ALBERT

Description: Menorrhagia is a common clinical problem among reproductive age women and annually 5% of reproductive age women seek medical attention, usually with gynecologists and other primary care physicians, for this symptom. Since underlying bleeding disorders are common in women presenting with menorrhagia, and referral for comprehensive hemostatic testing of substantial numbers of women with otherwise unexplained menorrhagia is problematic from the public health and cost perspective, a short, easy-to-administer screening tool comprised of 8 questions for identifying women with menorrhagia for hemostatic evaluation was previously developed (Am J Ob Gyn2008;198:e1–163e8). In the present study, the validity of the screening tool was evaluated in a multi-site, prospectively recruited cohort of women with menorrhagia. 232 women with menorrhagia age 18 and older with a pictorial blood assessment chart (PBAC) score 〉 100 were recruited from 5 US centers as potential subjects for a prospective cross-over study for evaluation of intranasal DDAVP versus tranexamic acid. All subjects underwent comprehensive laboratory testing for bleeding disorders, including VWF, platelet aggregation/ATP release, and factor assays. Study participants were administered a questionnaire which included the 8 screening tool questions in 4 categories, including history of duration and severity of menorrhagia, anemia treatment, excessive bleeding with hemostatic challenges, and family diagnosis of bleeding disorder. A screening tool was considered positive if there was a positive response for any of the questions in the four categories. Sensitivity of the screening tool with 95% confidence interval was calculated for bleeding disorders and also separately for low VWF (ristocetin cofactor 〈 50%), and platelet function defects.217 women with menorrhagia including 78% white and 16% black women with complete data were evaluated. In this population, a positive screening tool had a sensitivity of 89% (95% CI, 83–93) for bleeding disorders, 89% for platelet function defects (95% CI, 82–94), and 73% for low VWF (95% CI, 39–94). The sensitivity for bleeding disorders was 87% (95% CI, 79–92) among white women and 94% (95% CI, 79–99) among black women. Adding a PBAC score 〉 185 increased the sensitivity of the screening tool for bleeding disorders to 95% (95% CI, 90–98). Using a multi-site US population of adult women with menorrhagia, this study confirms the benefit of a short screening tool to assist primary care physicians in the selection of women with menorrhagia to refer for comprehensive hemostatic testing and evaluation. population of adult women with menorrhagia, this study confirms the benefit of a short screening tool to assist primary care physicians in the selection of women with menorrhagia to refer for comprehensive hemostatic testing and evaluation.

Description: The growing awareness to screen women with menorrhagia for an underlying bleeding disorder has led to an increase in enrollment of identified cases in Hemophilia Treatment Centers (HTCs). However, the outcome of menorrhagia management in these women has not been well-described. Objective : To determine the efficacy/outcome of the management of bleeding disorder-related menorrhagia in patients enrolled within the HTC network. Patients and Methods : Registry study of initial data collection of retrospective obstetrical and gynecological events with prospective yearly follow-up for 5 years for new obstetrical and gynecological events. Results : 99 women from five HTCs in New York-New Jersey Region II have been registered to date, mean age 38±16.3, median age 40. Diagnoses are: von Willebrand disease (VWD) in 71%; thrombocytopathy in 6%; factor deficiency in 23%. Menstrual status and outcomes presently: ⇒32/99 (32%) are not menstruating due to hysterectomy or post/peri-menopausal status; 13/99 have undergone a hysterectomy (n=10) or endometrial ablation (n=3) for menorrhagia control; in 7/10 of the women undergoing a hysterectomy for menorrhagia control, the diagnosis of VWD was previously established; 6/7of these women attempted medical treatment prior to hysterectomy ⇒68/99 (68%) are presently menstruating. Of those menstruating, menstrual status is as follows: Normal menses: 23.5% (16/68) Menorrhagia under control: 23.5% (16/68); of these patients; 11/16 have achieved control with oral contraceptive(OC), the remaining 5 patients have achieved control with intranasal DDAVP or Amicar Menorrhagia presently: 53% (36/68); 22/36 (61%) have undergone a course of ineffective menorrhagia treatment including intranasal DDAVP in 17/22 Conclusions : The majority of women with menorrhagia enrolled in HTCs have persistent menorrhagia despite evaluation and management within the HTC network. Only a small proportion have menorrhagia control due to intranasal DDAVP use and a proportion still necessitate hysterectomy for menorrhagia control. The value in United States HTCs of hemostatic measures alone such as intranasal DDAVP in the management of bleeding disorder related menorrhagia is uncertain at this time. Further study of combined therapy (intranasal DDAVP and Amicar ± OC) and novel approaches (levonorgestrel-intrauterine device) is warranted as are efforts to procure tranexamic acid for use in the U.S.

