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The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P <  6 × 10 - 10 after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits., (© 2024. The Author(s).)

Background: The incidence, risk factors, and outcomes of venous thromboembolism (VTE) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) are not well described., Objectives: We aimed to determine the clinical characteristics, risk factors, and outcomes of incident VTE in patients with newly diagnosed MBL/CLL and compare the incidence to the age- and sex-matched general population., Methods: Using the Mayo Clinic CLL Database, we identified 946 patients with newly diagnosed MBL/CLL between 1998 and 2021. Incidence of VTE was identified by querying the electronic health record for VTE-specific International Classification of Diseases-9 and -10 codes and reviewing results of radiographic studies., Results: Eighty patients developed VTE. The incidence of VTE in patients with newly diagnosed MBL/CLL was ∼1% per year. In multivariable analyses, prior history of VTE (hazard ratio [HR]: 5.33; 95% CI: 1.93-14.68, P = .001) and high/very high-risk CLL-International Prognostic Index score (HR: 2.63; 95% CI: 1.31-5.26; P = .006) were associated with an increased risk of VTE; receipt of CLL treatment or occurrence of nonhematologic malignancy was not. Development of VTE was associated with shorter overall survival (HR: 1.82, 95% CI: 1.30-2.55) after adjusting for age, sex, prior history of VTE, and Rai stage. The age- and sex-adjusted VTE incidence rate for patients with MBL/CLL and no prior history of VTE (n = 904) was 1254 per 100 000 person-years compared with 204 per 100 000 person-years in the general population, reflecting a 5.9-fold increase., Conclusion: Our study demonstrates a 6-fold increased risk of VTE in patients with MBL/CLL compared with the age- and sex-matched general population., Competing Interests: Declaration of competing interests P.J.H.: None. T.H.: Consulting: BeiGene. Research funding to the institution from BeiGene. S.A.P.: Research funding has been provided to the institution from Janssen, AstraZeneca, Merck, and Genentech for clinical studies in which Sameer A. Parikh is a principal investigator. Honoraria has been provided to the institution from Pharmacyclics, Merck, AstraZeneca, Janssen, BeiGene, Genentech, Amgen, MingSight Pharmaceuticals, TG Therapeutics, Novalgen Limited, Kite Pharma, and AbbVie for Sameer A. Parikh’s participation in consulting activities/advisory board meetings. E.M.: Consultancy fee from Protego (fee paid to institution). A.B.K.: Consulting: AstraZeneca, Pharmacyclics, Bristol Meyer Squib, AbbVie (money to institution). NEK Advisory Board for AbbVie, AstraZeneca, Beigene, Behring, Boehringer Ingelheim Pharmaceuticals, Inc, Dava Oncology, Janssen, Juno Therapeutics, Pharmacyclics. Data Safety Monitoring Committee for Agios Pharm, AstraZeneca, BMS–Celgene, Dren Bio Janssen. Researchfundingreceived from AbbVie, Acerta Pharma, Bristol Meyer Squib, Celgene, Genentech, Pharmacyclics, Sunesis, Vincerx. No other conflicts of interest were reported by the authors., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine the impact of residual platelets on dilute Russell's viper venom time (DRVVT) assay in frozen-thawed plasma submitted for lupus anticoagulant (LAC) testing., Methods: We measured platelet counts in frozen-thawed samples submitted for LAC testing and evaluated the association between platelet count and the DRVVT screening time and ratios. We also spiked platelets into a LAC-positive sample to observe the effect on the DRVVT., Results: Progressive increase in platelet count resulted in a statistically significant shortening of the DRVVT assay results on plasma after 1 freeze-thaw cycle. A similar effect was noted on the LAC-positive sample., Conclusions: Residual platelets in plasma samples result in shortening of DRVVT assay after 1 freeze-thaw cycle. This may result in a false-negative LAC test result., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The optimal duration of anticoagulation in patients with active cancer and venous thromboembolism (VTE) is unknown. Current clinical guidelines advocate anticoagulant therapy for 3-6 months and to continue anticoagulant therapy for as long as the cancer is active. However, an adequate systematic review on the rate of recurrent VTE after discontinuation of anticoagulant therapy has not been performed., Methods: For this systemic review and meta-analysis, we searched Embase.com, Medline (Ovid), Web of Science, Cochrane Library, and Google Scholar, from database inception to February 16, 2023, for studies on anticoagulant therapy in patients with cancer and the recurrence of venous thromboembolism after discontinuation of this therapy. We included randomised controlled trials and cohort studies published in English that reported on patients who met the following: cancer and a first VTE, completed at least 3 months of anticoagulant therapy, were followed after discontinuation of anticoagulant therapy, and with symptomatic recurrent VTE as an outcome during follow-up. Study-level data were requested from study authors. The primary outcome was the rate of recurrent VTE after discontinuation of anticoagulant therapy. A Bayesian random-effects meta-analysis was used to estimate the rate of recurrent VTE per 100 person-years for the pooled studies at different time intervals after discontinuation of anticoagulation therapy. We also calculated the cumulative VTE recurrence rate at different time intervals. Forest plots were mapped and the results were summarized by the median and 95% credible interval (CIs). This study was registered with PROSPERO, CRD42021249060., Findings: Of 3856 studies identified in our search, 33 studies were identified for inclusion. After requesting study-level data, 14 studies involving 1922 patients with cancer-associated thrombosis were included. The pooled rate of recurrent VTE per 100 person-years after discontinuation of anticoagulant therapy was 14.6 events (95% credible interval 6.5-22.8) in the first three months, decreasing to 1.1 events (95% CI 0.3-2.1) in year 2-3, and 2.2 events (95% CI 0.0-4.4) in year 3-5 after discontinuation of anticoagulant therapy. The cumulative VTE recurrence rate was 28.3% (95% CI 15.6-39.6%) at 1 year; 31.1% (95% CI 16.5-43.8%) at 2 years; 31.9% (95% CI 16.8-45.0%) at 3 years; and 35.0% (95% CI 16.8-47.4%) at 5 years after discontinuation of anticoagulant therapy., Interpretation: This meta-analysis