Citations

Abstract Background Ankle-brachial indices (ABI) predict mortality and major cardiovascular events (MACE); however, they are unable to assess the severity of peripheral artery disease in patients with non-compressible vessels. Toe brachial indices (TBI) are less affected by non-compressibility and could be good predictors of cardiovascular morbidity and mortality. Purpose To evaluate the predictive value of TBI for MACE and all-cause mortality in a large population. Methods The initial ABIs and TBIs of all patients referred to a noninvasive vascular laboratory were obtained. We categorized patients based on the worse TBI from either leg, and each patient was classified as normal (>0.8), borderline (0.8-0.61), mild-moderate PAD (0.6 - 0.21) and severe PAD (≤0.2). MACE occurring after the study were identified using ICD9/10 and procedural CPT codes and included myocardial infarction, coronary revascularization, or stroke. Survival analysis was performed using the Kaplan-Meier method with log-rank test to compare survival curves between groups. Results Of 13551 patients, we excluded 643 (5%) in whom TBI could not be obtained. Patient characteristics can be found in Table 1. There were 4,924 MACE and 3,125 deaths during the median follow up time of 8.39 years (Table1). There was a significant difference of MACE incidence (p <0.001) and mortality (p<0.001) by TBI categories, and the curves separate before the 1-year mark (Figure 1A and B). Conclusion TBI is a good predictor of MACE and all-cause mortality in the short and long term and can be obtained in 95% of patients.

Abstract Ferritin, consisting of ferritin heavy chain (FTH1) and light chain (FTL) subunits, is an essential intracellular iron storage protein fundamental for cellular function. However, the source and the biological role of extracellular ferritin (ex-ferritin) are less understood. Recent studies have linked elevated serum ex-ferritin with adverse outcomes in individuals with acute respiratory distress syndrome (ARDS). In this study, we demonstrate that both FTH1 and FTL are significantly enriched in the serum, blood monocytes, and alveolar macrophages (AMs) of individuals with ARDS, a phenomenon we successfully replicate in a murine hyperoxia-induced acute lung injury (HALI) model. We show that FTH1 is consistently upregulated in macrophages during lung injury development, and mice with a targeted deletion of FTH1 in myeloid (LysMcre) or resident lung macrophage (Cd11ccre) populations exhibit attenuated HALI. This reduced injury is linked to macrophage resistance to ferroptotic cell death, ferritinophagy, altered airway inflammatory responses, and lower lung extracellular iron and higher levels of FTL-ex-ferritin. Transplantation of FTL-ex-ferritin-enriched bronchoalveolar lavage fluid to wild-type mice protected against HALI. The ratio of FTL-ex-ferritin to FTH1 in the serum of individuals with ARDS who died was higher than that of those that survived, suggesting that the balance between FTH1 and FTL may play a role in injury modulation. Our findings highlight macrophage ferritin as a key regulator of macrophage survival and the response of the lung to injury, presenting a potentially targetable pathway for ARDS treatment.

Abstract Hematologic malignancies are associated with an increased risk of venous thromboembolism (VTE) with aggressive lymphomas and multiple myeloma exhibiting the highest VTE incidence. The performance of VTE risk scores in hematologic malignancies remains suboptimal. Concomitant thrombocytopenia and coagulopathies complicate thrombosis prevention and management. This review synthesizes current evidence on anticoagulation in hematologic malignancies (excluding myeloproliferative neoplasms), outlines key clinical challenges, and proposes practical strategies to guide decision-making.

