Anxiety and depression are associated with heightened risk of incident deep vein thrombosis: Mediation through stress-related neural mechanisms.

Controversy exists as to whether anxiety and depression increase deep vein thrombosis (DVT) risk, and the mechanisms mediating potential links remain unknown. We aimed to evaluate the association between anxiety and depression and DVT risk and determine whether upregulated stress-related neural activity (SNA), which promotes chronic inflammation, contributes to this link. Our retrospective study included adults (N = 118 871) enrolled in Mass General Brigham Biobank. A subset (N = 1520) underwent clinical 18F-FDG-PET/CT imaging. SNA was measured as the ratio of amygdalar to cortical activity (AmygAC). High-sensitivity C-reactive protein (hs-CRP) and heart rate variability (HRV) were also obtained. Median age was 58 [interquartile range (IQR) 42-70] years with 57% female participants. DVT occurred in 1781 participants (1.5%) over median follow-up of 3.6 years [IQR 2.1-5.2]. Both anxiety and depression independently predicted incident DVT risk after robust adjustment (HR [95% CI]: 1.53 [1.38-1.71], p < .001; and 1.48 [1.33-1.65], p < .001, respectively). Additionally, both anxiety and depression associated with increased AmygAC (standardized beta [95% CI]: 0.16 [0.04-0.27], p = .007, and 0.17 [0.05-0.29], p = .006, respectively). Furthermore, AmygAC associated with incident DVT (HR [95% CI]: 1.30 [1.07-1.59], p = .009). Mediation analysis demonstrated that the link between anxiety/depression and DVT was mediated by: (1) higher AmygAC, (2) higher hs-CRP, and (3) lower HRV ( < .05 for each). Anxiety and depression confer an attributable risk of DVT similar to other traditional DVT risk factors. Mechanisms appear to involve increased SNA, autonomic system activity, and inflammation. Future studies are needed to determine whether treatment of anxiety and depression can reduce DVT risk.

Evaluation of Bivalirudin During Adult Extracorporeal Membrane Oxygenation: A Retrospective Characterization of Dosing, Efficacy and Bleeding.

Objective: Although heparin is the current standard anticoagulant during venoarterial (VA) and venovenous (VV) extracorporeal membrane oxygenation (ECMO), factors including heparin-induced thrombocytopenia, heparin resistance and drug shortages necessitate alternative anticoagulants such as direct thrombin inhibitors. The aim was to characterize dosing, safety, and efficacy of bivalirudin during ECMO support. Methods: This retrospective single-center study included 24 adults on ECMO support who received ≥6 hours of bivalirudin. The primary endpoint was dose to first therapeutic activated partial thromboplastin time (aPTT). Secondary endpoints included evaluating dosing between ECMO modes, incidence of bleeding and thrombotic events, and time in therapeutic range (TTR). Results: The dose at time of first therapeutic aPTT was bivalirudin 0.05 [0.05-0.1] mg/kg/hour. Bivalirudin dosing requirements were lower in VAECMO compared to VV-ECMO patients and were not impacted by continuous venovenous hemofiltration. Time to therapeutic aPTT was 5.5 [2-13] hours for VA-ECMO and 4.5 [2-8.6] hours for VV-ECMO patients. During any mode of ECMO TTR was 58.3% [39.6-73.1]. Thrombotic events occurred in 3 (13%) patients and major bleeding occurred in 12 (50%) patients. Conclusions: Our findings demonstrated variable bivalirudin dosing requirements based on mode of ECMO and dosing modifications may not be required during CVVH. Factors including mode of ECMO, indication for bivalirudin and concomitant antiplatelet therapy may impact hematologic events. Application of this data can assist with developing a bivalirudin ECMO protocol which provides less variability in initial dosing and TTR.

Sex-Related Differences in Patient Characteristics, Risk Factors, and Symptomatology in Older Adults with Pulmonary Embolism: Findings from the SERIOUS-PE Study.

