Houghton, Damon E.

AbstractHospitalized patients with COVID‐19 infection frequently have coagulopathy resembling disseminated intravascular coagulation (DIC). An elevation of D‐dimer level is associated with a poor prognosis; however, the role of other fibrin degradation products, such as soluble fibrin monomers (SFMC), is not known.The objective of the study was to investigate the frequency and prognostic role of elevated SFMC in patients with COVID‐19. In this retrospective cohort study, patients hospitalized between April 1, 2020 and December 14, 2020 at Mayo Clinic with COVID‐19 infection who underwent DIC panel testing were identified. Results of laboratory tests and outcomes (thrombosis and death) within 40 days of testing were obtained via medical record review.Of 108 patients, D‐dimer was elevated in 82 (75.9%) patients. Of those with elevated D‐dimer, SFMC was elevated in 19/82 (23%) patients. There were 16 thrombotic events and 16 deaths during the 40‐day follow‐up. The incidence of overt‐DIC was 4.6%. In univariate analysis, D‐dimer ≥5 x highest upper limit normal (ULN) and elevated SFMC were each associated with higher 40‐day mortality. However, when used in combination with D‐dimer ≥5 x highest ULN, an elevated SFMC provided no further mortality predictive value.Compared to 75.9% of patients with elevated D‐dimers, of those tested, only 23% had elevated SFMC. These results support the hypothesis that elevated D‐dimer in COVID‐19 infection is a direct consequence of endothelial damage and not overt‐DIC.

Abstract Background: The precise anatomic location and extent of most venous thromboembolism (VTE) is not captured through diagnostic codes and is a major limitation to research. Correctly identifying the specific site of thrombosis, whether proximal or distal deep vein thrombosis (DVT) or superficial vein thrombosis (SVT) is critical.An accurate natural language processing (NLP) tool would make analysis of large datasets from electronic medical records possible and could be an significant improvement compared to analyses using the International Classification of Diseases codes. Using an open-source NLP tool, we evaluated existing algorithms and then created and validated new NLP algorithms to classify lower extremity thrombosis as not only a DVT or SVT, but also to identify more precise anatomic locations. Methods: A random sample of deidentified ultrasound reports were extracted from electronic medical records, manually reviewed, and classified as either positive or negative for a DVT or SVT (any chronicity). Reports with DVT were further classified into proximal (popliteal, femoral, deep femoral, common femoral, iliac veins, or vena cava) and distal (posterior tibial, anterior tibial, peroneal, soleal, or gastrocnemius veins) DVT. SVT was further classified into greater saphenous vein, small saphenous vein, or other site. Thrombosis near the junction of deep and superficial veins was only designated as involving specific vein segments if there was intraluminal thrombosis at that site. Initial sets of 100 ultrasound reports were used for derivation and reiterative testing of the algorithm, consisting of 50 that were positive for DVT/SVT and 50 that were negative for DVT/SVT. Text from radiology reports underwent cleaning to remove extraneous punctuation, text outside of the "findings" and "impression" section, and all text matches for "superficial femoral vein" were replaced with "femoral vein". Using target phrases, the simple NLP tool either classified the reports as present or absent, signifying either positive or negative for thrombosis at the site of interest. After maximizing accuracy in the derivation cohorts, each NLP algorithm was tested in the complete, manually reviewed dataset. Sensitivity (Sn) and specificity (Sp) were calculated and confidence intervals were determined by the binomial exact method. Results: A total of 1206 ultrasounds were reviewed, among which there was 687 positives for DVT (503 had proximal DVT and 378 had distal DVT involvement). A total of 176 had SVT, 114 with involvement of the great saphenous vein (GSV) and 65 with involvement of the small saphenous vein (SSV). The previously published NLP (designed to identify DVT) had a poor Sn 45.0%, but reasonable