Houghton, Damon E.

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.

Abstract Immune thrombocytopenia (ITP) carries an increased risk of thrombosis, which may be further amplified by splenectomy and thrombopoietin receptor agonists (TPO-RAs). Although each intervention has been individually studied for its thrombotic risk, data are lacking on the safety of postsplenectomy TPO-RA use. We conducted a retrospective cohort study of adult patients with ITP who underwent splenectomy between 2011 and 2024. Patients were stratified on the basis of postsplenectomy TPO-RA use. The primary outcome was incidence of thrombosis. Secondary outcomes included bleeding, mortality, and hematologic response. Time-to-event analyses and multivariate Cox regression were performed. Among 88 patients, 37 (42%) patients received TPO-RAs after splenectomy. Thrombosis occurred in 17 patients in the TPO-RA group vs 14 patients in the non–TPO-RA group (P = .07). The 10-year cumulative incidence of thrombosis was numerically higher in the TPO-RA group (57% vs 36%), with clustering of events within the 3 months of postsplenectomy TPO-RA initiation. Venous events predominated; arterial events were rare. No significant differences were observed in bleeding or mortality rates between groups. Platelet counts alone did not independently affect bleeding or thrombosis. TPO-RA use after splenectomy was not significantly associated with increased thrombosis risk. However, early initiation may coincide with a high-risk period, and the sustained numerical difference in cumulative incidence throughout follow-up highlights potential clinical relevance. These findings support the need for individualized thromboprophylaxis and prospective evaluation of TPO-RA safety in this setting.

Abstract Patients with cancer and venous thromboembolism (VTE) have higher complication rates of anticoagulation. However, studies supporting this data are relatively old reflecting the era of vitamin K inhibitors. To assess VTE recurrence, major bleeding, and clinically relevant non-major bleeding (CRNMB) in patients (March 1, 2013 to April 30, 2023) with cancer-associated VTE and patients without cancer, the prospective Mayo Clinic Thrombophilia Clinic Registry was analyzed. Over the study period, 4,711 patients with acute VTE were enrolled including 2,064 patients with cancer (mean age 62.5 ± 12.4, 46% female) and 2,647 patients without cancer (mean age 59.4 ± 16.0, 45% female). The most common cancers were gastrointestinal (n = 423, 21%), pancreatic (n = 287, 14%), and genitourinary (n = 198, 10%). Direct oral anticoagulants were used in 1,339 (65%) cancer and in 1,952 (74%) non-cancer patients. Among cancer patients, 12-month Kaplan–Meier probability of VTE recurrence was 2.4-fold greater (7.1% vs. 2.9%, p < 0.001) compared with the non-cancer group, including higher recurrent leg deep vein thrombosis (3.0% vs. 1.4%; p = 0.002) and pulmonary embolism (3.5% vs. 1.0%, p < 0.001). Patients with cancer also had 2.1-fold greater risk of major bleeding (6.3% vs. 3.0%; p < 0.001) including bleeding from the gastrointestinal tract (3.0 vs. 1.4, p = 0.01) compared with patients without cancer. Clinically relevant non-major bleeding events were similar between the groups. In this large prospective registry of VTE management, patients with cancer had significantly higher rates of VTE recurrence and major bleeding compared with patients without cancer, yet the rate of complications are substantially smaller relative to historic values of a prior vitamin K antagonist era.

Background: The use of validated risk stratification tools for the workup of suspected pulmonary embolism (PE) is a recommendation of the American Society of Hematology and the American College of Emergency Physicians. Methods: We designed and implemented electronic clinical pretest probability (PTP) tools for use in emergency departments (ED). Overall, 38 EDs (tertiary and regional EDs) in the United States were involved across three health systems. PTP use was analyzed between September 12, 2022 and January 11, 2023 in 270,247 ED visits. PTP use was examined in terms of the percentage of visits for which patients underwent computed tomography pulmonary angiography (CTPA). Each site chose the 3-tier Wells’ score for implementation and Site 2 designed a combined Wells’, pulmonary embolism rule-out criteria (PERC), and YEARS score. Results: At Site 3, forced use resulted in documented PTP scores in 49–53% of ordered CTPAs. At Sites 1 and 2, where PTP scores were optional, documented PTP scores occurred in 2–3% and 1–3% of CTPA orders, respectively. At Site 1, the use of PTP increased slightly over the study period, with signs that PE yield on imaging was also increasing (3.4–5.9%). At Site 2, PE yield on imaging was 9–10%, and it remained similar, with similar use of PTP tools over the study period. PE yield (6–8%) on imaging also remained similar throughout the study at Site 3. Conclusions: Guideline-endorsed PTP scores for PE at three independent health systems in the United States did not increase PE yield on imaging. Novel implementation strategies involving interdisciplinary teams are urgently needed.

Guidelines for diagnosing pulmonary embolism (PE) start with a risk assessment using a pretest probability (PTP) tool, followed by D-dimer testing or computed tomography pulmonary angiography (CTPA) depending on risk. The project aimed to develop an electronic clinical quality measure (eCQM) to encourage broader use of a validated PTP scoring tool in emergency departments (EDs) to more accurately diagnose PE and to reduce unnecessary CTPAs. To identify a value set to accurately identify CTPA and abnormal D-dimer tests using standard classification systems and clinical vocabularies (ie, Current Procedural Terminology [CPT], Logical Observation Identifiers Names and Codes [LOINC], systematized nomenclature of medicine clinical terms [SNOMED CT]) across 3 academic United States health care systems. A comprehensive value set to identify CTPAs was selected, which contained 31 codes. Additionally, each health care system had unique, site-specific codes to more granularly identify CTPAs. Three health care systems representing 38 EDs from across the country submitted data from all ED encounters between September 12, 2022, and January 11, 2023. Imaging types were reviewed from each of the CPT codes and LOINC. The project evaluated whether a D-dimer was obtained using CPT and LOINC and whether the D-dimer result was elevated using SNOMED CT. The number of ED encounters, PTP use, and diagnosis of PE using different codes were determined. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value for selected codes were calculated. Over a 4-month study period, 270,214 encounters were included from 38 EDs. 11,794 ED encounters with CTPAs during the study period, using the site-specific codes were identified. The comprehensive value set had a PPV of 63.4%. Restricting the CTPA value set to CPT code 71275 or LOINC 88322-3 improved the PPV to 82% with 100% sensitivity and 99% specificity. The restricted value set captured the highest proportion of relevant site-specific codes. D-dimer values were identified using LOINC codes 48065-7 and 91556-1 at Site 1 and 48067-3 at Site 2. SNOMED CT codes were not used at any site to identify elevated D-dimer results. Different D-dimer tests with different normal ranges were used at each site, and only one site provided an abnormal flag for D-dimer results. Heterogeneity in the use of nationally standardized codes for labs and imaging tests limits the ability to measure and compare quality across health care organizations for CTPA and D-dimer results. Restricting the identification of CTPA to CPT Code 71275 or LOINC 88322-3 resulted in high sensitivity and specificity, but false positives remain. Additionally, coding for an abnormal D-dimer test result is not standardized across institutions. Therefore, the currently available value sets cannot be used to develop eCQMs whose aim is to evaluate whether CTPA is ordered appropriately based on the PTP risk level and laboratory testing.