Houghton, Damon E.

Background: The calf muscle pump is an understudied contributor to venous return from the lower extremity. This study aimed to determine if calf pump function (CPF) is independently associated with the severity of chronic venous disease classified by CEAP (Clinical-Etiology-Anatomy-Pathophysiology). Methods: The Mayo Clinic Vascular Laboratory database was analyzed from January 2015 through September 2023. Ambulatory adults who underwent venous air plethysmography were included. Venous plethysmography assessed the severity of venous incompetence, and CPF was measured as ejection fraction (EF) per leg. The clinical component (C0 through C6) of the CEAP score was evaluated for each extremity at the time of the study. Results: A total of 7760 limbs from 3733 patients were analyzed. The mean age was 62 years, with 62% women. Venous obstruction was detected in 3.2% of limbs. Venous incompetence severity was categorized as normal (44%), mild (26%), moderate (19%), and severe (10%). A significant trend of reduced CPF was observed with higher CEAP scores ( p < 0.001). Multivariable logistic regression, adjusted for age, sex, degree of venous incompetence, and obstruction showed reduced CPF was a significant predictor (odds ratio 1.84, CI: 1.5–2.2) of active/prior ulcer (C5 or C6). In contrast to more severely reduced CPF, mildly reduced CPF (EF 40–49%) was not associated with active/prior ulcers. Conclusion: This large contemporary study demonstrates that decreased CPF is associated with worse chronic venous disease. Importantly, we demonstrate for the first time that CPF is independently associated with active/prior venous ulcers after accounting for other venous physiologic parameters and demographics.

Background: Myeloproliferative neoplasms (MPNs) are chronic leukemias with increased thrombotic risk. Venous thrombosis in MPN often occurs in atypical sites, such as splanchnic vein thrombosis (SVT), defined by thrombosis in the portal, hepatic, mesenteric, or splenic veins. Data to guide anticoagulation management of SVT in MPN patients is lacking. Objectives: The purpose of this study is to evaluate outcomes as well as the safety and efficacy of different anticoagulation strategies in MPN patients with SVT. Methods: A retrospective cohort study of MPN patients with SVT from 10 international centers was conducted. All centers performed systematic identification of adults with a World Health Organization 2016 diagnosis of an MPN (polycythemia vera [PV], essential thrombocythemia [ET], myelofibrosis [MF], prefibrotic MF, MPN-unclassifiable [MPN-U]) and confirmed SVT. Inclusion criteria were met if first SVT occurred after or within one year before MPN was diagnosed. The primary outcome was 1-year cumulative incidence of recurrent venous (VT) or arterial thrombosis (AT). Secondary outcomes included 1-year cumulative incidence of (1) major and clinically relevant non-major bleeding (CRNMB) by International Society on Thrombosis and Hemostasis criteria, (2) SVT recanalization; and (3) 1-year overall survival. Death as a competing risk was used for cumulative incidence analyses of recurrence and bleeding. Results: 486 MPN patients (median age at first SVT 51 years; 62.3% female) were identified. MPN diagnosis preceded SVT in 35.2% of patients (median time 4.8 years) and occurred simultaneously or within 1 year of first SVT in 64.8% of patients. 43.8% of patients had PV, 23.7% ET, 14.2% MF, 3.1% prefibrotic MF and 13.2% MPN-U. The most common driver mutation was in JAK2 (90.7%) followed by CALR (4.4%) and MPL (1.6%). SVT localization was isolated to portal (25.7%), hepatic (15.4%), mesenteric (1.9%), and splenic veins (4.3%), and in 51.2% of cases SVT occurred in multiple vessels. Prior VT or AT occurred in 8.8% and 4.1% of subjects, respectively. Cytoreduction (most commonly hydroxyurea [36.9%], interferon [9.6%] or JAK inhibitor [6.8%]) was started after SVT in 58.7% of newly diagnosed MPN patients and 40.6% of those with known MPN. 57.6% of patients were anticoagulated, 3.5% of patients were treated with an antiplatelet agent, and 11.7% were treated with both. The most common initial anticoagulants were vitamin K antagonists (VKA) (29.2%), direct oral anticoagulants (DOAC; 20.4%), and low-molecular-weight heparin (LMWH; 10.5%). DOACs were more commonly used in the USA and Asia than Europe (21.2%, 52%, and 13.5%; p&lt;0.001). The median duration of anticoagulation was 23.9 months, with 62.8% still on anticoagulation after 3 years or at last follow-up. 1-year cumulative incidence of recurrent VT and AT was 14% (95% CI 11-18) (5.8% for recurrent SVT [95% CI 3.9-8.3]; 6.3% for other VT [95% CI 4.3-8.8]; 2.4% for AT [95% CI 1.3-4.2]), with an overall time to event 89 (IQR 34-193) days. Thrombosis incidence was similar in patients initially treated with VKA (13%), DOAC (15%) or LMWH (16%) (p=0.93); in comparison, individuals not treated with anticoagulation had 1-year thrombosis incidence of 13% (p=0.22). 