demonstrates a high rate of recurrent VTE over time after discontinuation of anticoagulant therapy in patients with cancer-associated thrombosis. Our results support the current clinical guidelines to continue anticoagulant therapy in patients with active cancer., Funding: Erasmus MC., Competing Interests: All authors have completed the ICMJE uniform disclosure form. Luis Jara-Palomares: has received support for the present manuscript from MSD; grants from Leo Pharma; honoraria from Actelion Pharmaceuticals, Bayer HealthCare Pharmaceuticals, Leo Pharma, MSD, Pfizer, ROVI, and Bristol-Myers Squibb. Isabelle Mahé: has received grants from BMS Pfizer; honoraria from BMS Pfizer, Leo Pharma, and Sanofi; support for attending meetings/travel from BMS Pfizer and Leo Pharma. Andrea Marshall: my institution received unrestricted educational grant from Bayer AG for the select-D trial. Remedios Otero Candelera: LEO-PHARMA was partially involved in the financial support to Hispalis Study without interfering in the intellectual conception, design and data analysis; received financial support for attendance to congresses and scientific meetings, payment to conferences or advisory board from BAYER HISPANIA, MSD, LEO-PHARMA and ROV; participated on a Data Safety Monitoring Board or Advisory Board. Frederikus Klok: has received research support from Bayer, Bristol-Myers Squibb, Actelion, Boston Scientific, Leo Pharma, PharmX, The Netherlands Organisation for Health Research and Development, The Dutch Thrombosis Association, The Dutch Heart Foundation and the Horizon Europe program, all outside this work and paid to his institution. Marieke Kruip: has received an unrestricted research grant from Sobi; research grants from Netherlands Thrombosis Foundation and the Netherlands Organization for Health Research and Development; speakers fee from Sobi, Roche, and BMS; all grants and fees are paid to her institution (Erasmus MC). Carin van der Rijt: has received a payment to the institution from the Netherlands Organization for Health Research and Development for a project on deprescription of medication at the end of life; is Chair of the Dutch Association for Professional Palliative Care (unpaid); is member of the Supervisory Board of the Foundation Roparun (attendance fee is paid). Eric Geijteman: has received an internal grant from the Erasmus MC (50.000 euro). This is a payment to finance this study (together with an interview- and questionnaire study about the perspectives of patient, caregivers and healthcare professionals on anticoagulation therapy). All other authors report no conflict of interest., (© 2023 The Author(s).)

Background: Clinical picture and outcome of incidental pulmonary embolism (iPE) compared to symptomatic pulmonary embolism (sPE) remain unclear., Methods: Demographics, recurrent venous thromboembolism (VTE), mortality, major bleeding, and clinically relevant nonmajor bleeding (CRNMB) were compared between iPE and sPE patients who were followed prospectively at Mayo Thrombophilia Clinic (March 1, 2013 to August 1, 2020)., Results: Out of 3576 VTE patients, 1417 (39.6%) had PE: 562 (39.7%) iPE and 855 sPE. Patients with cancer were more likely to have iPE (400 iPE vs. 314 sPE) compared to those without cancer (162 iPE vs. 541 sPE). VTE recurrence rate (all per 100 person-years) was similar in all iPE and sPE patients (3.34 vs. 3.68, p = .50), with cancer (4.16 vs. 4.89, p = .370), and without cancer patients (0.89 vs. 2.80, p = .25). Higher mortality observed in all patients with iPE compared to sPE (46.45 vs. 23.47, p < .001) and with cancer (56.41 vs. 45.77, p = .03) became not significant after adjustment for age, antiplatelet therapy, metastases, and cancer location. Noncancer iPE patients had higher mortality (15.95 vs. 7.18, p = .006) even after adjustment (p = .05). The major bleeding rate was also higher in all patients iPE compared to sPE (7.10 vs. 3.68, p = .03), but not after adjustment (p = .974); higher major bleeding rate in noncancer patients (6.49 vs. 1.25, p = .007) remained significant after adjustment (.02). CRNMB rate was similar to iPE and sPE patients., Conclusion: iPE represents a more serious clinical condition compared to sPE as indicated by the higher mortality and major bleeding but these differences reflect underlying comorbidities rather than the seriousness of the embolic event., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: The outcome of anticoagulation for cancer-associated venous thromboembolism (Ca-VTE) differs according to cancer location, but data are limited and inconsistent., Materials and Methods: Patients with acute venous thromboembolism (VTE) enrolled between 03/01/2013 and 04/30/2021 were followed prospectively to assess VTE recurrence, major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and death., Results: There were 1702 (45.3 %) patients with Ca-VTE including: gastrointestinal (n = 340), pancreatic (n = 223), hematologic (n = 188), genitourinary (n = 163), lung (n = 139), ovarian (n = 109), breast (n = 97), renal (n = 75), prostate (n = 73), hepatobiliary (n = 70), brain (n = 57), and other cancers (n = 168); 2057 VTE patients had no cancer (NoCa-VTE). Hepatobiliary cancer had the highest VTE recurrence (all rates 100 person-years) of all cancers and higher compared to NoCa-VTE (13.69, p = 0.01), while the MB rate, although numerically higher (15.91), was not different (p = 0.09). Another 3 cancers had higher VTE recurrence but similar MB rates compared to NoCa-VTE: genitourinary [(9.59, p = 0.01) and (7.03, p = 1.0)], pancreatic [(9.74, p < 0.001) and (5.47, p = 1.00)], and hematologic [(5.29, p = 0.05) and (3.59, p = 1.0)]. Renal cancer had the highest rate of MB among all cancers and was higher than that of NoCa-VTE (16.49; p < 0.001), with no difference in VTE recurrence (1.62; p = 1.0). VTE recurrence and MB rates were not significantly different between NoCa-VTE and gastrointestinal, lung, breast, prostate, and brain cancers. CRNMB rates were similar and mortality higher in Ca-VTE patients, except for prostate and breast cancer, compared to NoCa-VTE., Conclusions: Significant differences in clinical outcomes indicate that anticoagulation strategies may need to be tailored to the primary cancer location., Competing Interests: Declaration of competing interest The authors have declared no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury 1-4 . These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries 5 . Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction., (© 2022. The Author(s).)