Sex-specific factors are implicated in pulmonary embolism (PE) presentation in young patients, as indicated by increased risk in pregnancy. Whether sex differences exist in PE presentation, comorbidities, and symptomatology in older adults, the age group in which most PEs occur, remains unknown. We identified older adults (aged ≥65 years) with PE in a large international PE registry replete with information about relevant clinical characteristics (RIETE registry, 2001-2021). To provide national data from the United States, we assessed sex differences in clinical characteristics and risk factors of Medicare beneficiaries with PE (2001-2019). The majority of older adults with PE in RIETE (19,294/33,462, 57.7%) and in the Medicare database (551,492/948,823, 58.7%) were women. Compared with men, women with PE less frequently had atherosclerotic diseases, lung disease, cancer, or unprovoked PE, but more frequently had varicose veins, depression, prolonged immobility, or history of hormonal therapy (p < 0.001 for all). Women less often presented with chest pain (37.3 vs. 40.6%) or hemoptysis (2.4 vs. 5.6%) but more often with dyspnea (84.6 vs. 80.9%) (p < 0.001 for all). Measures of clot burden, PE risk stratification, and use of imaging modalities were comparable between women and men. PE is more common in elderly women than in men. Cancer and cardiovascular disease are more common in men, whereas transient provoking factors including trauma, immobility, or hormone therapy are more common in elderly women with PE. Whether such differences correlate with disparities in treatment or differences in short- or long-term clinical outcomes warrants further investigation.

Artificial intelligence in the prediction of venous thromboembolism: A systematic review and pooled analysis.

BACKGROUND: Accurate diagnostic and prognostic predictions of venous thromboembolism (VTE) are crucial for VTE management. Artificial intelligence (AI) enables autonomous identification of the most predictive patterns from large complex data. Although evidence regarding its performance in VTE prediction is emerging, a comprehensive analysis of performance is lacking. AIMS: To systematically review the performance of AI in the diagnosis and prediction of VTE and compare it to clinical risk assessment models (RAMs) or logistic regression models. METHODS: A systematic literature search was performed using PubMed, MEDLINE, EMBASE, and Web of Science from inception to April 20, 2021. Search terms included "artificial intelligence" and "venous thromboembolism." Eligible criteria were original studies evaluating AI in the prediction of VTE in adults and reporting one of the following outcomes: sensitivity, specificity, positive predictive value, negative predictive value, or area under receiver operating curve (AUC). Risks of bias were assessed using the PROBAST tool. Unpaired t-test was performed to compare the mean AUC from AI versus conventional methods (RAMs or logistic regression models). RESULTS: A total of 20 studies were included. Number of participants ranged from 31 to 111 888. The AI-based models included artificial neural network (six studies), support vector machines (four studies), Bayesian methods (one study), super learner ensemble (one study), genetic programming (one study), unspecified machine learning models (two studies), and multiple machine learning models (five studies). Twelve studies (60%) had both training and testing cohorts. Among 14 studies (70%) where AUCs were reported, the mean AUC for AI versus conventional methods were 0.79 (95% CI: 0.74-0.85) versus 0.61 (95% CI: 0.54-0.68), respectively (p < .001). However, the good to excellent discriminative performance of AI methods is unlikely to be replicated when used in clinical practice, because most studies had high risk of bias due to missing data handling and outcome determination. CONCLUSION: The use of AI appears to improve the accuracy of diagnostic and prognostic prediction of VTE over conventional risk models; however, there was a high risk of bias observed across studies. Future studies should focus on transparent reporting, external validation, and clinical application of these models.

DOAC compared with warfarin for VTE in patients with obesity: a retrospective cohort study conducted through the VENUS network.

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/m2 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/m2 (N = 5412), 3.6% versus 3.8%, respectively [OR 1.08 (0.80, 1.46)]; for BMI ≥ 40 kg/m2 (N = 2321), 4.4% versus 3.5%, respectively [OR 0.80 (0.51, 1.26)]; and for BMI ≥ 50 kg/m2 (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.

COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection.