1-year major and CRNMB cumulative incidence in all patients was 5.8% (95% CI 3.9-8.2) and 8.5% (95% CI 6.1-11), with median time to event 68 (IQR 13-150) days. Incidence of major bleeding was similar in VKA, DOAC, and LMWH-treated patients (5.9%, 6.6%, and 4.0%; p=0.89). 1-year cumulative incidence of SVT (partial) recanalization was 13% (95% CI 9.8-16) in all patients, with a median time to recanalization of 127 (IQR 40-323) days; recanalization rates were similar in anticoagulated and non-anticoagulated patients (p=0.76). There was a trend toward higher recanalization rates in patients treated with DOAC (26.9%) than with VKA (21.5%) or LMWH (13.6%; p=0.28). 1-year overall survival was 94.2% (95% CI 91.8-96.1) and similar between treatment groups (VKA 96.7%, DOAC 95.6%, LMWH 89.7%; p=0.11) and for no anticoagulation (82.3%; p=0.32). Conclusions: This is the largest contemporary cohort of MPN patients with SVT. MPN patients with SVT remain at risk for short-term thrombosis and bleeding complications regardless of treatment. We found no significant differences in outcomes between anticoagulation strategies, including in patients treated with DOACs compared to VKA or LMWH.

Background: Risk stratification for suspected pulmonary emboli (PE) remains an area of active research. Current risk stratification algorithms have moderate discriminatory capabilities and are guideline-recommended, but they are poorly utilized in practice, with most clinicians relying predominantly on their clinical training and personal “gestalt.” Our group recently derived an Artificial Intelligence (AI) algorithm using electrocardiograms (ECG) to predict the presence of PE (AUC 0.69) on computed tomography scans of the pulmonary arteries (CTPA) in a cohort of 79K patients. Aim: Validate the AI-ECG algorithm in a contemporary dataset of patients with suspected PE. Methods: Emergency Department (ED) visits between 9/1/2022 and 12/31/2023 across the Mayo Clinic Enterprise were searched using a unified data platform. ED visits in patients over 18 years of age with a discretely documented Wells' PE or PERC Rule, a D-dimer result, or a CTPA were included. Only CTPA imaging and D-dimers performed within 48 hours of ED admission were eligible to be included. Patients were included in the final cohort if an ECG was performed within 6 hours of ED admission, D-dimer testing, or CTPA. Patients were considered negative for PE if CTPA was negative, and when this wasn't performed, a negative D-dimer (high sensitivity) or PERC rule of 0 was considered negative. A previously derived Artificial Neural Network algorithm to analyze the ECG to predict PE was applied to the dataset for validation. Results: A total of 27,028 ED visits in 24,288 unique patients meet inclusion criteria. Among this group, the first ED visit with a CTPA and an ECG within 6 hours was included, leaving 18,936 patients for the final validation cohort. The mean age of the cohort was 54.7 (SD 18.7), and 57% were male. Among the entire cohort, 13,573 underwent D-dimer testing for which 4,895 (36%) were positive at standard thresholds. A total of 10,486 patients underwent CTPA (55% of patients evaluated), of which 455 were positive for PE (4.3%). Using the AI-ECG model from the derivation cohort applied to this validation cohort resulted in an AUC of 0.69, identical to the derivation cohort. Using ECG model estimates alone, low (0.74%, n=2447, NPV 99.3%), elevated (2.27%, n=15404, NPV, 97.72%), and high-risk (8.02%, n=1085, NPV 91.98%) categories for PE can be created. A negative D-dimer in the elevated risk group increased the negative predictive value (NPV) to &gt;99.9% and could be used to reduce imaging in this group further. Using the proposed ECG to