Thrombosis Prophylaxis with Apixaban in Patients Treated with Asparaginase

Abstract Background: Acute Lymphoblastic Leukemia (ALL) outcomes have significantly improved over time with multi-agent chemotherapy, and the addition of asparaginase (ASP) has demonstrated the ability to prolong overall survival. ASP has multiple toxicities, and it remains a challenge to manage them safely, particularly coagulopathy and thrombosis (30-40% based on historical studies). The best prophylactic anticoagulation strategy in patients with acute leukemias, particularly ALL with asparaginase use, remains unclear due to severe coexisting thrombocytopenia and coagulopathy. Though the current guidelines recommend using Antithrombin (AT) replacement or low molecular weight heparin (LMWH) for thrombosis prophylaxis, the evidence is weak with concerns of thrombosis (Blood (2020) 136 (3): 328-338) with the use of fibrinogen concentrates(cryoprecipitate) and limited efficacy data with AT replacement and unfractionated heparin (UFH) for thrombosis prophylaxis. Due to potential "resistance" to LMWH and UFH from acquired AT deficiency with ASP use, our institution in 2017 has adopted the use of the direct Xa inhibitor, Apixaban for thrombosis prophyalxis. We report the safety and effectiveness of Apixaban for thrombosis prophylaxis with ASP. Methods: In this retrospective study, we reviewed the data on 20 patients treated with ASP between 2017-2020. Thrombosis prophylaxis was instituted with Apixaban 2.5 mg PO Q 12 hourly for three weeks along with cryoprecipitate as needed for bleeding or fibrinogen levels <100 mg/dL (normal 160-450 mg/dL) to balance the risk of bleeding. Apixaban was held if platelet count <20,000/µL and for invasive procedures or clinically significant bleeding events. We evaluated demographic data, ALL risk category, type of ASP use, laboratory data (Table 1 & 2) for four weeks following ASP, amount of cryoprecipitate used, major bleeding, clinically relevant non-major bleeding (CRNMB), and thrombosis incidence. The medians of pertinent laboratory data were plotted on a graph. Descriptive statistics with medians, quartiles, frequencies, and percentages are reported. Results: Among the 20 patients treated during this period, 18 (90%) had ALL, and 2(10%) had NK/T cell lymphoma. Of the patients with ALL, 67% had high risk and 33% with standard-risk ALL. The median age of this cohort was 29.5 years (range: 19-63 years), 80% were males, 70% white, 30% were Latino or Hispanic, median body mass index-BMI of 30.2 kg/m 2(19.4-40.7 kg/m 2) and 65% were non-smokers. The median baseline AT activity was 107% (79-221%), 95% used concurrent corticosteroids (65%- Prednisone, and 30% used Dexamethasone). The most common induction treatment was CALGB 10403 (55%). Of the total, 95% received pegylated ASP, and only one patient received Erwinia ASP due to prior history of anaphylaxis. The major toxicities attributed to ASP included 5% grade II and 15% grade III-IV aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, 20% had bilirubin elevation, 10% developed grade III-IV acute pancreatitis, and 5% developed severe hypertriglyceridemia needing aphaeresis. Two patients (10%) developed thrombosis [catheter associated deep venous thrombosis (DVT) and one patient with lower extremity proximal DVT] within 4 weeks of use of ASP, with one of the two patients (5%) developing (lower extremity proximal DVT) while on being off anticoagulation due to bleeding. Major bleeding or CRNMB developed in 5% (spontaneous splenic rupture from ALL leading to hemorrhagic shock). The median number of cryoprecipitate units used per patient during weeks 1,2,3, and 4 was 5(0-35), 5(0-40), 5(0-15), 7.5(0-15), respectively; No patients received fresh frozen plasma or AT concentrates. Conclusions: With the use of Apixaban prophylaxis, the incidence of thrombosis was 10% within four weeks from ASP and 5% while on anticoagulation. The incidence of major bleeding or CRNMB was 5%. Hypofibrinogenemia, acquired AT deficiency due to ASP, was seen between days 7-21 after using ASP (figure 1 & 2) and recovered subsequently. This study demonstrates initial evidence of the safety and efficacy of Apixaban for thrombosis prophylaxis and cryoprecipitate infusions in patients treated with ASP. Figure 1 Figure 1. Disclosures Gundabolu: Samus Therapeutics: Research Funding; Pfizer: Research Funding; BioMarin Pharmaceuticals: Consultancy; Bristol-Myers Squibb Company: Consultancy; Blueprint Medicines: Consultancy. Bhatt: Jazz: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Research Funding; Tolero Pharmaceuticals, Inc: Research Funding; National Marrow Donor Program: Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Partnership for health analytic research, LLC: Consultancy; Servier Pharmaceuticals LLC: Consultancy; Rigel: Consultancy. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Lunning: Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Kyowa Kirin: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Novartis: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AbbVie: Consultancy; TG Therapeutics: Consultancy; Daiichi-Sankyo: Consultancy; Legend: Consultancy; Kite, a Gilead Company: Consultancy; Verastem: Consultancy; Acrotech: Consultancy; Karyopharm: Consultancy; Spectrum: Consultancy; Beigene: Consultancy; Morphosys: Consultancy. Baljevic: BMS/Celgene: Consultancy; Oncopeptides: Other: Advisory Board; Janssen Research: Other: Advisory Board; Karyopharm: Other: Advisory Board; BMS/Celgene: Other: Advisory Board; Amgen: Research Funding; Exelixis: Research Funding. Ganti: Merck: Research Funding; Apexigen: Research Funding; Nektar: Research Funding; Top Alliance Biosceinces: Research Funding; Lovance: Research Funding; Novartis: Research Funding; WindMil Therapeitucs: Research Funding; Takeda: Research Funding; Flagship Biosciences: Consultancy; AstraZeneca: Consultancy, Other: Advisory Board; Mirati Therapeutics: Consultancy, Other: Advisory Board; G1 Therapeutics: Consultancy, Other: Advisory Board; Blueprint Medicines: Consultancy, Other: Advisory Board; Cardinal Health: Consultancy, Other: Advisory Board; Roche: Consultancy, Other: Advisory Board; YMabS Therapeutics: Other: DSMC Chair.