Abstract Introduction: Monoclonal gammopathy of thrombotic significance (MGTS) is a recently recognized thrombophilia where monoclonal platelet factor 4 (PF4)-specific IgG antibodies initiate a chronic prothrombotic state characterized by recurrent and potentially life-threatening thrombosis. Studies from large data sets demonstrate that patients with monoclonal gammopathy of undetermined significance (MGUS) have a heightened risk of experiencing thromboembolic events without a precise explanatory mechanism. The prevalence of MGTS in MGUS-related thrombosis is unknown; however, the recent identification of MGTS antibodies as a cause of thrombosis suggests a potentially causative mechanism. Emerging evidence indicates that detecting pathogenic MGTS antibodies presents diagnostic challenges due to the insensitivity of FDA-approved diagnostic assays adopted from HIT (HIT ELISAs) and gold-standard functional tests that use heparin-treated platelets, such as the serotonin release assay (SRA). Only PF4-enhanced functional assays, including the PF4-dependent P-selectin expression assay (PEA) and PF4-SRA, have proven sensitive for detecting MGTS antibodies. In this study, the PEA was utilized to better define the incidence of pathogenic anti-PF4 antibodies among a cohort of MGUS patients with a history of thrombosis. Methods: A search of the Mayo Clinic Dysproteinemia Bank was conducted to identify two cohorts of IgG MGUS patients, one with venous thromboembolism-associated diagnosis code(s) and the other without. A diagnosis of multiple myeloma was exclusionary. Each serum sample was assessed using the PEA. Mayo Clinic's Institutional Review Board approved the research study. Results: Among the 134 patients studied in the thrombosis cohort, 17 (13%) stimulated platelet activation in the PEA (positive cut-off ≥19%), some weakly. Of these, four patients (Patients 1-4) were confirmed to have PF4-dependent platelet-activating antibodies inhibitable with high concentrations of heparin and sensitive to blockade of the IgG receptor on platelets, FcGRIIa. The thrombotic complications experienced included recurrent deep venous thrombosis (DVT) over several years (Patient 1), a single DVT (Patient 2), a thrombotic cerebrovascular accident (CVA) (Patient 3), and a series of thrombotic events, including DVTs, left atrial thrombosis, pulmonary embolism, and acute limb ischemia (Patient 4). Notably, longitudinal samples spanning twelve years (Patient 1), six years (Patient 2), three years (Patient 3), and on a single sample date (Patient 4) were confirmed positive by PEA. The prolonged persistence of platelet-activating anti-PF4 antibodies in Patients 1-3 supported a diagnosis of MGTS in these patients. Strikingly, all four patients tested negative in two FDA-approved HIT ELISAs (Immucor PF4 IgG and Zymutest HIA IgG). SRA was negative for Patients 1 and 2, weakly positive for Patient 3 (33%), and positive for Patient 4 (72%). Of the 166 patients in the MGUS minus thrombosis cohort, one patient demonstrated a non-heparin induced HIT-like antibody that was HIT ELISA (Optical Density >1.0) and PEA-positive, and inhibitable using high concentrations of heparin and FcGRIIa blockade. No follow-up samples were available to assess antibody longevity. The patient had no history of thrombosis, and testing demonstrated that the anti-PF4 antibody was not synonymous with the MGUS antibody.Conclusions: Among a cohort of 134 MGUS patients with thrombosis, the prevalence of MGTS was found to be 2.2% (3 patients with persistent platelet-activating anti-PF4 antibodies). The identification of anti-PF4 antibodies among MGUS patients provides a mechanism contributing to the increased thrombotic risk associated with monoclonal gammopathies. Antibody negativity in HIT ELISA and variable positivity in the SRA highlight the nonclassical serology associated with anti-PF4 antibodies in MGTS and support performing PF4-enhanced functional testing. In addition, some patients appear to produce coincidental (non-monoclonal) platelet-activating anti-PF4 antibodies without evidence of thrombosis, although the longevity of such antibodies could not be examined in the one patient where it was identified. These findings highlight the need for larger, prospective MGUS studies to validate these observations, further define the interplay between monoclonal gammopathies and thrombotic risk, and to better understand the long-term outcomes of patients with MGTS.