D-dimer cascade risk stratification could further reduce the need for PE imaging for an overall NPV of 99.9% and sensitivity of 95.2%. We then used additional clinical parameters to train a new algorithm with additional clinical data and the AI-ECG algorithm estimates. Multiple machine learning algorithms were then evaluated in a dataset divided into training (2/3) and testing (1/3) datasets, after downsampling (to address class imbalance). The best results were obtained with AI-ECG results and D-dimer: Ada Boost (AUC 0.93, F1 score 0.895) compared to standard logistic regression (AUC 0.79, F1 score 0.746). The addition of age, sex, and oxygen saturation did not improve model performance. Conclusion: We have now validated the previously derived AI-ANN ECG algorithm for PE in a contemporary and independent cohort and demonstrate potential for integration into clinical PE assessment algorithms. Unlike prior risk stratification processes, ECGs are invariably performed in patients with cardiopulmonary symptoms and have the potential to prevent missed or delayed PE diagnosis by proactively identifying high-risk patients. Additionally, we demonstrate that the results of this algorithm can be combined with D-dimer values, resulting in a simple, powerful, predictive algorithm (AUC 0.93) that pairs cardiovascular electrophysiology with laboratory biomarkers and could lead to a new paradigm in clinical risk stratification for PE.

Introduction. Platelet-activating anti-Platelet factor 4 (PF4) antibodies mediate a number of thrombotic thrombocytopenic syndromes, including heparin-induced thrombocytopenia (HIT), and more recently recognized conditions, vaccine-induced immune thrombotic thrombocytopenia (VITT), adenovirus-associated thrombotic thrombocytopenia, and monoclonal gammopathy of thrombotic significance (MGTS). In MGTS (Blood. 2023 Apr 6;141(14):1772-1776), a monoclonal IgG antibody to PF4 mediates a chronic prothrombotic state characterized by recurrent thrombosis. More recent evidence suggests that MGTS may present with negative results in HIT enzyme-linked immunosorbent assay (ELISA) and serotonin release assay (SRA), and positivity only in PF4-dependent functional assays such as the PF4-dependent P-selectin expression assay (PEA; submitted). The presence of MGUS in patients has long been associated with high risks of thrombotic disease (Blood. 2010 Jun 17;115(24):4991-8), but the mechanism by which they predispose to thrombosis has been relatively unexplored. In this study, we evaluated a cohort of MGUS patients who experience thrombosis for the presence of platelet-activating anti-PF4 antibodies. M ethods. An administrative database search was performed of Mayo Clinic records to identify patients who had a diagnosis of MGUS, and thrombosis. Research samples from 134 MGUS patients with IgG monoclonal protein and thrombosis were obtained from Mayo Clinic's dysproteinemia biobank and subjected to PF4 antigen-based and functional screening. Research studies were approved by the Institutional Review Board of Mayo Clinic. Results. Of the 134 patients, 17 (12.7%) activated platelets in the PEA (≥19%). To exclude non-specific activation (e.g. due to HLA antibodies), secondary PEA testing was performed to assess whether platelet activation was mediated by a HIT-like antibody (i.e., PF4- and IgG-dependent, and inhibitable with high concentrations of heparin). Four patients, hereafter referred to as patients 1-4, were identified as having a HIT-like antibody, as demonstrated by PF4-dependent platelet activation that could be inhibited with high concentrations of heparin (100 U/mL), and blockade of the platelet IgG receptor, FcγRIIa. Patients 1 and 2 had persistent, platelet-activating anti-PF4 antibodies based on PEA testing of multiple samples obtained several years apart. Patient 1 had a recurrent, multi-year history of deep venous thrombosis (DVT), while patient 2 had one DVT episode. Patient 3 demonstrated a HIT antibody-like profile in the PEA in two of three samples available for testing and had a history of thrombotic cerebrovascular accident (CVA). Patient 4 demonstrated a HIT-like platelet-activating antibody in only one of four samples tested, and consistent with this finding, had an MGUS identified on clinical testing at only one time point (“small” IgG lambda, not quantified), 3 months prior