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Andrew B Song,1 Rachel P Rosovsky,1 Jean M Connors,2 Hanny Al-Samkari11Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 2Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USAAbstract: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in patients with cancer. Compared with the general population, cancer patients with VTE have higher rates of both VTE recurrence and bleeding. While low molecular weight heparin (LMWH) has been the mainstay of treatment for cancer-associated VTE for over a decade, direct oral anticoagulants (DOACs) have recently emerged as a new therapeutic option due to their ease of administration and because they do not require laboratory monitoring. Several large randomized clinical trials have been performed or are ongoing at the time of writing, comparing DOACs with LMWH in this population. Three of these trials have thus far been published and suggest that DOACs are a reasonable alternative to LMWH for management of cancer-associated VTE. Despite the advantages offered by DOACs, these agents may not be appropriate for certain patient groups owing to increased risk of bleeding, organ compromise, extremes of weight, and other issues. Finally, data are emerging suggesting that DOACs may be useful for primary thromboprophylaxis in cancer patients in conjunction with validated risk assessment scores. In this evidence-based review, data for the use of DOACs to treat cancer-associated VTE will be examined, focusing on efficacy, safety, and timing of treatment. Guidance on choosing the optimal anticoagulant for a given patient is also offered.Keywords: venous thromboembolism, malignancy, thrombosis, rivaroxaban, apixaban, edoxaban, DOAC

Background: The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with diffuse large-B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of diffuse large-B-cell lymphoma is unclear.Methods: We profiled gene expression in pretreatment biopsy specimens from 181 patients with diffuse large-B-cell lymphoma who received CHOP and 233 patients with this disease who received R-CHOP. A multivariate gene-expression-based survival-predictor model derived from a training group was tested in a validation group.Results: A multivariate model created from three gene-expression signatures--termed "germinal-center B-cell," "stromal-1," and "stromal-2"--predicted survival both in patients who received CHOP and patients who received R-CHOP. The prognostically favorable stromal-1 signature reflected extracellular-matrix deposition and histiocytic infiltration. By contrast, the prognostically unfavorable stromal-2 signature reflected tumor blood-vessel density.Conclusions: Survival after treatment of diffuse large-B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Asparaginase (ASP)-containing regimens for acute lymphoblastic leukemia (ALL) are associated with venous thromboembolism (VTE). We evaluated the prevalence, risk factors, role of prophylaxis and clinical impact of VTE among adolescents and young adult (AYA) patients (15-50 years) treated on Dana-Farber Cancer Institute (DFCI) ALL protocols. The 1- and 2-year cumulative incidence of VTE were 31.9% (95% CI: 27.0%, 36.9%) and 33.5% (95% CI: 28.5%, 38.5%) respectively, with most events occurring during ASP-based consolidation phase (68.6%). VTE was more frequent in patients with overweight/obese vs. normal BMI (39.2% vs. 29.0%, p = 0.048). In a 1-year landmark analysis, the 4-year overall survival was 91.5%, without difference between patients with vs. without VTE (93.8% vs. 90.0%, p = 0.93). Relapse and non-relapse mortality rates were also similar. Among patients treated at Dana-Farber/Harvard Cancer Center, cerebral sinus vein thrombosis occurred in 3.6% of patients (8.5% of VTE events) in comparison to pulmonary embolism (32.9%) and deep vein thromboses (58.6%, 24.4% line-associated). In a Cox regression model for VTE free-time, elevated BMI was associated with shorter VTE free-time (HR 1.94 [95% CI 1.13-3.35], p = 0.018), while low molecular weight heparin (LMWH) prophylaxis as time-varying covariate was not. In conclusion, we found that VTE was frequent in AYAs treated on DFCI ALL protocols but did not impact survival outcomes. Overweight/obese BMI increased risk for VTE., (© 2024. The Author(s).)