Abstract Background: Prophylactic-dose or low-dose apixaban and rivaroxaban have been studied in randomized controlled trials for the extended prevention of venous thromboembolism (VTE) after 6 months of treatment with therapeutic anticoagulation. However, the optimal timing of dose adjustment has not been fully explored, and the rationale for a precise transition at the 6-month mark is lacking. Aim: Evaluate the clinical outcomes and demographic differences between transition to low-dose DOAC before or after the previously studied 6-month timeframe. Methods: Consecutive patients with VTE were identified using the Mayo Clinic VTE Registry from March 1st, 2013 to December 31st, 2021. Patients with recurrent VTE or bleeding during the first 3 months were excluded. Patients were followed prospectively for outcomes of VTE recurrence, major bleeding, and clinically relevant non major bleeding (CRNMB), either in person or by survey. After completion of anticoagulation treatment for 3 months, the cohort of patients continuing anticoagulation with eventual transition to low-dose rivaroxaban or apixaban were evaluated. Results: A total of 466 patients were included with 167 (36%) undergoing transition to low dose prior to 6 months and 299 (64%) after 6 months of treatment. The average time to low-dose transition in the total population was 7.8 months (5.9, 3.0-55.8). The early transition group had less PE (82 versus 191, p=0.017) and significantly fewer patients with concurrent DVT and PE (32 versus 101, p=0.004). There was nearly equal representation of cancer in the two groups (34.7% versus 35.8%). Evaluation of clinical outcomes from transition time forward in the groupings before and after six months revealed no significant differences (VTE recurrence p=0.233, MB p=0.114, CRNMB p=0.745). Conclusions: This real-world patient population demonstrates that anticoagulant prescribers transition to low-dose DOACs ahead of the historically studied 6-month time point. The results of this study do not indicate a significant difference in clinical outcomes of VTE recurrence or bleeding complications based on time of transition to low-dose DOACs either before or after 6 months.

Abstract Background Antiphospholipid syndrome (APS) is diagnosed when vascular thrombosis or pregnancy morbidity occurs in the presence of persistent antiphospholipid antibodies (aPL). Although IgM-isotype antibodies are part of the laboratory criteria, their clinical value remains uncertain. We evaluated real-world aPL testing patterns to quantify the prevalence of isolated IgM positivity. Methods We analyzed aPL testing data across the Mayo Clinic sites between January 2006 and July 2025, lined up with the publication of the revised Sapporo (Sydney) classification criteria. For each patient, we identified the first time in which any aPL test was performed. We assessed available results for Lupus anticoagulant (LA), anticardiolipin (aCL) isotypes IgG and IgM, and anti–beta 2 glycoprotein (B2GP1) isotypes IgG and IgM. Positivity rates were calculated for each marker, and a subgroup of patients who had results for all three test categories at the initial workup was identified. In this cohort, we assessed the distribution of single, double, and triple positivity. We also quantified the number and percentage of patients who were positive only for IgM isotypes (aCL or B2GP1), with negative LA and IgG at initial testing. Antibodies were considered positive based on international criteria and internal standards. aCL and B2GP1 were positive if ≥40 units. LA positivity followed ISTH SSC guidelines, requiring demonstration of a phospholipid-dependent inhibitor in the following assays: screening, mixing, and confirmatory steps in DRVVT or aPTT-based platelet neutralization procedure (PNP), Staclot LA delta and HEX LA delta assays. Criteria for a positive result was as follows: DRVVT: prolonged screen and inhibited mix with screen/confirm ratio >1.2; Staclot LA delta: >7 seconds; PNP: shortening of the APTT clotting time with PNP by ≥5 seconds before 2023 and ≥2 seconds thereafter; HEX LA delta >13 seconds. Results A total of 99,814 unique patients underwent testing for at least one aPL marker. The most frequently tested was LA (n = 75,085), with a positivity rate of 10.29% (7,730/75,085). Among antibody isotypes, positivity rates were 1.2% (846/69,539) for aCL IgG, 1.7% (1,198/69,640) for aCL IgM, 1.9% (732/37,791) for B2GP1 IgG, and 2.0% (762/37,601) for B2GP1 IgM. Among the 30,274 patients who underwent simultaneous testing for LA, aCL IgG/IgM, and B2GP1 IgG/IgM, 1.3% (n = 407) were triple-positive, 1.4% (n = 427) were double-positive, and 9.9% (n = 3,009) had a single positive marker. The remaining 87.3% (n = 26,431) tested negative for all three. Of the 3,009 patients with only one positive marker, 9.8% (n = 296) were positive exclusively for aCL IgM, and 7.4% (n = 224) were positive exclusively for B2GP1 IgM. Among all fully tested patients, 2.2% (668/30,274) were positive for only IgM isotypes (either aCL or B2GP1) in the absence of IgG and LA positivity. Specifically, 0.9% (n = 296) were exclusively positive for aCL IgM and 0.7% (n = 224) for B2GP1 IgM. Additionally, 0.5% (n = 148) were simultaneously positive for both aCL IgM and B2GP1 IgM, without associated IgG or LA markers. Had only IgG and LA been assayed, 17.4 % (668/3843) of initially positive patients—and one-third of those classified as triple-positive—would have been missed. Conclusion Within this large-scale analysis of real-world APS test ordering practice, less than one-third of orders included a comprehensive characterization. Isolated IgM positivity, defined as aCL or B2GP1 IgM in the absence of IgG and LA, was infrequent yet represents a sizable proportion of initial positive aPL testing. How these results impact APS diagnosis and management of APS requires further study.