Background: Coagulopathy and thrombosis are well-described complications of asparaginase therapy. However, treatment practices in pediatric hematology/oncology (PHO) patients vary widely as evidence-based guidelines for clinical management of these complications in this population are lacking., Objective: The objective of this study was to assess management practices of asparaginase-related coagulopathy by pediatric hematologist/oncologist attending physicians., Design/method: Email survey sent to 2327 PHO physicians primarily practicing in the United States., Results: Two hundred eighty-five (12.2%) attending physicians completed the survey. Only 4.6% (n=13/285) routinely prescribe prophylactic anticoagulation during induction chemotherapy for leukemia. Slightly more than half (n=145/250, 50.9%) of all providers perform baseline coagulation studies. Most providers that were surveyed (n=185/285, 64.9%) only replete coagulant factors if the patient experiences bleeding or bruising. One hundred thirty (n=130/285, 45.6%) physicians replace low fibrinogen. The median fibrinogen replacement was 100 mg/dL (range: 40 to 200 mg/dL) with the median target of at least 100 mg/dL (range: 50 to 200 mg/dL). A minority of physicians (n=39/250, 13.7%) replace low antithrombin. The median antithrombin cutoff activity level was 60% (range: 40% to 100%) with a median target of 75% (range: 40% to 125%)., Conclusions: There is a significant variation in PHO physician practices for monitoring and management of asparaginase-associated hemostatic derangements. Evidence-based guidelines have the potential to standardize practices., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Rare cases of COVID-19 vaccinated individuals develop anti-platelet factor 4 (PF4) antibodies that cause thrombocytopenia and thrombotic complications, a syndrome referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). Currently, information on the characteristics and persistence of anti-PF4 antibodies that cause VITT after Ad26.COV2.S vaccination is limited, and available diagnostic assays fail to differentiate Ad26.COV2.S and ChAdOx1 nCoV-19-associated VITT from similar clinical disorders, namely heparin-induced thrombocytopenia (HIT) and spontaneous HIT. Here we demonstrate that while Ad26.COV2.S-associated VITT patients are uniformly strongly positive in PF4-polyanion enzyme-linked immunosorbent assays (ELISAs); they are frequently negative in the serotonin release assay (SRA). The PF4-dependent p-selectin expression assay (PEA) that uses platelets treated with PF4 rather than heparin consistently diagnosed Ad26.COV2.S-associated VITT. Most Ad26.COV2.S-associated VITT antibodies persisted for >5 months in PF4-polyanion ELISAs, while the PEA became negative earlier. Two patients had otherwise unexplained mild persistent thrombocytopenia (140-150 x 10 3 /µL) 6 months after acute presentation. From an epidemiological perspective, differentiating VITT from spontaneous HIT, another entity that develops in the absence of proximate heparin exposure, and HIT is important, but currently available PF4-polyanion ELISAs and functional assay are non-specific and detect all three conditions. Here, we report that a novel un-complexed PF4 ELISA specifically differentiates VITT, secondary to both Ad26.COV2.S and ChAdOx1 nCoV-19, from both spontaneous HIT, HIT and commonly-encountered HIT-suspected patients who are PF4/polyanion ELISA-positive but negative in functional assays. In summary, Ad26.COV2.S-associated VITT antibodies are persistent, and the un-complexed PF4 ELISA appears to be both sensitive and specific for VITT diagnosis., (© 2022 Wiley Periodicals LLC.)