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Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study: A Perioperative Management Plan for Patients with Atrial Fibrillation Who Are Receiving a Direct Oral Anticoagulant

Blood ◽

10.1182/blood-2018-120770 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. LBA-5-LBA-5 ◽

Cited By ~ 2

Author(s):

James Douketis ◽

Alex C. Spyropoulos ◽

Joanne M Duncan ◽

Marc Carrier ◽

Gregoire Le Gal ◽

...

Keyword(s):

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Perioperative Management ◽

Elective Surgery ◽

Bleeding Risk ◽

Advisory Board ◽

Advisory Committees ◽

Arterial Thromboembolism ◽

High Bleeding Risk

Abstract Introduction: The perioperative management of patients who are taking a direct oral anticoagulant (DOAC) for atrial fibrillation (AF) and require an elective surgery/procedure is uncertain. No studies have addressed the timing of perioperative DOAC interruption and resumption, and if perioperative heparin bridging and coagulation function testing are needed. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study hypothesized that a simple, standardized perioperative management strategy, based on DOAC-specific interruption and resumption intervals, that foregoes perioperative heparin bridging and coagulation function testing, is safe for patient care, with associated low rates of major bleeding (1%) and arterial thromboembolism (0.5%). We postulated that this management yields a high proportion of patients (>90%) with a minimal to no DOAC level at surgery/procedure. Methods: PAUSE is a prospective study with 3 parallel DOAC cohorts of patients with AF taking apixaban, dabigatran or rivaroxaban and requiring anticoagulant interruption for an elective surgery/procedure. Patients were managed using a standardized protocol based on DOAC pharmacokinetic properties, procedure-associated bleeding risk (Appendix 1) and creatinine clearance (CrCl). DOACs were interrupted for 1 day before and after surgery for a low bleed risk surgery and 2 days before and after a high bleed surgery; longer interruption was done in patients on dabigatran with a CrCl<50 mL/min (Figure 1). A blood sample was obtained just before the procedure to measure residual DOAC levels (Appendix 2). Heparin bridging and preoperative coagulation testing were not used to manage patients. Patient follow-up occurred weekly for 30 days post-procedure for the primary clinical outcomes of major bleeding and arterial thromboembolism (Appendix 3). The incidence (95% confidence interval [CI]) of clinical outcomes was determined for each DOAC cohort using an intention-to-treat (ITT) analysis (interrupted at least 1 DOAC dose) and per-protocol analysis (adhering to DOAC interruption and resumption protocol). Results: We enrolled 3007 patients from 23 sites in Canada, the U.S. and Europe (Appendix 4). The patient characteristics were (Figure 2): mean age 72.5 years; 66.1% male; 33.5% high bleeding risk surgery/procedure, with 1257 patients in the apixaban cohort, 668 in the dabigatran cohort and 1082 in the rivaroxaban cohort (Table 1). DOAC interruption and resumption intervals are shown in Table 2. The 30-day postoperative rate (95% CI) of major bleeding was 1.35% (0-2.00) in the apixaban cohort, 0.90% (0-1.73) in the dabigatran cohort and 1.85% (0-2.65) in the rivaroxaban cohort; the rate (95% CI) of arterial thromboembolism was 0.16% (0-0.48) in the apixaban cohort, 0.6% (0-1.33) in the dabigatran cohort and 0.37% (0-0.82) in the rivaroxaban cohort (Table 3). There were 2541 (84.5%) patients with preoperative DOAC levels measured: a level <50 ng/ml occurred in 90.5% of patients in the apixaban cohort, in 95.1% of the dabigatran cohort and in 96.8% of the rivaroxaban cohort. Of 1007 patients having a high bleeding risk procedure, 832 (82.6%) had DOAC levels measured: 98.8% had a level <50 ng/mL (Table 4). Rates of major bleeding and arterial thromboembolism in the per protocol analysis were comparable to those of the ITT analysis (Table 5). Conclusions: In patients with AF who were taking a DOAC (apixaban, dabigatran, rivaroxaban) and required anticoagulant interruption for an elective surgery/procedure, using a standardized DOAC-specific perioperative management strategy was safe for patient care, with associated low rates of perioperative MB (<2%) and ATE (<1%). Further, a high proportion of patients (>90% overall; 98.8% at high bleeding risk) had a minimal or no residual DOAC level at the time of the surgery/procedure. PAUSE is the largest study, to date, that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care. Study Funding: CIHR (313156) and the H&S Foundation of Canada (G-14-0006136). Aniara-Hyphen Biomed (assays). Acknowledgments: We thank Drs. Walter Ageno, David Garcia, Lehana Thabane, Wendt Lim, Lori Linkins, William Ristevski, and Demetrios J. Sahlas. Also, Kayla Lucier, Grace Wang, Tara McDougall, and HRLMP and CRLB. Supported by CanVector and REDCap. Disclosures Douketis: Bayer: Other: Advisory Board; Janssen: Consultancy; BMS: Other: Advisory Board; Biotie: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; The Medicines Company: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Portola: Other: Advisory Board; Pfizer: Other: Advisory Board. Spyropoulos:Janssen Scientific Affairs, LLC: Consultancy. Carrier:Bayer: Honoraria; Leo Pharma: Research Funding; Pfizer: Honoraria; BMS: Honoraria, Research Funding. Vanassche:Bayer: Consultancy; Boehringer Ingelheim: Consultancy; BMS/Pfizer: Consultancy. Verhamme:Bayer: Honoraria, Research Funding; Medtronic: Honoraria; Portola: Honoraria; Boehringer Ingelheim: Honoraria; Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Shivakumar:Pfizer: Honoraria; Servier: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria. Gross:Pfizer: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria; Servier: Honoraria. Lee:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Servier: Honoraria; LEO Pharma: Consultancy, Research Funding; Bayer: Consultancy, Honoraria. Le Templier:BMS-pfizer: Honoraria. Wu:Leo Pharma: Honoraria; Pfizer: Honoraria; BMS-Pfizer: Honoraria. Coppens:Bayer: Honoraria, Other: Non-financial support, Research Funding; CSL Behring: Honoraria, Other: non-financial support, Research Funding; Uniqure BV: Research Funding. Arnold:Bristol Myers Squibb: Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding. Caprini:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Recovery Force: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizor: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Membership on an entity's Board of Directors or advisory committees. Summer:Octapharma: Honoraria. Schulman:Daiichi-Sankyo: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Boehringer-Ingelheim: Honoraria, Research Funding.

