Carmen Escuriola-Ettingshausen

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

Epidemiology of Inhibitors in Haemophilia A

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).

Prophylaxis with FEIBA in paediatric patients with haemophilia A and inhibitors

The benefits shown with factor VIII (FVIII) prophylaxis relating to joint health and quality of life (QoL) provide the rationale for FEIBA prophylaxis in haemophilia A patients with persistent FVIII inhibitors. FEIBA has previously shown efficacy in preventing bleeds in inhibitor patients who failed to respond to, or were ineligible for immune tolerance induction (ITI). The study examined the outcome of paediatric patients undergoing long‐term FEIBA prophylaxis. A retrospective chart review included severe haemophilia A patients with persistent inhibitors aged ≤13 years at the start of FEIBA prophylaxis. Baseline characteristics captured dose, frequency of prophylaxis, history of inhibitor development, including baseline titre, historical peak titre and history of ITI. Outcome measurements included annual bleed rate before and during FEIBA prophylaxis, joint status and school days missed. Sixteen cases of FEIBA prophylaxis from two centres are presented. The mean age of subjects at prophylaxis initiation was 7.5 ± 3.6 years and median baseline inhibitor titre was 23 (range 3.1–170) BU. Prior to prophylaxis initiation, median annual joint bleeds among all patients was 4 (0–48), which dropped significantly after the first year of prophylaxis, to a median annual joint bleed rate of 1 (0–7; P = 0.0179). Subsequent years (median = 9) of prophylaxis therapy demonstrated similarly low annual joint bleed rates. There were no life‐threatening bleeds, no viral seroconversions or thrombotic events during FEIBA prophylaxis treatment. FEIBA prophylaxis was effective for preventing joint bleeds and subsequent joint damage, delaying arthropathy and improving outcomes in children with haemophilia A and inhibitors to FVIII, who failed or were ineligible for ITI.

Immune tolerance induction with a factor VIII concentrate containing von Willebrand factor (Haemoctin SDH ®) in 14 patients with severe haemophilia A

C. BIDLINGMAIER,* K. KURNIK,* C. ESCURIOLA-ETTINGSHAUSEN, R. JAGER, R. KLAMROTH,§ C. MALE,– A. MAROSI ,** L. NEMES, A. V O N STACKELBERG and W. KREUZ *Dr. von Hauner s Children s Hospital; Paediatric Haemophilia Centre, Munich, Germany; Johann-Wolfgang-Goethe University Hospital, Comprehensive Care Center for Thrombosis and Hemostasis, Frankfurt am Main, Germany; West Regional Haemophilia Centre, Szombathely, Hungary; §Haemophilia Centre, Vivantes Hospital Friedrichshain, Berlin, Germany; –Medical University of Vienna, Dept Paediatrics, Vienna, Austria; **Heim Pal Children Hospital, Department of Haematology, Budapest, Hungary; National Haemophilia Center and Haemostasis Department, State Health Center, Budapest, Hungary; and Paediatric Oncology and Haematology, Charité, Berlin, Germany

The application of bypassing-agent prophylaxis in haemophilia A patients with inhibitors: a meeting report

L. A. VALENTINO,* M. CARCAO, P. MATHEW, C. A. LEISSINGER,§ E. BERNTORP,– V. BLANCHETTE, C. ESCURIOLA-ETTINGSHAUSEN,** B. EWENSTEIN, N. EWING, A. GRINGERI,§§ W. K. HOOTS–– and C. NEGRIER*** *Departments of Pediatrics and Internal Medicine, Rush University Medical Center, Chicago, IL, USA; Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, NM, USA; §Louisiana Center for Bleeding and Clotting, Tulane University Medical Center, New Orleans, LA, USA; –Department of Coagulation Disorders, Malmo University Hospital, Malmo, Sweden; **Department of Pediatrics, J. W. Goethe University Hospital, Franklin, Germany; Baxter Bioscience, Westlake Village, CA, USA; Division of Pediatrics, City of Hope National Medical Center, Duarte, CA, USA; §§Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy; ––Department of Pediatrics, University of Texas Medical School, Houston, TX, USA; and ***Hemophilia Center, Hopital Edouart Herriot, Lyon, France

Epidemiology of Inhibitor Development in Haemophilia A Patients Treated with Virus– Inactivated Plasma–Derived Clotting Factor Concentrates

tor VIII (FVIII) or factor IX (FVIX) is one of the most serious complications in the treatment of haemophiliacs. The reported frequency of inhibitor development ranges widely and is affected by several variables in study design and study population. Five former studies and six recent previously treated patient (PUP) studies were analysed and compared. In all studies the patients received one virus inactivated plasma derived clotting factor concentrate. Former studies mostly considered the prevalence of inhibitor development, thus underestimating its true risk. Prevalence ranged between 7 and 18% [3, 4, 7, 9, 10]. Six recent, mostly prospective PUP studies on inhibitor incidence revealed inhibitor formation in between 22.3–33% in severe and moderate haemophiliacs. Inhibitor development occured after a median of 11–46 exposure days (ED) at a median age of between 1.7 and 3.3 years [5, 6, 8, 11–13, 18, 19].