Ischemic stroke is a common cause of morbidity and mortality worldwide. The majority of affected individuals are older, with clear cardiovascular or embolic risk factors; however, up to a fifth of cases may occur in patients under the age of 50 years. In this review, we discuss some common hematological causes of ischemic stroke in this age range, with a focus on antiphospholipid syndrome, myeloproliferative neoplasms, immune thrombocytopenic purpura, and sickle cell disease. We review the etiology of stroke associated with these conditions and explore important management considerations that may be unique to these settings. These include the choice of antithrombotic agents, cytoreduction in myeloproliferative neoplasms, management of thrombocytopenia in immune thrombocytopenic purpura, and treatment of sickle cell disease., Competing Interests: Declaration of competing interests G.O.: none; D.S.: none; J.M.C.: research funding: CSL Behring; consultancy fees: Abbott; honoraria: Bristol Myers Squibb, Roche, and Sanofi: advisory boards: Abbott, Alnylam, Anthos, Bristol Myers Squibb, Sanofi, and Takeda; J.T.: honoraria: LeoPharma, Bayer, BMS-Pfizer, Boehringer, and Daichii., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

The currently approved direct oral anticoagulants (DOACs) are increasingly used in clinical practice. Although serious bleeding risks are lower with DOACs than with vitamin K antagonists, bleeding remains the most frequent side effect. Andexanet alfa and idarucizumab are the currently approved specific reversal agents for oral factor (F)Xa inhibitors and dabigatran, respectively. Our prior guidance document was published in 2016, but with more information available on the utility and increased use of these reversal agents and other bleeding management strategies, we have updated this International Society on Thrombosis and Haemostasis guidance document on DOAC reversal. In this narrative review, we compare the mechanism of action of specific and nonspecific reversal agents, review the clinical data supporting their use, and provide guidance on when reversal is indicated. In addition, we briefly discuss the reversal of oral FXIa inhibitors, a new class of DOACs currently under clinical development., Competing Interests: Declaration of competing interests J.H.L.: Participation on Advisory or Steering Committees for Grifols, Octapharma, Takeda, and Werfen. J.R.S.: In-kind laboratory support from Diagnostica Stago. L.A.C.: L.A.C.’s research institution has received honoraria from Bayer, BMS-Pfizer Alliance, The Academy for Continued Advancement in Healthcare Education, Amag Pharmaceutical, LEO Pharma, Sanofi, Valeo Pharma, and Servier. L.A.C. holds a Tier 2 Research Chair from the University of Ottawa. J.M.C.: Participation on Scientific Advisory Boards and consulting for Abbott, Anthos, BMS, Pfizer, Roche, Sanofi, and Werfen; research funding from CSL Behring to the institution. J.D.: Serves on advisory committees for Pfizer, Sanofi, Leo Pharma, Bristol-Myers Squibb, and Janssen. E.L-L.: Lecture honoraria and advisory fees from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Portola, CSL Behring, Norgine, Roche, Leo, AstraZeneca, and Aspen; institutional research support from Bayer AG, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Werfen, and CSL Behring. B.R.: Consultant for AbocaSRL on medical devices; Advisory Committee for Bayer AG. C.M.S.: Advisory for Norgine Pharma. D.S.: Honoraria for educational presentations and advisory fees paid indirectly to research institute from AstraZeneca, BMS-Pfizer, Roche, Servier. D.S. is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease. J.I.W.: Consultant or member of Advisory Boards or Steering Committees for Anthos, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson and Johnson, Merck, and Regeneron., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

During extracorporeal membrane oxygenation (ECMO) support, the high shear stress in the ECMO circuit results in increased proteolysis of von Willebrand factor (VWF), loss of VWF high-molecular-weight multimers, and impaired ability to bind to platelets and collagen. These structural changes in VWF are consistent with acquired von Willebrand syndrome (AVWS) type 2A and may contribute to the bleeding diathesis frequently observed in ECMO patients. We performed a systematic review of all clinical studies evaluating the prevalence and associated outcomes of AVWS in ECMO patients. Our findings suggest that almost all ECMO patients develop partial or complete loss of VWF high-molecular-weight multimers within a few hours of device implantation. The AVWS persists as long as the patient is supported by ECMO. Weaning from ECMO rapidly and completely resolves the AVWS. Nevertheless, few studies have reported bleeding outcomes in ECMO patients with AVWS, and the extent to which AVWS contributes to the bleeding diathesis during ECMO support cannot be determined by current evidence. Data supporting the use of VWF concentrates to prevent bleeding complications in ECMO patients remain limited., Competing Interests: Declaration of