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Clinical and Laboratory Benefits of Early Initiation of Hydroxyurea with Pharmacokinetic Guided Dosing for Young Children with Sickle Cell Anemia

Blood ◽

10.1182/blood-2018-99-112909 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 507-507 ◽

Cited By ~ 1

Author(s):

Patrick T. McGann ◽

Omar Niss ◽

Min Dong ◽

Anu Marahatta ◽

Tomoyuki Mizuno ◽

...

Keyword(s):

Young Children ◽

Sickle Cell ◽

Cystatin C ◽

Sickle Cell Anemia ◽

Research Funding ◽

Laboratory Data ◽

Advisory Board ◽

Young Cohort

Abstract Background: Hydroxyurea is now the standard of care for children with sickle cell anemia (SCA). Results from the BABY HUG study and recommendations from the 2014 NHLBI Guidelines have led to early initiation (increasingly before 1 year of age) of hydroxyurea for many patients. Given the known variability in hydroxyurea pharmacokinetics (PK), treatment response (HbF%), and maximum tolerated dose (MTD), we hypothesized that individualized dosing would provide the optimal treatment approach. Methods: The Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154) is a prospective study of a personalized, PK-guided dosing model of hydroxyurea for children with SCA. Using population PK model-based Bayesian estimation, each participant's PK data are used to generate an individualized starting hydroxyurea dose that targets an area under the curve associated with actual MTD. Clinical follow-up and subsequent dose adjustments target MTD, usually defined by ANC<3.0x109/L. We analyzed clinical and laboratory data for TREAT participants who started hydroxyurea before 2 years of age, to allow for comparison to published results from BABY HUG, which included a similar young cohort but with conservative weight-based dosing of 20 mg/kg/day. TREAT participants had ongoing clinical and research evaluations of organ function, including transcranial doppler (TCD) studies, RBC pit counts, and cystatin C measurements. Results:The analysis of children starting hydroxyurea before 2 years of age included 33 participants (of 47 total TREAT enrollments), who contributed a total of 59.5 patient-years of hydroxyurea therapy. The mean age (±SD) at hydroxyurea initiation was 1.0±0.4 years of age. The average PK-guided, individualized starting dose was 27.8±5.3 mg/kg/day, higher than conventional and BABY HUG initial dosing (20 mg/kg/day). For children who have completed 12 months of therapy (n=24), effects in hematologic laboratory data are remarkable with average 35.9±8.9% HbF and hemoglobin concentration of 10.2±1.1 g/dL after 12 months of therapy (compared to 29.3±8.8% and 9.2±1.3 g/dL at baseline). The majority (70%) of these participants have HbF>30% and almost half achieved HbF>40% after 12 months of hydroxyurea. This hematological response is more robust than what was observed in BABY HUG (HbF=22.4%, Hb=9.1 g/dL after two years of therapy, Wang WC et al. Lancet 2011). In the TREAT cohort, there were no episodes of dactylitis, acute splenic sequestration, or stroke. There were 111 emergency room or sick outpatient clinic visits for this young cohort; 107 ED/clinic visits (without subsequent hospitalization) were for fever, URI symptoms, GI illness, or other non-specific complaints unrelated to SCA, while only 4 (3.6%) visits were for pain. There were 38 hospitalizations in 17 participants, mostly for routine evaluation of fever (66%), but no positive blood cultures and no admissions for febrile neutropenia. The average length of hospitalization was 2.8±2.4 days with 81% of participants discharged within 72 hours of admission. There were 3 episodes of acute chest syndrome in 2 patients, two of whom required PRBC transfusion. Including all types of visits, there were only 6 pain events, equivalent to 10.1 pain events per 100 patient-years, which is much lower than the published 94 events per 100 patient-years in the hydroxyurea treatment arm of BABY HUG (Thornburg CD et al. Blood 2012). There were 37 TCD exams performed in 16 participants, all normal except for one patient with conditional velocities that normalized with hydroxyurea. There were no significant differences from baseline to month 12 in either RBC pit counts or cystatin C values. Conclusions: Hydroxyurea initiation at an early age using PK-guided dosing provides significant clinical benefits for young children with sickle cell anemia. These TREAT study data suggest that initiating hydroxyurea around one year of life using a personalized dosing strategy can provide better clinical and laboratory benefits than starting at the conventional 20 mg/kg/day weight-based dose. Very high HbF levels are observed at modest and well-tolerated doses of hydroxyurea, perhaps because treatment was initiated before the process of HbF inactivation is complete. Continued long-term follow-up of these patients will determine whether these will be sustained and able to prevent both short- and long-term complications of SCA. Disclosures Malik: CSL Behring: Patents & Royalties. Quinn:Silver Lake Research Corporation: Research Funding; Global Blood Therapeutics: Research Funding; Amgen: Research Funding. Ware:Biomedomics: Research Funding; Nova Laboratories: Consultancy; Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Global Blood Therapeutics: Other: advisory board; Agios: Other: advisory board; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Reduced Costs and Length-of-Stay Associated with Rivaroxaban As Compared to Parenteral Bridging and Warfarin in Pulmonary Embolism Patients Managed in Observation Status

Blood ◽

10.1182/blood.v128.22.2337.2337 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2337-2337

Author(s):

Christine G Kohn ◽

Erin R Weeda ◽

W Frank Peacock ◽

Gregory J Fermann ◽

Christopher W. Baugh ◽

...