to the platelet-activating sample. This patient experienced multiple thrombotic events including DVTs, left atrial thrombus and embolic CVA, pulmonary embolism and acute limb ischemia. All patients tested negative in two FDA-approved antigen-based HIT assays tested (Immucor PF4 IgG and Zymutest HIA IgG), similar to a recent MGTS case (submitted). SRA was negative in both Patients 1 & 2, weakly positive in Patient 3 (33%, with high CV), and positive (72%) in Patient 4. Conclusions. Definitive diagnosis of patients with MGTS provides insight into a mechanism of “unexplained” thrombosis and may offer additional treatment pathways for these patients with recurrent thrombosis (New Eng J of Med, 2024 Aug 8). Serologic testing in two patients correlated strongly with observations of thrombosis, and the study confirmed recent findings that anti-PF4 antibodies may present with unusual serology that is neither HIT- nor VITT-like (with negative results in both ELISA and SRA). The incidence of confirmed/suspected MGTS was 3% (4/134) in this population of MGUS patients with thrombosis. Prospective studies are needed to confirm these observations.

Background: Exercise stress testing uses metabolic equivalents of tasks (METs) to measure the energy cost of activities, aiding in the assessment of exercise capacity and cardiovascular health. Despite its significance, the correlation between calf muscle pump function (CPF) and exercise stress testing remains unexplored. We aimed to evaluate the relationship between CPF and peak METs as determined by cardiopulmonary treadmill exercise stress testing. Methods: The study included adults who underwent exercise cardiopulmonary stress testing and venous plethysmography at Mayo Clinic between April 2017 and March 2020. The protocols other than Bruce, Mayo, Modified Naughton, and Naughton protocols were excluded. The CPF ejection fraction (EF) was calculated per leg based on refill volumes post-exercise as a percentage of passive drain refill. The classification of CEAP (Clinical-Etiology-Anatomy-Pathophysiology) was utilized to better understand chronic venous insufficiency (CVI). Results: A total of 155 patients who underwent both exercise stress testing and venous plethysmography were included, with a mean age of 61.31 ± 14.03 years, and 84 (54.2%) were male. The peak measured METs for normal, unilaterally reduced, and bilaterally reduced CPF were 8.5 (2.5), 7.3 (2.1), and 7.1 (2.4), respectively (p=0.004, Figure 1). Multiple linear regression models were developed with METs as the outcome to determine if CPF was an independent predictor of METs on cardiopulmonary exercise stress testing. IIn model 1, the following independent variables were included: resting heart rate, peak heart rate, peak systolic blood pressure, recovery heart rate at minute 1, and worst EF (Table 1). In model 1, with only exercise parameters, lower EF was associated with lower METs (p=0.03). In a second analysis, variables identified as statistically significant with METs in the initial model were included, along with CEAP class (model 2) and CCI (model 3) (Table 2). In model 2, CEAP class 3 or higher was associated with decreased METs on the exercise stress test. This correlation implies that individuals with moderate to severe CVI may influence exercise capacity, demonstrating the interconnectedness of the cardiovascular system. Moreover, in model 3, the CCI, a predictor for mortality, was not significantly associated with METs. Conclusion: Our findings revealed that more severe CVI (CEAP class and reduced CPF) was associated with reduced exercise capacity after accounting for other factors.

Abstract: Paradoxical embolism represents a critical and potentially fatal complication that can be associated with pulmonary embolism (PE). This case details a unique case of massive PE, further complicated by embolic stroke occurring during catheter-directed thrombolytic therapy. There was no evidence of thrombosis during the initial evaluation with lower extremity Doppler ultrasound, abdominal computed tomography scan, and transthoracic echocardiography. Differentials for the source of the emboli include unrecognized left atrial appendage thrombus, pulmonary arteriovenous malformations, and a patent left foramen ovale. Our findings highlight the complexities and treatment challenges of massive PE.

