Piercarla Schinco

Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: A four-year prospective study from the italian registry

PURPOSE To assess the natural history and risk factors for thrombosis in a large cohort of unselected patients with antiphospholipid antibodies. PATIENTS AND METHODS Three hundred sixty consecutive patients (118 males, 242 females, median age 39 years [range 2 to 78]) fulfilling the currently accepted criteria for diagnosis of lupus anticoagulant (LAC) (n = 326) and/or raised immunoglobulin G anticardiolipin antibodies (IgG ACA) (n = 185) were collected from 16 Italian institutions and prospectively observed for a median of 3.9 years (range 0.5 to 5). Main endpoints were the occurrence of arterial or venous thrombosis, the outcome of pregnancies, and any severe complications leading to hospitalization or death. RESULTS Thirty-four patients developed a thrombotic complication, with a total incidence of 2.5% patient-years. Multivariate logistic regression analysis identified two independent risk factors for thrombotic events: a previous thrombosis (RR 4.9; 95% CI, 1.76 to 13.7; P < 0.005) and IgG ACA titer above 40 units (RR 3.66; 95% CI, 1.24 to 10.8; P < 0.01). A total of 28 pregnancies were observed in 25 women and 11 (39%) were abortive. Adverse pregnancy outcomes were significantly more frequent in women with a history of miscarriage or vascular occlusion (9/16, 56%) than in asymptomatic women (2/12, 17%) (P = 0.035). Four patients developed non-Hodgkins lymphoma during the follow-up. Eighteen patients died. Vascular events and hematological malignancies represented the most frequent causes of death (n = 5 for each). CONCLUSIONS The present study shows that: (a) previous thrombosis and ACA titer > 40 U are independent predictors of thrombosis; (b) history of miscarriage or vascular disease is significantly associated with adverse pregnancy outcome; (c) hematological malignancies can develop during follow-up in patients with antiphospholipid antibodies.

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.

Emerging issues on comprehensive hemophilia care: Preventing, identifying, and monitoring age-related comorbidities

Life expectancy for persons with hemophilia (PWH) has considerably increased in the last decades as a direct result of the availability of modern therapies to control the clotting defect. Because their life expectancy now matches that of the general population, PWH are experiencing age-related comorbidities, such as, cardiovascular diseases, metabolic syndrome, renal diseases, sexuality issues, malignancies, and neurologic problems, that until recently have been rarely seen in this group of patients. In this article, we present a summary of the current knowledge on the aging PWH along with the clinical approaches that may be integrated into the routine comprehensive care of these patients for preventing, diagnosing, and monitoring age-related comorbidities. In general, patients with and without hemophilia should receive similar care, with close collaboration between the physician treating PWH and the specialty expert treating the comorbid disease.

Forum on: the role of recombinant factor VIII in children with severe haemophilia A

Summary.  The development of recombinant FVIII (rFVIII) products, fuelled by the need for improved safety of treatment arising from the dramatic widespread blood‐borne virus transmission in the 1970–1980s revolutionized the care of children with haemophilia A over the last two decades. The larger availability of perceived safer replacement therapy associated with the introduction of rFVIII products reassured the haemophilia community and there was a strong push in some Western countries to treat haemophilic children only with rFVIII. Moreover, this significantly contributed in the 1990s to the diffusion outside Northern Europe of prophylactic regimens implemented at an early age to prevent bleeding and the resultant joint damage (i.e. primary prophylaxis), together with the possibility of home treatment. These changes led to a substantial improvement of the quality of life of haemophilic children and of their families. The general agreement that primary prophylaxis represents the first‐choice treatment for haemophilic children has been recently supported by two randomized controlled trials carried out with rFVIII products, providing evidence on the efficacy of early prophylaxis over on‐demand treatment in preserving joint health in haemophilic children. However, the intensity and optimal modalities of implementation of prophylaxis in children, in particular with respect to the issue of the venous access, are still debated. A number of studies also supports the role of secondary prophylaxis in children, frequently used in countries in which primary prophylaxis was introduced more recently. With viral safety now less than an issue and with the more widespread use of prophylaxis able to prevent arthropathy, the most challenging complication of replacement therapy for children with haemophilia remains the risk of inhibitor development. Despite conflicting data, there is no evidence that the type of FVIII concentrate significantly influences the complex multifactorial process leading to anti‐FVIII alloantibodies, whereas other treatment‐related factors are likely to increase (early intensive treatments due to surgery or severe bleeds) or reduce (prophylaxis) the risk. Although the optimal regimen is still uncertain, eradication of anti‐FVIII antibodies by immune tolerance induction (ITI), usually with the same product administered at inhibitor detection, should be the first‐choice treatment for all patients with recent onset inhibitors. This issue applies particularly to children, as most patients undergo ITI at an early age, when inhibitors usually appear. The availability of a stable and long‐lasting venous access represents a leading problem also in this setting. These and other topics concerning rFVIII treatment of haemophilic children were discussed in a meeting held in Rome on 27 February 2008 and are summarized in this report.

