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Description: In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective., Methods: The U.S. Department of Health and Human Services requested that the National Institutes of Health (NIH) take the lead in expeditiously convening a panel of experts to create "living" guidelines that would be widely accessible and capable of frequent updating as important new information became available., Recommendations: The purpose of this article is to expand on the experiences of the NIH COVID-19 Treatment Guidelines Panel (the Panel) over the past 4 years, summarize the Panel's final recommendations for COVID-19, highlight some challenges and unanswered questions about COVID-19 management, and inform future responses to public health emergencies. The Panel was formed in March 2020, and the first iteration of the guidelines was released in April 2020. Now that the public health emergency has ended, the NIH COVID-19 Treatment Guidelines have sunsetted. This role will now fall to professional societies and organizations, such as the American College of Physicians, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the World Health Organization, all of which have been active in this area., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Background: Baseline anemia is associated with poor intracerebral hemorrhage (ICH) outcomes. However, underlying drivers for anemia and whether anemia development after ICH impacts clinical outcomes are unknown. We hypothesized that inflammation drives anemia development after ICH and assessed their relationship to outcomes., Methods and Results: Patients with serial hemoglobin and iron biomarker concentrations from the HIDEF (High-Dose Deferoxamine in Intracerebral Hemorrhage) trial were analyzed. Adjusted linear mixed models assessed laboratory changes over time. Of 42 patients, significant decrements in hemoglobin occurred with anemia increasing from 19% to 45% by day 5. Anemia of inflammation iron biomarker criteria was met in 88%. A separate cohort of 521 patients with ICH with more granular serial hemoglobin and long-term neurological outcome data was also investigated. Separate regression models assessed whether (1) systemic inflammatory response syndrome (SIRS) scores related to hemoglobin changes over time and (2) hemoglobin changes related to poor 90-day outcome. In this cohort, anemia prevalence increased from 30% to 71% within 2 days of admission yet persisted beyond this time. Elevated systemic inflammatory response syndrome was associated with greater hemoglobin decrements over time (adjusted parameter estimate: -0.27 [95% CI, -0.37 to -0.17]) and greater hemoglobin decrements were associated with poor outcomes (adjusted odds ratio per 1 g/dL increase, 0.76 [95% CI, 0.62-0.93]) independent to inflammation and ICH severity., Conclusions: We identified novel findings that acute anemia development after ICH is common, rapid, and related to inflammation. Because anemia development is associated with poor outcomes, further work is required to clarify if anemia, or its underlying drivers, are modifiable treatment targets that can improve ICH outcomes., Registration: https://www.clinicaltrials.gov Unique identifier: NCT01662895.

Objectives: To derive systematic review informed, modified Delphi consensus regarding monitoring and replacement of specific coagulation factors during pediatric extracorporeal membrane oxygenation (ECMO) support for the Pediatric ECMO Anticoagulation CollaborativE., Data Sources: A structured literature search was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2020, with an update in May 2021., Study Selection: Included studies assessed monitoring and replacement of antithrombin, fibrinogen, and von Willebrand factor in pediatric ECMO support., Data Extraction: Two authors reviewed all citations independently, with conflicts resolved by a third reviewer if required. Twenty-nine references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form., Data Synthesis: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. A panel of 48 experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. We developed one weak recommendation and four expert consensus statements., Conclusions: There is insufficient evidence to formulate recommendations on monitoring and replacement of antithrombin, fibrinogen, and von Willebrand factor in pediatric patients on ECMO. Optimal monitoring and parameters for replacement of key hemostasis parameters is largely unknown., Competing Interests: Dr. Zantek received funding from the North American Specialized Coagulation Laboratory Association (NASCOLA), the American Society for Apheresis (ASFA), and Blood Network subgroup of Pediatric Acute Lung Injury and Sepsis Investigators; she disclosed that she is a Board Member of External Quality Assurance in Thrombosis and Hemostasis, a committee member of NASCOLA, ASFA, the Association for the Advancement of Blood and