Description: Introduction: Patients with common inherited bleeding disorders (IBDs) including hemophilia and von Willebrand disease (VWD) are at risk of coronary artery disease (CAD) as they age, albeit lower than the general population. Intuitively, these patients would appear to have a higher mortality rate given an increased risk of hemorrhagic complications and/or possibly cardiovascular complications from undertreatment with antithrombotic agents and/or procedures. Methods: Data from National Hospital Discharge Survey (NHDS) from 2001-2010 were analyzed using diagnosis codes (ICD 9) to identify patients with hemophilia, VWD and myocardial infarction (MI). Demographics and discharge information were compared amongst patients who had an MI with and without these coagulopathies, using chi-squared tests, Fisher's exact tests, and linear regressions. All tests were adjusted for survey design with sampling weights. Yearly rates of MI were compared between patients with and without these coagulopathies. All analyses were performed in STATA 12.0. Results: During the years 2001-2010, about 0.2 million patients (weighted data) were discharged with IBD i.e. hemophilia and VWD. Among them, the incidence of MI was 0.26% in hemophilia and 1.61% in VWD patients. Hemophilia patients were more likely to be men (76.9% vs 56.2%) and Caucasians (66% vs 65%) while VWD patients were more likely to be younger (67 vs 69 years), women (52% vs 44%) and Caucasians (66% vs 65%) compared to the normal population (all p-values

Description: According to the CDC’s 2006 National Hemophilia Data Set, females comprise 0.7% of the moderately and severely affected hemophilia A (HA) population and 1.3% of those similarly affected with hemophilia B (HB) in the US. Since no comprehensive data have been published on this patient group since 1978, we conducted this study to collect and analyze epidemiological, clinical, psychosocial, and molecular genetic data on females with severe (s) or moderate (mod) HA or HB. Potential subjects with factor VIII or IX activity levels

Description: Introduction: Low Von Willebrand factor (VWF) activity, considered a bleeding risk factor, is prevalent in some adolescents with heavy menstrual bleeding (HMB), wherein upfront hemostatic therapy may not be readily considered. There is a need to better define this patient subset phenotypically and genotypically, to stratify their risk to bleed, and to tailor their therapy in hopes of preventing complications. In adolescents with HMB and low VWF, we hypothesized that a significant proportion will have disease-causing sequence variations in the VWF gene and/or modifier genes that affect hemostasis, thrombosis or vascular biology, and these will correlate with their bleeding phenotype. Methods: The objectives of this multi-center, single arm, observational cohort study were to 1) study the genotype of adolescent females with HMB and low VWF (≥ 30 and ≤ 50 IU/dL), 2) correlate genotype with bleeding phenotype by Pictorial Blood Assessment Chart (PBAC) score and ISTH bleeding assessment tool (BAT) score. Post-menarchal females 〈 21 years, with HMB (defined as PBAC score 〉100) and low VWF were eligible for the study. Patients who did not meet these criteria or diagnosed with other bleeding disorders were ineligible. Members of the Foundation for Women and Girls with Blood Disorders are participating centers in the study. Clinical phenotype data including HMB characteristics, PBAC, BAT, response to desmopressin challenge, management details, clinical outcomes, and laboratory values were obtained. Blood samples were collected for analysis of a 142 gene array that includes VWF, genes involved in hemostasis, thrombosis and vascular biology. DNA sequencing of all exons and intron/exon boundaries was performed; variants were called presumably pathogenic if categorized as damaging by the pipeline with allele frequency