Keyword(s):

Pulmonary Embolism ◽

New Jersey ◽

Major Bleeding ◽

Research Funding ◽

Hospital Costs ◽

Advisory Board ◽

Hospital Treatment ◽

Total Hospital ◽

Employment Equity ◽

Equity Ownership

Abstract Background: Observation stays are intended to assess patients for short periods (i.e., <2-midnights) to determine need for inpatient admission or discharge. Unlike rivaroxaban, treatment of pulmonary embolism (PE) with parenteral bridging to warfarin requires frequent coagulation monitoring and dosing adjustments that may prolong length-of-stay (LOS) and increase hospital treatment costs. Objective: To compare LOS, hospital treatment costs, and readmissions in PE patients managed through observation stays treated with either rivaroxaban or parenterally-bridged warfarin. Methods: US Premier Hospital claims data spanning 11/2012-9/2015 was used to identify patients with a primary diagnosis code for PE (415.1x) managed through an observation stay and having ³1 claim for a PE-related diagnostic test on day 0-2. Rivaroxaban users, allowing ²2 days of prior parenteral therapy, were 1:1 propensity-score matched to patients parenterally bridged to warfarin. LOS, the proportion of encounters lasting >2-midnights, total hospital costs and risk of readmission for venous thromboembolism (VTE) or major bleeding during the same month or 2 months subsequent to the index event were compared between propensity-score-matched treatment cohorts. Results: A total of 401 rivaroxaban patients were matched to 401 patients receiving parenteral bridging to warfarin.Rivaroxaban use was associated with a shorter LOS (-0.25 days), fewer encounters lasting >2 midnights (21.1% vs. 32.7%) and lower total hospital costs (-$240) vs. parenteral bridging to warfarin (p²0.03 for all) (Table). Readmission was similar between cohorts (p>0.99 for both VTE and major bleeding readmission). Conclusion: Shorter LOS and lower hospital costs occurred with rivaroxaban vs. parenteral bridging to warfarin in PE observation stay patients. This was achieved without increasing short-term risk of VTE or major bleeding readmission. Table Table. Disclosures Peacock: Portola: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Research Funding. Fermann:Janssen Pharmaceuticals: Other: Advisory Board, Speakers Bureau; Pfizer: Research Funding. Baugh:Janssen Pharmaceuticals: Consultancy; Roche Diagnostics: Other: Advisory Board. Wells:Janssen Pharmaceuticals: Consultancy; Bristol Myers Squib: Research Funding; Pfizer: Research Funding; Bayer Healthcare: Other: Advisory Board, Speakers Bureau; Itreas: Other: Writing Committee. Ashton:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment. Crivera:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Wildgoose:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Schein:Johnson & Johnson: Employment, Equity Ownership, Other: Own in excess of $10,000 of J&J stock. Coleman:Boehringer-Ingelheim Pharmaceuticals, inc.: Consultancy, Research Funding; Bayer Pharmaceuticals AG: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Research Funding.

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Thrombotic and Bleeding Outcomes Following Perioperative Interruption of Direct Oral Anticoagulants and Vitamin K Antagonists in Patients with Non-Valvular Atrial Fibrillation - a Comparative Analysis

Blood ◽

10.1182/blood-2018-99-111698 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1234-1234

Author(s):

Joseph R. Shaw ◽

Tinghua Zhang ◽

Gregoire Le Gal ◽

James Douketis ◽

Marc Carrier

Keyword(s):

Major Bleeding ◽

Research Funding ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Risk ◽

Advisory Board ◽

Bleeding Events ◽

Chads2 Score ◽

High Bleeding Risk

Abstract Background: Atrial fibrillation (AF) is a common disorder that will affect up to 5.6 million patients in the U.S. by 2050. Both direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs), typically warfarin, are used for stroke prevention in AF and such patients frequently undergo invasive procedures requiring anticoagulant interruption. Temporary interruption of anticoagulants can be associated with significant morbidity and mortality in the form of thromboembolic and bleeding complications. DOACs have a short half-life and fast onset of action, thereby facilitating their perioperative management as compared to VKAs. Despite important differences in perioperative management and pharmacokinetics between DOACs and VKAs, there is a paucity of data comparing perioperative outcomes in DOAC and VKA-treated patients. Methods: We undertook a single-center, retrospective chart review that compared consecutive DOAC- or warfarin-treated patients with AF who underwent perioperative anticoagulant interruption for invasive procedures between January 2017 and March 2018. Perioperative warfarin interruption was done as per CHEST guidelines (Douketis et al. Chest 141,2 Suppl). Perioperative bridging with low-molecular-weight heparin was only used for patients with CHADS2 scores of 5-6 or in patients with stroke within the past 6 months. Perioperative interruption of DOACs was done as per Thrombosis Canada guidelines, with anticoagulation held for 3 half-lives prior to low bleeding risk procedures and 5 half-lives for high bleeding risk procedures. Primary outcomes included the 30-day post-operative thromboembolic and major bleeding rates. Secondary outcomes included the 30-day clinically relevant non-major bleeding (CRNMB) andl mortality rates. Major bleeding and CRNMB were defined according to ISTH definitions. Procedural bleeding risk was defined as per Schulman et al (Circulation 2015; 132(3)). Outcome events were independently adjudicated by two investigators. Outcomes from patients on DOACs and VKAs were compared. Demographic data was analyzed on a per-patient basis, p-values were calculated using independent T-Test, Chi-Square/Fisher's Exact Test where appropriate. Outcome data was analyzed on a per-interruption basis. P-values for unadjusted and adjusted comparisons were calculated using generalized estimating equations (GEE) to account for correlation between multiple procedures on the same patients. Results: 325 DOAC patients and 199 warfarin patients underwent 351 and 221 periprocedural interruptions, respectively. Warfarin patients had a significantly higher mean age, CHADS2 score, and proportion with renal dysfunction (Table 1). There was no statistically significant difference in 30-day post-operative rates of thromboembolism, CRNMB, and overall mortality, but warfarin patients had a significantly higher rate of major bleeding (Table 2). This latter result remained statistically significant following multivariate logistic regression correction for age, CHADS2 score and level of renal dysfunction. All bleeding events occurred post-procedure, with major bleeding events occurring from post-operative day 1 to post-operative day 25. None of the warfarin patients with major bleeding received perioperative bridging; the mean international normalized ratio (INR) at the time of major bleeding was 3.3. Most major bleeding events (7/8) in the VKA arm were surgical, with a single non-surgical major-bleed (spontaneous ICH on post-operative day 15 following urological surgery). Conclusions: The perioperative interruption of warfarin was associated with a higher 30-day rate of major bleeding as compared with DOAC interruption. Re-initiation of warfarin should be done judiciously following high bleeding risk procedures, and close INR monitoring may be warranted. Disclosures Shaw: Portola Pharmaceuticals: Research Funding. Douketis:Janssen: Consultancy; Pfizer: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; Portola: Other: Advisory Board; The Medicines Company: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Biotie: Other: Advisory Board; Bayer: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; BMS: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board. Carrier:Bayer: Honoraria; Pfizer: Honoraria; BMS: Honoraria, Research Funding; Leo Pharma: Research Funding.

