Deborah M. Siegal

BACKGROUND: Andexanet reduces hematoma expansion compared with usual care for acute FXa (factor Xa) inhibitor-associated intracerebral hemorrhage but is associated with a risk of thrombotic events (TE). We pooled data from andexanet-treated trial participants to determine baseline predictors of TE. METHODS: Secondary analyses of andexanet-treated participants in ANNEXA-I (Andexanet Alfa, a Novel Antidote to the Anticoagulant Effects of Factor Xa Inhibitors in ICH) and ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors), which included adults with acute life-threatening hemorrhage on FXa inhibitors. Stratified Cox proportional hazards models were used to examine associations between baseline variables and arterial or all TE and mortality. A stratified Cox regression model with arterial events as time-dependent covariates was used to examine associations of arterial events with mortality, adjusted for clinical covariates. RESULTS: Of 741 participants (mean age, 78.5 years; 54.5% male), 593 (80.0%) had intracranial hemorrhage and 109 (14.7%) had gastrointestinal hemorrhage. Seventy-seven (10.4%) participants had ≥1 TE, and 147 (19.8%) died. Arterial and venous thromboembolism events occurred a median of 3.5 days (interquartile range, 2.0–12.0) and 14.0 days (interquartile range, 10.0–20.0), respectively, after randomization. No baseline factors were associated with all TE. Arterial TE were associated with prior myocardial infarction (hazard ratio [HR], 2.64 [95% CI, 1.33–5.26]), high-dose eligibility (HR, 2.44 [95% CI, 1.33–4.48]), female sex (HR, 1.78 [95% CI, 1.00–3.16]), and age (HR per year, 1.04 [95% CI, 1.00–1.08]). Mortality was associated with arterial TE (HR, 2.68 [95% CI, 1.64–4.36]), prior congestive heart failure (HR, 2.53 [95% CI, 1.76–3.63]), intracerebral hemorrhage or intraventricular hemorrhage (HR, 1.90 [95% CI, 1.20–3.01]), and age (HR per year, 1.06 [95% CI, 1.03–1.08]). The initiation of anticoagulation after randomization was associated with a reduction in TE. CONCLUSIONS: In FXa inhibitor-associated hemorrhage treated with andexanet, baseline factors are associated with arterial TE and can be used to inform treatment decisions. Initiation of anticoagulation reduces the occurrence of TE. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02313909. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02329327.

BACKGROUND: Extracranial bleeding is the most common complication of oral anticoagulant (OAC) therapy for atrial fibrillation (AF), but its clinical importance for patients may be underrecognized. We sought to characterize extracranial bleeding events according to standardized severity definitions, identify baseline risk factors for bleeding, and quantify their population attributable fraction in patients with AF receiving OACs. METHODS: We analyzed patients receiving OACs from 5 pivotal randomized trials testing a direct OAC or warfarin in patients with AF (COMBINE-AF [A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation]). The primary outcome was extracranial clinically relevant bleeding, defined as a first episode of extracranial major or clinically relevant nonmajor bleeding according to International Society on Thrombosis and Haemostasis criteria. The Kaplan-Meier method was used to calculate the cumulative incidence of bleeding by category. Multivariable Cox regression models were used to estimate adjusted hazard ratios (HRs) with 95% CI. Logistic regression models were used to calculate average population attributable fraction with 95% CI. RESULTS: Of 73 737 patients treated with OACs, 10 634 experienced clinically relevant extracranial bleeding over a mean follow-up of 705 days (cumulative incidence, 26% [95% CI, 18%–35%]; 7.6 per 100 person-years). This included 3188 major bleeds (cumulative incidence, 7% [95% CI, 6%–7%]; 2.1 per 100 person-years) and 7446 clinically relevant nonmajor bleeds (cumulative incidence, 19% [95% CI, 12%–28%]; 5.2 per 100 person-years). The distribution of bleeding sites differed by severity, with gastrointestinal bleeds comprising 26% of clinically relevant bleeds, 49% of major bleeds, and 15% of clinically relevant nonmajor bleeds. Risk factors for extracranial bleeding were consistent across severity bleeding categories, and baseline covariates in our multivariable models accounted for 66% to 69% of the population attributable bleeding risk. CONCLUSIONS: Extracranial clinically relevant bleeding is common among patients with AF treated with OACs and may more accurately reflect the overall burden of bleeding than major bleeding alone. Our models explained about two-thirds of the average population attributable risk, suggesting that additional unmeasured or unknown factors contribute to bleeding risk.

Prothrombin complex concentrates (PCC) are used off-label to treat direct factor Xa inhibitor (FXaI)-associated bleeding or before urgent surgery. GAUGE was a prospective observational cohort study of the effects of PCC on thrombin generation and hemostasis in FXaI-treated patients. FXaI-treated patients with major bleeding or needing urgent surgery received PCC (50 IU/kg). Platelet-poor plasma was collected pre-/post-PCC. TGA parameters (LT=lag time, TTP=time-to-peak, peak, ETP=endogenous thrombin potential, mVRI=mean velocity rate index) were measured using calibrated automated thrombography. Hemostatic efficacy, thromboembolism, and mortality were adjudicated in duplicate. Multivariable log-linear regression was used to evaluate PCC effects on FXaI levels. Unsupervised K-means clustering was used to identify patients with the largest ETP increment. GAUGE included 101 episodes of FXaI-associated PCC use (FXaI-associated bleeding = 71; urgent surgery = 30). Median PCC dosing was 48.0 IU/kg [42.0-50.0]. PCC did not affect FXaI levels (p>0.05). PCC increased ETP (Δ868.9±766.6 nM·min), peak (Δ85.7 nM±108.2), and the mVRI (Δ16.5 nM/min [4.4-45.0]). PCC did not affect the LT or TTP (p>0.05). Patients in Cluster 1 had significantly lower pre-PCC FXaI levels (79 ng/mL [55-93] vs 165 ng/mL [77-219]; p = 0.009) and a greater ΔETP increment (p < 0.0001) than patients in Cluster 2. Effective hemostasis occurred in 50.0% [95%CI 38.4-61.6] of major bleeds; procedural hemostasis was normal in 76.7% [95%CI 59.1-88.2]. The 30-day risks of thromboembolism and mortality were 6.9% [95%CI 3.4-13.6] and 12.9% [95%CI 7.7-20.8], respectively. PCC increased quantitative thrombin generation without shortening LT or TTP, supporting a prohemostatic effect rather than true FXaI reversal.