Sp (91.0%) for DVT. Among the incorrect positive determinations (n=47), 33 were incorrectly positive due to presence of SVT (in the absence of DVT). Our newly developed NLP algorithm correctly identified DVT at any site (Sn: 96.2% 95% CI 94.5-97.5; 661/687 and Sp: 93.8% 95% CI 91.4-95.7; 487/519). Among ultrasounds positive for DVT, the NLP algorithm to determine proximal DVT site had a 96.0% Sn (95% CI 93.9-97.6; 483/503) and a 97.8% Sp (95% CI 94.5-99.4; 179/183). The algorithm for distal DVT had a 96.8% Sn (95% CI 94.5-98.4; 366/378) and a 96.1% Sp (95% CI 93.3-98.0; 296/308). The algorithm to identify SVT was also highly accurate (Sn 97.7%, 95% CI 94.3-99.4; 172/176 and Sp 95.5%, 95% CI 94.1-96.7; 984/1030). Among ultrasounds positive for SVT, the Sn to determine GSV site was 94.7% (95% CI 88.9-98.0; 108/114) and Sp was 95.1% (95% CI 86.3-99.0; 58/61). The algorithm to identify SSV site had a Sn of 98.5% (95% CI 91.7-99.9; 64/65) and a Sp of 100% (95% CI 96.7-100.0; 110/110). Conclusion: Using a previously published, open source, simple NLP program, we have improved the sensitivity and specificity for identification of DVT and created an algorithm to accurately identify SVT. Using a multifaceted analysis approach, we were able to accurately further subclassify the anatomic location of thrombosis on ultrasound reports. This tool and the developed algorithms will allow analysis of large data sets with minimal effort and great accuracy, capitalizing on the power of large electronic datasets to offer new insights on pathophysiology and clinical prognosis. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Reduced or low-dose direct oral anticoagulants (DOACs) have been studied in randomized control trials for the extended prevention of venous thromboembolism (VTE) after 6 months of treatment at the therapeutic doses. The real-world effectiveness as well as utilization of this approach in clinical practice compared to continuing at therapeutic doses is unknown. Aims: Evaluate the efficacy of reduced-dose DOACs compared to standard therapeutic anticoagulation in patients with extended anticoagulation. Methods: Consecutive patients with VTE were identified using the Mayo Clinic VTE Registry from March 1st , 2013 to December 31st, 2020. Patients were followed prospectively for outcomes of VTE recurrence, death, major bleeding and clinically relevant non major bleeding (CRNMB) either in person or by survey. Type of anticoagulation and dose changes were recorded, and progressing to a low dose was treated as an endpoint. In the models relating it to the outcome, it was treated as a time-dependent covariate in the cox models. After completing standard anticoagulation treatment for 3 months with any anticoagulant, patients continuing anticoagulation were divided into two groups: standard therapeutic anticoagulation (any drug) vs those who transitioned to rivaroxaban 10 mg daily or apixaban 2.5mg twice daily any time after 3 months. Patients with recurrent VTE, major or CRNMB during the first 3 months were excluded from further analysis. Results: 219 patients (153 on Apixaban and 66 on Rivaroxaban) were identified in the low dose DOAC and 2521 in the standard anticoagulation group. The mean age was 60.7 years, mean weight was 93.2 Kg and 55.9% were males (Table 1). Patients on low dose DOACs were about the same age and weight compared to standard anticoagulation group. Among all diagnosis categories, patients with active cancer were less likely to be prescribed low dose DOACs (HR 0.56; 95%CI 0.42-0.73; P<0.001), while low dose DOACs prescription was more likely in patients with pulmonary embolism (HR 1.45; 95%CI 1.11-1.89; P=0.007). The median months to start a low dose DOAC after completing the 3 months was 3.1 months with standard deviation of 6.6 months and interquartile range 2.8 months. There was no statistically significant association in the likelihood of going to a low dose group in relation to VTE recurrence (HR 1.36; 95%CI 0.42-4.45; P=0.61) or major bleeding (HR 0.59; 95%CI 0.08-4.37; P=0.61). However, transitioning to low dose DOAC was associated with reduced mortality (HR 0.53; 95%CI 0.35-0.80; P=0.003). Also, patients on low dose DOACs were more likely to have a CRNMB (HR 2.76; 95%CI 1.15-6.62; P=0.02). Conclusion: In this study of patients continuing anticoagulation past 3 months for an initial acute venous thromboembolic event, transitioning to low dose DOACs was not associated with any statistically significant association with VTE recurrence or major bleeding. However, mortality was lower and CRNMB was higher in this unadjusted analysis. Our results show that physicians are not always waiting until 6 months to transition to low doses and low doses are being utilized in cancer patients. Further research is needed to better understand the higher risk for CRNMB identified in this group. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: Patients with coronavirus disease 2019 (COVID-19) have an increased risk for venous thromboembolic events. Thrombotic events contribute to the morbidity and mortality associated with COVID-19 infection, and have prompted investigation into strategies for mitigating thrombosis risk in patients hospitalized with COVID-19 infection. Our team reviewed the charts of patients hospitalized with COVID-19 pneumonia at a tertiary hospital in metropolitan Phoenix Arizona between 2020-2021, to assess frequency and efficacy of utilizing a VTE prophylaxis algorithm designed to prevent thrombosis in patients infected with COVID-19. Methods: A total of 846 patients were retrospectively evaluated to determine if they were treated with guideline-appropriate anticoagulation while hospitalized with COVID-19, as well as if they developed venous or arterial thrombotic events, or major or minor bleeds. 317 patients were excluded for taking therapeutic anticoagulation prior to admission, or for having a COVID-19 diagnosis >7 days after admission. Appropriate anticoagulation was determined by an institutionally designed COVID-19 thromboprophylaxis algorithm, based on platelet count, d-dimer, bleeding risk, and level of medical care required. Regimen options included: no anticoagulation, prophylactic enoxaparin (40 mg SQ daily) or heparin in the setting of kidney dysfunction, weight-based dosing of enoxaparin (40 mg SQ BID if BMI>40), intermediate intensity enoxaparin without thrombus (30 mg BID if BMI<40, or 40 mg BID if BMI>40), and therapeutic anticoagulation (for example enoxaparin 1 mg/kg BID) with thrombus. Demographics: Demographic data and clinical characteristics were collected for 529 patients. Average age was 59 years old, and the majority were men (58.4%). Most patients were White (58.3%), followed by Hispanic (17.8%), or Native American (15.7%). Fewer patients had a normal BMI (21.3%; BMI 18.5 - 24.9) compared to those who were overweight (31.2%; BMI 25-29.9) or obese (43.1% BMI > 30). Other comorbidities included Type 1 or Type 2 diabetes mellitus (N= 172, 32.5%), hypertension (N = 271, 51.2%), and hyperlipidemia (N = 176, 33.3%). Results: A total of 42 patients (8%), were diagnosed with a venous thrombosis during hospitalization. Patients admitted to the ICU were significantly more likely to have a thrombotic event of any type compared to non-ICU patients (21.6% to 5.7%; p < 0.001). Specifically, critically ill patients had higher incidences of deep vein thrombosis (9.5% to 0.7%), pulmonary emboli (8.1% to 4.8%), and superficial thrombi (2.7% to 0.2%). Only 1.1% of patients (6/529) experienced any bleeding, of which 3 were classified as a major bleed. Discussion: Among patients hospitalized at our institution with COVID-19, the majority were anticoagulated appropriately according to the COVID-19 thromboprophylaxis algorithm. Overall incidence of thrombosis in the study population was 8%. A significantly higher percent of critically ill patients had thrombi, supporting reports of correlation between severity of illness and thrombosis risk. The two regimens of anticoagulation least adhered to were weight-based and intermediate-based dosing, likely reflecting a departure from the hospital's thromboprophylaxis regimens prior to COVID-19 pandemic. Further studies are needed to characterize whether identifiable risk factors correlate with the incidence of thrombosis, and whether treatment with lower than recommended doses of anticoagulation, based on the COVID-19 thromboprophylaxis algorithm, were associated with thrombosis. Disclosures No relevant conflicts of interest to declare.

