Pruthi, Rajiv K.

7055 Introduction: Cytogenetic abnormalities have been shown to be the most important determinant of prognosis in patients with acute myeloid leukemia (AML). In AML, trisomy 13 has been placed in the intermediate prognostic category although recent reports associate it with a more dismal outcome. The number of cases reported in the literature are relatively few, we reviewed our experience with trisomy 13 in hematologic malignancies to determine its significance and prognosis. Methods: We conducted a clinicopathological review of cases seen in our institution from January of 1990 to October of 2006. Our cytogenetic records were searched for patients, who had a hematological disorder whose non-stimulated bone marrow karyotype was found to have trisomy 13 as a sole abnormality. In men the absence of the Y chromosome was not regarded as a separate abnormality. Results: A total of 27 patients were identified. The median age was 76 years (range 25–87), 22/27 were male. The number of cases and diseases identified were 15 with AML, 5 with a myelodysplastic syndrome, 4 with an uncategorized myelodysplastic/myeloproliferative disorder, 2 with acute lymphoblastic leukemia and 1 with a chronic myeloproliferative disorder. Of the AML group 7 were M0 according to the FAB classification, 2 patients were identified to have M4 and another two M2. A single case each of M1 and M6 was also identified. In these 15 patients, 9 underwent induction chemotherapy, which consisted of intermediate dose Ara-C in 3 cases, anthracycline plus Ara-C in 5 patients, and daunorubicin, vincristine and prednisone in 1. Another 3 patients were given palliative treatment. For the rest of the subjects the type of treatment was unknown. A CR was obtained in 6 patients, 1 patient underwent a myeloablative stem cell transplant. Death has occurred in 24 patients, the median survival of the entire group was 5.4 months. In the patients with AML the median survival was 4.7 months, of the patients who achieved a CR the median survival was 9.5 months. Conclusions: We describe one of the largest series reported to date of trisomy 13 in hematologic malignancies and found that trisomy 13 is associated with male gender and an older age at presentation, as well as a poor prognosis. In AML its presence is associated with an FAB-M0 phenotype and its occurrence should be regarded as a high-risk feature. No significant financial relationships to disclose.

AbstractIntroductionHemostatic prophylaxis (HP) is recommended for patients with bleeding disorders (PWBD) before invasive procedures. However, evidence‐based guidelines are needed to determine optimal HP strategies.AimTo determine outcomes of HP for PWBD undergoing colonoscopy.MethodsWe undertook a retrospective cohort study of HP and outcomes of colonoscopy procedures performed between 9 November 1993 and 13 February 2018 for PWBD who received care in the Mayo Clinic Comprehensive Hemophilia Treatment Center.ResultsDuring the study period, 73 PWBD (58 with milder phenotypes: haemophilia, von Willebrand disease [subtypes 1 and 2; II, VII and XI deficiency]) underwent 141 procedures. Preprocedural HP was given to 61%, and interventions were performed in 47%. Of the 39% without preprocedural HP, postprocedural HP was given for 11%. One major (0.7%; 6 days postprocedure despite HP) and 10 minor (7%) bleeding complications occurred, which tended to be in patients with severe disease and/or after excision of larger polyps. There was no significant difference in the rate of bleeding complications with or without preprocedural HP (8.1% vs 5.5%, respectively; P = .74, Fisher's exact test).ConclusionThe low bleeding rates in our cohort suggest that preprocedure HP may be withheld for patients with mild bleeding disorders who undergo colonoscopy with a low likelihood of requiring an intervention or who require only low‐risk intervention. This strategy may be best used in experienced centres, provided optimal local hemostasis measures are undertaken and postprocedural HP is rapidly available if high‐risk intervention is required. Further studies are needed to determine optimal evidence‐based HP strategies for PWBD undergoing colonoscopy.

