Kulkarni, Roshni

Introduction: Among the most challenging complications of hemophilia A is inhibitor formation. A T-cell dependent B-cell response to exogenous factor VIII (FVIII), inhibitors result in a high burden of disease, with poorly controlled bleeding, twice the hospitalizations, 10-fold the cost, and 3.5-fold the mortality of non-inhibitor patients. Thus, a major goal of hemophilia management is to prevent and eradicate inhibitors. With the availability of novel therapies, including eloctate, a recombinant Fc-fusion protein (rFVIII-Fc) which induces regulatory T cells to promote FVIII tolerance, and emicizumab, a bispecific monoclonal FVIII mimetic, we designed the INHIBIT Clinical Trials Platform (X01HL143024), Fig.1. The platform is composed of two linked randomized phase III trials, the Inhibitor Prevention Trial (NCT04303559), comparing rFVIII-Fc vs emicizumab prophylaxis to prevent inhibitors, and the Inhibitor Eradication Trial (NCT04303572), comparing rFVIII-Fc immune tolerance induction (ITI) plus emicizumab vs rFVIII-Fc ITI alone to eradicate inhibitors. The platform uses adaptive design to incorporate historical data (Bayesian priors) on inhibitor formation to increase power and promote efficient use of rare data. Yet, there is equipoise regarding the optimal approach to inhibitor prevention and eradication, and, as clinical practice is changing, we aimed to test the feasibility of the INHIBIT trial design. Methods: To establish design feasibility, we conducted interviews with 30 hemophilia treatment center (HTC) physicians participating in the INHIBIT trials, to determine prophylaxis and tolerance regimens they prescribe and perceived barriers to the INHIBIT trials design. A 4-question survey was subsequently emailed to these physicians to ascertain the initial prophylaxis regimens they prescribe in previously untreated patients (PUPs) with severe hemophilia A, and the initial immune tolerance induction (ITI) they prescribe in high-responding inhibitor patients with severe hemophilia A; if new inhibitors had been observed during emicizumab prophylaxis, and willingness to participate in post-trial surveillance. Results: In interviews, HTC physicians indicated the issues that influenced choice of prophylaxis/ ITI regimen were patient preference, family history of inhibitors, infusion frequency, IV access, port requirement, and family fatigue. In the absence of clinical trials data in PUPs, there was general agreement that emicizumab prophylaxis, with it simpler subcutaneous (SQ) administration, might delay or potentially prevent inhibitors. Survey findings in Table 1 indicated 75% of physicians prescribe extended half-life (EHL) FVIII in a once-weekly prophylaxis regimen, as planned in the Prevention Trial, despite the persistent 27% inhibitor rate (ALong PUPs Trial, Königs et al, ISTH 2020) and potential risks with port use. There was support for the 1:3 preferential randomization to emicizumab in the Prevention Trial due to the simpler SQ route, despite concern it might delay rather than prevent inhibitor formation, although no inhibitors were reported by physician survey with emicizumab use alone. There was also concern that breakthrough bleeds requiring FVIII during emicizumab prophylaxis, might lead to immune activation and inhibitor formation. There was strong agreement, however, in 29 (97%) of physicians to participate in post-trial surveillance for long-term inhibitor outcomes. FVIII ITI was considered essential to eradicate inhibitors, despite the intensity of the infusion regimen. Notably, 60% prescribe emicizumab with FVIII ITI, as planned in the Eradicate Trial, although the every-other-day infusion was considered a potential barrier to participation. Omitting FVIII ITI was not favored due to the risk of inhibitor anamnesis if FVIII treatment was subsequently required