Intensity of factor VIII treatment and the development of inhibitors in non-severe hemophilia A patients: results of the INSIGHT case–control study

Essentials Research suggests that intensive treatment episodes may increase the risk to develop inhibitors. We performed an international nested case‐control study with 298 non‐severe hemophilia A patients. Surgery and a high dose of factor VIII concentrate were associated with increased inhibitor risk. Physicians need to review arguments for factor VIII dose and elective surgery extra critically.

Risk Factors for the Progression from Low to High Titres in 260 Children with Severe Haemophilia A and Newly Developed Inhibitors

In children with severe haemophilia A, inhibitors to factor VIII (FVIII) usually develop during the first 50 treatment exposure days and are classified as low or high titre depending on the peak inhibitor titre being greater or less than 5 Bethesda units/mL (BU/mL). Classification of the inhibitor may change with time, as some low-titre inhibitors progress to high titre following re-exposure to FVIII concentrate. The aim of this study was to investigate potential risk factors for such a progression in children with severe haemophilia A and newly diagnosed inhibitors. This study was a follow-up study of the PedNet Registry and included 260 children with severe haemophilia A and inhibitors born between 1990 and 2009 and recruited consecutively from 31 haemophilia centres. Clinical and laboratory data were collected from the date of each childs first positive inhibitor test for at least 3 years. At the time of first positive inhibitor test, 49% (n = 127) had low-titre inhibitors, with 50% of them progressing to high titre and only 25% maintaining low titres. The FVIII gene (F8) mutation type was known in 247 patients (95%), and included 202 (82%) null mutations. The progression to high-titre inhibitors was associated with null F8 mutations (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.0–6.5), family history of inhibitors (OR: 7.2; 95% CI: 1.8–28.4) and the use of high-dose immune tolerance induction, defined as ≥100 IU FVIII concentrate/kg/d (OR: 3.9; 95% CI: 1.5–10.0). These results suggest that high-dose immune tolerance induction should be avoided as the initial strategy in patients who develop low-titre FVIII inhibitors.

Prophylaxis re-visited: The potential impact of novel factor and non-factor therapies on prophylaxis

1Division of Haematology/Oncology, Department of Paediatrics, Child Health Evaluative Sciences, Research Institute, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada 2Haemophilia Care Centre, Bicêtre APHP University Hospital, Le Kremlin-Bicêtre, France 3Tulane University School of Medicine, New Orleans, LA, USA 4HZRM Haemophilia Centre Rhein Main, Frankfurt-Moerfelden, Germany 5Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy 6Icahn School of Medicine, New York, NY, USA

Clinical presentation of inhibitor development in non-severe hemophilia A: Half of patients have high titer inhibitors and present with bleeding complications

