Houghton, Damon E.

Myeloproliferative neoplasm (MPN) patients are at risk of splanchnic vein thromboses (SVT). Prior studies have failed to demonstrate a benefit of hydroxyurea therapy in preventing recurrent thrombosis after SVT, but are limited by small sample sizes and inability to account for starting, stopping, or switching of cytoreductive therapies. To better assess the impact of cytoreductive therapy on thrombosis recurrence, we performed a retrospective cohort study of MPN-SVT patients from the international GASTRO-MPN Consortium, treating cytoreductive therapy as a time-dependent covariate. We identified 757 patients, of which 43% were treated with cytoreductive therapy. During a median follow-up of 7.4 years, 256 patients (34%) had thrombosis recurrence; 145 (19%) had SVT extension/recurrence/TIPS thrombosis, 138 (18%) an thrombosis recurrence outside the splanchnic bed (74% were venous). Additionally, 262 patients (35%) experienced clinically relevant bleeding and 170 (22%) died. After adjusting for age, sex, prior thrombosis, timing of MPN diagnosis relative to SVT, anticoagulation initiation within 30 days of SVT diagnosis, MPN type, JAK2 status, other cancers and cirrhosis, cytoreductive therapy was associated with a decreased risk of recurrent thrombosis (HR 0.67 95%CI 0.50-0.89, p=0.01). This was driven by a lower risk of SVT extension/recurrence (HR 0.62 95%CI 0.42-0.90, p=0.01) but not by extra-splanchnic thrombosis recurrence (HR 0.97 95%CI 0.72-1.30, p=0.82). In a subgroup of patients without erythrocytosis/thrombocytosis at initial SVT (n=275), cytoreductive therapy was associated with a HR 0.65 (95%CI 0.40-1.07, p=0.09) for recurrent thrombosis. These data support the use of cytoreductive therapy in MPN-SVT patients to prevent recurrent thrombosis, particularly SVT extension/recurrence.

Background: Chronic venous insufficiency (CVI) can be evaluated using Duplex ultrasonography (US) and air plethysmography (PG), yet comparative performance remains unclear. Methods: We retrospectively identified patients who underwent venous insufficiency US and PG within a 90-day interval from March 1, 2015 through July 31, 2024. CVI severity was classified by the clinical (C) component of the Clinical, Etiologic, Anatomic, and Pathophysiologic (CEAP) classification system and categorized as mild (C0–2), moderate (C3), or severe (C4–6). PG and insufficiency US findings were compared across categories and machine learning models were trained to predict severe CVI. Results: We analyzed 1478 limbs from 839 patients who were predominantly women (62%) with a mean age of 61 years (± 14 years). Severe CVI was present in 32.3% of limbs. US detected venous incompetence in 67.4% of limbs overall and in 75.3% of severe CVI limbs. Abnormal PG findings occurred in 72.9% of limbs overall and in 88.5% of severe CVI limbs. PG parameters in machine learning models outperformed US parameters in predicting severe CVI (area under the receiver operating characteristic curve [AUROC] 0.82 vs 0.65). The top PG model (multilayer perceptron [MLP]) achieved an AUROC of 0.82, versus the best US model (gradient boosting) with an AUROC of 0.65. Limiting PG data to incompetence and obstruction parameters modestly reduced performance but remained higher than US (logistic regression AUROC 0.72). Conclusion: Our findings indicate that PG assessment in CVI offers superior performance compared to US. Overall, these results validate the quantitative whole-limb hemodynamic approach using PG, which provides a more complete understanding of the pathology behind CVI.