Efficacy and safety during formulation switch of a pasteurized VWF/FVIII concentrate: results from an Italian prospective observational study in patients with von Willebrand disease

Von Willebrand disease (VWD) is an inherited bleeding disorder caused by the quantitative or qualitative deficiency of von Willebrand factor (VWF). Replacement therapy with plasma‐derived VWF/factor VIII (FVIII) concentrates is required in patients unresponsive to desmopressin. To assess the efficacy, safety and ease of use of a new, volume‐reduced (VR) formulation of VWF/FVIII concentrate Haemate® P in patients requiring treatment for bleeding or prophylaxis for recurrent bleeding or for invasive procedures. Pharmacoeconomic variables were also recorded. Data were analysed using descriptive statistics. This was a multicentre, prospective, observational study. Consecutively enrolled patients received Haemate® P VR according to their needs, and were followed for 24 months. Of the 121 patients enrolled, 25.6% had type 3 VWD and more than 40% had severe disease. All patients were followed for 2 years, for a total of 521 visits. On‐demand treatment was given to 61.9% of patients, secondary long‐term prophylaxis to 25.6% and prophylaxis for surgery, dental or invasive procedures to 45.5%. The response to treatment was rated as good to excellent in >93–99% of interventions. The new formulation was well tolerated by all patients with no report of drug‐related adverse events. The switch to volume‐reduced Haemate® P was easy to perform and infusion duration was decreased twofold compared with the previous formulation. Volume‐reduced Haemate® P was at least as effective and well‐tolerated as the previous formulation.

The incidence and treatment of bleeding episodes in non-severe haemophilia A patients with inhibitors

The development of an inhibitory antibody in non-severe haemophilia A patients may aggravate the bleeding phenotype considerably. Effective treatment of bleeding episodes may be challenging, with ensuing severe complications. At present, evidence is scarce for optimal treatment of bleeding episodes in this patient group. The aim of this study was to describe the incidence and the treatment of bleeding episodes in inhibitor patients in a population-based unselected cohort of non-severe haemophilia A patients with clinically relevant inhibitors. Data were available for 100 of the 107 non-severe haemophilia A patients (factor VIII (FVIII) baseline, 2-40 IU/dl) from 29 centres in Europe and one centre in Australia who had developed a clinically relevant inhibitor between 1980 and 2011. The majority (89 %) of the patients were treated during the inhibitor period for bleeding episodes or a surgical intervention: 66 % needed treatment for bleeding episodes, at a median annual bleeding rate (ABR) of 1.1 (interquartile range (IQR) 0.1-2.5) and a median total of 2 (IQR 1-6) bleeding episodes. Compared to the median ABR before inhibitor development of 0.095 bleeds per year (IQR 0.02-0.42), the increase in ABR is more than a 10-fold. More than 90 % of the bleeding episodes were treated with only one type of product, most frequently (51 %) FVIII concentrates. This study provides the incidence of bleeding episodes and treatment choices in non-severe haemophilia A patients with inhibitors. The 10-fold increase to a median ABR of 1.1 episodes per year emphasizes the impact of inhibitor development for non-severe haemophilia A patients.

Continuous infusion of recombinant factor VIII formulated with sucrose in surgery: Non-interventional, observational study in patients with severe haemophilia A

In haemophilia A, continuous infusion (CI) of FVIII perioperatively provides a more constant FVIII level than conventional bolus injections, avoiding low trough levels that could increase bleeding risk. Due to the low number of surgical cases in clinical trials, especially in haemophilia, more information on the clinical practice of CI from observational studies is helpful. We aimed to evaluate the effectiveness and safety of CI with recombinant factor VIII formulated with sucrose (rFVIII‐FS) in a typical surgery practice setting. This was a non‐interventional study in 12 centres. Patients with severe haemophilia A who received rFVIII‐FS by CI during and after surgery were included in this study if they had more than 150 exposure days (EDs) to any FVIII product and had no history of inhibitors before CI. Patients were observed during the entire course of CI, with monitoring up to 3 months thereafter. Twenty‐five patients with 28 surgeries were included in the analysis. Median age was 51.7 (range 10–75). Most (75%; 21/25) patients underwent orthopaedic surgeries. The median dose of rFVIII‐FS consumed during CI was 376 IU kg−1 (range 157.9–3605.6 IU kg−1) with a greater median dose for orthopaedic surgeries (424.0 IU kg−1) compared to non‐orthopaedic surgeries (278.5 IU kg−1). 95% of all FVIII measurements (214/224) were on target. Efficacy and tolerability were rated as good/excellent in 89.3% (25/28) of surgeries. No inhibitors were observed during or after surgery. This study demonstrates the effectiveness of CI with rFVIII‐FS during surgery in patients with severe haemophilia A in a clinical practice setting.

The case for wider use of recombinant factor VIII concentrates

The introduction of clotting factor concentrates led to major advances in hemophilia care. Rather than simply providing an alternative to plasma-derived concentrates, the introduction in the 1990s of recombinant concentrates added value to replacement therapy particularly with respect to prophylaxis and immune-tolerance induction. While the safety of plasma-derived concentrates has improved considerably, these concentrates may still pose an infectious risk through as-yet unknown pathogens and poor impurity constituent characterization. Recombinant concentrates are increasingly used because of their benefits in pathogen safety, convenience and the potential for unfettered supply. Yet worldwide they remain accessible only to a limited number of patients due to fear of the potential for inhibitor development, overestimation of their costs and underestimation of their benefits. This article reviews the characteristics and properties of recombinant FVIII concentrates to help physicians and patient representatives promote the right of access of patients to the safest products.

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

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