Description: Introduction: Over a three-year period, U.S. men with hemophilia were found to be 50 times more likely to die from renal disease than the general population (SMR 50; 95% CI 26.8-92.8) (Soucie et al., Blood 2000). Despite this finding, data regarding chronic kidney disease (CKD) and its risk factors in patients with hemophilia remain limited. The objective of this study is to determine the prevalence of CKD and CKD risk factors among older men with moderate and severe hemophilia. Methods: This CKD cohort study is an extension of a U.S. national study sponsored by the American Thrombosis and Hemostasis Network (ATHN). The study, entitled ATHN 1: A Cross-Sectional Analysis of Cardiovascular Disease (CVD) in the Hemophilia Population, began enrollment in 10/2012. Inclusion criteria are men with moderate or severe congenital hemophilia A or B (FVIII or IX level ≤ 5%), age 54-73. Men with an additional bleeding disorder (besides liver dysfunction) were excluded. In this extension study, CKD risk factors, historical creatinine levels, and history of renal events were obtained from patient interview and chart review after obtaining informed consent. Glomerular filtration rate (GFR) values were calculated using the CKD-EPI equation and compared to values in the general population using the NHANES dataset (Coresh et al., JAMA 2007). CKD is defined as the presence of either kidney damage or decreased kidney function with GFR 〈 60 ml/min/1.73 m2 for ≥ 3 months, irrespective of cause. Results: As of 6/30/2018, 134/200 planned subjects have been enrolled and interim analysis on 134 subjects from 18 U.S. hemophilia treatment centers (HTCs) is presented here. The majority were white (119; 88.8%) or African-American (13; 9.7%). Mean age was 64 years (SD: 5; range: 56-77). Most used factor on demand, with only 38.8% (52/134) on prophylaxis, defined as ≥2 doses of FVIII or ≥ 1 dose FIX/week. Four (3.0%) had a current inhibitor. Viral infection was common; 28.4% currently had hepatitis C, and 19.4% HIV. Hypertension (HTN) was reported in 51.5% of subjects, 14.9% diabetes mellitus (DM); and average BMI was 28.2 kg/m2 (36.6% obese). 11.6% (16/134) were found to have CVD (defined as angina, MI, TIA, or ischemic or embolic stroke). Acute kidney injury was common. Fasting blood work showed an abnormally elevated creatinine in 26.9% subjects (mean 1.1 mg/dl, SD 0.4). Mean historical maximum creatinine reported in the cohort was 1.0 (range 0.5-4.8), with mean GFR 67 (range 11-126). 