Biotherapies, the College of American Pathologists, and the International Society for Laboratory Hematology; and she disclosed that her spouse is an employee of Boston Scientific and has a financial interest in Boston Scientific and Endo International. Dr. Steiner’s institution received funding from the Department of Defense; she received funding from Medtronic, Octapharma, and Pumps for Kids, Infants and Neonates (PumpKIN) trial Data Safety and Monitoring Board; she disclosed the off-label product use of recombinant factor VIIa. Drs. Teruya, Kreuziger, and Raffini disclosed the off-label product use of antithrombin concentrate. Dr. Raffini received funding from CSL Behring and Boehringer Ingelheim. Drs. Muszynski’s and Alexander’s institutions received funding from the National Institutes of Health (NIH); they received support for article research from the NIH. Dr. Alexander’s institution received funding from the Extracorporeal Life Support Organization and Novartis. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Mortality due to immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains significant. Predicting mortality risk may potentially help individualize treatment. The French Thrombotic Microangiopathy (TMA) Reference Score has not been externally validated in the United States. Recent advances in machine learning technology can help analyze large numbers of variables with complex interactions for the development of prediction models., Objectives: To validate the French TMA Reference Score in the United States Thrombotic Microangiopathy (USTMA) iTTP database and subsequently develop a novel mortality prediction tool, the USTMA TTP Mortality Index., Methods: We analyzed variables available at the time of initial presentation, including demographics, symptoms, and laboratory findings. We developed our model using gradient boosting machine, a machine learning ensemble method based on classification trees, implemented in the R package gbm., Results: In our cohort ( n = 419), the French score predicted mortality with an area under the receiver operating characteristic curve of 0.63 (95% CI: 0.50-0.77), sensitivity of 0.35, and specificity of 0.84. Our gradient boosting machine model selected 8 variables to predict acute mortality with a cross-validated area under the receiver operating characteristic curve of 0.77 (95% CI: 0.71-0.82). The 2 cutoffs corresponded to sensitivities of 0.64 and 0.50 and specificities of 0.76 and 0.87, respectively., Conclusion: The USTMA Mortality Index was acceptable for predicting mortality due to acute iTTP in the USTMA registry, but not sensitive enough to rule out death. Identifying patients at high risk of iTTP-related mortality may help individualize care and ultimately improve iTTP survival outcomes. Further studies are needed to provide external validation. Our model is one of many recent examples where machine learning models may show promise in clinical prediction tools in healthcare., (© 2024 The Author(s).)

Background: Patients with COVID-19 have a higher risk of thrombosis and thromboembolism, but the underlying mechanism(s) remain to be fully elucidated. In patients with COVID-19, high lipoprotein(a) (Lp(a)) is positively associated with the risk of ischemic heart disease. Lp(a), composed of an apoB-containing particle and apolipoprotein(a) (apo(a)), inhibits the key fibrinolytic enzyme, tissue-type plasminogen activator (tPA). However, whether the higher Lp(a) associates with lower tPA activity, the longitudinal changes of these parameters in hospitalized patients with COVID-19, and their correlation with clinical outcomes are unknown., Objectives: To assess if Lp(a) associates with lower tPA activity in COVID-19 patients, and how in COVID-19 populations Lp(a) and tPA change post infection., Methods: Endogenous tPA enzymatic activity, tPA or Lp(a) concentration were measured in plasma from hospitalized patients with and without COVID-19. The association between plasma tPA and adverse clinical outcomes was assessed., Results: In hospitalized patients with COVID-19, we found lower tPA enzymatic activity and higher plasma Lp(a) than that in non-COVID-19 controls. During hospitalization, Lp(a) increased and tPA activity decreased, which associates with mortality. Among those who survived, Lp(a) decreased and tPA enzymatic activity increased during recovery. In patients with COVID-19, tPA activity is inversely correlated with tPA concentrations, thus, in another larger COVID-19 cohort, we utilized plasma tPA concentration as a surrogate to inversely reflect tPA activity. The tPA concentration was positively associated with death, disease severity, plasma inflammatory, and prothrombotic markers, and with length of hospitalization among those who were discharged., Conclusion: High Lp(a) concentration provides a possible explanation for low endogenous tPA enzymatic activity, and poor clinical outcomes in patients with COVID-19., (© 2023 The Author(s).)

