Elevated Gas6 Plasma Level As a Predictor of Venous Thromboembolism Recurrence and Mortality in a Prospective Multicenter Cohort of Elderly Patients with Venous Thromboembolism

Introduction:

Venous thromboembolism (VTE) represents a worldwide major health issue and is a leading cause of cardiovascular death. Its incidence rises with age and in the elderly population, VTE not only carries a higher mortality but also a higher rate of VTE recurrence and major bleeding than in younger patients. An elevated D-dimer level after cessation of anticoagulant treatment is associated with a high rate of VTE recurrence, and might indicate the need for prolonged anticoagulation in unclear situations. However, since D-dimer plasma levels decline under anticoagulation therapy, their use to guide the duration of anticoagulation requires that patients stop their antithrombotic medication before the D-dimer testing assessment, thereby risking VTE recurrence in the meantime. Growth arrest-specific gene 6 (Gas6) is a pro-hemostatic protein with multiple functions, including an effect on coagulation and platelet function, enhancing platelet aggregation and expression of tissue factor in endothelial cells as well as promoting the recruitment of platelets and leukocytes to the endothelial cell membrane. The goal of this study was the assessment of the predictive ability of Gas6 levels for recurrent venous VTE and mortality, as well as the comparison to D-Dimer levels.

Methods:

The study was conducted between September 2009 and December 2013 as part of the Swiss Cohort of Elderly Patients with VTE (SWITCO65+), a prospective multicenter cohort study to assess medical outcomes and quality of life in elderly patients with acute VTE from all five universities and four high-volume non-university hospitals in Switzerland. For the present study, the clinical outcomes were VTE recurrence and mortality, which were assessed over a 3 year period. Blood-samples for assessment of Gas6 levels and D-Dimer levels were drawn at diagnosis of the index VTE and at 12 month follow-up.

Results:

The study included 864 patients. During the 3-years follow-up period, 100(11.6%) patients developed recurrent VTE and 170 (19.7%) died. At the time of index VTE diagnosis, median Gas6 level was 129.3% (IQR 108.9,156.6) and was significantly lower (93%, IQR 77.1, 111.7) at 12-months follow-up. Median D-dimer was 2493 ng/mL (IQR 1572.5, 3819.3) at time of index VTE diagnosis and was 644.5 ng/mL (IQR 399.3, 1153.5) 12 months after the index VTE. Correlation between Gas6 and D-dimer was weak, both at time of the index VTE (Spearman correlation, r_s = 0.06) and 12 months later (r_s = 0.24). Based on the C-Statistics, Gas6 (95% confidence interval [CI], 0.56, 0.51-0.62, p=0.031) and D-dimer (95% CI, 0.56, 0.50-0.62, p=0.043) levels at the time of the index event were predictive of VTE recurrence up to 36 months. Gas6 (95%CI, 0.69, 0.65 - 0.73, p<0.001) but not D-dimer (95%CI, 0.56, 0.50 - 0.62, p=0.043) levels at the diagnosis of the index VTE were predictive of mortality up to 36 months (p<0.001). VTE recurrence up to 24 months was predicted by Gas6 (95%CI, 0.62, 0.54-0.71, p=0.003) and D-dimer (95%CI, 0.59, 0.51-0.67, p=0.036) levels at 12-month follow-up. However, mortality up to 24 months was predicted by D-dimer (95%CI, 0.71, 0.65-0.78, p<0.001) but not Gas6 (95%CI, 0.52, 0.44-0.61, p=0.566) levels at 12-month follow-up. Continuous Gas6 levels at diagnosis of the index event were associated with VTE recurrence up to 6 months (adjusted hazard ratio [HR] 5.04, 95% CI, 2.14-11.88, p<0.001) and death up to 36 months (adjusted HR 5.00, 95%CI, 3.16-7.92, p<0.001). Changes in Gas6 levels from time of the index VTE diagnosis to 12 months later were predictive of VTE recurrence up to 24 months (95%CI, 0.59, 0.51-0.67, p=0.036) but not overall mortality (95%CI, 0.52, 0.44-0.61, p=0.566).

Conclusion:

Gas6 levels measured at diagnosis of acute VTE were associated with higher risk of VTE recurrence and mortality in an elderly population. In addition, 12 month after the first VTE episode, only Gas6 levels were associated with higher risk of VTE-recurrence, whereas higher D-Dimer levels were associated with higher mortality. Our findings suggest that a clinical decision to avoid prolonged anticoagulation could be made based on Gas6 plasma level in the elderly.