11.4% (13/114) met the definition of CKD. Stages of CKD by GFR in the hemophilia cohort were similar to the NHANES general population (p=0.561). See Table 1 for subject reported history of renal events, and Table 2 for specific diagnoses of renal disease. In our cohort, hemophilia subjects with CKD tended to have a diagnosis of intrinsic kidney disease (60.0% vs 11.6%, p=0.02), and non-significantly tended to have DM (23.1% vs 12.8%), age ≥65 years (21.1% vs 9.4%), and HTN (18.0% vs 9.8%) compared to subjects without CKD. No other significant trends were identified, including no association with CVD, HCV, HIV, BMI, or hematuria. Conclusions: In this interim analysis of an ongoing national prospective cohort study, older men with moderate to severe hemophilia commonly report risk factors for CKD, including HTN (51.5%), DM, viral infection, and potential renal damaging medication use. Only 11.6% had CVD. Urological symptoms were also common, including hematuria and obstructive symptoms with urination. In our cohort, 11.4% met the definition of CKD, defined as the presence of either kidney damage or GFR 〈 60 ml/min/1.73 m2 for ≥ 3 months. The distribution of GFR values appeared similar to the general population. As with risk factors associated with CKD in the general population, diagnosis of intrinsic kidney disease was significantly associated with CKD in hemophilia subjects, with non-significant trend for increased DM, older age, and HTN compared to subjects without CKD. It is reassuring that the prevalence of CKD does not appear to be increased in men with hemophilia compared to the general population, despite a known and unexplained high incidence of HTN in the hemophilia population. We plan to formally compare the prevalence of CKD and CKD risk factors with similarly aged men in the ARIC database once enrollment is complete, as understanding the risk factors that contribute to CKD is essential to halt its progression. Disclosures Sood: Bayer: Research Funding. Shapiro:BioMarin: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Sangamo Biosciences: Consultancy; Octapharma: Research Funding; OPKO: Research Funding; Daiichi Sankyo: Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Bio Products Laboratory: Consultancy; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kessler:Biomarin: Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees; DSMB: Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; Novo Nordisk: Honoraria, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Key:UniQure BV: Research Funding. Quon:Bioverativ, a Sanofi Company: Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Bayer: Consultancy; Shire: Speakers Bureau; Genetech: Consultancy, Speakers Bureau; Octapharma: Consultancy. Manco-Johnson:Novo Nordisk: Honoraria; CSL Behring: Honoraria; Bayer AG: Honoraria, Research Funding; Biogentek: Honoraria; Baxalta, now part of Shire: Honoraria. Cuker:Kedrion: Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy; Spark Therapeutics: Research Funding; Synergy: Consultancy. Ragni:Novo Nordisk: Research Funding; Shire: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo: Research Funding; SPARK: Consultancy, Research Funding; CSL Behring: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Consultancy, Research Funding; SPARK: Consultancy, Research Funding. von Drygalski:UniQure BV, Bayer, Bioverativ/Sanofi, Pfizer, Novo Nordisk, Biomarin, Shire, CSL Behring: Consultancy. Kouides:UniQure: Other: DSMB; Octapharma: Research Funding. Escobar:Bayer, CSL Behring, Genentech, Hemabiologics, Kedrion, Novo Nordisk, Octapharma, Pfizer and Shire: Consultancy; Pfizer: Research Funding. Wang:Daiichi Sankyo: Consultancy, Other: Travel. Konkle:Shire: Research Funding; Genentech: Consultancy; Bioverativ: Research Funding; BioMarin: Consultancy; Pfizer: Research Funding; Gilead: Consultancy; Spark: Consultancy, Research Funding; CSL Behring: Consultancy; Sangamo: Research Funding.