The effectiveness and safety of direct oral anticoagulants (DOAC) compared with warfarin remains uncertain in obese patients. We assessed the comparative effectiveness and safety of DOACs with warfarin for the treatment of VTE among obese patients. This multi-center retrospective cohort study included adults with a BMI ≥ 35 kg/m 2 or weight ≥ 120 kg prescribed either DOAC (apixaban, dabigatran, edoxaban, rivaroxaban) or warfarin for a VTE diagnosis. The primary outcome was the 12-month rate of recurrent VTE. The secondary outcome was the 12-month rate of major bleeding. Among 5626 patients, 67% were prescribed warfarin and 33% were prescribed a DOAC. The 12-month VTE recurrence rate was 3.6% (67/1823) for patients treated with DOAC compared with 3.8% (143/3664) for patients treated with warfarin [odds ratio for recurrent VTE on warfarin versus DOAC (OR) (95% CI).07 (0.80, 1.45)]. The 12-month major bleeding rate was 0.5% (10/1868) for patients on DOAC versus 2.4% (89/3758) on warfarin [OR 4.25 (2.19, 8.22)]. Similar proportions of recurrent VTE occurred across BMI thresholds on DOAC and warfarin: for BMI ≥ 35 kg/m 2 (N = 5412), 3.6% versus 3.8%, respectively [OR 1.08 (0.80, 1.46)]; for BMI ≥ 40 kg/m 2 (N = 2321), 4.4% versus 3.5%, respectively [OR 0.80 (0.51, 1.26)]; and for BMI ≥ 50 kg/m 2 (N = 560), 3.1% versus 3.7%, respectively [OR 1.18 (0.39, 3.56)]. Similar proportions of recurrent VTE occurred in patients with obesity treated for VTE with DOACs and warfarin. DOACs were associated with lower major bleeding compared to warfarin in patients with obesity and VTE., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Due to platelet availability limitations, platelet units ABO mismatched to recipients are often transfused. However, since platelets express ABO antigens and are collected in plasma which may contain ABO isohemagglutinins, it remains controversial as to whether ABO non-identical platelet transfusions could potentially pose harm and/or have reduced efficacy., Study Design and Methods: The large 4-year publicly available Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) database was used to investigate patient outcomes associated with ABO non-identical platelet transfusions. Outcomes included mortality, sepsis, and subsequent platelet transfusion requirements., Results: Following adjustment for possible confounding factors, no statistically significant association between ABO non-identical platelet transfusion and increased risk of mortality was observed in the overall cohort of 21,176 recipients. However, when analyzed by diagnostic category and recipient ABO group, associations with increased mortality for major mismatched transfusions were noted in two of eight subpopulations. Hematology/Oncology blood group A and B recipients (but not group O) showed a Hazard Ratio (HR) of 1.29 (95%CI: 1.03-1.62) and intracerebral hemorrhage group O recipients (but not groups A and B) showed a HR of 1.75 (95%CI: 1.10-2.80). Major mismatched transfusions were associated with increased odds of receiving additional platelet transfusion each post-transfusion day (through day 5) regardless of the recipient blood group., Discussion: We suggest that prospective studies are needed to determine if specific patient populations would benefit from receiving ABO identical platelet units. Our findings indicate that ABO-identical platelet products minimize patient exposure to additional platelet doses., (© 2023 AABB.)

Background: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear., Objective: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization., Design: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087)., Setting: Done during 2021 to 2022 among 127 U.S. hospitals., Participants: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation., Intervention: 2.5 mg of apixaban versus placebo twice daily for 30 days., Measurements: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding., Results: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment., Limitations: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity., Conclusion: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive., Primary Funding Source: National Institutes of Health.

Background: The direct oral anticoagulants (DOACs), apixaban and rivaroxaban, have been studied for extended-phase treatment of venous thromboembolism (VTE). Yet, scant evidence exists surrounding clinician practice and decision-making regarding dose reduction., Aims: Report clinician practice and characteristics surrounding dose reduction of DOACs for extended-phase VTE treatment., Methods: We conducted a 16-question REDCap survey between July 14, 2021, and September 13, 2021, among ISTH 2021 Congress attendees and on Twitter. We explored factors associated with dose reduction using logistic regression. We used k-means clustering to identify distinct groups of dose-reduction decision-making. Random forest analysis explored demographics with respect to identified groups., Results: Among 171 respondents, most were attending academic physicians from North America. Clinicians who treated larger volumes of patients had higher odds of dose reduction. We identified five clusters that showed distinct patterns of behavior regarding dose reduction. Cluster 1 rarely dose reduces and likely prescribes rivaroxaban over apixaban; cluster 2 dose reduces frequently, does not consider age when dose-reducing, is least likely to temporarily reescalate dosing, and prescribes apixaban and rivaroxaban equally; cluster 3 dose reduces <50% of the time, and temporarily reescalates dosing during increased VTE risk; cluster 4 dose reduces frequently, temporarily reescalates dosing, and is most likely to prescribe apixaban over rivaroxaban; and cluster 5 dose reduces most frequently, and takes the fewest risk factors into consideration when deciding to dose