Patients with coronavirus disease 2019 (COVID-19) have elevated D-dimer levels. Early reports describe high venous thromboembolism (VTE) and disseminated intravascular coagulation (DIC) rates, but data are limited. This multicenter retrospective study describes the rate and severity of hemostatic and thrombotic complications of 400 hospital-admitted COVID-19 patients (144 critically ill) primarily receiving standard-dose prophylactic anticoagulation. Coagulation and inflammatory parameters were compared between patients with and without coagulation-associated complications. Multivariable logistic models examined the utility of these markers in predicting coagulation-associated complications, critical illness, and death. The radiographically confirmed VTE rate was 4.8% (95% confidence interval [CI], 2.9-7.3), and the overall thrombotic complication rate was 9.5% (95% CI, 6.8-12.8). The overall and major bleeding rates were 4.8% (95% CI, 2.9-7.3) and 2.3% (95% CI, 1.0-4.2), respectively. In the critically ill, radiographically confirmed VTE and major bleeding rates were 7.6% (95% CI, 3.9-13.3) and 5.6% (95% CI, 2.4-10.7), respectively. Elevated D-dimer at initial presentation was predictive of coagulation-associated complications during hospitalization (D-dimer >2500 ng/mL, adjusted odds ratio [OR] for thrombosis, 6.79 [95% CI, 2.39-19.30]; adjusted OR for bleeding, 3.56 [95% CI, 1.01-12.66]), critical illness, and death. Additional markers at initial presentation predictive of thrombosis during hospitalization included platelet count >450 × 109/L (adjusted OR, 3.56 [95% CI, 1.27-9.97]), C-reactive protein (CRP) >100 mg/L (adjusted OR, 2.71 [95% CI, 1.26-5.86]), and erythrocyte sedimentation rate (ESR) >40 mm/h (adjusted OR, 2.64 [95% CI, 1.07-6.51]). ESR, CRP, fibrinogen, ferritin, and procalcitonin were higher in patients with thrombotic complications than in those without. DIC, clinically relevant thrombocytopenia, and reduced fibrinogen were rare and were associated with significant bleeding manifestations. Given the observed bleeding rates, randomized trials are needed to determine any potential benefit of intensified anticoagulant prophylaxis in COVID-19 patients.

Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19.

BACKGROUND: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival. DESIGN: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used. SETTING: 67 hospitals in the United States. PARTICIPANTS: Adults with COVID-19 admitted to a participating ICU. MEASUREMENTS: Time to death, censored at hospital discharge, or date of last follow-up. RESULTS: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]). LIMITATION: Observational design. CONCLUSION: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation. PRIMARY FUNDING SOURCE: None.

Temporal Trends in Inpatient Oncology Census Before and During the COVID-19 Pandemic and Rates of Nosocomial COVID-19 Among Patients with Cancer at a Large Academic Center.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted health care systems. However, to date, the trend of hospitalizations in the oncology patient population has not been studied, and the frequency of nosocomial spread to patients with cancer is not well understood. The objectives of this study were to evaluate the impact of COVID-19 on inpatient oncology census and determine the nosocomial rate of COVID-19 in patients with cancer admitted at a large academic center. MATERIALS AND METHODS: Medical records of patients with cancer diagnosed with COVID-19 and admitted were reviewed to evaluate the temporal trends in inpatient oncology census during pre-COVID-19 (January 2019 to February 2020), COVID-19 (March to May 2020), and post-COVID-19 surge (June to August 2020) in the region. In addition, nosocomial infection rates of SARS-CoV-2 were reviewed. RESULTS: Overall, the daily inpatient census was steady in 2019 (median, 103; range, 92-118) and until February 2020 (median, 112; range, 102-114). However, there was a major decline from March to May 2020 (median, 68; range, 57-104), with 45.4% lower admissions during April 2020. As the COVID-19 surge eased, the daily inpatient census over time returned to the pre-COVID-19 baseline (median, 103; range, 99-111). One patient (1/231, 0.004%) tested positive for SARS-CoV-2 13 days after hospitalization, and it is unclear if it was nosocomial or community spread. CONCLUSION: In this study, inpatient oncology admissions decreased substantially during the COVID-19 surge but over time returned to the pre-COVID-19 baseline. With aggressive infection control measures, the rates of nosocomial transmission were exceedingly low and should provide reassurance to those seeking medical care, including inpatient admissions when medically necessary. IMPLICATIONS FOR PRACTICE: The COVID-19 pandemic has had a major impact on the health care system, and cancer patients are a vulnerable population. This study observes a significant decline in the daily inpatient oncology census from March to May 2020 compared with the same time frame in the previous year and examines the potential reasons for this decline. In addition, nosocomial rates of COVID-19 were investigated, and rates were found to be very low. These findings suggest that aggressive infection control measures can mitigate the nosocomial infection risk among cancer patients and the inpatient setting is a safe environment, providing reassurance.

