Frans J. Smiers

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 44u2009800 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.

Human Bocavirus in an Immunocompromised Child Presenting with Severe Diarrhea

ABSTRACT Human bocavirus (HBoV) is frequently detected in young children with respiratory symptoms. However, the prevalence and pathogenicity of HBoV in immunocompromised patients are largely unknown. This report describes a case of life-threatening hypovolemic shock due to diarrhea associated with disseminated HBoV infection in an immunocompromised child.

Inhibitors in nonsevere haemophilia A: outcome and eradication strategies

In nonsevere haemophilia A (HA) patients the presence of an inhibitor may exacerbate the bleeding phenotype dramatically. There are very limited data on the optimal therapeutic approach to eradicate inhibitors in these patients. We aimed to describe inhibitor eradication treatment in a large cohort of unselected nonsevere HA patients with inhibitors. We included 101 inhibitor patients from a source population of 2,709 nonsevere HA patients (factor VIII 2-40 IU/dl), treated in Europe and Australia (median age 37 years, interquartile range (IQR) 15-60; median peak titre 7 BU/ml, IQR 2-30). In the majority of the patients (71u2009%; 72/101) the inhibitor disappeared; either spontaneously (70u2009%, 51/73) or after eradication treatment (75u2009%, 21/28). Eradication treatment strategies varied widely, including both immune tolerance induction and immunosuppression. Sustained success (no inhibitor after rechallenge with factor VIII concentrate after inhibitor disappearance) was achieved in 64u2009% (30/47) of those patients rechallenged with FVIII concentrate. In high-titre inhibitor patients sustained success was associated with eradication treatment (unadjusted relative risk 2.3, 95u2009% confidence interval 1.3-4.3), compared to no eradication treatment. In conclusion, in nonsevere HA patients most inhibitors disappear spontaneously. However, in 35u2009% (25/72) of these patients an anamnestic response still can occur when rechallenged, thus disappearance in these patients does not always equal sustained response. Treatment for those requiring eradication has to be decided case by case, as one single approach is unlikely to be appropriate for all.

Four decades of stem cell transplantation for Fanconi anaemia in the Netherlands.

This article presents the haematopoietic stem cell transplantation (SCT) results of the complete Dutch Fanconi anaemia (FA) patient cohort. Sixty‐eight Dutch FA patients have been transplanted since 1972. In total, 63 (93%) patients engrafted, 54 after first SCT and 9 after second SCT. Fludarabine (FLU)‐based conditioning was associated with decreased graft failure (odds ratio 0·21, P = 0·01), decreased early mortality (hazard ratio 0·25, P = 0·01) and improved 5‐year overall survival (FLU 87·8% [standard error (SE) 5·1%] versus non‐FLU 59·3% [SE 9·5%], P = 0·01). Late mortality was mainly caused by squamous cell carcinoma. Twenty‐two patients were treated with the current Dutch FA conditioning regimen (FLU 150 mg/m2 and cyclophosphamide 30 mg/kg ± anti‐thymocyte globulin ‐ no irradiation). Stem cell donors were matched related (n = 8) or alternative donors (n = 14). Stable engraftment after first SCT was achieved in 19 (86%) patients. At a median follow‐up of 3·9 years 20 (91%) patients are alive. Our study provides a unique overview of a nation‐wide SCT cohort illustrating the major improvements in treatment regimen and patient outcome in recent years. It shows that a non‐irradiation and busulfan‐free conditioning regimen can be used successfully, also in alternative donor SCT. Furthermore, it underlines the importance of late cancer screening and comprehensive care for this complex disorder.

High interpatient variability of treosulfan exposure is associated with early toxicity in paediatric HSCT: a prospective multicentre study

Treosulfan‐based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drugs relationship with regimen‐related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30 g/m2, administered over 3 consecutive days in infants <1 year old (n = 12) and 42 g/m2 in children ≥1 year old (n = 65). Mean day 1 treosulfan exposure was 1744 ± 795 mg*h/l (10 g/m2) and 1561 ± 511 mg*h/l (14 g/m2), with an inter‐individual variability of 56 and 33% in the respective groups. High treosulfan exposure (>1650 mg*h/l) was associated with an increased risk of mucosal [Odds ratio (OR) 4·40; 95% confidence interval (CI) 1·19–16·28, P = 0·026] and skin toxicity (OR 4·51; 95% CI 1·07–18·93, P = 0·040). No correlation was found between treosulfan exposure and the early clinical outcome parameters: engraftment, acute graft‐versus‐host disease and donor chimerism. Our study provides the first evidence in a large cohort of paediatric patients of high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long‐term disease‐specific outcome and late treatment‐related toxicity.

Intravenous immunoglobulin vs observation in childhood immune thrombocytopenia: a randomized controlled trial

Management of children with newly diagnosed immune thrombocytopenia (ITP) consists of careful observation or immunomodulatory treatment. Observational studies suggest a lower risk for chronic ITP in children after intravenous immunoglobulin (IVIg) treatment. In this multicenter randomized trial, children aged 3 months to 16 years with newly diagnosed ITP, platelet counts 20 × 109/L or less, and mild to moderate bleeding were randomly assigned to receive either a single infusion of 0.8 g/kg IVIg or careful observation. Primary outcome was development of chronic ITP, which at the time of study initiation was defined as a platelet count lower than 150 × 109/L after 6 months. Two hundred six children were allocated to receive IVIg (n = 102) or careful observation (n = 104). Chronic ITP occurred in 18.6% of the patients in the IVIg group and 28.9% in the observation group (relative risk [RR], 0.64; 95% confidence interval [CI], 0.38-1.08). Platelet counts lower than 100 × 109/L at 12 months (current definition of chronic ITP) were observed in 10% of children in the IVIg group and 12% in the observation group (RR, 0.83; 95% CI, 0.38-1.84). Complete response rates in the first 3 months were significantly higher in the IVIg group. Immunoglobulin G Fc receptor IIb genetic variations were associated with early complete response in both groups. Grade 4 to 5 bleeding occurred in 9% of the patients in the observation group vs 1% in the IVIg group. This trial was registered at www.trialregister.nl as NTR 1563.

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

Inhibitors increase the burden of disease in nonsevere haemophilia A patients - treatment strategies to obtain hemostasis

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