for surgery or acute hemorrhages. Despite these concerns, there was agreement to participate in the trials. Discussion: Physician interviews and surveys confirm there is heterogeneity in current hemophilia clinical practice, specifically in initial prophylaxis regimens and in initial immune tolerance regimens, including agent choice and duration. However, there is physician consensus with the INHIBIT trial aims and with the proposed INHIBIT trial regimens to prevent and eradicate inhibitors. Disclosures Ragni: Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam/Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioMarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; ATHN: Research Funding; Sangamo: Research Funding. Seaman:Bayer: Consultancy; Genentech: Consultancy; Spark Therapeutics: Consultancy; Takeda: Consultancy. Acharya:Novonordisk: Membership on an entity's Board of Directors or advisory committees; BPL: Membership on an entity's Board of Directors or advisory committees; Bayer Pharma Inc.: Research Funding. Wheeler:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; UniQure: Membership on an entity's Board of Directors or advisory committees. Tarango:Takeda/Shire: Honoraria, Other; Bayer: Consultancy, Other; Sanofi: Honoraria, Other. Dunn:ATHN: Research Funding; Spire: Honoraria; Medscape: Honoraria; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; BioMarin: Research Funding; uniQure: Consultancy; Genentech, Inc.: Consultancy; Nationwide Children's Hospital: Current Employment. Kulkarni:Sanofi/ Bioverativ, Bayer, Biomarin, Shire/Takeda, Novo Nordisk, Freeline: Other: clinical trial research grants ; Bioverativ/Sanofi, BPL, Genentech, Kedrion, Novo Nordisk, Octapharma, Pfizer, Takeda, Catalyst Bioscience Bayer: Membership on an entity's Board of Directors or advisory committees. Ahuja:Genentech: Consultancy, Honoraria; Sanofi Genzyme: Consultancy, Honoraria; XaTek, Inc.: Consultancy, Patents & Royalties, Research Funding. Chitlur:Takeda: Honoraria; Biovertiv: Honoraria; Agios Pharmaceuticals: Research Funding; Pfizer: Honoraria; Novo Nordisk: Consultancy, Honoraria. Pipe:Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding; Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees. Malec:Sanofi Genzyme: Consultancy, Research Funding, Speakers Bureau; CSL: Consultancy; Takeda: Consultancy; Bayer: Consultancy; SOBI: Consultancy. Leissinger:Bayer: Consultancy; Kedrion: Consultancy; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; HEMA Biologics: Consultancy; Takeda: Consultancy; Uniqure: Consultancy; Spark: Consultancy. Carpenter:Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board; Kedrion: Honoraria; Novo Nordisk: Honoraria; Genentech, Inc.: Honoraria; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Shire: Research Funding. Knoll:NovoNordisk: Membership on an entity's Board of Directors or advisory committees. Wang:Bioverativ Inc: Honoraria; Bayer: Honoraria; CSL Behring: Honoraria; Biomarin: Honoraria; Genentech: Honoraria; Takeda: Honoraria. Young:Genentech/Roche, Grifols, and Takeda: Research Funding; Bayer, CSL Behring, Freeline, UniQure: Consultancy; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria. Thornburg:Genentech: Speakers Bureau; Spark Therapeutics: Consultancy; Bluebird Bio: Consultancy; Ironwood Pharmaceuticals: Consultancy, Other: Data Safety Monitoring Board; American Thrombosis and Hemostasis Network: Research Funding; Sanofi Genzyme: Consultancy, Other: Data Safety Monitoring Board, Research Funding; NovoNordisk: Research Funding; Biomarin: Consultancy, Speakers Bureau; Bayer Pharmaceuticals: Research Funding; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lucas:CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hwang:Shire: Honoraria; Takeda: Honoraria.

Abstract 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.