Description: Abstract 3508 Poster Board III-445 Introduction Selective serotonin reuptake inhibitors (SSRI) are antagonists of the serotonin transporter and lead to a lower concentration of serotonin in platelets. Recently there have been a number of observational studies and case reports highlighting the association of SSRI use with various hemorrhagic complications ranging from gastrointestinal hemorrhage to hemorrhagic stroke and bleeding during orthopedic surgery. On the other hand, there is not enough data on the clinical correlation between the effect of SSRIs on platelet function testing and relation to bleeding symptoms in terms of the bleeding score. Patients and Methods A retrospective, cohort study was done to assess the relationship of bleeding symptoms and laboratory assays of platelet function in patients referred for muco-cutaneous bleeding after von Willebrand disease was ruled out. The cohort was analyzed for the effect of SSRI use on platelet function and bleeding symptoms. Ninety eight patients were studied and their bleeding symptoms were assessed by the European Union Von Willebrand disease bleeding scoring system (EUVWD). Hemostatic tests including whole blood platelet aggregation (Chrono-Log™) and closure time (PFA-100™, Dade/Behring) were assessed. Results 23/98 patients reported SSRI as an active medication. Baseline characteristics were similar with respect to age, sex, race, hematocrit and platelet count among SSRI users and non-users. The majority (96%) were females. The median bleeding score was not statistically different in SSRI users vs. non-users (4 vs. 5). The bleeding symptoms were similar in the two groups with the exception of epistaxis which was more frequent in SSRI non-users. Whole blood platelet aggregation was decreased in 17.4% patients in SSRI users and 4.2% in non-users (p=0.035). Likewise, 52% patients in SSRI users and 29% in non-user had decreased release to any agonist (p=0.04). SSRI users had a higher prevalance of decreased aggregation with low dose collagen, arachidionic acid and ADP. ATP release in response to arachidionic acid and ADP was also lower in SSRI users. PFA-100 closure time with collagen-epinephrine (n=96) was prolonged in SSRI users vs. non users (144.5 vs. 126 sec, p=0.009) while closure time with collagen-ADP (n=22) was 105.5 vs. 108.5 in SSRI users vs. non users (p= 0.94). Conclusions SSRI use is associated with abnormalities in platelet function and this finding probably does warrant testing such patients with a suspected thrombocytopathy off SSRI. Their use, nonetheless, is not associated with a clinically significant difference in bleeding symptoms as assessed by the bleeding score. SSRI users with bleeding symptoms and associated abnormalities in platelet function should be investigated further for the cause of clinically significant bleeding. Bleeding score was assessed using EU-VWD scoring system. The aggregation and release studies were done with whole blood using Chronolog device in 98 patients. Results are represented as percentage abnormal. Closure times were done by PFA-100 (Dade-Behring) and results are expressed in seconds. † CEPI-collagen and epinephrine, CADP-collagen and ADP. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: In the general population, von Willebrand factor (VWF) and factor VIII (FVIII) levels are known to increase with age. However, in patients with bleeding disorders such as von Willebrand's disease (VWD), the effect of ageing is unclear. With a growing population of elderly patients with bleeding disorders, it is important to understand these changes and their effects on hemostasis, which may preclude the need for hemostatic therapy. The results of two prior studies conducted in the Netherlandsand Canada suggest that VWF levels increase with age in patients with VWD. Our study looks at the trends of VWF with age and the extent of normalization of levels in patients with Type 1VWD. It is the first to be conducted in a United States (U.S.) population, and the largest of its kind to date. Methods: In a retrospective cohort study, we reviewed the medical records of 266 patients registered at the Mary M. Gooley Hemophilia Center between 1996 and 2016 with a laboratory (lab) diagnosis of presumed Type 1 VWD based on normal multimers and/or ristocetin cofactor (VWF:RCo)/VWF antigen (VWF:Ag) ratio ≥ 0.6. The diagnosis of VWD was based on symptoms of bleeding episodes in conjunction with lab data of either VWF:Ag level 〈 30 U dL-1 or VWF:RCo level 〈 30 U dL-1, whereas the diagnosis of "Low VWF" was made for levels between 30-50 IU/dL (per NHLBI definition). Lab diagnosis required two subnormal sets taken at a minimum of 2 weeks apart. We collected all their historically documented VWF:Ag, VWF:RCo, and FVIII levels over time. We excluded patients whose levels were followed for less than 5 years, and we excluded all lab data that were related to the effects of desmopressin, products containing VWF