competing interests C.F. reports honoraria for lectures from Bristol Myers Squibb, Bayer, Leo Pharma, and Sanofi; M.M. reports consulting fees from Hemosonics, Novo Nordisk, and Octapharma; J.H. reports honoraria from Asahi Kasei, Diagnostica Stago, Pfizer PFE France, Sanofi Aventis France, Inotrem, MSD, and Shionogi; K.A.T. reports research funding from Instrumentation Laboratory, CSL Behring, and Octapharma data safety committee; B.A.S. is on Scientific Advisory Boards for Basking Bio, SomaLogic, and AZURNA and reports consulting fees from Eli Lilly; J.M.C. reports consulting fees or scientific advisory board honoraria from Abbott Laboratories, Anthos Pharmaceuticals, Bristol Myers Squibb, Pfizer, Roche, Sanofi, and Werfen, and research funding to the institution from CSL Behring; J.H.L. is on Advisory or Steering Committees for Merck, Octapharma, Takeda, and Werfen; C.L.M. and M.E.S. report no conflict of interests., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Patients with left ventricular assist devices (LVADs) require interruption of warfarin for invasive procedures, but parenteral bridging is associated with many complications. Four-factor prothrombin complex concentrate (4F-PCC) can temporarily restore hemostasis in patients undergoing anticoagulation with warfarin., Objectives: This pilot study evaluated the strategy of using variable-dose 4F-PCC to immediately and temporarily reverse warfarin before invasive procedures without holding warfarin in patients with LVADs. The duration of effect of 4F-PCC on factor levels and time to reestablish therapeutic anticoagulation post procedure were assessed., Methods: Adult patients with LVADs and planned invasive procedures were enrolled from a single center. Warfarin was continued uninterrupted. The 4F-PCC dose administered immediately pre-procedure was based on study protocol. International normalized ratio (INR)- and vitamin K-dependent factor levels were collected before and during the 48 hours after 4F-PCC administration. The use of parenteral bridging, International Society for Thrombosis and Haemostasis major and clinically relevant nonmajor bleeding (CRNMB) and thromboembolic events at 7 and 30 days were collected., Results: In 21 episodes of 4F-PCC reversal, median baseline INR was 2.7 (IQR 2.2-3.2). The median dosage of 4F-PCC administered was 1794 units (IQR 1536-2130). At 24 and 48 hours post 4F-PCC administration, median INRs were 1.8 (IQR 1.7-2.0) and 2.0 (IQR 1.9-2.4). Two patients required postoperative bridging. One patient experienced major bleeding within 72 hours, and 2 experienced CRNMB within 30 days. There were no thromboembolic events. Baseline and post 4F-PCC vitamin K-dependent factor levels corresponded with changes in INR values. The median time to achieve therapeutic INR post-procedure was 2.5 days (IQR, 1-4)., Conclusion: Administration of 4F-PCC for temporary reversal of warfarin for invasive procedures in patients with LVADs allowed for continued warfarin dosing with minimal use of post-intervention bridging, limited bleeding and no thromboembolic events., Competing Interests: Disclosures JMC is a consultant for Abbott, Bristol Myers Squibb, and Pfizer and served on a scientific advisory board for Anthos, Bristol Myers Squibb, Roche, Sanofi, Werfen. MM reports payments made to Brigham and Women's Hospital from Abbott for consulting, consulting fees from Broadview Ventures, Natera, Paragonix, Moderna, and Baim Institute for Clinical Research; he is a scientific advisory board member for NuPulseCV, Leviticus, Transmedics, and FineHeart. MMG, ASW, SS, AEJ, KS, LC, BR have no conflicts to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Brigham and Women's Hospital historically used titratable weight-based heparin nomograms with as needed boluses managed by extracorporeal membrane oxygenation specialists to achieve a predetermined goal-activated partial thromboplastin time (aPTT). Due to concern amongst providers that as needed boluses may lead to supratherapeutic aPTT's and subsequent bleeding, new nomograms without as needed boluses were implemented. The purpose of this retrospective observational analysis is to provide a comparison in safety and efficacy between the heparin nomograms with as needed boluses and the new nomograms without boluses., Methods: Adult patients who were cannulated on extracorporeal membrane oxygenation and initiated on an approved heparin bolus nomogram (January 1, 2018-December 31, 2019) or an approved heparin no-bolus nomogram (October 20, 2020-March 31, 2021) were screened for inclusion. The major endpoint evaluated was the percentage of supratherapeutic aPTTs, defined as an aPTT above the upper limit of the specified nomogram goal, within the first 72 hours., Results: A total of 23 patients were included in the bolus nomogram cohort and 9 patients in the no-bolus nomogram cohort. Within the first 72 hours of initiation, there were 11.5% supratherapeutic aPTTs in the bolus group and 5.1% in the no-bolus group ( P = 0.101). Overall there was 1 bleeding event in the no-bolus group (11.1%) and 7 in the bolus group (30.4%) ( P = 