Abstract Aims/Objective:Congenital antithrombin (AT) deficiency, estrogen-containing oral contraceptive pills (OCPs) and pregnancy are associated with increased risk of venous thromboembolism (VTE). Little is known about reproductive decision-making in women with AT deficiency. We sought to explore the attitudes and choices regarding reproductive health in this population. Study Design/Methods:We conducted a provider-administered survey of women identified from the Mayo Clinic congenital AT deficiency database. Participants were asked to discuss their diagnosis of AT deficiency (age at diagnosis and VTE history including diagnosis and treatment) and questioned about (1) any lifetime methods of contraception, (2) pregnancies and pregnancy outcomes, (3) use of assisted reproductive technology, (4) history of menorrhagia, and (5) how their AT diagnosis had impacted each reproductive health experience and how this impact made them feel (open-ended question). Results:Of 31 women with congenital AT deficiency, 18 (58%) were reached, 8 (26%) were not reachable and 5 (16%) were deceased. Of the 18 women who completed the survey, median age at AT deficiency diagnosis was 40 years (range 7 - 65). Twelve (67%) women had experienced a VTE; 2 and 5 women had VTE in the setting of pregnancy OCP use, respectively. Reported contraceptive methods included OCPs, intrauterine device (IUD), and male condoms. Of the 5 women diagnosed with AT deficiency while taking OCPs, three switched to IUD, one to condoms, and one did not report an alternative method of contraception. Fifteen (83% ) women reported at least one pregnancy (median number of pregnancies = 2; range 1 - 6). Of 42 total pregnancies among the 18 women, 33 (79%) resulted in live term birth, 3 (7%) in live preterm birth, and 6 (14%) in miscarriage/spontaneous abortion at a median of 12 weeks into the pregnancy. Four women (22%) reported the use of anticoagulation during pregnancy (presumed to be low molecular weight heparin, but most women could not specify), and 1 woman reported use of assisted reproductive technology leading to a successful pregnancy. Eleven women (61%) reported menorrhagia, 4 (36%) while on anticoagulation for VTE events. Ten of 18 women (56%) reported that the AT deficiency diagnosis had affected their reproductive health in at least one way. Patient-reported comments are presented in Table 1, and a "word cloud" diagram (an image composed of words from the women's comments regarding contraception), in which the size of each word indicates its frequency) is presented in Figure 1. Conclusion:Women with AT deficiency require careful multidisciplinary management to avoid complications in the settings of hormonal contraception and pregnancy. Many women reported that their reproductive health experiences were impacted by their diagnosis, but also reported successful pregnancy outcomes. Validated questionnaires should be developed to assess women's reproductive health experiences. Strategies for reproductive risk management should be discussed carefully, and patient involvement in reproductive decision-making is key in this population. Word Cloud depicting frequency of women's comments regarding AT deficiency and contraception Word Cloud depicting frequency of women's comments regarding AT deficiency and contraception Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Noonan syndrome, characterized by dysmorphic facies, webbed neck, short stature, chest deformity, developmental delay and congenital heart defects, occurs as a result of mutations affecting the RAS-MAPK signaling pathway. A wide range of coagulation abnormalities are observed in these patients including: thrombocytopenia, platelet dysfunction and coagulation factor deficiencies. Screening for coagulation defects is recommended in childhood and especially prior to surgical procedures. Data available is limited and the extent of the hemostatic evaluation needed is not clearly defined. We carried out this study to outline the spectrum of coagulation abnormalities seen in patients with Noonan syndrome and their impact on surgical outcomes. Methods: In this retrospective cohort study, the electronic medical record system was queried for patients with Noonan syndrome seen at Mayo Clinic between 2000 and 2016. A detailed chart review was undertaken. Results i) Phenotypic correlates: 142 patients (58% male) met our study criteria, median age 21 years (range 14 days to 68 years). The referral specialty