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting 1% of the population, and characterized by deficient or defective von Willebrand factor (VWF). Among women with VWD, up to 80% have heavy menstrual bleeding (HMB), many of whom have depleted iron stores and iron deficiency anemia with reduced physical functioning, anxiety, depression, and poor quality of life. HMB is a serious problem causing significant health burden for those affected. The lack of effective therapies for menorrhagia is a major unmet healthcare need in women with VWD: in up to 30% desmopressin (DDAVP), combined oral contraceptives (COCs) hormones, or the recommended non-hormonal agent, tranexamic acid (Lysteda®, TA) may be ineffective or poorly tolerated. VWF concentrates, including plasma-derived VWF (pdVWF, Humate-P®) and recombinant VWF (rVWF, Vonvendi®) safely reduce bleeds in VWD, but few data exist on VWF use in menorrhagia, and no prospective trials are available to guide treatment. As rVWF has higher purity, potency, and a longer half-life than pdVWF, this phase III trial will compare rVWF with TA in reducing menorrhagia in women with type 1 VWD. Methods: This is an NHLBI-funded U01 phase III multicenter, prospective, randomized, crossover trial in to compare IV rVWF vs. po TA in reducing menorrhagia in type 1 VWD, clinicaltrials.gov, NCT02606045. Women with type 1 VWD, VWF:RCo<0.50 IU/dL and menorrhagia, defined as pictorial blood assessment chart score (PBAC)>100 in at least one of the last two cycles, are eligible. Exclusions include hypothyroidism, past thrombosis, and renal disease. Subjects are randomized to rVWF 40 IU/kg IV day 1 vs. TA 1300 mg po three times daily days 1-5 in each of two consecutive cycles. The order of treatment is determined by randomization: in Group 1, rVWF is given in cycles 1 and 2, and TA in cycles 3 and 4; while in Group 2, TA is given in cycles 1 and 2, and rVWF in cycles 3 and 4. A rescue dose day of rVWF 40 IU/kg may be given day 2 of cycles in which rVWF is given. The primary endpoint is a 40-point reduction in PBAC, a validated measure of menstrual loss, after 2 cycles. As rVWF is a greater burden (IV, cost), to show it is superior to TA, it should improve PBAC 40 points more from baseline than TA. Secondary endpoints are cycle severity, cycle length, QoL (SF-36, Ruta, CDC-HRQ0L-14, CES-D), and satisfaction survey. Treatment response will also be compared with VWF assays and VWF genotype. Safety is assessed by number of rescue doses, other bleeding, thrombosis, and allergic reaction. Our research hypothesis is that rVWF will be superior, producing a greater improvement, by at least 40 points, in PBAC, than TA. We also hypothesize that rVWF will be as safe, tolerable, and acceptable as TA, and that VWF assays and VWF genotype will predict response to treatment. A sample size of 60 (inflated to 66 for 5% attrition) will provide 84% power to detect a difference in improvement of 40 points between rVWF and TA. Analysis will be by intent-to-treat analyses, with a two-tailed alternative hypothesis with type 1 error rate of 0.05, a 4-period 2-group (AABB/BBAA) crossover design, and an estimated between-subject standard deviation (SD) of 63 points and within subject SD of 100 points. Results: A total of 442 potential subjects have been identified at 19 participating HTCs, of whom 33 (7.5%) are eligible, and 2 enrolled. The most common reason for ineligibility is use of an IUD (15.6%), COCs (9.4%), age <18 years (6.2%), pregnancy (6.2%), breastfeeding (6.2%), and VWF prophylaxis (3.1%). Nursing services have been contracted for weekend rVWF infusions. In-person site visits include hands-on web portal training, including a password-protected, FDA-validated data entry system, eSYSDM, use of real-time data form completion by tablet, infusion tracking and training, real-time cycle reporting, patient-training checklists, and protocol training and monitoring. Local gynecologists have been invited to refer potentially eligible patients. Discussion: In conclusion, rVWF is a high-purity VWF concentrate with a longer half-life than