No abstract

Essentials Predictive ability of pro‐hemostatic Gas6 for recurrent venous thromboembolism (VTE) is unknown.We measured Gas6 levels in 864 patients with VTE over 3 years.High Gas6 (> 157%) at diagnosis is associated with VTE recurrence, major bleeding and mortality.Gas6 plasma levels measured 12 months after the index VTE are discriminatory for VTE recurrence. SummaryBackgroundGrowth arrest‐specific gene 6 (Gas6) is a prohemostatic protein with an unknown predictive ability for recurrent venous thromboembolism (VTE). In the elderly, VTE results in higher mortality but does not have a higher rate of recurrence than in younger patients. Consequently, anticoagulation management in the elderly is challenging.ObjectiveTo prospectively investigate the performance of Gas6 in predicting VTE recurrence, major bleeding and mortality in the elderly.MethodsConsecutive patients aged ≥ 65 years with acute VTE were followed for a period of 3 years. Primary outcomes were symptomatic VTE recurrence, major bleeding, and mortality. Plasma Gas6 was measured with ELISA.ResultsGas6 levels were measured in 864 patients at the time of the index VTE (T1) and, in 70% of them, also 12 months later (T2). The Gas6 level at T1 was discriminatory for VTE recurrence (C‐statistic, 0.56; 95% confidence interval [CI] 0.51–0.62), major bleeding (0.60, 95% CI 0.55–0.65) and mortality (0.69, 95% CI 0.65–0.73) up to 36 months. VTE recurrence up to 24 months after T2 was discriminated by the Gas6 level at T2 (0.62, 95% CI 0.54–0.71). High Gas6 levels (> 157%) and continuous Gas6 levels at T1 were associated with VTE recurrence up to 6 months and 12 months, respectively.ConclusionsIn elderly patients, a high Gas6 level is associated with higher risks of VTE recurrence, major bleeding, and death. These findings support further studies to assess the performance of Gas6 in adjusting the length of anticoagulation.

Aging causes chronic low-grade inflammation known as inflamm-aging. It is a risk factor for several chronic disorders, including chronic myelomonocytic leukemia (CMML), a hematological malignancy that is most prevalent in older people. Recent studies suggest a critical role for the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome in inflamm-aging. However, the mechanisms involved in NLRP3 activation in aging and its involvement in CMML progression are not fully understood. In this study, we report that aging increases IL-1β production upon NLRP3 activation in human CD14+ monocytes. Interestingly, we found that the TLR1/2 agonist Pam3CSK4 directly activates the NLRP3 inflammasome in monocytes from older but not from younger healthy donors. Furthermore, we observed a dichotomous response to NLRP3 inflammasome activation in monocytes from a small cohort of CMML patients, and some patients produced high levels of IL-1β and some patients produced low levels of IL-1β compared with older healthy donors. Intriguingly, CMML patients with heightened NLRP3 activation showed increased treatment dependency and disease severity. Collectively, our results suggest that aging causes increased sensitivity to NLRP3 inflammasome activation at a cellular level, which may explain increased inflammation and immune dysregulation in older individuals. Furthermore, NLRP3 inflammasome activation was dysregulated in a small cohort of CMML patients and was positively correlated with disease severity.

No abstract