or FVIII, pregnancy, or other acute stress situations. The primary outcome studied was complete normalization of most recent levels, defined as both VWF:Ag 〉 50 U dL-1 and VWF:RCo 〉 50 U dL-1 on two consecutive occasions separated at least 2 weeks apart. Furthermore, we defined "possible normalization" if only the last set of levels was normal, and "partial normalization" if only one level (either VWF:Ag or VWF:RCo alone) became normal for two consecutive times. Results: A total of 125 patients were analyzed (n=125), with an average duration of follow-up of 10.4 ± 3.7 years (SD) between the first set of values obtained until the most recent. Forty-five patients (26.4%) initially met the criteria for Type 1 VWD, while 80 patients (73.6%) had Low VWF. In the VWD group, 20.0% patients exhibited complete normalization, 11.1% showed possible normalization, and 55.6% had no normalization. The Low VWF cohort had complete normalization in 36.3% of patients, and possible normalization in 35.0% of patients. The total population had complete normalization in 30.4% of patients (Figure 1). An additional 13.3% and 3.8% had partial normalization in the VWD and Low VWF cohorts respectively. Only five patients, all of whom had "partial normalization", exhibited "relapse" where a normalized level dropped again. None of the other normalization groups had any incidence of relapse over the studied period of time. Conclusion: Our preliminary findings suggest that in about one third of patients with Type 1 von Willebrand's disease or Low VWF, the VWF:Ag and VWF:RCo levels completely normalize on repeat testing with age, over an average period of 10 years. Our study population is the largest to date whose levels were followed over time, and appears to be the first in a U.S. population. The rate and degree of normalization with time, as well as correlation with bleeding symptoms, are still being investigated. This may help determine whether rescinding the lab diagnosis precludes pre-operative hemostatic therapy. At the very least, clinicians should consider repeat testing in their Type 1 VWD patients 5 to 10 years post initial lab diagnosis. Figure 1 Stacked columns showing percentages of complete, possible, partial and no normalization in the total, VWD, and Low VWF cohorts. Figure 1. Stacked columns showing percentages of complete, possible, partial and no normalization in the total, VWD, and Low VWF cohorts. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Menorrhagia is a common health problem affecting ∼5-10% of women. The optimal management of menorrhagia among women with abnormal laboratory hemostasis is uncertain. The goal of this study was to determine the effect of intranasal desmopressin (IN-DDAVP) vs. oral tranexamic acid (TA) on menstrual blood loss (MBL) and quality of life (QOL). Methods: In a cross-over study design, 117 consenting women 18–50 years of age with menorrhagia (defined as subjective report of heavy bleeding and a pictorial blood assessment chart [PBAC] score 〉 100) with a negative gynecological evaluation and abnormal laboratory hemostasis (62% platelet dysfunction, 15% von Willebrand disease, 23% other coagulation defect or combined) were randomly assigned to initial IN-DDAVP or TA therapy each for two menstrual cycles, followed by cross-over to the second study drug for an additional two cycles. MBL by PBAC was measured at baseline and after each menstrual cycle while QOL was assessed by four validated instruments: Health Related Quality of Life (HRQOL), SF-36®, Center for Epidemiologic Studies Depression Scale (CES-D) and the Ruta menorrhagia questionnaire. Results: There was a statistically significant decrease in the PBAC for both treatments. On average, the estimated decrease in the PBAC from baseline for IN-DDAVP was −66.0 (CI = (−89.5, −42.6)) and for TA, −107.8 (CI = (−131.5, −84.1)). The decrease in the PBAC score was larger for TA with a difference of 41.8 (p-value = 0.0002, CI = (20.4, 63.2)) between the two treatments. In the multivariable analysis, the test for treatment-cycle number interaction was not significant, suggesting no carry-over effect. The test for a treatment type effect was significant (p

Description: Abstract 712 Background: Von Willebrand disease (VWD) is the single most common congenital bleeding disorder. The Tosetto Bleeding Score (BS), a quantitative measure of bleeding, has improved specificity of diagnosis, but symptoms are variable, and, among children a diagnosis of VWD may be missed as they may not have lived long enough to experience symptoms on which the score is based. As many as 25% of affected children come to clinical attention after postoperative bleeding: thus, a better diagnostic tool is needed in children. A Tosetto BS modified for children by one additional question on early life bleeding, known as the James BS, has been validated for a small cohort of VWD children, but its utility in type 1 VWD diagnosed by the 2008 NHLBI-defined VWF:RCo