Introduction: We hypothesize that a patient (pt) with accelerated thrombin generation, time to peak height (ttPeak), will have a greater odds of meeting critical administration threshold (CAT) criteria (> 3 packed red blood cell [pRBC] transfusions [Tx] per 60 min interval), within the first 24 h after injury, independent of international normalized ratio (INR)., Methods: In a prospective cohort study, trauma patients were enrolled over a 4.5-year period and serial blood samples collected at various time points. We retrospectively stratified pts into three categories: CAT+, CAT- but receiving some pRBC Tx, receiving no Tx within the first 24 h. Blood collected prior to Tx was analyzed for thrombin generation parameters and prothrombin time (PT)/INR., Results: A total of 484 trauma pts were analyzed: injury severity score = 13 [7,22], age = 48 [28, 64] years, and 73% male. Fifty pts met criteria for CAT+, 64 pts CAT-, and 370 received no Tx. Risk factors for meeting CAT+: decreased arrival systolic blood pressure (OR 2.82 [2.17, 3.67]), increased INR (OR 2.09, [1.66, 2.62]) and decreased time to peak OR 2.27 [1.74, 2.95]). These variables remained independently associated with increased risk of requiring Tx in a multivariable logistic model, after adjusting for sex and trauma type., Conclusions: Pts in hemorrhagic shock, who meet CAT+ criteria, are characterized by accelerated thrombin generation. In our multivariable analysis, both ttPeak and PT/INR have a complementary role in predicting those injured patients who will require a high rate of Tx., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

Purpose: This study aimed to characterize the white blood cell differential of tobacco smoking-induced leukocytosis and describe the longitudinal impact of smoking cessation on this peripheral blood abnormality., Methods: Medical records of patients undergoing evaluation by hematologists for persistent leukocytosis were reviewed. Patients in whom leukocytosis was determined to be secondary to tobacco use after exclusion of other causes were identified. Demographic and laboratory data were collected at time of diagnosis. Patients were longitudinally followed and information regarding smoking cessation and follow-up white blood cell values were recorded., Results: Forty patients were determined to have smoking-induced leukocytosis. The median age was 49.5 years (range: 28-75 years), 24 patients were female, and the mean body mass index (BMI) was 31.5 kg/m 2 . The mean white blood cell count was 13.3 × 10 9 /L (range: 9.8-20.9 × 10 9 /L); 39 patients had absolute neutrophilia (98%), 21 had lymphocytosis (53%), 20 had monocytosis (50%), and 19 had basophilia (48%). During follow-up, 11 patients either quit (n = 9) or reduced (n = 2) tobacco use. Reduction in tobacco smoking led to a significant decrease in mean white blood cell count (13.2 × 10 9 /L vs 11.1 × 10 9 /L, P = 0.02). The median time to decrease in white blood cell count following reduction in tobacco use was 8 weeks (range: 2-49 weeks)., Conclusions: Tobacco-induced leukocytosis was characterized by a mild elevation in total white blood cell count and was most commonly associated with neutrophilia, lymphocytosis, monocytosis, and basophilia. Cessation of smoking led to improvement in leukocytosis. Tobacco history should be elicited from all patients presenting with leukocytosis to limit unnecessary diagnostic testing, and counseling regarding smoking cessation should be offered., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of pathologic immune activation in children that is increasingly being recognized in adults. Efficacy data for the HLH-04 protocol in adults is lacking. This study retrospectively analyzed 31 adult patients, median age 46 years, who received HLH-04 from 1/1/2004 to 5/1/2018. HLH etiology included malignancy ( n  = 9), autoimmune ( n  = 8), infection ( n  = 8), and idiopathic ( n  = 6). Eighteen patients were evaluable for response at week 4 with 7 having no response, 11 reaching partial response, and 0 reaching complete response (CR). Six patients eventually achieved CR at a median 195 days. The 1-year overall survival (OS) was 35% and median OS was 3.2 months. Univariate analysis showed shorter survival for hemoglobin <9 g/dL (HR 4.29, p  = 0.003), platelets <100 × 10 9 /L (HR 4.06, p  = 0.027), ANC <1 × 10 9 /L (HR 5.24, p  = 0.001), and total bilirubin >1.2 mg/dL (HR 3.30, p  = 0.022). Outcomes of adults treated with HLH-04 remain dismal and newer treatment modalities are needed.

Introduction: Hemostatic prophylaxis (HP) is recommended for patients with bleeding disorders (PWBD) before invasive procedures. However, evidence-based guidelines are needed to determine optimal HP strategies., Aim: To determine outcomes of HP for PWBD undergoing colonoscopy., Methods: We 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., Results: During 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)., Conclusion: The 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., (© 2020 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Objective: To describe the multifactorial etiologies of extreme thrombocytosis (EXT) in different care settings and the frequency of finding an occult malignancy., Patients and Methods: We conducted a retrospective chart review at Mayo Clinic from January 1, 2011, through December 31, 2016. Adult patients who had at least 2 readings of platelet counts greater than 1000×10 9 /L within 30 days of each other were included. We determined the causes of EXT on the basis of preset definitions of precipitating factors and identified the dominant causes on the basis of the trend of platelet counts., Results: A total of 44,490 patients had thrombocytosis, and 305 patients (0.7%) had EXT. In 242 patients (79.3%), EXT was multifactorial. Surgical complications (54.1%) and hematologic malignancies (27.9%) were the 2 most dominant causes. Thirty-eight patients (12.5%) had new diagnoses of malignancies, mostly myeloproliferative neoplasms. In inpatients, surgical complications (71.9%), concurrent/previous splenectomy (50.5%), and infections (44.9%) were the most common causes, whereas hematologic malignancies (56.9%), iron deficiency (36.7%), and previous splenectomy (28.4%) were the most common causes in outpatients. Hematologic malignancy was 3.4 times more likely to be the cause of EXT in outpatients than in inpatients (56.9% vs 16.8%), and a new diagnosis of hematologic malignancy was 1.9 times more likely to be made in outpatients (15.6% vs 8.2%). Eighty-four percent of patients had resolution of EXT within 30 days. One patient died during the period of EXT. Nonsurgical patients with hematologic malignancies had the most prolonged period of EXT., Conclusion: Extreme thrombocytosis is a multifactorial hematologic condition, and its etiology differs substantially between inpatients and outpatients. Occult hematologic malignancies are uncommon in EXT when other major causes are present., (Copyright © 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the clinical efficacy and safety of apixaban with those of rivaroxaban for the treatment of acute venous thromboembolism (VTE)., Patients and Methods: Consecutive patients enrolled in the Mayo Thrombophilia Clinic Registry (between March 1, 2013, and January 30, 2018) and treated with apixaban or rivaroxaban for acute VTE were followed forward in time. The primary efficacy outcome was VTE recurrence. The primary safety outcome was major bleeding; the second safety outcome was clinically relevant nonmajor bleeding (CRNMB); and the third was a composite of major