for initial evaluation was: cardiology 69 (49%), endocrinology 10 (7%), urology 10 (7%), neurology 8 (6%), pulmonary 6 (4%), orthopedic surgery 3 (2%), gastroenterology 2 (1%), psychiatry 2 (1%) and other specialties 4 (3%). Ten patients (7%) were referred for developmental delay, 13 (9%) for dysmorphism and 4 (3%) after having a family member diagnosed with Noonan syndrome. One patient (1%) presented with hematochezia. Twenty-seven (52%) of the 52 patients screened with genetic testing had a Noonan-associated gene defect. Bleeding was reported by 22 patients (15%) with a median International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) score of 2 (range 1-8). Of those tested, 11/121 (9%) patients had thrombocytopenia (platelets < 150 x 10^9/L). Screening coagulation tests were done in 58 (41%) patients, and included PT/aPTT in 43 (74%) and extended coagulation panels (including platelet function studies) in 15 (26%). Of the 22 patients with history of bleeding, 20 (90%) had screening coagulation testing. Twenty-two (38%) of patients screened had one or more coagulation laboratory abnormality. Ten (66%) patients with clinically suspected platelet dysfunction had normal platelet function analyzer (PFA)-100 testing and normal light transmission aggregometry, while 5 (33%) had decreased platelet aggregation with epinephrine. Four patients (7%) (including 2 siblings) had low vWF levels consistent with type 1 vWD, 9 (16%) had mild clotting factor deficiencies ( FIX- 3, FXII-2 and multiple clotting factors-5) and 4 (7%) had a prolonged baseline PT and/or aPTT without additional coagulation factor assessment (Table 1). Thirteen patients (9%) had both a bleeding phenotype and abnormal coagulation laboratory results. ii) Surgical outcomes: A total of 274 surgical procedures were performed in 89 patients (63%). These included: cardiac 118 (43%), orthopedic 30 (11%), ENT 27 (10%), neurosurgical 26 (10%), abdominal 17 (6%), urologic 17 (6%), gynecologic 12 (4%) thoracic 8 (3%), ophthalmologic 7 (3%), plastic surgery 5 (2%), maxillofacial 4 (1%) and lymph node dissection 3 (1%). Platelets were utilized in 26 procedures (10%), fresh frozen plasma in 19 (7%) and cryoprecipitate in 7 (3%). Two procedures were performed in patients with type 1 vWD using vWF concentrates. Abnormal intra or postoperative bleeding was seen in 5/274 procedures (1.8%) performed in 4 patients. One patient had a known functional platelet disorder, one had normal PT and aPTT and two were not screened for coagulation defects. Bleeding was managed with transfusional supportive care in 3 (60%) surgical cases, while in 2 (40%) cases patients required re-intervention to achieve surgical hemostasis (bleeding from femoral access site and pacemaker pocket hematoma). There was no mortality related to the excess perioperative bleeding. Conclusion: Varying hemostatic abnormalities are seen in patients with Noonan syndrome, ranging from thrombocytopenia to multiple coagulation factor deficiencies. Frank bleeding manifestations however are uncommon and when present are usually mild. Clinical evaluation focused on the bleeding history and basic coagulation screening allows for successful perioperative hemostatic support and good surgical outcomes. Disclosures No relevant conflicts of interest to declare.

Introduction: The compulsive craving and consumption of non-food substances, known as pica, is a well-documented symptom associated with iron deficiency anemia (IDA). Olfactory cravings associated with IDA are a recently described phenomenon known as desiderosmia. In our practice we observed a subset of patients with IDA who report specific tactile cravings associated with mastication. Methods: This study included patients from the Mayo Clinic (Rochester, MN) and Ankara Training and Research Hospital (Ankara, Turkey) Hematology practices who self-reported tactile mastication cravings during initial evaluation for IDA between 1/1/18 and 6/30/19. Information including sociodemographics, substance craved, values of hemoglobin (Hgb), mean corpuscular volume (MCV), and ferritin before and after iron replacement therapy, and symptom resolution after treatment were recorded. Results: We observed 12 patients with IDA who self-reported chew cravings during initial evaluation. All patients were female and the median age was 41.5 years (33-59). Of these 12 patients, median baseline Hgb, MCV, and ferritin were 9.4 g/dL (6.6-12.9), 73.7 fL (59.1-95.1), and 6 µg/L (2-21), respectively. Tactile cravings included chewing gum (3), mastic gum (2), ginseng (1), dry oats (1), crackers (1), pickles (1), chips (1), sawdust (1), and knitting rope (1). Many patients reported the frequency and satisfaction of these cravings resulted in jaw pain as well as the persistence of cravings despite this discomfort. Only 16.7% (2/12) reported concurrent ice pica. In total, 9 patients proceeded with observed treatment of their IDA with clinical follow-up and laboratory confirmation of iron repletion. Oral (ferrous glyconate or ferrous fumarate) and intravenous (ferric carboxymaltose, iron sucrose, or low molecular weight iron dextran) iron replacement were used in 33.3% (3/9) and 66.7% (6/9) patients, respectively. Post-treatment median laboratory values include: Hgb 12.7 g/dL (10.8-14.7), MCV 80.1 fL (76.1-91.7), and ferritin 98 µg/L (24-398). Overall, 88.9% (8/9) reported resolution of chew cravings after iron repletion. The lone patient with persistent symptoms had a baseline ferritin of 10 µg/L, improved to 398 µg/L after replacement, and settled back at 42 µg/L three months later. Discussion: Our patient experience provides suggestive evidence that oral tactile craving symptoms, distinct from ice pica, exists in a subset of patients suffering from IDA. For this, we propose the term "desideromastica" derived from the Latin words "desiderare" for desire and "mastica" for chew. "Desidero" can also be indicative of a reduction in iron, which relates to iron deficiency. Our hope in naming this relatively unexplored symptom associated with IDA will encourage additional clinicians to share their experience and guide future investigation. Disclosures No relevant conflicts of interest to declare.

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.

Introduction: Germline RUNX1 mutations/deletions result in a Familial Platelet Disorder with propensity to Myeloid Malignancy (FPDMM); an autosomal dominant condition characterized by thrombocytopenia, qualitative platelet defects, and myeloid clonal evolution (MDS and AML). The advent of next generation sequencing (NGS) has allowed detection of clonal cytopenias of unclear significance (CCUS) prior to bone marrow (BM) morphological changes. Somatic RUNX1 mutations (RUNX1MT) can be seen in myeloid malignances, including MDS/MPN overlap syndromes, with an indeterminate prognostic impact. We carried out this study to define the landscape of clonal evolution in FPDMM patients and to compare germline RUNX1MT with somatic mutations. Methods After IRB approval, families with RUNX1MT FPDMM (detected by germline sequencing and deletion/duplication assays) and patients with 2016, WHO-defined MDS/MPN overlap syndromes (except JMML) were included in the study. Index patients with FPDMM underwent BM biopsies and in select cases NGS at diagnosis and then as indicated for follow up, or at disease progression. All MDS/MPN overlap syndrome patients underwent a 29-gene panel NGS assay on BM samples obtained at diagnosis by previously described methods (Patnaik et al., BCJ 2016). Results Eight index patients with FPDMM were included; median age at diagnosis 58 (range, 0-71) years, 3 (38%) males (Figure A). Four (50%) had intragenic deletions involving multiple exons in 3 cases and 2 nucleotides in 1 case, 1 (13%) each had missense, frameshift and splice site mutations, while 1 (13%) patient had a whole gene deletion (Figure C). Notably, in 4 (100%) of 4 patients with large deletions, NGS testing was negative for RUNX1 abnormalities. Four (50%) index patients presented with a myeloid neoplasm; JAK2, SRSF2, ASXL1 mutant CMML, MDS/MPN-U with trisomy 8, AML with del7q and normal karyotype AML (negative NGS). Three (38%) index patients had CCUS at diagnosis with TET2 (67%) being the most common acquired mutation, and others including SRSF2, EZH2, and SF3B1. Cumulatively, myeloid clonal evolution was seen in 7 (88%) patients. Three (38%) index patients (AML-2, CMML-1) underwent allogeneic HCT, and at last follow up were in remission. Median age at myeloid clonal evolution was 61 (range, 4-71) years; median overall survival (OS) from date of myeloid clonal evolution was 12 (range, 7-53) months. For the comparative analysis, 499 patients with MDS/MPN overlap syndromes were included; 382 (77%) with CMML, 48 (10%) with MDS/MPN-RS-T (MDS/MPN with ring sideroblasts and thrombocytosis), 17 (3%) with aCML (atypical CML), and 52 (10%) with MDS-MPN-U (unclassifiable). Median age at