reduce., Conclusions: Most clinicians elect to dose-reduce DOACs for extended-phase anticoagulation. The likelihood of a clinician to dose reduce increases with volume of patients treated. Clinician prescribing patterns cluster around VTE risk factors as well as reescalation during high-risk periods., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Thrombotic complications continue to pose challenges to patients on left ventricular assist device (LVAD) support. The Hoplon system was developed to administer catheter-based lytic therapy with a novel approach to embolic protection., Methods: Two porcine non-survival surgeries were performed in which off-pump LVAD insertion was followed by injection of thrombus into the impeller, isolation of the pump using the Hoplon system, and administration of lytic therapy to the pump chamber. Successful thrombus resolution was confirmed by pathological examination of the LVAD and brain tissue after animal sacrifice., Results: Limitations of the prototype design resulted in the extrusion of thrombus from around the catheter in the first animal. Subsequent device modifications resulted in the resolution of LVAD thrombus as confirmed on removal and examination of the pump. Pathological examination of the brain tissue revealed the absence of any embolic or hemorrhagic complications., Conclusions: Early animal studies suggest feasibility in restoring function to an LVAD while at the same time preventing cerebroembolic events using the Hoplon system., (© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: This is the 2nd update to the 9th edition of these guidelines. We provide recommendations on 17 PICO (Population, Intervention, Comparator, Outcome) questions, four of which have not been addressed previously., Methods: We generate strong and weak recommendations based on high-, moderate-, and low-certainty evidence, using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology., Results: The panel generated 29 guidance statements, 13 of which are graded as strong recommendations, covering aspects of antithrombotic management of VTE from initial management through secondary prevention and risk reduction of postthrombotic syndrome. Four new guidance statements have been added that did not appear in the 9th edition (2012) or 1st update (2016). Eight statements have been substantially modified from the 1st update., Conclusion: New evidence has emerged since 2016 that further informs the standard of care for patients with VTE. Substantial uncertainty remains regarding important management questions, particularly in limited disease and special patient populations., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards., Design: Randomised controlled, adaptive, open label clinical trial., Setting: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US., Participants: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237)., Interventions: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death., Main Outcome Measures: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated., Results: The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m 2 . At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69)., Conclusions: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial., Trial Registration: ClinicalTrials.gov NCT04362085., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: MS reports receiving funding from Task 54, Defense Research Development Canada, Department of National Defense, Ottawa, Canada (to institution), St Michael’s Hospital Foundation, Toronto, Canada (to institution), St Joseph’s Health Centre Foundation, Toronto, Canada (to institution), International Network of Venous Thromboembolism Clinical Research Networks (INVENT) Kickstarter Award (to institution) during the conduct of this study. LBK reports receiving funding from the INVENT Kickstarter Award during the conduct of the study. FNA reports receiving Science Foundation Ireland, Enterprise Ireland, IDA Ireland COVID-19 Rapid Response Funding Call 20/COV/0157 (to Institution; University College Dublin) during the conduct of this study; and grants or contracts from Sanofi, Daiichi-Sankyo, Irish Health Research Board (a state agency under the Department of Health, supporting and funding health and social care research), and Bayer; and reports patent submitted (European Application No 20166826.6) outside of the submitted work. LAC reports receiving honorariums for lectures and presentations for Bristol Meyers Squibb, Pfizer, Bayer, Boehringer Ingelheim, Leo Pharma, Sanofi, The Academy for Continued Advancement in Healthcare Education outside of the submitted work. PDJ reports receiving research grant funding from Bayer, Takeda, CSL Behring outside of the submitted work and reports receiving funding from SEAMO (South-eastern Ontario Academic Medical Organization) COIVD-19 Innovation Fund during the conduct of this study. DL reports receiving research support from Bayer, Biomarin, CSL-Behring, Octapharma, Sanofi; and serving on Data Safety Monitoring and Advisory Boards for Biomarin, CSL Behring, Takeda, Sanofi, and Spark outside of the submitted work. MCa reports grant or contracts from Bristol Meyers Squibb, Leo Pharma, Pfizer (to institution); consulting fees from Bayer, Pfizer, Bristol Meyers Squibb, Sanofi, Servier, Leo Pharma (to institution) outside of the submitted work. CC reports stock options from BioCogniv, Burlington, Vermont, USA outside of the submitted work. CW reports receiving payment or honorariums for speaking engagements from Leo Pharma, Pfizer, Bristol Meyers Squibb-Pfizer, and Servier and serving on advisory board meetings for LEO Pharma, Pfizer, Bristol Meyers Squibb-Pfizer, Servier outside of the submitted work. KD reports receiving honorariums from LEO Pharma and Pfizer outside of the submitted work. ERA reports receiving funding from 2020 TD Community