bleeding or CRNMB., Results: Within the group of 1696 patients with VTE enrolled, 600 (38%) were treated either with apixaban (n=302, 50%) or rivaroxaban (n=298, 50%) within the first 14 days of VTE diagnosis and who completed at least 3 months of therapy or had a study event. Recurrent VTE was diagnosed in 7 patients (2.3%) treated with apixaban and in 6 (2%) treated with rivaroxaban (adjusted hazard ratio [aHR], 1.4; 95% CI, 0.5-3.8). Major bleeding occurred in 11 patients (3.6%) receiving apixaban and in 9 patients (3.0%) receiving rivaroxaban (aHR, 1.2; 95% CI, 0.5-3.2). Clinically relevant nonmajor bleeding was diagnosed in 7 patients (2.3%) receiving apixaban and in 20 (6.7%) receiving rivaroxaban (aHR, 0.4; 95% CI, 0.2-0.9). The rates of composite major bleeding or CRNMB were similar (aHR, 0.6; 95% CI, 0.3-1.2). Most study events occurred in patients with cancer., Conclusion: In the setting of a standardized, guideline-directed, patient-oriented clinical practice, the efficacy and safety of apixaban and rivaroxaban for the treatment of acute VTE were comparable., (Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Coagulation factor V inhibitors (FV-i) may occur in patients with congenital FV deficiency or previously hemostatically normal patients (autoimmune (AI)-FV-i). Most of the published literature is confined to case reports., Objective: Describe clinical and laboratory features of AI-FV-i identified through the Special Coagulation Laboratory at Mayo Clinic, Rochester, Minnesota., Methods: In this retrospective study individuals with FV-i screens performed from January 1999 to February 2017 were identified through the special coagulation laboratory database. Clinical presentation, management, and outcomes were collected for our institutional patients while detailed laboratory data was collected for all tested patients., Results: Of patients with FV-i managed at our institution, 2/8 (25%) patients experienced no bleeding. There was no correlation between inhibitor titers and/or FV activity (FV:C) levels and clinical bleeding. Hemostatic management included fresh frozen plasma, platelet transfusion, activated prothrombin complex concentrates, and recombinant factor VIIa. Only 2 patients received immunomodulatory treatment. FV-i mixing studies with normal pooled plasma (n = 26) demonstrated inhibition on immediate mix but progressive inhibition after 1 h of incubation could not be demonstrated. 71% of platelet neutralization procedures were falsely positive while 59% of DRVVT assays were indeterminate., Conclusion: FV-i demonstrates immediate inhibition on mixing studies; however our limited data does not support a time dependent inhibition. Our clinical cohort confirms the variable clinical phenotype for individuals with FV-i and supports the notion that management of FV-i should be guided by clinical symptoms and not FV:C or FV-i titer., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Overall incidence of hemostatic complications in pediatric recipients of Hematopoietic Stem Cell Transplant (HSCT) is scarcely studied. This retrospective review explored the incidence and underlying risk factors of bleeding and thrombotic complications in children., Procedure: Clinical characteristics, hemorrhagic events (HE), thrombotic events (TE) and follow up data were abstracted from medical records on patients aged <21 years undergoing HSCT during January 2000-June 2015., Results: From start of conditioning until last follow up, 238 pediatric patients were reviewed during this study. There were 16 symptomatic thrombotic complications in 15 patients, along with 13 major bleeding events. Incidence of HE or TE was higher in allogeneic HSCT compared to autologous HSCT (p = 0.02). Severe thrombocytopenia could not be identified as a major contributor to bleeding. All patients with HE had platelets between 20,000-50,000 × 10 9 /L, except one patient, who had platelets <20,000 × 10 9 /L. All patients with hemorrhagic cystitis (n = 7) had received cyclophosphamide (Cy). For patients with sinusoidal obstruction syndrome, conditioning included either busulfan (Bu)/Cy (n = 5), Cy with total body irradiation (n = 4), or thiotepa (n = 2). Among allogeneic HSCT recipients, 60% of HE and 92% with TE had underlying myeloid neoplasms. Graft versus Host disease contributed to both types of complications (p = 0.07), although not reaching statistical significance., Conclusions: Allogeneic pediatric HSCT patients had higher overall risk of hemorrhagic or thrombotic complications compared to autologous recipients in this study. HSCT for myeloid malignancies was a risk factor for higher complications., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Nursing home (NH) residency is an independent risk factor for venous thromboembolism (VTE), but the VTE burden within the NH population is uncertain. This study estimates VTE incidence and VTE-associated mortality among NH residents. We identified all NH residents in any NH in Olmsted County, Minnesota, United States, 1 October 1998 to 31 December 2005 and all first lifetime VTE among county residents to estimate VTE incidence while resident of local NHs (NHVTE), using Centers for Medicare and Medicaid Services Minimum Data Set and Rochester Epidemiology Project resources. We tested associations between NHVTE and age, sex and time since each NH admission using Poisson modelling. Additionally, we tested incident NHVTE as a potential predictor of survival using Cox proportional hazards, adjusting for age, sex and NH residency. Between 1 October 1998 and 31 December 2005, 3,465 Olmsted County residents with ≥1 admission to a local NH, contributed 4,762 NH stays. Of the 3,465 NH residents, 111 experienced incident NHVTE (2.3% of all eligible stays), for an overall rate of 3,653/100,000 NH person-years (NH-PY). VTE incidence was inversely associated with time since each NH admission, and was highest in the first 7 days after each NH admission (18,764/100,000 NH-PY). The adjusted hazard of death for incident NHVTE was 1.90 (95% confidence interval [CI]: 1.38-2.62). In conclusion, VTE incidence among NH residents was nearly 30-fold higher than published incidence rates for the general Olmsted County population. VTE incidence was highest within 7 days after NH admission, and NHVTE was associated with significantly reduced survival. These data can inform future research and construction of clinical trials regarding short-term prophylaxis., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Solitary plasmacytomas are uncommon plasma cell disorders, which may present as a single bone lesion (P-bone) or extramedullary plasmacytoma (P-EM). There is a paucity of large studies analyzing prognostic factors and outcomes of plasmacytomas. While the treatment of choice is radiation therapy (RT), there is a lack of data evaluating optimal RT dose. In this study, we sought to answer these questions by utilizing the National Cancer Database plasmacytoma data from 2000 to 2011. A total of 5056 patients were included in the study (median age 62 years; range 52-72). To obtain a pure plasmacytoma cohort, potential multiple myeloma patients were excluded from the study (bone marrow involvement, systemic chemotherapy use). P-bone constituted 70% of the patients. The median overall survival (OS) of P-EM was significantly longer than P-bone (132 vs. 85 months), and for soft/connective tissue it was worse than remainder of P-EM (82 vs. 148 months). On multivariable analysis, factors associated with worse OS included older age (≥65), presence of P-bone, and treatment with a radiation dose <40 Gy.

