Saturnino Haya

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.

Variation in baseline factor VIII concentration in a retrospective cohort of mild/moderate hemophilia A patients carrying identical F8 mutations

Essentials Factor VIII levels vary in mild and moderate hemophilia A (MHA) patients with the same mutation. We aimed to estimate the variation and determinants of factor VIII levels among MHA patients. Age and genotype explain 59% of the observed inter‐individual variation in factor VIII levels. Intra‐individual variation accounted for 45% of the variation in the three largest mutation groups.

Mortality caused by intracranial bleeding in non-severe hemophilia A patients

Essentials Data on bleeding‐related causes of death in non‐severe hemophilia A (HA) patients are scarce. Such data may provide new insights into areas of care that can be improved. Non‐severe HA patients have an increased risk of dying from intracranial bleeding. This demonstrates the need for specialized care for non‐severe HA patients.

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

Prediction of DDAVP response in 850 non-severe hemophilia A patients

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