Health Solutions Fund COVID-19 research grant (to institution) during the conduct of this study; honorariums from Pfizer and Bayer; support for attending meetings and/or travel from Pfizer, and participation in advisory board for Tavalisse outside of the submitted work. MF reports consulting fees from Pine Trees Health outside of the submitted work. SM reports grants and personal fees from Daiichy Sankyo, grants and personal fees from Bayer, Pfizer, and Boehringer-Ingelheim, personal fees from Portola, Abbvie, Bristol Meyers Squibb-Pfizer, and Sanofi, outside the submitted work. AYYL reports receiving consulting fees from LEO Pharma; payment or honorariums for speaking engagements and/or consulting from LEO Pharma and Pfizer, and serving on a data safety monitoring board or advisory board for CONNECTS program (COVID-19 clinical trials involving anticoagulation) outside of the submitted work. MC reports receiving an honorarium from the International Society on Thrombosis and Haemostasis outside of the submitted work. PJü reports receiving funding from Task 54, Defense Research Development Canada, Department of National Defense, Ottawa, Canada (to institution), St Michael’s Hospital Foundation, Toronto, Canada (to institution), St Joseph’s Health Centre Foundation, Toronto, Canada (to institution), International Network of Venous Thromboembolism Clinical Research Networks (INVENT) Kickstarter Award (to institution) during the conduct of this study; receiving a grant from Appili Therapeutics (to the institution); payment for participation in advisory boards and/or consulting for Amgen and Fresenius (to the institution); honorariums and travel reimbursement from Amgen, Ava, and Fresenius (to the institution); participation in advisory boards and/or consulting for Amgen and Fresenius; and serves as unpaid member of the steering group of trials funded by Appili Therapeutics, Terumo, and Abbott Vascular outside of the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Alteration in blood triglyceride levels have been found in patients with coronavirus disease 2019 (COVID-19). However, the association between hypertriglyceridemia and mortality in COVID-19 patients is unknown., Objective: To investigate the association between alteration in triglyceride level and mortality in hospitalized COVID-19 patients., Methods: We conducted a retrospective study of 600 hospitalized patients with COVID-19 diagnosis (ICD10CM:U07.1) and/or SARS-CoV-2 positive testing results between March 1, 2020 and December 21, 2020 at a tertiary academic medical center in Milwaukee, Wisconsin. De-identified data, including demographics, medical history, and blood triglyceride levels were collected and analyzed. Of the 600 patients, 109 patients died. The triglyceride value on admission was considered the baseline and the peak was defined as the highest level reported during the entire period of hospitalization. Hypertriglyceridemia was defined as greater than 150 mg/dl. Logistic regression analyses were performed to evaluate the association between hypertriglyceridemia and mortality., Results: There was no significant difference in baseline triglyceride levels between non-survivors (n = 109) and survivors (n = 491) [Median 127 vs. 113 mg/dl, p = 0.213]. However, the non-survivors had significantly higher peak triglyceride levels during hospitalization [Median 179 vs. 134 mg/dl, p < 0.001]. Importantly, hypertriglyceridemia independently associated with mortality [odds ratio=2.3 (95% CI: 1.4-3.7, p = 0.001)], after adjusting for age, gender, obesity, history of hypertension and diabetes, high CRP, high leukocyte count and glucocorticoid treatment in a multivariable logistic regression model., Conclusions: Hypertriglyceridemia during hospitalization is independently associated with 2.3 times higher mortality in COVID-19 patients. Prospective studies are needed to independently validate this retrospective analysis., Competing Interests: Declaration of Competing Interest The authors have declared that no relevant conflict of interest exists., (Copyright © 2021 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

Background: Patient safety indicators (PSI) were developed for hospitals to screen for healthcare-associated adverse events. PSIs are believed to be preventable and have become a part of major pay-for-performance programs. PSI-12 captures perioperative venous thromboembolism (VTE), which contributes to morbidity and mortality of hospitalized patients. We aimed to evaluate PSI-12 events at our institution to identify areas for improvement of perioperative VTE prevention., Methods: We identified PSI-12 events from June 2015 to June 2017 using the Agency for Healthcare Research and Quality software version 5. Events were reviewed using our electronic medical record to identify further details of each event., Results: A total of 154 perioperative VTE cases were analyzed in the 2-year period. Pulmonary embolism (PE) occurred in 62.9% of cases, deep venous thrombosis (DVT) in 24%, and concurrent DVT/PE in 12.9%. The mean age of patients was 56 years old. Deficiencies in guideline-appropriate prophylaxis were identified in only 17 (11%) of cases. Unfractionated heparin was used in 61 cases, enoxaparin in 31 cases, and nine events occurred on therapeutic anticoagulation. Mechanical prophylaxis was used in 51 cases because of bleeding risk, thrombocytopenia, and/or liver associated coagulopathy. Four events occurred prior to the index procedure, with another eight cases occurring intraoperatively, or on the day of the procedure., Conclusions: PSI-12 has several limitations in identifying quality of care issues in perioperative VTE. While it may be useful as a screening tool, further research for improvements are needed if it will remain one of the key measures in pay-for-performance., (© 2020 Society of Hospital Medicine.)