Abstract Background Patients with myeloproliferative neoplasms (MPNs) are at risk of splanchnic vein thrombosis (SVT). Prior studies failed to demonstrate a benefit of hydroxyurea in preventing SVT extension/recurrence, but these were limited by small sample sizes and inability to account for starting, stopping, or switching of cytoreductive therapies. We therefore investigated the role of cytoreduction as a time-dependent covariate on thrombosis recurrence in a large, international cohort of MPN-SVT patients. Methods We performed a retrospective cohort study of MPN-SVT patients included in the international GASTRO-MPN consortium. Patients diagnosed with MPN at any time before, concurrently with, or up to 60 days after initial SVT were included. Primary outcome was time from initial SVT to first thrombosis recurrence, defined as the composite of SVT extension/recurrence, transjugular intrahepatic portosystemic shunt (TIPS) thrombosis, or venous/arterial thrombosis outside the splanchnic veins. Secondary outcomes included SVT extension/recurrence, TIPS thrombosis or extra-SVT thrombosis individually, clinically relevant bleeding (composite of major and clinically relevant non-major bleeding), MPN progression to myelofibrosis or blast phase, and death. Cytoreductive therapy was treated as a time-dependent covariate to account for discontinuation and therapy changes. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results A total of 757 patients were included for this analysis. Median age was 51 years (IQR 38-62), 59% were female. SVT involved the portomesenteric veins in 558 (77%) patients, hepatic veins in 95 (13%), and both in 54 (7.4%). MPN was known prior to initial SVT in 316 patients (42%) and diagnosed concurrently or up to 60 days after SVT in 441 (58%). Polycythemia vera (PV) was the most common MPN subtype (43%), followed by essential thrombocythemia (ET) in 24%, and primary myelofibrosis in 14%. JAK2V617F mutation was present in 86% and CALR in 2.9%. 13% had prior non-SVT thrombosis. 607 patients (83%) were treated with cytoreduction. At time of SVT, 131 patients (17%) were already on cytoreduction; in those who started after SVT, median time to initiation was 54 days after SVT, and median duration of cytoreduction per patient was 63 months. Cytoreductive therapies used at any point in treatment included hydroxyurea in 504 (69%), ruxolitinib in 182 (25%), and interferon-based in 85 (12%) patients. Anticoagulation (AC) was started within 30 days after SVT in 504 (68%) patients. Median duration of any AC per patient was 24.6 months. During a median follow up of 7.4 years, 245 patients (33%) had thrombosis recurrence; 143 (20%) had SVT extension/recurrence/TIPS thrombosis, 129 (18%) extra-SVT thrombosis (of which 74% venous), 237 patients (32%) experienced clinically relevant bleeding, and 163 (22%) died. After adjusting for age, sex, timing of MPN diagnosis relative to SVT diagnosis, AC within 30 days of SVT, PV/ET vs other MPN, JAK2 mutation, previous thrombosis, non-MPN cancer, and cirrhosis, cytoreductive therapy was associated with a significantly decreased risk of recurrent thrombosis (HR 0.67 95%CI 0.50-0.89, p=0.01). Age was associated with an increased risk of recurrent thrombosis (p=0.01). When considering types of recurrent thrombosis, cytoreduction was associated with a decreased risk of SVT extension/recurrence/TIPS thrombosis (HR 0.62 95%CI 0.42-0.90, p=0.01), but not thrombosis outside the splanchnic veins (HR 0.97 95%CI 0.72-1.30, p=0.82). There was no association between cytoreduction and bleeding (HR 1.10 95%CI 0.82-1.47, p=0.52). Similarly, there was no association between cytoreduction and time to MPN progression (p=0.24) or overall survival (p=0.30). In a subgroup of patients without erythrocytosis/thrombocytosis at initial SVT (n=271), cytoreductive therapy was associated with a HR 0.65 (95%CI 0.40-1.10, p=0.09) for recurrent thrombosis. Limited sample size and low event-rate precluded evaluation of the impact of individual cytoreductive therapies. Conclusions In the largest cohort of MPN-SVT patients to date, we show for the first time that cytoreductive therapy is associated with a decreased risk of thrombosis recurrence, driven largely by decreased SVT extension/recurrence/TIPS thrombosis. Collectively, these findings support use of cytoreductive therapy in individuals with MPN-SVT to prevent recurrent thrombosis.