Background: The independent association of recent infection with venous thromboembolism is uncertain. The study aims were to test both overall infection (site unspecified) and specific infection sites as potential risk factors for deep vein thrombosis and pulmonary embolism adjusting for other known venous thromboembolism factors., Methods: By using Rochester Epidemiology Project resources, we identified all Olmsted County, Minnesota, residents with objectively diagnosed incident deep vein thrombosis or pulmonary embolism over the 13-year period 1988 to 2000 (cases; n = 1303) and 1 to 2 residents without venous thromboembolism matched to each case on age, sex, and incident venous thromboembolism date (controls; n = 1494). Using conditional logistic regression, we tested recent infection and infection site(s) for an association with venous thromboembolism, adjusting for body mass index, smoking, current/recent hospitalization with/without surgery, nursing home confinement, active cancer, trauma/fracture, leg paresis, prior superficial vein thrombosis, transvenous catheter/pacemaker, ischemic heart disease, congestive heart failure, chronic lung or renal disease, serious liver disease, asthma, diabetes mellitus, hormone therapy, and pregnancy/postpartum., Results: A total of 513 cases (39.4%) and 189 controls (12.7%) had an infection in the previous 92 days (odds ratio, 4.5; 95% confidence interval, 3.6-5.5; P < .0001). In a multivariable analysis adjusting for common venous thromboembolism risk factors, pneumonia and symptomatic urinary tract, oral, intra-abdominal, and systemic bloodstream infections were associated with significantly increased odds of venous thromboembolism., Conclusions: Infection as a whole and specific infection sites in particular are independent risk factors for venous thromboembolism and should be considered as potential indications for venous thromboembolism prophylaxis., (Copyright © 2018. Published by Elsevier Inc.)

Background: Women with inherited antithrombin (AT) deficiency are at high risk for venous thromboembolism (VTE), especially during times of estrogen exposure, but little is known about patient-oriented reproductive decision-making in this population., Materials and Methods: Provider-administered survey of women with AT deficiency. Participants were asked to discuss their diagnosis of AT deficiency and questioned about (1) contraception, (2) pregnancies, and (3) menorrhagia, and the impact of their AT deficiency on each reproductive health experience., Results: Of 31 women with inherited AT deficiency, 18 (58%) were surveyed, 8 (26%) were unreachable, and 5 (16%) were deceased. Twelve (67%) had a VTE, including two which occurred during pregnancy and five during oral contraceptive (OCP) use. Women reported using OCPs, intrauterine device (IUD), and condoms for contraception. Of five women diagnosed with AT deficiency while taking OCPs, three switched to an IUD, one to condoms, and one used no alternative method. Eighteen women reported 42 total pregnancies, with 33 (79%) resulting in live term birth, 3 (7%) in live preterm birth, and 6 (14%) in spontaneous abortion at a median of 12 weeks. Four (22%) women reported the use of anticoagulation during pregnancy. Eleven (61%) women reported menorrhagia and 4 (36%), while on anticoagulation for VTE events. Ten of 18 women (56%) reported that the diagnosis of AT had affected their reproductive health in some way., Conclusion: Women with AT deficiency require careful multidisciplinary management to avoid complications in the setting of contraception and pregnancy. AT deficiency impacts women's reproductive health experiences and patient-oriented reproductive decision-making is key.