Abstract Background: COVID-19 vaccinations in the United States (Janssen, Moderna, and Pfizer) have been deemed generally safe and effective. Rare thrombotic events, now termed vaccine-induced thrombotic thrombocytopenia (VITT), have been reported after the Janssen and Moderna vaccinations. With millions of vaccinations being administered to adults, it is expected that some deep vein thrombosis (DVT) will occur coincidentally with vaccination. Whether COVID-19 vaccinations may contribute to DVT risk more generally (outside of VITT) has not been well studied outside of the initial clinical trials. Aims: Evaluate trends in DVT diagnosis before and after COVID-19 vaccination Methods: Vaccinated patients ≥ 18 years between 11/6/2020 through 6/1/2021 were analyzed using electronic medical records across the Mayo Clinic enterprise. Upper and lower DVT venous Duplex ultrasound (DUS) reports occurring 90 days before and after vaccination date (first dose for Pfizer and Moderna vaccines) were extracted and analyzed with a highly accurate, previously validated, Natural Language Processing (NLP) algorithm for acute DVT. Results: 382,527 patients with at least 1 COVID-19 vaccination were identified. The median age was 61 (IQR 44-72) and 55.3% were male. Pfizer was the most common vaccine administered (n=245,572, 64.2%), followed by Moderna (n=120,683, 31.6%) and Janssen (n=16,272, 4.3%). Most patients (91.5%) receiving vaccinations were from states with Mayo Clinic health services (Minnesota, n=197,834; Wisconsin, n=80,720; Florida, n=42,391; Arizona, n=28,882). The mean age at vaccination was 61.0 (SD 17.7), 56.5 (SD 19.1), and 54.7 (SD 16.3) for Moderna, Pfizer, and Janssen vaccines respectively. Women were most likely to receive the Pfizer (56.3%) compared to Moderna (54.1%) and Janssen (49.5%) vaccines. Non-white patients were most likely to receive Janssen (21%) compared to Moderna (7.7%) and Pfizer (8.2%) vaccines. Among all patients, 7,265 upper and lower venous DUS were performed in 5,960 patients. Figure 1 shows the utilization of DUS before and after COVID-19 vaccination and shows that more patients underwent DUS in the 90 days after vaccination compared to 90 days pre-vaccination. Acute DVT was identified by the NLP algorithm in 808 (714 patients) ultrasounds (11.1%); 656 out of 6136 lower extremity DUS (10.7%) and 152 out of 1129 upper extremity DUS (13.5%). The overall rate of acute DVT (upper and lower) was 1.86 per 1000 patients, consistent with the expected background epidemiologic rate. Figure 2 shows the daily probability of acute DVT by ultrasound report in the 90 days before and after vaccination with a linear regression best fit line showing no overall correlation (R 2 = 0.0). Overall acute DVT post-vaccination occurred on 10.8% of DUS compared to 11.6% pre-vaccination (p=0.28). Among ultrasound reports in Janssen vaccinated patients, 7.0% of post-vaccination compared to 18.0% of pre-vaccination were positive for acute DVT (p=0.003). Among ultrasound reports in Moderna vaccinated patients, 11.0% of post-vaccination compared to 12.7% of pre-vaccination were positive for acute DVT (p=0.15). Among ultrasound reports in Pfizer vaccinated patients, 11.0% of post-vaccination compared to 10.4% of pre-vaccination were positive for acute DVT (p=0.56). Using a Cox proportional hazard model, pre vs post-vaccination time among the same patient cohort was compared for each vaccine. The hazard ratio for DVT post-vaccination was 0.68 (95% CI 0.34-1.38) for Janssen, 1.08 (95% CI 0.86-1.35) for Moderna, and 1.20 (95% CI 0.99-1.46) for Pfizer. After adjusting for age and sex, Pfizer and Janssen's vaccines did not have different risks for DVT compared to Moderna in the 90 days post-vaccination (HR 0.80, 95% CI 0.98-1.25 and HR 0.75, 95% CI 0.42-1.32 respectively). Conclusions: In this large cohort of COVID-19 vaccinated patients, no increased risk for acute DVT post-vaccination was identified for any of the approved vaccinations in the United States. Additionally, no significant difference was seen in the risk for DVT post-vaccination when comparing each vaccine to each other. The probability of acute DVT on ultrasounds in the 90 days post-vaccination was lower than the pre-vaccination period with the Janssen vaccine possibly indicating over-testing in this group. These results provide additional reassurance of the safety of approved COVID-19 vaccines. Figure 1 Figure 1. Disclosures Padmanabhan: Veralox Therapeutics: Membership on an entity's Board of Directors or advisory committees. Pruthi: HEMA Biologics: Honoraria; CSL Behring: Honoraria; Genentech: Honoraria; Instrumentation Laboratory: Honoraria; Bayer Healthcare AG: Honoraria; Merck: Honoraria.