Venous Thromboembolism: Genetics and Thrombophilias.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality throughout the world. Up to one half of patients who present with VTE will have an underlying thrombophilic defect. This knowledge has led to a widespread practice of testing for such defects in patients who develop VTE. However, identifying a hereditary thrombophilia by itself does not necessarily change outcomes or dictate therapy. Furthermore, family history of VTE by itself can increase an asymptomatic person's VTE risk several-fold, independent of detecting a known inherited thrombophilia. In this article, we will describe the current validated hereditary thrombophilias including their history, prevalence, and association with VTE. With a focus on evaluating both risks and benefits of testing, we will also explore the controversies of why, who, and when to test as well as discuss contemporary societal guidelines. Lastly, we will share how these tests have been integrated into clinical practice and how to best utilize them in the future.

Evaluation of direct thrombin inhibitors during a critical heparin shortage.

A recent heparin shortage related to an outbreak of African Swine Flu in China led to substantial increase in the use of direct thrombin inhibitors (DTI) as an alternative. We evaluated the safety and efficacy of DTIs by assessing the anticoagulation assays within the initial 48 h of therapy comparing before and during shortage. A retrospective evaluation of bivalirudin and argatroban was conducted at a single center before (May 24, 2018 through August 25, 2019) and during heparin shortage (August 26, 2019 through February 20, 2020). The primary outcome was time to first therapeutic activated partial thromboplastin time (aPTT). Secondary outcomes included the percentage of time in therapeutic aPTT range, in-hospital mortality, incidence of recurrent thrombosis, and hemorrhagic events. Of the 204 patients included in the study, 95 patients [bivalirudin (n = 35), argatroban (n = 60)] were included in the pre-shortage cohort and 109 patients [bivalirudin (n = 68), argatroban (n = 41)] were during shortage. No significant difference was observed in the time to first therapeutic aPTT pre- and during shortage (8.9 h ± 10.8 vs 8.8 h ± 10.2, P = 0.62). Compared to pre-shortage cohort, a greater percentage of time was spent in therapeutic aPTT range within the initial 48 h (32% (0-50) vs. 41.6% (0-63), P = 0.04) during shortage without statistically significant differences in the rates of in-hospital mortality, thrombosis, or bleeding. While the optimal DTI protocol is still be determined, the protocols presented in this study allowed for wide-spread utilization of DTIs during a critical heparin shortage without compromising patient safety and effectiveness, likely reflective of the enhancement of DTI protocols, clinician education, and multidisciplinary collaboration and guidance from pharmacy and hematology.

When Pigs Fly: A Multidisciplinary Approach to Navigating a Critical Heparin Shortage.

A recent outbreak of African swine fever (ASF) in China has claimed the lives of millions of pigs, and although this virus has no health impacts on humans, the disruption of the global pig population has far-reaching negative impacts on economic and pork-derived products, including the creation of the critical drug heparin. The active pharmaceutical ingredient in heparin is derived from pig intestines, and because of the ASF outbreak, the U.S. faces an imminent shortage of heparin. This drug shortage has the potential for profound implications, as heparin is used in a substantial and varied number of medical conditions. In response to notification of the heparin shortage crisis, our institution, Massachusetts General Hospital, activated its Hospital Incident Command System to streamline organization of major stakeholders and oversee operational and clinical activities required to mitigate the potential risks and optimize alternative effective strategies. This article describes the essential elements of our institution's emergency response plan, including detailed clinical algorithms developed by our experts for maximal heparin conservation and waste reduction by promoting safe and effective alternative strategies. Through this practice, we have also identified opportunities to change providers' prescribing and utilization behaviors for the better. As the ASF has not yet been contained and this crisis continues, the strategies and policies employed by our institution can provide a framework for other institutions to tackle this ongoing challenge and future drug shortage crises. IMPLICATIONS FOR PRACTICE: A detailed description of how one institution addressed the current heparin crisis, to support heparin conservation and waste reduction, is provided. The strategies used helped decrease heparin use by 80% in less than 2 months of establishing the task force. This accomplishment can be credited to the development of a task force and strategic plan in which experts and stakeholders were quickly identified, offered a part in the decision-making process, and frequently updated. Furthermore, the response system was dynamic, accessible, and one in which challenges were recognized and acted upon. The key to any crisis management is respect for one another and constant and open communication. Heparin is such a widespread drug that this shortage can potentially affect every patient population and provider. Understanding one's institutional needs and the effect of this crisis on those needs is one of the first steps when developing a strategic plan. Continually evaluating and adjusting that approach in response to the needs of the institution are critical to its success. Moreover, as it did for the authors' institution, a constant appraisal of the strategies can lead to opportunities for improvements in organization and practice that can be sustained well beyond the crisis.