Abstract Aims Echocardiographic assessment of cancer-associated non-bacterial thrombotic endocarditis (Ca-NBTE) is limited to case reports and small clinical series. The study aimed to identify heart valve abnormalities and its relation to embolic complications and cancer types. Methods and results Manual review of echocardiographic images and medical records of Mayo Clinic patients (31 March 2002–30 June 2022) was performed. Ca-NBTE in 111 patients (mean age 63.2 ± 9.7 years, 66.7% female) predominantly affected mitral valves (MV) (69), 56 aortic (AV), 8 tricuspid (TV), and rarely pulmonic (PV) (1). In 18 patients, 2 valves were involved, 3 and 4 valve involvement in only a single patient each. Embolic complications were prevalent (n = 102, 91.9%). Ca-NBTE affected MV more frequently on the upstream (atrial) (90% vs. 49.3%) and TV downstream (ventricular) side (75% vs. 37.5%). NBTE size (cm) varied significantly among valves, with TV hosting the largest masses (0.63–2.40 × 0.39–1.77), compared with MV [(0.11–1.81 × 0.11–1.62), (length P = 0.001; width P = 0.03)] and AV [(0.20–2.70 × 0.11–1.51), (length P = 0.001; width P = 0.056)]; MV masses were borderline longer in systemic compared with cerebral emboli (P = 0.057). Majority of MV (79.6%) and AV (69.6%) had thickened leaflets. NBTE lesions commonly affected closing margins (73.9% MV, 85.7% AV, and 62.5% of TV) but rarely commissures of MV (8.7%), yet fairly frequently of AV (41.1%). Five patients had severe regurgitation of MV and 5 AV. Conclusion Ca-NBTE manifests mainly as thrombotic mobile masses attached to thickened MV and AV, with distinct variations in size based on valve type. Embolic destination but not cancer type is associated with NBTE mass size and location.

Abstract Premortem clinical presentation of cancer‐associated non‐bacterial thrombotic endocarditis (Ca‐NBTE), therapy, and the clinal course is limited to case reports and small clinical series. An electronic search of Mayo Clinic records (03/31/2002–06/30/2022) with a subsequent manual review was performed to identify adult patients with echocardiographically detected NBTE and active malignancy, excluding those with infectious endocarditis or lupus anticoagulant/antiphospholipid antibodies. In this retrospective cohort study, we analyzed 115 Ca‐NBTE patients (mean age 63.2 ± 9.7 years, 66.1% female) involving 71 (61.7%) mitral, 58 (50.4%) aortic, 8 (6.9%) tricuspid, and 1 (0.9%) pulmonary valve. The most common cancer was lung ( n = 45 cases (39.1%), followed by pancreatic ( n = 19, 16.5%), gynecological (17, 14.8%), gastrointestinal ( n = 10, 8.7%), and 10 (8.7%) with hematologic malignancy; 6 patients had two active cancers. Embolic complications at presentation were frequent: 94 (81.7%) brain, 11 splenic, 10 renal, 6 coronary, and 4 to the extremities. Of 104 anticoagulated patients, 60 received low molecular weight heparin, 17 unfractionated heparin, 16 apixaban, 8 warfarin, and 3 rivaroxaban. There were 18 arterial thromboembolisms; the Kaplan–Meier estimates of the incidence at 2 years were consistent with a rate of 15.9% [95% Confidence Interval (CI) 9.9–23.3], including 14 strokes (12.4%, 95%CI, 7.1–19.2), and 8 other arterial emboli (10.5%, 95%CI, 4.7–18.9); there were 10 venous thromboembolisms (8.9%, 95%CI, 4.5–15.0). Fourteen major bleedings occurred (12.8%, 95%CI, 7.3–19.9) and 94 patients died during follow‐up (77.9%, 95%CI, 71.1–85.8). Ca‐NBTE predominantly affected women with lung adenocarcinoma or digestive tract cancers and manifested by stroke with high mortality and frequent embolic and bleeding complications during anticoagulation therapy.