Background: Factor XI (FXI) deficiency (hemophilia C [HEM-C]) is a bleeding disorder with unpredictable severity that correlates poorly with FXI coagulation activity (FXI:C). It poses a perioperative hemostatic management challenge. For US patients with severe disease, fresh frozen plasma (FFP) or, in current use, thawed plasma is the most readily available option but comes with risk of volume overload. We report our experience of using therapeutic plasma exchange (TPE) as an alternative perioperative management strategy., Methods: A retrospective review of all HEM-C patients who underwent surgical procedures. Data were collected, including demographics, bleeding history, surgical site, perioperative hemostatic intervention, and outcome., Results: Between July 1997 and September 2014, 28 HEM-C patients (12 men) were identified, 4 with severe disease (FXI:C <2% or excessive bleeding). Nineteen patients underwent 91 invasive procedures. For nearly 60% of the procedures, no periprocedural hemostatic intervention was provided; before 4 procedures (3 patients), 1 plasma volume TPE preoperatively with FFP was administered. Patient 1, a 28-year-old woman (FXI:C, 35%) with a history of excessive surgical bleeding, underwent 2 TPE procedures before laparoscopic pelvic biopsy and subsequent abdominal hysterectomy with salpingo-oophorectomy that increased her FXI:C to 48%. Patient 2, a 79-year-old man (FXI:C, <2%), had TPE before total hip arthroplasty, increasing his FXI:C to 24%. Patient 3, a 59-year-old man (FXI:C, <2%), had TPE before prostate laser enucleation, increasing his FXI:C to 46%. Patients 1 and 3 had mild reactions during TPE; no patient had evidence of volume overload. All patients had adequate intraoperative surgical hemostatic outcomes., Conclusion: TPE is an effective alternative presurgical hemostatic intervention in HEM-C with potentially lower risk of circulatory volume overload., (© 2017 Wiley Periodicals, Inc.)

Background: Reliable biomarkers predictive of venous thromboembolism (VTE) after acute trauma are uncertain. The objective of the study was to identify risk factors for symptomatic VTE after trauma, including individual plasma coagulome characteristics as reflected by thrombin generation., Methods: In a prospective, case-cohort study, trauma patients were enrolled over the 4.5-year period, 2011 to 2015. Blood was collected by venipuncture into 3.2% trisodium citrate at 0, 6, 12, 24, and 72 hours after injury and at hospital discharge. Platelet poor plasma was stored at -80 °C until analysis. Thrombin generation, as determined by the calibrated automated thrombogram (CAT) using 5 pM tissue factor (TF)/4 μM phospholipid (PS), was reported as peak height (nM thrombin) and time to peak height (ttPeak [minutes]). Data are presented as median [IQR] or hazard ratio with 95% CI., Results: Among 453 trauma patients (injury severity score = 13.0 [6.0, 22.0], hospital length of stay = 4.0 [2.0, 10.0] days, age = 49 [28, 64] years, 71% male, 96% with blunt mechanism, mortality 3.2%), 83 developed symptomatic VTE within 92 days after injury (35 [42%] after hospital discharge). In a weighted, multivariate Cox model that included clinical and CAT characteristics available within 24 hours of admission, increased patient age (1.35 [1.19,1.52] per 10 years, p < 0.0001), body mass index ≥30 kg/m (4.45 [2.13,9.31], p < 0.0001), any surgery requiring general anesthesia (2.53 [1.53,4.19], p = 0.0003) and first available ttPeak (1.67 [1.29, 2.15], p < 0.00001) were independent predictors of incident symptomatic VTE within 92 days after trauma (C-statistic = 0.799)., Conclusion: The individual's plasma coagulome (as reflected by thrombin generation) is an independent predictor of VTE after trauma. Clinical characteristics and ttPeak can be used to stratify acute trauma patients into high and low risk for VTE., Level of Evidence: Prognostic, level III.

The annual number of US venous thromboembolism (VTE) events, the number of potentially preventable events, and the effect of hospitalization-based prophylaxis are uncertain. We estimated VTE attack (incident plus recurrent VTE) rates and the total annual number of US VTE events related and unrelated to hospitalization using Rochester Epidemiology Project resources to identify all Olmsted County, Minnesota, residents with incident or recurrent VTE over the 6-year period 2005-2010. The average annual VTE attack rates related and unrelated to hospitalization were 282 and 8 per 10 000 person-years, respectively. The estimated average number of US VTE events was 495 669 per year (48% unrelated to hospitalization). Among Olmsted County residents hospitalized at a Mayo Clinic hospital from 2005 to 2010, the proportion of patients receiving VTE prophylaxis or with an indication that prophylaxis was unnecessary increased from ∼40% in 2005 to ∼90% by 2010. The annual age- and sex-adjusted hospitalization-related (in-hospital) VTE attack rates from 2005 to 2010 ranged from 251 to 306 (1155 to 1751) per 10 000 person-years (bed-years) and did not change significantly. The median durations of hospitalization and in-hospital prophylaxis were 3 days and 70 hours, respectively. A total of 75% of VTE events occurred after hospital discharge, with a 19.5-day median time to VTE. Additional efforts are needed to identify the individual inpatient and outpatient at high risk for incident and recurrent VTE and target (longer duration) primary and secondary prophylaxis to high-risk individuals who would benefit most., (© 2017 by The American Society of Hematology.)

Venous thromboembolism (VTE) contributes to significant morbidity, mortality, and socioeconomic burden. There is a paucity of literature regarding sex-based sociodemographic differences in VTE presentation and short-term outcomes. We aimed to compare clinical outcomes between men and women hospitalized for VTE management. We performed a retrospective analysis using data from the National Inpatient Sample (NIS) database from 2012 to 2013. Inclusion criteria were age 18 years and older and a primary discharge diagnosis of VTE. Sociodemographic features and medical comorbidities were analyzed, as were hospital length of stay and in-hospital mortality rates. A total of 107,896 patients met the inclusion criteria; 53% were female. Median age was 65 years (interquartile range 51-77) and women were older than men (65 vs 62 years, p<0.001). There were significant differences between men and women with respect to race, primary insurance payer and medical comorbidities, and small differences with respect to VTE location. Female sex was associated with a small but significantly longer hospital length of stay (mean ratio 1.04, 95% CI 1.03-1.05, p<0.001) but no significant difference in in-hospital mortality (2.2% vs 2.1%, p=0.15). In a multivariate model, there was no significant difference between women and men with respect to hospital length of stay or in-hospital mortality. In conclusion, we used data from the NIS to study over 100,000 patients hospitalized for VTE, and identified several sex-based disparities in sociodemographic factors and location of VTE. However, in a multivariable analysis correcting for these factors, sex was not associated with significant differences in clinical outcomes.