Introduction: Systemic light chain (AL) amyloidosis can lead to an acquired coagulopathy secondary to acquired factor X (aFX) deficiency. However, it is not very clear who develops aFX deficiency in AL amyloidosis., Methods: We therefore undertook this single centre, retrospective study to better characterize AL amyloidosis-associated aFX deficiency., Results: Out of 121 AL patients who had FX testing at the time of their first evaluation at our institution, including 17 patients on warfarin at the time of testing, 10 out of 104 patients (9.6%) with systemic AL amyloidosis were found to have FX levels below 50%. Acquired FX deficiency was associated with advanced stage of AL amyloidosis and elevated cardiac biomarkers. Lower FX activity, advanced stage, and cardiac involvement by disease were associated with higher hazard of death on univariate analysis. On multivariate analysis, stage of AL amyloidosis was the only significant predictor of survival. Median survival time of patients with FX deficiency was 9.3 months compared to 118.4 months in those without., Conclusions: We conclude that while aFX deficiency is rare in systemic AL amyloidosis, it is a marker of advanced disease., (Copyright © 2018 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

Venous thromboembolism (VTE) is a highly morbid condition with several available oral anticoagulant treatment options. Numerous studies have been published comparing warfarin to direct oral anticoagulants; however, several populations remain underrepresented in these reports. We surveyed members of The Venous ThromboEmbolism Network U.S. working group regarding their oral anticoagulant preferences for the treatment of VTE in different and challenging populations. In individuals with VTE and no other medical comorbidities, respondents preferred either rivaroxaban (48.7%) or apixaban (48.7%). Apixaban (53.3%) was preferred in elderly individuals with an increased risk of bleeding. Warfarin was preferred in individuals with liver or kidney dysfunction (42% and 47%), altered metabolism (>55%), and antiphospholipid antibody syndrome (84.2%). Low-molecular-weight heparin was preferred in individuals with malignancy (56.6%), followed by edoxaban (23.7%). These findings may help guide clinicians when choosing an anticoagulant in these challenging situations and demonstrate the urgent need for additional study in these groups.

Mechanical circulatory support (MCS) is the overarching term that encompasses the temporary and durable devices used in patients with severe heart failure. MCS disturbs the hematologic and coagulation system, leading to platelet activation, activation of the contact pathway of coagulation, and acquired von Willebrand syndrome. Ischemic stroke and major hemorrhage occur in up to 30% of patients. Hematologists are an essential part of the MCS team because they understand the delicate balance between bleeding and clotting and alteration of hemostasis with antithrombotic therapy. However, prior to this important collaborative role, learning the terminology used in the field and types of MCS devices allows improved communication with the MCS team and best patient care. Understanding which antithromobotic therapies are used at baseline is also required to provide recommendations if hemorrhage or thrombosis occurs. Additional challenging consultations in MCS patients include the influence of thrombophilia on the risk for thrombosis and management of heparin-induced thrombocytopenia. This narrative review will provide a foundation to understand MCS devices how to prevent, diagnose, and manage MCS thrombosis for the practicing hematologist., Competing Interests: Conflict-of-interest disclosures: L.B.K. declares no competing financial interests. M.P.M. has consulted for the National Institutes of Health/National Heart, Lung, and Blood Institute PumpKIN study: Pumps in children, infants, and neonates., (© 2018 by The American Society of Hematology. All rights reserved.)