Abstract Optimal management of anticoagulation for patients with aortic mechanical heart valves (MHVs) receiving vitamin K antagonists (VKAs) undergoing gastrointestinal endoscopic procedures is clinically challenging. Risk of bleeding from an unanticipated polypectomy or biopsy further complicates this issue. Current guidelines on use of bridging with low-molecular-weight heparin (LMWH) for these procedures are based on low-quality evidence. We conducted a subanalysis of a retrospective, multicenter observational study of adult patients with aortic MHVs receiving VKAs who underwent elective gastrointestinal endoscopies (colonoscopy or upper endoscopy). We included patients who underwent the procedure between July 1, 2020, and July 1, 2023, at five centers in Canada and the United States Patients with procedures performed on separate days within a 30-day period were excluded. Efficacy and safety outcomes included thromboembolic events, major bleeding (MB), and clinically relevant non-major bleeding (CRNMB) in the 30 days post procedure. A total of 192 endoscopic procedures were analyzed. Median (interquartile range [IQR]) patient age was 66 years (58.2–72.8) and 22% were female. Warfarin was interrupted for 185 procedures (96%). Among these, 119 (64%) received LMWH bridging: 33 (17%) pre-procedure only, 10 (5%) post-procedure only, and 76 (40%) both pre- and post-procedure. Post-procedure LMWH was initiated a median (IQR) of 1 day (1–1) and discontinued 5 days post-procedure (3–8). MB occurred in two patients (1%), CRNMB in two patients (1%), and one death (0.5%) was identified; no thromboembolic events occurred. Prior to propensity score matching (PSM), post-procedure LMWH with or without pre procedure LMWH was associated with the composite outcome of MB and CRNMB (P = 0.034), although not with MB or CRNMB individually. After stepwise regression and PSM analyses, no significant differences in bleeding outcomes were observed between patients who received LMWH bridging and those who did not. Our findings indicate that although adverse thrombotic events were rare and use of post-procedure LMWH bridging was significantly associated with a small absolute increased risk of bleeding, it was not significant after PSM. Larger prospective studies are needed to better inform antithrombotic management guidelines for patients with aortic MHVs undergoing gastrointestinal endoscopy.

Post-pulmonary embolism syndrome (PPES) encompasses a diverse spectrum of long-term complications that are associated with persistent dyspnea, exercise intolerance, and a decrease in quality of life. The PPES constellation ranges from life-threatening conditions such as chronic thromboembolic pulmonary hypertension (CTEPH) to nonlife-threatening but still debilitating conditions such as chronic thromboembolic pulmonary disease (CTED) or post-PE deconditioning. The safety and efficacy of exercise and cardiopulmonary rehabilitation programs to prevent and manage these symptoms in PPES has not been well established. Herein, we review contributors to PPES and synthesize the evidence for exercise training after PE to treat and prevent PPES.

Abstract Guidelines recommend placement of inferior vena cava filters (IVCFs) in patients with acute proximal lower extremity deep vein thrombosis (DVT) and a contraindication to anticoagulation. IVCF placement during pregnancy or immediately postpartum presents technical challenges and is not extensively described in the existing literature. This study aimed to describe the use of IVCFs in the obstetric population along with outcomes related to filter placement. Retrospective chart review of all patients at Mayo Clinic from 2001 to 2020 with an IVCF at the time of conception or who underwent placement during pregnancy/postpartum. About 24 pregnancies in 23 women (mean age 26.3 years, range 18–41) were included: 5 (21%) with IVCF placement prior to pregnancy, 7 (29%) during pregnancy, and 12 (50%) during postpartum. IVCFs placed during pregnancy were frequently in the suprarenal position, in 5 (71%) cases. Meanwhile, 16 (94%) were deployed in an infrarenal position prior to pregnancy and postpartum. Complications included multiple attempts to remove the IVCF (n = 2), severe angulation (n = 4), embedded struts (n = 3), fracture (n = 1), and one case of cardiac tamponade (n = 1). Complications were more common when placement was performed prior to pregnancy or during pregnancy (2, 40% and 4, 57% respectively) versus postpartum (2, 17%). IVCF placement prior or during pregnancy/postpartum is uncommon and is associated with a high incidence of complications, although most did not fundamentally impact clinical outcomes. While IVCFs remain an option for clinicians treating pregnant and postpartum patients, these should be considered a last resource.

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 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.