Category: Communication Models. Objective(s): The objective of this activity was to increase international awareness of girls and women with bleeding disorders by creating a collection of interesting videos and sharing them through social media. Methods: Women attending several bleeding disorder conferences were given an opportunity to participate in a video activity. Permission forms were obtained from each woman. Several video themes were used to capture information. Some women provided a brief self-introduction. Another video shows a woman holding up posters telling about the signs and symptoms of bleeding and where to find a hemophilia treatment center anywhere in the world. Several videos are groups of girls and women who are dancing and waving. The videos were edited and posted on the MyGirlsBlood Facebook and website. A compilation of the women’s introductions was posted on the World Federation of Hemophilia Facebook page in support of World Hemophilia Day. Results: The statistics below are from November, 2012 – October, 2013: There are over 25 videos created in this collection. There were 6,563 viewings across 46 countries. Top counts were: United States (4,609), India (627), Poland (200), Israel (110), Canada (131), Taiwan (113), China (163), United Kingdom (124), Spain (87), and Argentina (40). Conclusion: Providing video(s) of women with bleeding disorders, the signs and symptoms of bleeding and fun videos all help provide awareness throughout the world of bleeding disorders found in girls and women. Contribution to the Practice/Evidence base of Hemophilia and Bleeding Disorders: The majority of social media, videos and educational materials in the bleeding disorder community are related to boys and men. Materials created directly for women and shared on social networking sites will provide continued growth of the knowledge library of our women’s community. Pregnancy management in inherited bleeding disorders MARIA V INOGRADOVA , ROMAN SHMAKOV , TAT IANA FEDOROVA , EUGEN IA POLUSHK INA and OLEG ROGACHEVSKY Federal Scientific Centre for Obstetrics, Gynecology and Perinatology, Moscow, Russia Introduction and Objectives: In recent years the quality of life of patients with several inherited bleeding disorders (IBD) has improved considerably due to implementation of new medicines as well as the optimization of diagnostic approaches. For this reason the issues of reproductive health with respect to these patients are becoming very important. Early diagnosis, pregnancy planning and establishment of protocols for management of pregnancy and delivery are crucial to their quality of life. Our multidisciplinary team has been optimizing strategy for the management of pregnant patients with IBD. Materials and Methods: Since 2010 we have analyzed 31 pregnancies in 28 women with IBD: 18 with von Willebrand disease (VWD), three carriers of hemophilia A, seven patients with partial deficiency of clotting factors (CF): FI, FVII, FXI, FX. All of them underwent monitoring and preventive treatment when necessary. In VWD, we used the DDAVP and the CF concentrate containing VWF until the levels of CF were above 50 IU/ml. In cases of other CF deficiencies we prescribed the fresh frozen plasma. Recombinant FVIIa has been used to cover Caesarean section and postpartum hemorrhage (PPH). Results: Spontaneous miscarriage has been observed in two (6,5%) patients. No neonatal mortality has occurred. We detected IBD in three newborns. No bleeding events were registered during pregnancy. Most women with type 1 VWD and moderate forms of FVII deficiency, developed an increase of CF levels as a physiological response to pregnancy. Only two (6,9%) cases required regular treatment throughout pregnancy. Therapy administration was based on the mother’s factor levels. Caesarean sections were administered in 12(38,7%) births. We observed the intraoperative hemorrhage in one case (3,4%) of placenta previa, secondary PPH in 3(10,3%) cases. Intracranial hemorrhage has been diagnosed in 3 neonates. Conclusion: The risk of hemorrhagic complications during pregnancy and postpartum in IBD may be minimized by applying of the management algorithm with preventive treatment. For women with low factor levels preventive treatment with CF concentrates is necessary. Women with IBD need clinical vigilance during puerperium. Umbilical cord blood should be taken to measure CF levels in the newborn for prompt diagnosis of IBD. The Self-BAT (Self-administered Bleeding Assessment Tool) is an effective screening tool for von Willebrand disease in women referred to hematology MEGHAN DEFOREST , 1 JUL IE GRABELL , 1 WILMA HOPMAN and PAULA JAMES 1 Queen’s University, Kingston, Canada The value of standardized, quantitative bleeding scores (BS) has been recognized in the assessment of hemorrhagic symptoms, particularly when used as a screening tool to identify patients in need of laboratory testing. Most BATs (bleeding assessment tools) are expert administered; we developed the Self-BAT by converting the ISTHBAT (International Society on Thrombosis and Haemostasis) into lay language and optimized it by studying individuals previously known to have Type 1 VWD and healthy controls. After revision, the Intraclass Correlation Coefficient of Self-BAT BS and ISTH-BAT BS was high at 0.869. The objective of the current study is to test the diagnostic utility of the Self-BAT as a screening tool for women referred to hematology for the first time for a possible bleeding disorder. Female subjects over the age of 18 were recruited in the hematology clinic. Subjects were ineligible if they had a previous diagnosis of a bleeding disorder, were pregnant or had an acquired cause of bleeding (ie: medications, renal or hepatic disease). After informed consent, subjects were provided the Self-BAT and asked to complete it, without assistance, prior to the appointment. BSs were calculated using the 0 to +4 scoring system. Blood was drawn for CBC, ferritin, ABO, VWF:Ag, VWF:RCo and FVIII. To date, 22 females have been enrolled. Subject characteristics can be found in Table 1. Nineteen had a positive or abnormal BS (≥5) and of those five had laboratory results consistent with Type 1 VWD. Therefore, the sensitivity =100%, specificity=18%, positive predictive value=0.26, negative predictive value=1.0. Additional testing of those without VWD (including platelet aggregometry and platelet dense granule quantitation) is ongoing. In conclusion, our preliminary data strongly suggest that the Self-BAT is an effective screening tool to incorporate into the hematologic assessment of women referred for a possible bleeding disorder. VWD (n=5) No VWD (n=17) P value