Patients with thrombotic antiphospholipid syndrome (APS) frequently require interruption of anticoagulation for invasive procedures; however, data to guide the perioperative management remain limited. We conducted a single-center, retrospective cohort study of adults with thrombotic APS who underwent planned periprocedural interruption of anticoagulation between 2016 and 2025. The primary outcomes were the 30-day risks for arterial thromboembolism (ATE), venous thromboembolism, and major bleeding; secondary outcomes included clinically relevant nonmajor bleeding (CRNMB), microvascular APS manifestations, and catastrophic APS (CAPS). Among 172 patients who underwent 282 interruptions, most (84.9%) received warfarin and 25% were triple-positive (anticardiolipin, anti–β2-glycoprotein I, and lupus anticoagulant). Bridging with low-molecular-weight heparin (LMWH) was used in 84.7% of warfarin interruptions. Therapeutic-dose bridging was more frequently used in patients with triple-positive APS (odds ratio [OR], 7.6; 95% confidence interval [CI], 3.2-18.2) and in those with a previous ATE (OR, 3.4; 95% CI, 1.5-7.8). The 30-day risk for ATE was 0.7% (95% CI, 0.2-2.6). Major bleeding occurred in 0.7% (95% CI, 0.2-2.6) of patients with both events following high bleed–risk procedures. One bleeding event was fatal, corresponding to a mortality risk of 0.4% (95% CI, 0.1-2.0). CRNMB occurred in 3.2% (95% CI, 1.7-6.0) of patients. A single case of probable CAPS occurred in a triple-positive patient who received postoperative prophylactic LMWH. Guideline-directed perioperative anticoagulation management tailored to individual thrombotic and procedural bleeding risks seems feasible and safe. Our findings support individualized, risk-adapted perioperative anticoagulation management in APS.

Antiphospholipid antibodies (aPL) are directed against phospholipids and phospholipid-binding proteins. Laboratory assays used to detect aPL include serological tests for aPL against β₂-glycoprotein 1, cardiolipin and other molecules, as well as functional assays for lupus anticoagulant. The presence of aPL can lead to endothelial dysfunction or a hypercoagulable state through prothrombotic and antifibrinolytic mechanisms. These processes, often in conjunction with a ‘second hit’, such as trauma, surgery, or other causes of hypercoagulability or stasis, can lead to venous or arterial thrombosis. The thrombotic risk associated with aPL is best recognized in thrombotic antiphospholipid syndrome, characterized by a persistently positive test for lupus anticoagulant or seropositivity for aPL associated with venous, arterial or microvascular thrombosis. However, aPL seropositivity and its clinical effect on thrombotic events have been increasingly recognized in a broader group of individuals who do not meet traditional research criteria for thrombotic antiphospholipid syndrome. In this Review, we provide an overview of the evidence related to aPL seropositivity in individuals with or without previous thrombosis and the clinical relevance of aPL seropositivity in predicting the risk of thrombotic cardiovascular events. We discuss potential management strategies and identify key knowledge gaps that warrant further research.

Background: The risk of ischemic stroke is highest during the first year following a new diagnosis of cancer, but no tools exist to identify patients at highest risk. Methods: Using linked clinical and administrative databases, we conducted a population‐based retrospective cohort study of adults in Ontario, Canada, with newly diagnosed cancer from 2010 to 2021. Patients were randomly selected for prediction model derivation (60%) or validation (40%). The final model predicting ischemic stroke within 1 year following cancer diagnosis was derived using multivariable Fine‐Gray regression with candidate predictors selected via backward elimination. Subdistribution‐adjusted hazard ratios and 95% CIs were calculated, where all‐cause mortality was treated as a competing event. Performance of the prediction model was assessed in the validation cohort based on the C statistic and calibration plots for discrimination and calibration, respectively. Results: There were 698 566 eligible patients, with 418 911 in the derivation cohort and 279 576 in the validation cohort. The overall rate of stroke per 1000 person‐years was 6.7 (95% CI, 6.4–6.9). The final model included 22 predictors, including age, sex, demographic factors, cancer characteristics, and treatment characteristics. Discrimination was good, with a C statistic of 0.73. The model was well calibrated, with points following the desired 45‐degree line. Conclusions: We derived and validated the PRIME (Predicting Risk of Ischemic Stroke in Malignancy Estimation) tool with good discrimination for ischemic stroke in patients with a new cancer diagnosis. The model was built into an online calculator ( https://study.ohri.ca/PRIME/ ) and has the potential to stratify patients with cancer based on their risk of stroke within a year following their diagnosis.