0.26). There were no thromboembolic events in either group., Conclusions: Overall, there was no difference found in the percentage of supratherapeutic aPTTs within the first 72 hours of heparin initiation between the bolus and no-bolus nomograms., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Patients with cancer have an increased risk of developing venous thromboembolism (VTE) but also have an increased risk of both recurrent VTE and bleeding with anticoagulation compared to anticoagulated patients without cancer. CANVAS, a randomized pragmatic effectiveness trial, compared the direct oral anticoagulants a class to low molecular weight heparin for treatment of a new VTE in patients with cancer. The aim of this prespecified secondary analysis of the CANVAS trial is to identify predictors of both recurrent VTE and major bleeding in patients with cancer and new VTE., Methods: Data from the 671 participants in the analysis population were used to identify predictors of recurrent VTE and bleeding during the 6-month treatment period. Significant predictors identified in the univariable models were carried forward in the multivariable models to identify independent predictors of both risks., Results: Independent predictors of recurrent VTE include ECOG performance status ≥2 (HR, 3.19 [95 % CI, 1.45-7.02]; P < .005), presence of metastatic disease (HR, 2.57 [95 % CI, 1.14-5.80]; P = .023), treatment with bevacizumab (HR, 2.50 [95 % CI, 1.04-5.99]; P = .041), and deep vein thrombosis without pulmonary embolus as index VTE (HR, 1.86 [95 % CI, 1.04-3.33]; P = .037). Independent predictors of major bleeding include serum albumin <3.5 g/dL (HR 1.97 [95 % CI, 1.02-3.79]; P = .044) and metastatic disease (HR 2.80 [95 % CI, 1.08-7.22]; P = .034)., Conclusion: Findings from this pre-specified analysis of the CANVAS trial identified risk factors for recurrent VTE and major bleeding in a population of participants with cancer and new VTE that reflect current oncology clinical practice. Results can be used to identify at risk patients in practice and inform new risk prediction models to improve the care of these patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jean Connors reports financial support was provided by Patient-Centered Outcomes Research Institute. Jean Connors reports administrative support was provided by Alliance for Clinical Trials in Oncology Foundation. Jean Connors reports a relationship with Abbott that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Anthos that includes: board membership and consulting or advisory. Jean Connors reports a relationship with BMS that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Janssen that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Pfizer that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Perosphere that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Roche that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Sanofi that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Werfen that includes: board membership and consulting or advisory. Jean Connors reports a relationship with CSL Behring that includes: funding grants. Deborah Schrag reports a relationship with JAMA that includes: consulting or advisory. Deborah Schrag reports a relationship with Swiss Re Management Ltd that includes: consulting or advisory. Deborah Schrag reports a relationship with Merck that includes: equity or stocks. Deborah Schrag reports a relationship with AACR that includes: funding grants. Deborah Schrag reports a relationship with Grail that includes: funding grants. Deborah Schrag has intellectual property. Specifically, the PRISSMM model is trademarked and curation tools are available to academic medical centers and government under creative commons license. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Balancing the safety and efficacy of antithrombotic agents in patients with gastrointestinal disorders is challenging because of the potential for interference with the absorption of antithrombotic drugs and for an increased risk of bleeding. In this Review, we address considerations for enteral antithrombotic therapy in patients with cardiovascular disease and gastrointestinal comorbidities. For those with gastrointestinal bleeding (GIB), we summarize a general scheme for risk stratification and clinical evidence on risk reduction approaches, such as limiting the use of concomitant medications that increase the risk of GIB and the potential utility of gastrointestinal protection strategies (such as proton pump inhibitors or histamine type 2 receptor antagonists). Furthermore, we summarize the best available evidence and potential gaps in our knowledge on tailoring antithrombotic therapy in patients with active or recent GIB and in those at high risk of GIB but without active or recent GIB. Finally, we review the recommendations provided by major medical societies, highlighting the crucial role of teamwork and multidisciplinary discussions to customize the antithrombotic regimen in patients with coexisting cardiovascular and gastrointestinal diseases., (© 2024. Springer Nature Limited.)