening revealed no abnormalities except heterozygous F V G1691A. Conclusion The coexistence of a common prothrombotic risk factor and haemophilia may cause severe complications, in particular if the bleeding disorder has to be corrected temporarily by administration of the concerning deficient agent.

First prospective report on immune tolerance in poor risk haemophilia A inhibitor patients with a single factor VIII/von Willebrand factor concentrate in an observational immune tolerance induction study

Development of neutralizing inhibitors against factor VIII (FVIII) is a major complication of haemophilia A treatment.

Prevention of joint damage in hemophilic children with early prophylaxis

SummaryRadiological 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.ZusammenfassungPatienten mit schwerer Hämophilie A und B leiden unter rezidivierenden Gelenkblutungen, deren Folge osteoarthropathische Veränderungen im Sinne einer hämophilen Arthropathie sind. Im Rahmen einer prospektiven Studie untersuchten wir die Bedeutung des Alters bei Beginn einer Langzeitprophylaxe sowie den Einfluß der Anzahl der Gelenkblutungen vor und während Prophylaxe auf das radiologische und orthopädische „Outcome“ des Gelenkstatus bei Patienten mit schwerer und mittelschwerer Hämophilie A und B. Bisher ausgewertet wurden 21 schwere und mittelschwere Hämophilie-A- und -B-Patienten, die zwischen 3,1 und 16,1 Jahren eine Langzeitprophylaxe mit Faktor-(F)-VIII- bzw. IX-Konzentraten durchführten. Die Patienten wurden nach dem Alter bei Beginn der Prophylaxe in 3 Gruppen unterteilt:•In Gruppe I wurde innerhalb der ersten beiden Lebensjahre, spätestens nach der ersten Gelenkblutung, mit der prophylaktischen Behandlung begonnen.•In Gruppe II begann die Prophylaxe zwischen dem 3. und 6. Lebensjahr nach 6 Gelenkblutungen (Median) und in•Gruppe III ab dem 6. Lebensjahr, nachdem es zu rezidivierenden Gelenkblutungen (> 10) gekommen war. Patienten mit Hämophilie A wurden 3mal wöchentlich oder alle 2 Tage mit 30–40 IE, in manchen Fällen bis zu 50 IE F VIII/kg KG substituiert, während Hämophilie-B-Patienten F IX-Konzentrate in gleicher Dosierung 2mal wöchentlich oder alle 3 Tage verabreicht wurden. Zur Erfassung und Quantifizierung möglicher Gelenkveränderungen wurden die von der WFH (World Federation of Hemophilia) empfohlenen standardisierten orthopädischen und radiologischen Scores in 3 bis 4jährigen Abständen erhoben. Zusätzlich wurde die Anzahl der Gelenkblutungen vor und unter prophylaktischer Behandlung dokumentiert. In Gruppe I wiesen 7 von 8 Patienten einen unauffälligen radiologischen und orthopädischen Gelenkstatus sowohl bei Studienbeginn als auch bei Kontrolle nach 4 Jahren auf. Ein unauffälliger radiologischer und orthopädischer Gelenkscore konnte ebenfalls bei Studienbeginn in Gruppe II detektiert werden. Allerdings kam es nach 4 Jahren prophylaktischer Behandlung zu Erstmanifestationen osteoarthropathischer Gelenkveränderungen (orthopädischer Score im Median 4, radiologischer Score im Median 8). Bei den Patienten der Behandlungsgruppe III lagen bereits zu Studienbeginn Gelenkveränderungen vor (radiologischer Score 11 im Median, Spannweite 0–33; orthopädischer Score 4 im Median, Spannweite 0–11 Punkte). Zwar konnte unter prophylaktischer Behandlung eine deutliche Reduktion der Gelenkblutungen erzielt werden; dennoch kam es zu einer Progredienz der bereits vorhandenen Gelenkschäden, zu erkennen an einem Anstieg der radiologischen und orthopädischen Scores im Verlauf (radiologischer Score: 19,5 Punkte im Median; orthopädischer Score: 8 Punkte im Median). Beim statistischen Vergleich des radiologisch untersuchten Gelenkstatus innerhalb der 3 Behandlungsgruppen konnte ein signifikanter Gruppenunterschied festgestellt werden (p < 0,01; Wilcoxon-Rank-Sum-Test): Die Gruppe I, die frühzeitig behandelte Gruppe wies den besten und die Gruppe III, die sekundärprophylaktisch behandelte Gruppe den schlechtesten Gelenkstatus auf. Ein signifikanter Zusammenhang konnte ebenfalls zwischen der Anzahl der Gelenkblutungen und den im Verlauf erhobenen radiologischen Scores erhoben werden (r = 0.921, p < 0.01), wobei die Anzahl der Gelenkblutungen mit der Höhe des radiologischen Scores positiv korrelierte. Bereits wenige Gelenkblutungen führen zu irreversiblen osteoarthropathischen Veränderungen. Die einzige effiziente Möglichkeit der Prävention der hämophilen Arthropathie bei schweren Hämophilen stellt demzufolge eine frühzeitig begonnene Langzeitprophylaxe zur Vermeidung von Gelenkblutungen dar.