Introduction: Haemostatic assessments of patients with von Willebrand disease (VWD) who undergo total knee arthroplasty (TKA) and total hip arthroplasty (THA) have mainly relied on subjective parameters., Aims: To compare objective haemostatic outcomes of TKA/THA in VWD patients and controls without bleeding disorders., Methods: We retrospectively analysed haemostatic outcomes in VWD patients undergoing TKA/THA from 1993 to 2011 and compared them with two matched controls per operation. Using one-way analysis of variance, we tested the effect of VWD on bleeding risk after TKA and THA., Results: Twelve VWD patients (6 type 1, 3 type 2M, 1 each of types 2A/2B/3) undergoing 19 operations (12 TKA, 7 THA) were matched to 38 controls. One (5%) of 19 operations in VWD patients and none of the control operations met clinical criteria for major bleeding. Baseline and postoperative day 1 haemoglobin levels, postoperative blood loss, transfused red blood cells (RBCs) and mean hospitalization days were not significantly different. More VWD patients than controls received RBC transfusions [12 (63%) vs. 12 (32%)]. Only 9 (47%) VWD patients vs. 38 (100%) controls received pharmacologic VTE prophylaxis. No postoperative symptomatic VTE occurred in either group., Conclusion: In this largest, single-institutional study, von Willebrand factor replacement based on daily levels resulted in low frequency of major bleeding in VWD patients after TKA/THA. RBC transfusion was more frequent compared with matched controls, but other objective measures of haemostasis were similar. Lack of sufficient details in published reports precluded comparison of haemostatic outcomes., (© 2016 John Wiley & Sons Ltd.)

Thrombotic microangiopathies (TMAs) comprise a heterogeneous set of conditions linked by a common histopathologic finding of endothelial damage resulting in microvascular thromboses and potentially serious complications. The typical clinical presentation is microangiopathic hemolytic anemia accompanied by thrombocytopenia with varying degrees of organ ischemia. The differential diagnoses are generally broad, while the workup is frequently complex and can be confusing. This statement represents the joint recommendations from a multidisciplinary team of Mayo Clinic physicians specializing in the management of TMA. It comprises a series of evidence- and consensus-based clinical pathways developed to allow a uniform approach to the spectrum of care including when to suspect TMA, what differential diagnoses to consider, which diagnostic tests to order, and how to provide initial empiric therapy, as well as some guidance on subsequent management., (Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study is to estimate medical costs attributable to venous thromboembolism among patients with active cancer., Methods: In a population-based cohort study, we used Rochester Epidemiology Project (REP) resources to identify all Olmsted County, Minn. residents with incident venous thromboembolism and active cancer over the 18-year period, 1988-2005 (n = 374). One Olmsted County resident with active cancer without venous thromboembolism was matched to each case on age, sex, cancer diagnosis date, and duration of prior medical history. Subjects were followed forward in REP provider-linked billing data for standardized, inflation-adjusted direct medical costs from 1 year prior to index (venous thromboembolism event date or control-matched date) to the earliest of death, emigration from Olmsted County, or December 31, 2011, with censoring on the shortest follow-up to ensure a similar follow-up duration for each case-control pair. We used generalized linear modeling to predict costs for cases and controls and bootstrapping methods to assess uncertainty and significance of mean adjusted cost differences. Outpatient drug costs were not included in our estimates., Results: Adjusted mean predicted costs were 1.9-fold higher for cases ($49,351) than for controls ($26,529) (P < .001) from index to up to 5 years post index. Cost differences between cases and controls were greatest within the first 3 months (mean difference = $13,504) and remained significantly higher from 3 months to 5 years post index (mean difference = $12,939)., Conclusions: Venous thromboembolism-attributable costs among patients with active cancer contribute a substantial economic burden and are highest from index to 3 months, but may persist for up to 5 years., Competing Interests: All authors report no conflict of interest., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Predictors of venous thromboembolism (VTE) after trauma are uncertain., Objective: To identify independent predictors of VTE after acute trauma., Methods: Using Rochester Epidemiology Project (REP) resources, we identified all Olmsted County, MN residents with objectively-diagnosed incident VTE within 92days after hospitalization for acute trauma over the 18-year period, 1988-2005. We also identified all Olmsted County residents hospitalized for acute trauma over this time period and chose one to two residents frequency-matched to VTE cases on sex, event year group and ICD-9-CM trauma code predictive of surgery. In a case-cohort study, demographic, baseline and time-dependent characteristics were tested as predictors of VTE after trauma using Cox proportional hazards modeling., Results: Among 200 incident VTE cases, the median (interquartile range) time from trauma to VTE was 18 (6, 41) days. Of these, 62% cases developed VTE after hospital discharge. In a multiple variable model including 370 cohort members, patient age at injury, male sex, increasing injury severity as reflected by the Trauma Mortality Prediction Model (TMPM) Mortality Score, immobility prior to trauma, soft tissue leg injury, and prior superficial vein thrombosis were independent predictors of VTE (C-statistic=0.78)., Conclusions: We have identified clinical characteristics which can identify patients at increased risk for VTE after acute trauma, independent of surgery. Almost two thirds of all incident VTE events occurred after initial hospital discharge (18day median time from trauma to VTE) which questions current practice of not extending VTE prophylaxis beyond hospital discharge., Competing Interests: All authors report no conflict of interest., (Copyright © 2016. Published by Elsevier Ltd.)