diagnosis was 71 (range, 18-99) years, and 329 (66%) were male. RUNX1MT were detected in 57 (11%) patients; 43 (11%) with CMML, 5 (30%) with aCML, and 9 (17%) with MDS-MPN-U. No RUNX1MT were found in MDS-MPN-RS-T. Overall, 62 RUNX1MT were identified in 57 patients, with 52 (39 CMML, 4 aCML, 9 MDS-MPN-U) and 5 (4 CMML, 1 aCML) patients harboring 1 and 2 RUNX1MT, respectively. RUNX1MT spanned the entire coding sequence without specific hotspots (Figure B): 27 (44%) were missense, 2 (3%) involved the splicing sites, 5 (8%) were nonsense and 28 (45%) were frameshift. There was only one RUNX1MT (R273K), seen in both germline and somatic patients (Figures B and C). Compared to wild type patients, RUNX1MT patients with MDS/MPN overlap syndromes had significantly lower platelet counts (median 72 vs 117 x109/L, p<0.0001), without any other phenotypic differences. In the somatic RUNX1MT cohort, co-occurring mutations included ASXL1 (54%), SRSF2 (54%), TET2 (49%), and NRAS (28%), with NRAS (28% vs 13%, p=0.0028), and SRSF2 (54% vs 39%, p=0.0218) mutations clustering with RUNX1MT. Median OS of the entire cohort was 29 (range, 0-170) months. On univariate analysis, while there was a trend for an inferior OS in RUNX1MTvs wild type patients (20 vs 29 months, p=0.0523), the leukemia-free survival was clearly inferior (p=0.0175, Figure D). Conclusion RUNX1 MT FPDMM is a germline predisposition syndrome with a high rate of myeloid clonal evolution (88%), including clonal cytopenias (38%). Germline RUNX1MT have minimal overlap with somatic mutations seen in myeloid malignancies, with NGS testing often missing RUNX1 deletions. Somatic RUNX1MT in myeloid malignancies are significantly associated with thrombocytopenia and an inferior leukemia-free survival. Figure Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Myeloproliferative neoplasms (MPN) are associated with an increased risk of venous (VTE) and arterial (ATE) thromboembolic events (TE). Anticoagulation needs to be balanced between the risk of incident and recurrent TE and risk of hemorrhage. While data on outcomes of anticoagulation with warfarin in patients with MPN are available, data on safety and efficacy of direct oral anticoagulants (DOACs) in this subgroup are not. Herein, we present outcomes of use of DOACs in patients with MPN at our institution. Methods: In this retrospective cohort study, we searched the Mayo Clinic clinical databases for patients meeting the WHO criteria for MPN who had been prescribed a DOAC between 2011 and 2017. The MPN diagnosis had to have predated the DOAC prescription. Medical records of consenting patients meeting study criteria were reviewed and data on demographics, diagnosis of MPN, indication for DOAC prescription, and their efficacy (incident or recurrent TE) and safety (hemorrhagic events) were abstracted. Results: Over the study period, 19 patients (female = 10) met inclusion criteria. The median age of patients at MPN diagnosis was 67 years (35-83), and 73 years (53-86) at initiation of DOAC. Prescribed DOACs included rivaroxaban (n=12), apixaban (n=6), and dabigatran (n=2) (one patient received rivaroxaban and was switched to apixaban). MPN diagnoses included polycythemia vera (PV) (n=9), essential thrombocythemia and chronic myeloproliferative neoplasm NOS (3 each), chronic myeloid leukemia and myelofibrosis (2 each). Indications for DOAC included thromboembolism (n=13; 68%) (arterial:2 and venous:11), and atrial fibrillation (afib) (n=6; 31%). The median duration of DOAC therapy was 241.5 days (range 13-1879). Five patients were switched from warfarin to rivaroxaban (n=4) and apixaban (n=1) at patient and/or provider preference; the rest were initiated on the DOAC de novo based on provider preference. Of the 19 patients, one patient each experienced a major hemorrhagic and TE event. One patient with PV who was on rivaroxaban for afib required hospitalization for gastrointestinal hemorrhage due to gastritis; DOAC was discontinued following this episode. One other patient with PV had a non-ST elevation myocardial infarction while on rivaroxaban for afib and prior stroke; DOAC was continued. There were no deaths attributable to DOAC use. Discussion: Our limited data suggests that use of DOACs in patients with MPN is feasible with an acceptable balance between risk of hemorrhage and recurrent thrombosis. Additional data on long term outcomes of DOACs in MPNs are needed. Disclosures No relevant conflicts of interest to declare.