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Prothrombin Time and Bleeding Events in Patients Undergoing Total Hip or Knee Replacement Surgery Receiving 10 Mg Rivaroxaban.

Blood ◽

10.1182/blood.v114.22.2099.2099 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2099-2099

Author(s):

Sylvia Haas ◽

Alexander GG Turpie ◽

Michael Rud Lassen ◽

Ajay K Kakkar ◽

Bengt Eriksson ◽

...

Keyword(s):

Prothrombin Time ◽

Major Bleeding ◽

Research Funding ◽

Factor Xa ◽

Advisory Board ◽

Bleeding Events ◽

Total Hip ◽

Replacement Surgery ◽

Scientific Advisory Board ◽

Scientific Advisory

Abstract Abstract 2099 Poster Board II-76 Rivaroxaban is a new, oral, direct Factor Xa inhibitor with a linear dose-relationship between Factor Xa inhibition and drug concentrations in plasma. It also affects global clotting tests such as prothrombin time (PT), particularly when Neoplastin® is used for testing. Rivaroxaban was investigated in four randomized, double-blind phase III studies (RECORD1, 2, 3, and 4) for the prevention of venous thromboembolism (VTE) after total hip or knee replacement surgery. This post hoc, explorative analysis evaluated the relationship between PT and bleeding events from pooled RECORD1–4 data. Patients were randomized to receive oral rivaroxaban 10 mg once daily (od) starting 6–8 hours after surgery, or subcutaneous enoxaparin 40 mg od starting the evening before surgery (RECORD1–3), or 30 mg twice daily starting 12–24 hours after wound closure (RECORD4). RECORD1, 3, and 4 were head-to-head comparisons of rivaroxaban and enoxaparin; RECORD2 compared extended-duration rivaroxaban with short-duration enoxaparin. Pooled analysis of the results of these studies showed that rivaroxaban significantly reduced the incidence of symptomatic VTE and death compared with enoxaparin regimens. The relationship between PT (measured by Neoplastin reagent) and adjudicated bleeding events was evaluated in 6,040 subjects valid for the safety analysis who underwent surgery and had taken at least one dose of rivaroxaban. The day of the surgery was defined as day 1. PT was measured on day 0 (baseline) and day 6 (trough and peak, and grouped according to quartiles). All adjudicated bleeding events were analyzed with respect to the day 6 measurements. The analysis focused on treatment-emergent adjudicated bleeding events up to 12±2 days after the initiation of active rivaroxaban administration. Bleeding events were grouped as major and clinically relevant non-major bleeding (composite) or any bleeding. A total of 5,912 patients had PT measurements at baseline; 345 experienced any bleeding event, of which 149 events were major or clinically relevant non-major bleeding events. Baseline mean PT ranged from 13.5 (with no bleeding) to 14.0 seconds (with any bleeding). Mean trough values on day 6 ranged from 14.3 (no bleeding) to 15.3 seconds (any bleeding). Mean peak values for PT on day 6 (measured at 2–4 hours after dosing) ranged from 18.9 (no bleeding) to 20.5 seconds (any bleeding). The peak/baseline PT ratios were 1.42 (no bleeding events), 1.46 (with major and clinically relevant non-major bleeding events), and 1.49 (any bleeding events). Of the patients with bleeding events, most events occurred in those with PT values in the extreme (Q4) peak and trough quartiles (Table). This explorative analysis indicated that PT values (seconds) in patients with no bleeding or with different types of bleeding were similar for each time point (baseline, day 6 trough and peak). The reproducible effects of rivaroxaban on PT are consistent with its known pharmacokinetics in plasma. Although extreme PT trough and peak values were associated with an increased risk of bleeding, this analysis suggests that PT over a wide range is not an accurate predictor of bleeding events in individual patients undergoing total hip or knee replacement surgery receiving 10 mg rivaroxaban. Refinement of PT testing methods has focused specifically on vitamin K antagonist (VKA) monitoring; therefore PT testing may be of greater utility for monitoring VKAs than Factor Xa inhibitors. Table. Percentage of patients with bleeding events grouped by prothrombin time peaks and troughs according to quartiles in rivaroxaban-treated patients from the RECORD1–4 studies Prothrombin time range (seconds) Patients with bleeding events (%) 95% confidence interval Any bleeding Prothrombin time day 6 trough Q1 9.1–12.9 3.00 2.11–4.10 Q2 >12.9–13.6 3.43 2.40–4.74 Q3 >13.6–14.7 4.89 3.66–6.38 Q4 >14.7–36.4 8.17 6.60–9.96 Prothrombin time day 6 peak Q1 10.0–16.0 3.70 2.66–4.98 Q2 >16.0–18.4 3.48 2.47–4.74 Q3 >18.4–21.1 4.11 3.01–5.45 Q4 >21.1–70.4 8.09 6.52–9.87 Major and clinically relevant non-major bleeding Prothrombin time day 6 trough Q1 9.1–12.9 1.54 0.92–2.39 Q2 >12.9–13.6 1.86 1.12–2.89 Q3 >13.6–14.7 1.92 1.17–2.94 Q4 >14.7–36.4 3.71 2.66–5.02 Prothrombin time day 6 peak Q1 10.0–16.0 1.62 0.96–2.55 Q2 >16.0–18.4 2.20 1.41–3.25 Q3 >18.4–21.1 1.73 1.04–2.69 Q4 >21.1–70.4 3.44 2.43–4.70 Day 6 trough: value at pre-dose on day 6. Day 6 peak: value at 2–4 hours post-dose on day 6. Q, quartile. Disclosures: Haas: Bayer Healthcare: Honoraria; BMS: Honoraria; Sanofi-Aventis: Honoraria; CSL-Behring: Honoraria; Novartis: Honoraria. Turpie:Astellas: Consultancy; Takeda: Consultancy; GSK: Consultancy; sanofi-aventis: Consultancy; Bayer Schering Pharma AG: Consultancy, Speakers Bureau; Johnson & Johnson Pharmaceutical Research & Development, L.L.C: Consultancy; Portola: Consultancy. Lassen:Bayer Schering Pharma: Consultancy, Honoraria; sanofi-aventis: Consultancy; Astellas Pharma: Consultancy; Bristol-Myers Squibb: Consultancy; Pfizer Inc.: Consultancy. Kakkar:Aryx therapeutics: Consultancy; Eisai: Consultancy, Honoraria, Research Funding, Scientific Advisory Board; Bristol–Myers Squibb: Consultancy, Honoraria, Research Funding, Scientific Advisory Board; Pfizer: Consultancy, Honoraria, Research Funding, Scientific Advisory Board; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding, Scientific Advisory Board; Sanofi-Aventis: Consultancy, Honoraria, Research Funding, Scientific Advisory Board; Bayer HealthCare: Consultancy, Honoraria, Research Funding, Scientific Advisory Board; GSK: Honoraria. Eriksson:Bayer Schering Pharma: Consultancy, Honoraria. Vogtlaender:Bayer Schering Pharma AG: Employment. Kubitza:Bayer Schering Pharma AG: Employment. Mueck:Bayer Schering Pharma AG: Employment. Misselwitz:Bayer Schering Pharma AG: Employment, Patents & Royalties. Berkowitz:Bayer HealthCare Pharmaceuticals : Employment.