Background: Heparin-induced thrombocytopenia can be a life-threatening and limb-threatening complication of heparin therapy. Incidence and complication rates of this condition have been extrapolated from studies with modest sample sizes, and despite the availability of therapeutic interventions the outcomes of heparin-induced thrombocytopenia are not well understood. We aimed to estimate disease burden, complication rates, and costs of heparin-induced thrombocytopenia in the USA., Methods: In this population-based study we analysed data from 2009 to 2013 from the Nationwide (National) Inpatient Sample (NIS), a large, all-payer inpatient health-care database in the USA. To validate the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for heparin-induced thrombocytopenia (289.84), we defined the sensitivity and specificity of this code using patient data from 2013 from a local hospital (Froedtert Memorial Lutheran Hospital, Milwaukee, WI, USA). The primary outcomes assessed were the incidence of hospital discharges with codes for heparin-induced thrombocytopenia and of discharges for heparin-induced thrombocytopenia associated with cardiopulmonary bypass, haemodialysis, hip or knee arthroplasty, trauma or injury (or both), and gingival or periodontal disease (or both). We also assessed the incidence of thrombosis, bleeding, limb or digit amputation, mortality, length of hospital stay, and associated hospital charges., Findings: Between 2009 and 2013, 97 566 discharges from the NIS assigned the ICD-9-CM code for heparin-induced thrombocytopenia, and 149 911 247 discharges coded for non-heparin-induced thrombocytopenia, were analysed. Overall, heparin-induced thrombocytopenia was identified in 97 566 (0·065%; SE 0·0012) of 150 008 813 discharges, corresponding to approximately one in 1500 hospital admissions. Patients undergoing cardiopulmonary bypass had the highest rates of heparin-induced thrombocytopenia (7702 [0·63%; SE 0·03] of 1 230 362), followed by those undergoing haemodialysis (23 012 [0·47%; 0·01] of 4 908 100), those with gingival or periodontal disease, or both (106 [0·12%; 0·03] of 88 621), and those with trauma or injury, or both (541 [0·09%; 0·01] of 602 944); patients with hip (845 [0·04%; 0·004] of 1 943 353) and knee (676 [0·02%; 0·002] of 3 022 602) arthroplasty had the lowest rates of heparin-induced thrombocytopenia. Thrombosis (29 079 [29·8%; SE 0·4] of 97 566) and bleeding (6044 [6·2%; 0·2] of 97 566) were common complications in heparin-induced thrombocytopenia, and 1446 (23·9%; 1·2) of 6044 patients with heparin-induced thrombocytopenia who had haemorrhage died. 742 (0·76%; SE 0·06) of 97 566 patients with heparin-induced thrombocytopenia discharges underwent amputations compared with 173 043 (0·12%; 0·001) of 149 911 247 with non-heparin-induced thrombocytopenia discharges (adjusted odds ratio 5·095 [95% CI 4·309-6·023]; p<0·0001). Overall, in-hospital mortality was 9842 (10·1%; SE 0·2) of 97 508 in discharge summaries coded for heparin-induced thrombocytopenia compared with 3 206 700 (2·1%; 0·01) of 149 811 891 in discharges for non-heparin-induced thrombocytopenia (adjusted odds ratio 4·075 [95% CI 3·846-4·317]; p<0·0001). The median length of stay among live discharges was 8·9 days (IQR 4·6-17·1) and total hospital charges were US$83 072 (IQR 37 240-188 419) for heparin-induced thrombocytopenia discharges compared with 2·6 days (1·4-4·8) and $21 360 (11 426-41 917) for non-heparin-induced thrombocytopenia discharges (p<0·0001 for both). 333 discharges from a local hospital were analysed to assess the diagnostic sensitivity and specificity of the heparin-induced thrombocytopenia ICD-9-CM code; sensitivity was 90·9% (95% CI 57·1-99·5) and specificity was 94·4% (91·1-96·6)., Interpretation: Complication rates for heparin-induced thrombocytopenia remain high and more effective preventive and treatment interventions are needed., Funding: None., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Venous thromboembolism (VTE) represents a major global burden of disease and requires collaborative efforts to conduct large, high-quality investigator-initiated and academically sponsored studies addressing the most relevant clinical questions. Owing to increasing regulatory requirements, the highly competitive nature of peer-reviewed funding and costs associated with conducting large, multinational clinical trials, completing practice-changing research constitutes a growing challenge for clinical investigators. As clinical trialists interested in VTE, we founded INVENT (International Network of Venous Thromboembolism Clinical Research Networks) in an effort to promote and accelerate