Abstract BACKGROUND: Glanzmann's thrombasthenia (GT) is an inherited platelet disorder (IPD) that leads to clinically significant bleeding. Platelets from patients with GT can show qualitative or quantitative defects of platelet membrane glycoprotein (GP) IIb/IIIa complex. Most GT are caused by autosomal recessive genetic defects in ITGA2B and ITGB3 (genes for GPIIb and GPIIIa, respectively) with rare cases showing an autosomal dominant pattern. Accurate diagnosis of GT requires a constellation of both phenotypic and genetic studies. Here we report a unique case of autosomal dominant GT resulted from thorough phenotypic and genetic studies. PATIENTS AND METHODS: A 19 year-old woman was recently evaluated for life-long history of easy bruising and severe menorrhagia that was only partially responsive to medroxyprogesterone. She has severe thrombocytopenia first recognized shortly after birth with a platelet count around 20x109/L. Platelet size was normal. She was presumed to have immune-mediated thrombocytopenia (ITP) since early infancy, but lacking responsiveness to the conventional treatments of ITP including immunomodulation, splenectomy and thrombopoietin receptor agonists. Family history was negative for a bleeding diathesis. Both von Willebrand factor antigen and activity were within normal range. Bone marrow aspirate and biopsy with associated chromosome studies were all normal. Platelet surface glycoprotein assessment by flow cytometry using antibodies to GP IIb, IIIa, Ia, Ib-a, VI, IX, and whole exome sequencing (WES) utilizing a predefined list of 53 clinically significant genes* related to genetically IPDs were performed. Due to thrombocytopenia platelet aggregation studies could not be performed. METHODS/RESULTS: Platelet surface expression of GPIIb (CD41) and GPIIIa (CD61) were markedly decreased suggestive of a variant of GT (Figure). WES performed with Illumina HiSeq 2500 sequencing system by using Agilent SureSelelct CRE kit V1 to capture and target the exonic regions showed presence of a heterozygous mutation in ITGB3 gene (c2213T>G; p.Leu738Arg). By in silico prediction modeling, this mutation is likely to be pathogenic and results in the substitution of hydrophobic leucine with hydrophilic arginine in the transmembrane domain of the β3 subunit of alpha IIb/beta 3 integrin (αIIbβ3), the platelet receptor that binds to fibrinogen. Interestingly, GPVI is also decreased which may be associated with GPIIb and GPIIIa deficiency or due to accelerated shedding since no GPVI mutation was identified. CONCLUSION: We describe a patient with GT associated with a novel heterozygous autosomal dominant mutation in ITGB3 gene with substitution of leucine with arginine (c2213T>G; p.Leu738Arg). This deletion caused a low expression of αIIbβ3 integrin on her platelets surface and severe thrombocytopenia. This case underscores the importance of an integrated phenotyping and genotyping approach to render a definitive diagnosis of an IPD. *Platelet exome gene list: ABCG5, ABCG8, ACBD5, ACTN1, ANKRD26, ANO6, AP3B1, BLOC1S3, BLOC1S6, CYCS, DTNBP1, ETV6, FLI1, FLNA, GATA1, GFI1B, GP1BA, GP1BB, GP6, GP9, HOXA11, HPS1, HPS3, HPS4, HPS5, HPS6, ITGA2B, ITGB3, LYST, MASTL, MPL, MYH9, NBEAL2, ORAI1, PSRX1, P2RY12, PLA2G4A, PRKACG, RASGRP2, RBM8A, RUNX1, STIM1, STX11, STXBP2, TBXA2R, TBXAS1, THPO, TUBB1, UNC13D, VIPAS39, VPS33B, VPS45, WAS Figure Figure. Disclosures No relevant conflicts of interest to declare.