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Periprocedural Interruption of Anticoagulation in Patients with Cancer-Associated VTE: An Analysis of Thrombotic and Bleeding Outcomes

Blood ◽

10.1182/blood-2018-99-117715 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1235-1235

Author(s):

Joseph R. Shaw ◽

James Douketis ◽

Gregoire Le Gal ◽

Marc Carrier

Keyword(s):

Major Bleeding ◽

Patient Population ◽

Research Funding ◽

Bleeding Risk ◽

Advisory Board ◽

Bleeding Complications ◽

Invasive Procedures ◽

Patients With Cancer ◽

High Bleeding Risk ◽

Active Cancer

Abstract Background: Approximately 10-20% of patients with venous thromboembolic events (VTE) have underlying malignancy. VTE is considered the second leading cause of death in patients with cancer, and patients with cancer-associated VTE are at higher risk of anticoagulant-related bleeding. Although patients with cancer often undergo diagnostic or therapeutic invasive procedures, there is a paucity of data on adverse outcomes following the periprocedural interruption of anticoagulation in this patient population. Methods: We did a single-center, retrospective chart review of consecutive patients with cancer-associated VTE who had periprocedural interruption of anticoagulation for invasive procedures between November 2015 and March 2018. Perioperative interruption of warfarin/low-molecular-weight heparin was done as per CHEST guidelines (Douketis et al. Chest 141(2 Suppl). Heparin bridging anticoagulation was used only for patients with recent (< 3 months) VTE. Perioperative interruption of direct oral anticoagulants (DOACs) was done as per Thrombosis Canada guidelines, with anticoagulation held for 3 half-lives prior to low bleeding risk procedures and 5 half-lives for high bleeding risk procedures. Active cancer was defined as per the HOKUSAI VTE CANCER trial (Raskob et al. NEJM 378(7)). Primary outcomes were 30-day post-operative rates of VTE and major bleeding. Secondary outcomes were 30-day post-operative rates of clinically relevant non-major bleeding (CRNMB) and mortality. Major bleeding and CRNMB were defined according to ISTH definitions. Data are reported on a per-interruption basis. Herein, we present an interim analysis of results. Results: To date, 82 perioperative interruptions are included, of whom 69.5% were receiving a DOAC. Mean age of the cohort was 65.8 years, 62.2% were male, 92.6% had active cancer and 41.5% had metastatic cancer. Thrombocytopenia (platelet count < 100 x 106/L) was present in 12.2% of interruptions. Procedures were stratified as high bleeding risk in 65.9% of cases. The 30-day rates of thromboembolism and major bleeding were both 3.70 % (95% confidence interval [CI] 1.25 to 10.2%), as was the 30-day rate of CRNMB. There were no deaths during the 30-day follow-up period. Conclusions: The periprocedural interruption of anticoagulation in patients with cancer-associated VTE appears to be associated with high rates of post-operative thrombotic and bleeding complications. Prospective studies are required to better quantify the risks of periprocedural anticoagulation interruption in this patient population. Disclosures Shaw: Portola Pharmaceuticals: Research Funding. Douketis:BMS: Other: Advisory Board; Janssen: Consultancy; Bayer: Other: Advisory Board; Pfizer: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Portola: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; Biotie: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; The Medicines Company: Other: Advisory Board. Carrier:Pfizer: Honoraria; Bayer: Honoraria; BMS: Honoraria, Research Funding; Leo Pharma: Research Funding.