pdVWF. In this multicenter phase III trial, rVWF is being compared to the current non-hormonal standard, TA, to reduce menorrhagia in adult women with type 1 VWD. rVWF is safe and effective in prevention and treatment of bleeds, and this trial will determine if rVWF reduces menorrhagia to a degree sufficient to justify its IV route and cost. Disclosures Ragni: Sangamo: Research Funding; Alnylam/Sanofi: Consultancy, Research Funding; ICER: Consultancy; OPKO: Research Funding; Bioverativ/Sanofi: Consultancy, Research Funding; Bayer: Consultancy; Biomarin: Consultancy, Research Funding; Shire/Takeda: Consultancy, Other: Study drug; Spark Therapeutics: Consultancy, Research Funding. Seaman:Spark Therapeutics: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Takeda: Consultancy. Sidonio:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees. Kuriakose:Alexion: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy. Malec:Hemostasis and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bayer: Honoraria; CSL: Honoraria. Rodgers:AstraZeneca: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy. Wheeler:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Compared to Whites, Black-Americans may have a 40% higher incidence of idiopathic VTE. However, whether other VTE characteristics vary by race is uncertain. Objective: To compare demographic and baseline characteristics among White- and Black-Americans with VTE. Methods: Using a standardized data-collection form, demographic and baseline characteristics were prospectively collected from consecutive consenting patients enrolled in seven Thrombosis and Hemostasis Centers from August 2003 to March 2008. For patients with objectively diagnosed VTE, demographic and baseline characteristics were compared among White- and Black-American VTE patients, both overall, and by age and gender. Results: Among 1960 White- and 368 Black-Americans with VTE, compared to Whites, Blacks had significantly less isolated DVT (73.9% vs. 86.5%, p<0.001) and significantly more PE ± DVT (45.1 vs. 39.6%, p=0.05). Blacks and Whites did not differ in mean age (43.4 vs. 44.3 years), but a significantly higher proportion of Black men VTE patients were in age groups 20–39 and 80+ years. Blacks and Whites differed significantly by gender, with a significantly higher proportion of Black women with VTE (69.8% vs. 59.1%, p=0.0001). Blacks had a significantly higher mean BMI (32.3 vs. 29.4 kg/m2, p<0.0001), a significantly lower proportion with recent surgery or trauma, active cancer and infection, and a significantly lower proportion with a family history of VTE or documented thrombophilia (solely due to reduced Factor V Leiden and Prothrombin G20210A prevalence). Conversely, Blacks had a significantly higher proportion with hypertension, hyperlipidemia, diabetes mellitus, chronic renal disease and dialysis, HIV and sickle cell disease. The two races did not differ significantly regarding the proportion with idiopathic VTE, CHF, CAD/MI, peripheral artery disease, stroke or other chronic neurological disease (i.e., cerebral palsy), chronic liver disease or autoimmune disease, including antiphospholipid syndrome. Compared to White women VTE patients, Black women VTE patients had a significantly lower proportion with recent surgery, trauma, infection, oral contraceptive use and possibly hormone therapy; and a significantly higher proportion with idiopathic VTE, hypertension, diabetes mellitus, chronic renal disease, HIV and sickle cell disease. Compared to White men VTE patients, Black men VTE patients did not differ significantly regarding recent surgery, trauma, cancer, infection or autoimmune disease, but Black men had a significantly higher proportion with hypertension, diabetes mellitus, HIV and sickle cell disease. Black and White men with VTE did not differ significantly regarding idiopathic VTE, CHF, CAD/MI, stroke, peripheral arterial disease and chronic renal disease. Conclusion: White- and Black-Americans with VTE differ significantly regarding demographic and baseline characteristics that may be risk factors for VTE.