Abstract Background The non-invasive calculation of right ventricular hemodynamics such as the pulmonary artery capacitance (PAC) has proven to be feasible and easy to perform. The simplified pulmonary embolism severity index (sPESI) and pulmonary vascular resistance (PVR) are other prognostic tools that have been used in the past. Purpose To evaluate if baseline PAC can outperform PVR and sPESI to predict all-cause short-term mortality in patients with acute pulmonary embolism (PE). Methods 373 patients with acute PE and a transthoracic echocardiogram performed within one day of diagnosis from March 2013 through June 2020 were followed prospectively. PAC was calculated as: Left ventricular stroke volume/ (Pulmonary artery systolic pressure – Pulmonary artery diastolic pressure). PVR was calculated as: Tricuspid regurgitant velocity / Right ventricular outflow tract velocity time integral x 10 + 0.16. The sPESI was used to evaluate prognosis by categorizing patients into low and high-risk categories. Multiple logistic regression analyses and receiver-operating characteristic curves were used to evaluate the ability of PAC, PVR, and sPESI to predict all-cause mortality up to six months. The Youden index was used to determine the cut-off value with the highest sensitivity and specificity. Kaplan–Meier curves were performed to determine event-free survival rate, differences between groups were assessed using the Wilcoxon Test. Results Mean age was 64±15 years (58% male, 28% cancer). PAC was associated with mortality at thirty days (p 0.0003), three months (p 0.003), and six months (p 0.011) (Table). PVR was associated with mortality at thirty days, three months, and six months (p 0.045, 0.012, and 0.031 respectively). The sPESI score ≥1 (high risk) was associated with all-cause mortality at three months and six months (p 0.0136 and <0.0001 respectively). PAC was the strongest predictor of all-cause mortality with an AUC of 0.95 (CI 0.82- 0.99) at thirty days, 0.84 (CI 0.65–0.99) at three months, and 0.77 (CI 0.57–0.96) for six months. Corresponding Kaplan-Meier survival curve of PAC and thirty days all-cause mortality is presented in the Figure. PVR had an AUC of 0.75 (CI 0.48–0.95) at thirty days, 0.79 (CI 0.58–0.94) at three months, and 0.72 (CI 0.50–0.90) at six months. The sPESI had an AUC of 0.62 (CI 0.54–0.66) at three months and 0.64 (CI 0.59–0.67) at six months. Conclusion In patients with acute PE, PAC outperforms sPESI and PVR as a predictor of short-term all-cause mortality at thirty days, three months, and six months. These three variables should be explored head to head prospectively for their utility to predict short term all-cause mortality. Funding Acknowledgement Type of funding sources: None.

Abstract Standard treatment of catheter-associated upper extremity deep vein thrombosis (UE-DVT) is anticoagulation, although catheters are often removed for this indication. The optimal time for catheter removal and whether the act and/or timing of catheter removal is associated with pulmonary embolism (PE) remain unknown. A retrospective cohort study was performed at 8 participating institutions through the Venous thromboEmbolism Network US. Patients with hematologic malignancies and central venous catheter (CVC)–associated UE-DVT were included from 1 January 2010 through 31 December 2016. The primary outcome was objectively confirmed PE within 7 days of UE-DVT diagnosis in anticoagulated patients comparing early (≤48 hours) vs delayed (>48 hours) catheter removal. A total of 626 patients were included, among whom 480 were treated with anticoagulation. Among anticoagulated patients, 255 underwent early CVC removal, while 225 had delayed or no CVC removal; 146 patients received no anticoagulation, among whom 116 underwent CVC removal alone. PE within 7 days occurred in 2 patients (0.78%) with early removal compared with 1 patient (0.44%) with delayed or no CVC removal (P > .9). PE or any cause of death within 7 days occurred in 3 patients in both the early removal (1.18%) and delayed/no removal (1.33%) groups (P > .9). In patients treated with CVC removal only (no anticoagulation), there were no PEs but 3 deaths within 7 days. In patients with hematological malignancy and CVC-associated UE-DVT, early removal of CVCs was not associated with an increased risk of PE compared with delayed or no removal.