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Impact of Pain and Functional Impairment in US Adult People with Hemophilia (PWH): Patient-Reported Outcomes and Musculoskeletal Evaluation in the Pain, Functional Impairment, and Quality of Life (P-FiQ) Study

Blood ◽

10.1182/blood.v126.23.39.39 ◽

2015 ◽

Vol 126 (23) ◽

pp. 39-39 ◽

Cited By ~ 2

Author(s):

Christine L Kempton ◽

Michael Recht ◽

Anne Neff ◽

Michael Wang ◽

Tyler W. Buckner ◽

...

Keyword(s):

Quality Of Life ◽

Mental Health ◽

Physical Activity ◽

Lower Extremity ◽

Board Of Directors ◽

Functional Impairment ◽

Research Funding ◽

Advisory Board ◽

Advisory Committees

Abstract Introduction: Pain and functional impairment associated with joint disease are major problems affecting adults with congenital hemophilia. Various standardized and disease-specific patient-reported outcome (PRO) instruments have been used in clinical studies of PWH or other diseases, but the use of these tools in the hemophilia comprehensive care setting for individual patient assessment or overall outcome tracking is limited and inconsistent. P-FiQ was designed to assess the impact of pain on functional impairment and quality of life (QoL) in adult PWH. Objectives: To assess pain and functional impairment in nonbleeding adult PWH through 5 PRO instruments and a clinical joint health evaluation. Methods: Adult males with mild to severe hemophilia and a history of joint pain or bleeding were enrolled from 15 US sites between October 2013 and October 2014. During routine clinical care visits, participants completed a pain history and 5 PROs (EQ-5D-5L with visual analog scale [VAS], Brief Pain Inventory v2 Short Form [BPI], International Physical Activity Questionnaire [IPAQ], SF-36v2, Hemophilia Activities List [HAL]) and underwent a Hemophilia Joint Health Score v2.1 (HJHS) evaluation completed by a trained physical therapist. Results: Overall 381 patients were enrolled, with a median age of 34.0 years. PRO and HJHS summary scores are presented in the table below. On EQ-5D-5L, most participants reported problems with mobility, usual activities, and pain/discomfort. On BPI, median worst pain was 6.0, least pain 1.0, average pain 3.0, and current pain 2.0. Ankles were most frequently reported as the joints with the most pain (37.4%), followed by knees (23.7%) and elbows (18.9%). On IPAQ, approximately half of participants (51.0%) reported no physical activity in the prior week. Median SF-36v2 subscores were lower for the 4 physical health domains than for the 4 mental health domains. Among HAL domains, self-care was the least impacted (median, 100.0) and functions of the legs (median, 66.7) and lying/sitting/kneeling/standing (median, 67.5) were the most impacted. On HJHS, elbow, knee, and ankle scores did not differ appreciably (median, 4.0, 4.0, and 6.0, respectively). Table. Assessment Tool Median (Q1, Q3) Range EQ-5D-5LVAS Health index 80.0 (66.0, 90.0) 0.796 (0.678, 0.861) 0 to 100a-0.11 to 1.0a BPIPain severity Pain interference 3.3 (1.3, 5.0) 2.7 (0.6, 5.4) 0 to 10b IPAQTotal physical activity 530.2 (264.0, 1039.5) Metabolic equivalents of task (MET)/minutes per week: Walking = 3.3 METs Moderate activities = 4.0 METs Vigorous activities = 8.0 METs SF-36v2Physical functioning Role physical Bodily pain General health Vitality Social functioning Role emotional Mental health Physical health summary Mental health summary Overall health 44.4 (29.7, 52.8) 44.6 (32.4, 56.9) 41.8 (37.2, 51.1) 45.8 (35.3, 52.9) 49.0 (42.7, 55.2) 45.6 (34.9, 56.4) 55.9 (36.4, 55.9) 52.8 (41.6, 58.5) 39.2 (29.5, 49.4) 50.7 (41.4, 55.7) 3.0 (2.0, 4.0) 0 to 100a1 to 5a HALUpper extremity activities Basic lower extremity activities Complex lower extremity activities Overall sum score 88.9 (73.3, 97.8) 73.3 (46.7, 96.7) 55.6 (30.0, 88.9) 76.6 (58.0, 94.3) 0 to 100a HJHSElbow Knee Ankle Global gait Total score 4.0 (0.0, 11.0) 4.0 (0.0, 10.0) 6.0 (1.0, 15.0) 3.0 (0.0, 4.0) 19.5 (6.0, 36.0) 0 to 40c0 to 124c aHigher scores indicate better QoL or functional status bLower scores indicate less pain severity cLower scores indicate better function Conclusions: Results of this analysis demonstrated challenges of lower extremity pain and functional impairment in US adult PWH. Pain was frequently observed, and it impacted physical function and quality of life across PROs and HJHS. Further analyses are underway to correlate assessments of pain and function across different PROs and with the exam-based HJHS. Disclosures Kempton: CSL Behring: Consultancy; Biogen: Consultancy; Baxter: Consultancy. Recht:Baxalta: Research Funding; Kedrion: Consultancy. Neff:Novo Nordisk: Other: Advisory Board; Kedrion: Other: Advisory Board. Wang:Biogen: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees. Buckner:Novo Nordisk: Consultancy; Baxalta, Inc. US: Consultancy. Soni:Bayer: Other: member of the Global Emerging HEmophilia Panel (GEHEP); Novo Nordisk: Speakers Bureau. Quon:Bayer: Other: Advisory Board; Grifols: Speakers Bureau; Novo Nordisk: Other: Advisory Board, Speakers Bureau; Biogen: Other: Advisory Board, Speakers Bureau; Baxter: Other: Advisory Board, Speakers Bureau. Witkop:Pfizer: Other: Advisory Board, Research Funding; Baxter Bioscience: Other: Advisory Board; Novo Nordisk: Other: Advisory Board, Speakers Bureau. Boggio:Baxter: Consultancy, Research Funding; OctaPharma: Consultancy, Research Funding; OPKO: Research Funding; CSL Behring: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Selexys: Research Funding; Bayer: Consultancy, Research Funding. Cooper:Novo Nordisk: Employment.