Abstract Abstract 4000 Poster Board III-936 Background There is insufficient information regarding the epidemiology and outcomes of DVT in children. The CDC began a consented registry in August 2003 at eight pilot Centers for Thrombosis and Thrombophilia including six pediatric sites in order to assess the scope and severity of DVT morbidity in children. Methods Data for this analytic project were extracted from the CDC thrombosis registry. We performed a nested case-control study within the registry cohort. Children and adults are eligible to enroll onto this consented registry if they have a history of thrombosis, thrombophilia or a positive family history or either. DVT site, extent, recurrence and BMI were determined clinically. In addition, thrombophilia testing batteries, imaging protocols and determinations of PTS outcomes of DVT were made locally and criteria were not standardized among participating centers. Results As of March 2009 the CDC registry included 316 cases of DVT in infants and children (ages 0-21), and 2414 cases in adults (> 21). There were 16 cases reported to have lower extremity (LE) PTS in children and 184 in adults. Table 1 displays effects of thrombus site, recurrence and BMI on PTS prevalence. The proportion of LE DVT involving the inferior vena cava (IVC) was 5.5-fold higher in children compared to adults (11% vs 2%). Furthermore, among cases of IVC involvement, the prevalence of PTS following IVC thrombosis was remarkably higher in children compared with adults (38.9 vs 6.3%, P < 0.001). The prevalence of PTS following LE DVT overall in children did not differ from adults. Results for upper extremity DVT and resultant PTS were similar. Fifteen percent of children had recurrence. Increasing number of DVT events was associated with an increased risk of PTS. BMI was higher in children who developed PTS (p = 0.06; BMI > 28, OR 3.3 [1.08, 9.59]). In addition, thrombophilia was a risk factor for developing PTS in children (p = 0.02; OR = 2.9 [CI 1.03, 8.05]), with the highest risk determined with antiphospholipid syndrome (p = 0.02; OR = 3.4 [1.09, 9.93]) and protein C deficiency (p = 0.02, OR = 10.9 [0.84, 99.3]). Discussion Children with LE DVT demonstrate a high rate of IVC thrombosis, and a higher relative risk of PTS in cases of IVC involvement. Elevated BMI and thrombophilia augment the risk of PTS in children. The limitations of this study include the lack of standardization in DVT diagnostic and PTS evaluations. The study findings support application of standardized approaches to the diagnosis and follow-up evaluation of children with DVT in order to more meaningfully determine outcomes for future interventive trials. Disclosures: Moll: Ovation: Consultancy; GTC Biotherapeutics: Consultancy; Talecris: Consultancy.

Abstract Abstract 4219 Background: Clinical characteristics associated with abdominal vein thrombosis (including hepatic, portal, and mesenteric veins; renal veins; and inferior vena cava [IVC]) overlap with characteristics associated with deep vein thrombosis (DVT) in the legs and pulmonary embolism (PE) but also possess unique attributes. These characteristics may differ between adult and pediatric patient groups. Methods: Using a standardized data-collection form, demographic and baseline characteristics were prospectively collected from consecutive consenting patients enrolled within one of seven Thrombosis and Hemostasis Centers over a seven-year period, August 2003 to June 2010. Patients with intra-abdominal venous thrombosis (defined as abdominal and renal veins, and IVC) were divided into pediatric (age <18 years) and adult (age ≥18 years) groups and compared to patients in the same age ranges with lower extremity DVT and/or PE. RESULTS: As of June 2010, the Patient Registry contained a total of 3105 patients with venous thromboembolism (VTE). A total of 270 patients had intra-abdominal thrombosis (9%) compared to 2276 with lower extremity DVT and/or PE (73%). Of the intra-abdominal clots, pediatric patients were more likely to have IVC thrombus (22 of 42; 52%) than adults (38 of 228; 17%; p<0.0001); conversely, pediatric patients were less likely to have hepatic, portal, and mesenteric thrombosis (n=25; 60%) than adults (n=195; 86%, p<.0001). For adult patients, proportionately more women had abdominal thrombosis (157 of 228; 68.9%) than DVT/PE (1306 of 2140; 61%; p=0.02); in contrast, comparable numbers of female pediatric patients had abdominal thrombosis (20 of 42; 47.6%) and DVT/PE (68 of 136; 50%). The mean age for patients having abdominal thrombosis was lower than patients having DVT/PE for both adults (38.3 vs 43.0 yrs; p<0.0001) and pediatric patients (9.0 vs 11.9 yrs; p=0.014). Similarly, the mean body mass index was lower for patients having abdominal thrombosis than patients having DVT/PE for both adults (28.1 