patient-oriented, investigator-initiated, international collaborative research, to identify, prioritize and answer key clinical research questions for patients with VTE. We report on our activities to formalize the INVENT network and our accomplishments in our first year., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Drug-induced transplant-associated thrombotic microangiopathy (DTA-TMA) is a rare but serious complication that can occur after hematopoietic cell transplantation (HCT) or solid organ transplantation (SOT) without guidelines for optimal management of this condition., Study Design and Methods: Given the ambiguity surrounding the treatment for DTA-TMA, we conducted a retrospective review to evaluate the impact of different treatment strategies in DTA-TMA patients. Our primary endpoint was to determine the overall response rate (ORR) for DTA-TMA based on the type of treatment modality chosen while secondary endpoints included the time to response, relapse rates, and overall survival for DTA-TMA cases., Results: There were a total of 14 DTA-TMA patients of whom nine were post-HCT and five were post-SOT. Most of the DTA-TMA cases were due to tacrolimus (n = 11) with a minority related to sirolimus (n = 3). A total of nine of 14 patients demonstrated response and five had no response to therapy. The ORR among the DTA-TMA patients after HCT and SOT who received plasma exchange (PLEX) were 25 and 100%, respectively. The ORRs among the patients (includes HCT and SOT) who received rituximab (n = 3) and eculizumab (n = 5) were 67 and 60%, respectively. There were two relapses noted in our study and both were in the HCT group., Conclusion: While discontinuation of the offending agent may be sufficient for treatment of DTA-TMA after HCT, PLEX may be a reasonable option for DTA-TMA after SOT. Although the results are encouraging with rituximab and eculizumab in the treatment of DTA-TMA, larger prospective studies are needed to validate our findings., (© 2017 AABB.)

Background: Risk of venous thromboembolism (VTE) in patients with inflammatory bowel disease (IBD) is well established; however, there is paucity of data on the potential added risk of VTE in patients with IBD with Clostridium difficile infection (CDI). We sought to study the difference in VTE rates in hospitalized patients with IBD with CDI compared to those without CDI., Methods: We queried Nationwide Inpatient Sample from year 2011 to identify patients ≥18 years of age with a discharge diagnosis of IBD (i.e., Crohn's disease and ulcerative colitis) based on ICD-9-CM codes 555.xx and 556.xx, respectively. Patients were further divided into 2 groups: those with and without CDI. To adjust and control for potential baseline differences between groups, 1:1 propensity matching was performed. Multivariate regression analysis was used to evaluate the difference in VTE rates in 2 groups., Results: Of 312,147 patients with the discharge diagnosis of IBD, 12,560 (4%) had CDI. VTE was present 6% in group with CDI versus 3% in group without CDI (P < 0.001). On performing multivariate analysis after propensity-score matching, CDI was significantly associated with VTE (adjusted odds ratio 1.7, 95% confidence interval 1.4-2.2, P < 0.001). On subgroup analysis, Crohn's disease with CDI had a higher association with VTE compared with Crohn's disease only. Similarly, ulcerative colitis with CDI had a higher association with VTE compared with ulcerative colitis only., Conclusions: Rate of VTE was higher in hospitalized patients with IBD with CDI compared with those without CDI, necessitating extra vigilance in this patient population.

A 68-year-old man developed a right femoral vein deep vein thrombosis and bilateral pulmonary embolism while receiving chemotherapy for stage IV prostate cancer. His creatinine at diagnosis is 1.4 mg/dL, with an estimated clearance of 63 mL/min. In patients with cancer, should low-molecular-weight heparin treatment be dosed according to weight, or adjusted using anti-Xa levels?, (© 2016 by The American Society of Hematology. All rights reserved.)

In this issue of Blood, Donato et al report that treatment of venous thromboembolism (VTE) with anticoagulation does not increase the risk of intracranial hemorrhage (ICH) in patients with solid tumors metastatic to the brain.

A 75-year-old male with metastatic pancreatic cancer is undergoing chemotherapy with gemcitabine. A portal vein thrombosis was incidentally found on surveillance CT scan. He does not report any new abdominal pain or ascites. Should anticoagulation be used to treat asymptomatic portal vein thrombosis?, (© 2014 by The American Society of Hematology. All rights reserved.)