Background: Whether oral anticoagulation (OAC) can be discontinued after the resolution of left ventricular thrombus (LVT) remains controversial, particularly in patients without risk factors such as left ventricular aneurysms. This study aimed to identify patients who may safely discontinue OAC. Methods: We conducted a retrospective cohort study of patients with LVT resolution who completed their anticoagulation course and excluded patients with left ventricular (LV) aneurysm. Clinical and echocardiographic factors were compared between patients who experienced LVT recurrence (n = 22) and those without recurrence during follow-up (n = 94). Results: The cohort had a mean age of 64.5 ± 15.0 years, and half (50%) were male. Most had an ischemic cardiomyopathy (64.6%). LVT recurred in 19% (22/116) of patients following initial resolution. Patients with recurrence were older (mean age 71.3 ± 11.9 vs. 63.4 ± 15.7 years, p = 0.03) and were more likely to have prior ischemic stroke and arterial thromboembolism (18.2% vs. 4.3%, p = 0.02 for both). At the time of thrombus resolution, LVEF was significantly lower among patients who had recurrence (33.4 ± 13.6% vs. 42.5 ± 15.5%, p = 0.012). Stroke, systemic embolism, and mortality rates were similar regardless of recurrence status. Recurrence risk by presence or absence of stroke and LEVF >50% on the LVT resolution echocardiogram is shown in Figure 1. Notably, no recurrences were observed among patients with both LVEF > 50% and no history of stroke (0/32), which was statistically significant compared to each other category. Conclusion: Among patients without left ventricular aneurysm who discontinued oral anticoagulation after LVT resolution, those with preserved LVEF (>50%) and no prior history of stroke had a very low risk of recurrence, with no events observed in this subgroup. These findings suggest that some patients may safely discontinue anticoagulation after LVT resolution.

Goals: A systematic review and meta-analysis of published clinical validity studies was conducted to evaluate the predictive performance of the TSP-9 test. Background: Identifying patients with Barrett’s esophagus (BE) who will progress to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) is challenging. The tissue systems pathology (TSP-9) test can predict risk of progression to HGD/EAC in BE patients. Study: Databases were searched for studies that assessed the clinical validity of TSP-9, and data describing progressors, non-progressors, TSP-9 results, and hazard ratios (HR) with 95% confidence intervals (CIs) were extracted. Odds ratios (OR), sensitivity, specificity, and prevalence-adjusted positive and negative predictive values (PPV adj /NPV adj ) were calculated and used for meta-analysis. Results: Six studies met eligibility criteria, comprising 699 patients. ORs and HRs for TSP-9 had mean common effect size estimates of 6.52 (95% CI: 4.40-9.66, P <0.0001, I 2 =33%) and 6.66 (95% CI: 4.59-9.66, P <0.0001, I 2 =0%), respectively, for predicting progression to HGD/EAC. Mean common effect size estimates were 61% (95% CI: 54%-68%) for sensitivity, 81% (95% CI: 78%-84%) for specificity, 28% (95% CI: 17%-42%) for PPV adj (high risk), 14% (95% CI: 9%-21%) for PPV adj (high/int risk), and 97% (95% CI: 96%-98%) for NPV adj with minimal inter-study heterogeneity ( I 2 =79%, 21%, 0%, 0%, and 0%, respectively). Conclusions: Effect estimates of TSP-9 performance demonstrate that the test provides risk stratification for BE patients. The TSP-9 test can provide clinically impactful results to enable escalation of care for high-risk patients or to identify low-risk patients who can be safely managed with routine surveillance.