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Unfractionated Heparin Use in Children: Clinical Outcomes in a Pediatric Cohort Managed Using an Anti-Factor Xa Based Nomogram

Blood ◽

10.1182/blood.v130.suppl_1.701.701 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 701-701

Author(s):

Surbhi Saini ◽

Katherine L Harsh ◽

Joseph R Stanek ◽

Sarah O'Brien ◽

Amy L. Dunn ◽

...

Keyword(s):

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Bleeding Risk ◽

Advisory Board ◽

Minor Bleeding ◽

Direct Oral Anticoagulant ◽

Bleeding Events ◽

Advisory Committees ◽

Educational Grant

Abstract Background: Given its short half-life and immediate, complete reversibility with protamine sulfate, unfractionated heparin (UFH) remains the anticoagulant of choice for critically-ill children. The American College of Chest Physicians recommends that a therapeutic activated partial thromboplastin time (APTT) range in children on treatment doses of UFH should reflect an anti-FXa level of 0.35-0.7 IU/mL. A previous study from our institution showed moderate correlation between APTT and anti-FXa, prompting an institution-wide change to an anti-FXa based nomogram. Per the new nomogram, APTT and anti-FXa levels were simultaneously collected at pre-specified time points, though dose titrations were made on anti-FXa levels alone. In this study, we present our 20-month experience using this nomogram. Objectives: To assess the utility of anti-FXa based UFH dosing guidelines in children over a 20-month period (September 2015-May 2017). Methods: Permission for this study was obtained from the Institutional Review Board. Data was abstracted for all pediatric patients (age<21 yrs.) receiving therapeutic dosing of UFH (≥18 u/kg/hr) at Nationwide Children's Hospital (NCH) over the study period. Patients receiving UFH for <24 hrs, patients with mechanical circuits (ECMO and ventricular assist devices), and patients receiving concomitant anti-platelet therapy were excluded. Data were analyzed using descriptive statistics and comparisons were made using non-parametric methods. Correlations were assessed using the Bland-Altman method for repeated measures. Results: Over a 20-month period, 176 patients received UFH therapy at NCH. Of these, 95 patients met our pre-specified inclusion criteria. These 95 patients had 1102 simultaneous APTT and anti-FXa measurements performed. Baseline demographic information is described in Table 1. Mean duration of UFH therapy was 5.2 days (range: 1-45 days). Median UFH dose required to reach therapeutic anti-FXa goal was 22 units/kg/hr (range: 18-55 units/kg/hr), and was significantly higher in infants (<1yr of age) compared to older children (33.9 u/kg and 20 u/kg respectively; p<0.0001). Median time to achieve therapeutic anti-Xa was 10 hours (range: 2-96 hours), and was significantly shorter in patients who received a bolus (n=44) compared to those who did not (5 hrs and 12 hrs respectively; p=0.03). Five patients never achieved therapeutic anti-FXa levels. In patients with thrombo-embolism (n=75), 65 had end-of-therapy imaging (complete response: 36; partial or no response: 29). Time to achieve therapeutic anti-FXa was not predictive of radiological response (p=0.27). Moderate linear correlation between the APTT and anti-FXa (r = 0.74; 95% CI = 0.71-0.77) (Figure 1) was noted for the entire cohort. Eleven (10.6%) major and non-major bleeding events and 10 (10.5%) minor bleeding events were noted. When comparing coagulation parameters of patients with major and non-major bleeding to those with no-bleeding and minor bleeding age, indication for anticoagulation, peak anti-FXa, peak APTT, lowest platelet count and fibrinogen were not predictive of bleeding. Critically high APTT (>250 sec) was noted on 43 occasions in 21 unique patients and not associated with an increased risk of major and non-major bleeds (p=0.07). Conclusions: UFH monitoring is challenging in children. Time to achieve therapeutic anticoagulation and bleeding risk in our cohort is consistent with previous publications. Contrary to previous publications, extreme elevation of APTT was not associated with increased bleeding risk. Disclosures O'Brien: Pfizer: Consultancy, Other: study of direct oral anticoagulant in treatment of pediatric VTE; Glaxo Smith Kline: Other: DSMB for Arixtra Study in Pediatric VTE; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: advisory board - von Willebrand Disease diagnosis & management; Bristol Myers Squibb: Other: study of direct oral anticoagulant in prevention of pediatric VTE, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: advisory board - VWD diagnosis and management. Dunn: Alnylam: Other: Unrestricted educational grant; Bayer: Consultancy, Other: Unrestricted educational grant; Kedrion: Other: Unrestricted educational grant; NovoNordisk: Other: Unrestricted educational grant; Octapharma: Other: Unrestricted educational grant; Shire: Consultancy, Other: Unrestricted educational grant, Research Funding; Biogen: Other: Unrestricted educational grant, Research Funding; CSL Behring: Consultancy, Other: Unrestricted educational grant; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees. Kumar: Bayer: Consultancy; CSL Behring: Consultancy.

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