Considerations for Use of Hematopoietic Growth Factors in Patients With Cancer Related to the COVID-19 Pandemic.

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.

Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel.

Bleeding is the most common complication of anticoagulant use. The evaluation and management of the bleeding patient is a core competency of emergency medicine. As the prevalence of patients receiving anticoagulant agents and variety of anticoagulants with different mechanisms of action, pharmacokinetics, indications, and corresponding reversal agents increase, physicians and other clinicians working in the emergency department require a current and nuanced understanding of how best to assess, treat, and reverse anticoagulated patients. In this project, we convened an expert panel to create a consensus decision tree and framework for assessment of the bleeding patient receiving an anticoagulant, as well as use of anticoagulant reversal or coagulation factor replacement, and to address controversies and gaps relevant to this topic. To support decision tree interpretation, the panel also reached agreement on key definitions of life-threatening bleeding, bleeding at a critical site, and emergency surgery or urgent invasive procedure. To reach consensus recommendations, we used a structured literature review and a modified Delphi technique by an expert panel of academic and community physicians with training in emergency medicine, cardiology, hematology, internal medicine/thrombology, pharmacology, toxicology, transfusion medicine and hemostasis, neurology, and surgery, and by other key stakeholder groups.

Comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: implications for clinical practice and future investigations.

Critically ill patients with COVID-19 are at increased risk for thrombotic complications which has led to an intense debate surrounding their anticoagulation management. In the absence of data from randomized controlled clinical trials, a number of consensus guidelines and recommendations have been published to facilitate clinical decision-making on this issue. However, substantive differences exist between these guidelines which can be difficult for clinicians. This review briefly summarizes the major societal guidelines and compares their similarities and differences. A common theme in all of the recommendations is to take an individualized approach to patient management and a call for prospective randomized clinical trials to address important anticoagulation issues in this population.

Treatment of submassive and massive pulmonary embolism: a clinical practice survey from the second annual meeting of the Pulmonary Embolism Response Team Consortium.

There is a paucity of robust clinical trial data to guide the treatment of acute pulmonary embolism (PE) thus the clinical guidelines rely heavily on expert opinion. Pulmonary Embolism Response Teams (PERT) have been developed to streamline the care of patients with acute PE. We conducted a survey among 100 experts in the field of PE during the second annual meeting of the PERT Consortium. Respondents were queried with respect to their demographic information, clinical practice questions and clinical vignettes. Clinical practice questions were focused questions about the risk stratification and treatment of patients with acute submassive PE, anticoagulation strategies for patients receiving thrombolysis and the use of inferior vena cava filters. Clinical vignettes were designed to assess participants' preferred choice of treatment for a variety of commonly encountered clinical scenarios. Among physicians affiliated with a PERT, there is overall agreement with regards to the criteria used for risk classification of patients with PE and its application to patients in the provided clinical vignettes. In contrast, there is substantial variability in the treatment strategies of patients presenting with commonly encountered clinical scenarios. The results of this survey highlight the need for more clinical trial data along with accepted algorithms for treatment of acute PE. In the absence of this, PERTs can facilitate multidisciplinary discussions in order to standardize treatment and provide evidence-based therapies to patients with acute PE.