vs 30.8; p<0.0001) and pediatric patients (21.5 vs. 24.7; p=0.05). There were no relationships with race, ethnicity, or inherited thrombophilic disorders. In adults, autoimmune conditions (21.9 vs 13.6; p=0.0007) and recent surgery (14.0 vs 9.2; p=0.02) were more common in patients with abdominal thrombosis, whereas, hyperlipidemia was more frequent in patients with DVT/PE (8.3 vs 13.2; p=0.04). None of these relationships were seen in the pediatric patients, but trauma was more frequently seen in pediatric patients with DVT/PE than abdominal thrombosis. Sixty-one adult (26.8%) and 6 pediatric patients (14.3%) had another VTE elsewhere, with most occurring after the initial event (21 DVT and 7 PE). Similar proportions of adult and pediatric patients had arterial thromboembolic events for both abdominal thrombosis and DVT/PE. CONCLUSIONS: Adult patients with abdominal thrombosis are more likely female, have hepatic, portal and/or mesenteric vein thrombosis, and common co-morbid conditions include recent surgery and autoimmune disorders. Pediatric patients are evenly divided between male and female, more commonly have IVC thrombosis, and co-morbid conditions include recent trauma. Both adult and pediatric patients with abdominal thrombosis tend to be younger and have a lower BMI than patients with DVT and/or PE. We also found a high rate of concurrent thrombosis in both adult and pediatric patients with abdominal thrombosis. In summary, patients with abdominal thrombosis display different clinical characteristics when compared to those with DVT/PE, specifically in terms of gender, location of thrombosis, and associated co-morbidities. Some of these differences, such as higher rates of IVC thrombosis in pediatric patients with abdominal thrombosis, might be caused by variance between genetic and anatomic factors. Further studies are warranted to explain these differences. Disclosures: Kulkarni: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Participate in clinical trials. Philipp:Baxter: Research Funding; Wyeth: Research Funding; Octapharma: Research Funding. Ortel:Sanofi-Aventis: Consultancy, Research Funding; Ortho-McNeil: Consultancy; GlaxoSmithKline: Research Funding; Eisai: Research Funding; Pfizer: Research Funding.

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<0.0001) suggesting a greater reduction in PBAC score with TA compared to IN-DDAVP. Both IN-DDAVP and TA generally improved QOL as assessed by each of the four instruments. Over-all, the Ruta Menorrhagia Questionnaire and the Center for Epidemiologic Studies Depression Scale measurements showed the most statistically significant improvements. Conclusion: Both TA and IN-DDDAVP reduce MBL and improve QOL in females with menorrhagia and abnormal laboratory hemostasis.The significance of these findings are underscored by the fact that prior studies of menorrhagia treatment in these patients have not included validated QOL instruments. The marked improvement in MBL and QOL noted with TA and IN-DDAVP appears to justify hemostasis screening in women presenting with menorrhagia for whom no gynecological cause can be found.

IntroductionCentral venous access devices (CVADs) are frequently required as stable long‐lasting venous access in children with haemophilia, especially those requiring immune tolerance induction (ITI) for inhibitors. CVAD infection is one of the most frequently reported catheter‐related complications in this patient population.AimDetailed review of CVAD complications from the International ITI (I‐ITI) study and analysis of potential risk factors for such complications.MethodsRetrospective analysis of prospectively obtained data from the I‐ITI study primarily focused on CVAD‐related complications.ResultsA total of 115 children were recruited and 183 CVADs were placed in 99 subjects resulting in 121,206 CVAD‐days observed on‐study. A total of 124 CVAD infections were reported in 41 of 99 (41%) subjects with an overall infection rate of 0.94 per 1000 CVAD‐days (interquartile ranges 0–1.7). A similar number of infections were observed in the two treatment arms (median: 2 and 3 in high dose and low dose respectively). Infections occurred more frequently in the presence of external catheters than with fully implanted catheters (P = 0.026). Infected patients were significantly younger at the time of CVAD insertion (median age: 22 vs. 25 months, P = 0.020). Patients with Gram‐positive infections were also significantly younger than those with Gram‐negative infections (median age: 17 vs. 25 months, P < 0.0001).ConclusionCVAD infection was the most common complication observed in children with severe haemophilia and inhibitors in the frame of the I‐ITI study. Younger age at CVAD insertion and external CVAD were associated with higher risk for infection. ITI outcome was unaffected by CVAD infections.