The immune tolerance induction (ITI) dose debate: does the International ITI Study provide a clearer picture?

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.

Achievements, challenges and unmet needs for haemophilia patients with inhibitors

Over the past 20 years, there have been many advances in haemophilia treatment that have allowed patients to take greater control of their disease. However, the development of factor VIII (FVIII) inhibitors is the greatest complication of the disease and a challenge in the treatment of haemophilia making management of bleeding episodes difficult and surgical procedures very challenging. A meeting to discuss the unmet needs of haemophilia patients with inhibitors was held in Paris on 20 November 2014. Topics discussed were genetic and non‐genetic risk factors for the development of inhibitors, immunological aspects of inhibitor development, FVIII products and inhibitor development, generation and functional properties of engineered antigen‐specific T regulatory cells, suppression of immune responses to FVIII, prophylaxis in haemophilia patients with inhibitors, epitope mapping of FVIII inhibitors, current controversies in immune tolerance induction therapy, surgery in haemophilia patients with inhibitors and future perspectives for the treatment of haemophilia patients with inhibitors. A summary of the key points discussed is presented in this paper.

Spotlight on the human factor: building a foundation for the future of haemophilia A management: report from a symposium on human recombinant FVIII at the World Federation of Hemophilia World Congress, Melbourne, Australia on 12 May 2014.

Inhibitor development is the most serious and challenging complication in the treatment of severe haemophilia A. Up to 38% of such patients develop inhibitors with current recombinant factor VIII (rFVIII) products produced in hamster cell lines. Human‐cl rhFVIII is a new generation fully sulfated B‐domain‐deleted FVIII coagulant glycoprotein, which is generated from a human cell line. Thus, there are no non‐human epitopes which would be potentially immunogenic. This molecule has significantly higher VWF‐binding affinity compared with existing full‐length rFVIII produced in hamster cell lines. The development aim of Human‐cl rhFVIII is to address the challenges of FVIII inhibitors and frequent infusions during prophylaxis. Human‐cl rhFVIIIs mean half‐life is very comparable to some of the newer products which involve modification of the FVIII molecule to extend the circulating half‐life. There are promising data concerning the use of a personalized prophylaxis regimen with Human‐cl rhFVIII. Preliminary data indicate a median dosing interval of 3.5 days with 66.7% of the patients on a twice per week or fewer infusions schedule combined with a low bleeding rate and no increased FVIII consumption when compared to standard prophylaxis. No product‐specific laboratory assay is required to monitor the coagulation activity for Human‐cl rhFVIII. The results of registration clinical trials with Human‐cl rhFVIII as well as the ongoing studies in previously untreated patients (NuProtect) and personalized prophylaxis study in previously treated patients (NuPreviq), will be discussed. The manufacturer has received marketing authorization for Human‐cl rhFVIII in Europe and Canada under the name Nuwiq® and plans to launch it in the USA and globally in 2015.