Sars-CoV2 Associated Thromboinflammatory Biomarkers for the Prediction of in-Hospital and Long-Term Mortality in Acute Coronary Syndrome (ACS): Development of a Risk Assessment Score

Background: In hospitalized patients, the SARS-CoV2 infection induces a thromboinflammatory state characterized by endothelial cell dysfunction, platelet activation, and hypercoagulability, leading to an increased risk of thrombosis. In ACS patients with concomitant SARS-CoV2 infection, a higher in-hospital mortality rate is reported; however, no information on the impact of this infection on the thromboinflammatory profile of patients presenting with ACS is currently available. Similarly, no role of hemostatic biomarkers in predicting in-hospital or long-term mortality risk has been established in this population.

Aim: In a prospective cohort of ACS patients, we aimed to 1) characterize the contribution of concomitant SARS-CoV2 infection to the thromboinflammatory status by measuring a panel of hemostatic and inflammatory biomarkers; and 2) assess the role of these biomarkers in predicting in-hospital and/or two-year mortality.

Methods: Consecutive patients admitted to interventional cardiology for ACS (i.e., ST-elevation myocardial infarction [STEMI], non-STEMI [NSTEMI], or unstable angina [UA]) during the first wave of the pandemic in Bergamo, Italy, from March to May 2020, were enrolled and followed-up for 2 years. Coronary angiography and percutaneous coronary intervention (PCI) data were collected. At admission, patients underwent complete blood cell count and an extensive coagulation profiling, including biomarkers of endothelial-cell activation (von Willebrand factor [vWF] antigen and activity, and ADAMTS13); hypercoagulation (prothrombin fragment 1+2 [F1+2], and D-dimer); and fibrinolytic proteins (tissue plasminogen activator [t-PA], and inhibitor [PAI-1]). In addition, the inflammatory biomarkers fibrinogen, factor VIII (FVIII), neutrophil extracellular traps (NETs), and C reactive protein (CRP) were tested. The occurrence of in-hospital and two-year mortality was prospectively recorded.

Results: A total of 99 (76M/23F, median age 67 years) ACS patients (56 STEMI, 34 NSTEMI, 9 UA) were analyzed. Based on nasal swabs, 24 positive and 75 negative SARS-CoV-2 patients were identified. At admission, all patients showed significantly (p<0.05) higher levels of thromboinflammatory biomarkers compared to normal range values. Furthermore, ACS SARS-CoV-2-positive patients displayed significantly (p< 0.05) higher levels of fibrinogen, FVIII, D-dimer, vWF, t-PA, PAI-1, CRP, and NETs, together with significantly (p<0.05) lower levels of lymphocytes, hemoglobin, platelets, and ADAMTS-13 as compared to negative patients. The STEMI SARS-CoV2-positive group exhibited the highest values of the biomarkers. When performed, PCI ended more frequently with partial coronary reperfusion (TIMI grade flow <3) in SARS-CoV2-positive compared to negative patients (p= 0.004).

The cumulative incidence of in-hospital mortality was 10%. The univariable analysis identified SARS-CoV-2 positivity as the strongest independent risk factor for mortality (HR 5.9 [95%CI 1.2-31.1]). Regarding the other clinical and laboratory parameters, the multivariable analysis identified dyspnea at presentation, vWF antigen, and leukocytes as independent risk factors for in-hospital mortality. These variables were used to develop a continuous score. Based on this score, the cumulative incidence of mortality was 0 % in the low-risk group, 19% in the intermediate-risk group (95% CI 6.1- 48.2%), and 71% in the high-risk group (95% CI 28.2-113.2%).

After a 2-year observation, the mortality rate was 8%. Age was the sole independent risk factor for a 2-year mortality, with a HR of 1.2 (95% CI 1.04-1.3), regardless of the initial SARS-CoV2 status.

Conclusions: For the first time, our study demonstrates that SARS-CoV2 infection worsens the thromboinflammatory state of ACS patients. This harmful effect might explain the observed heightened mortality rate among ACS patients concomitantly infected with SARS-CoV-2, which in our study was six times higher than in non-infected ACS patients. Additionally, the proposed scoring system, based on thromboinflammatory biomarkers, has proven effective in identifying ACS patients with elevated risks of in-hospital mortality. The potential role of this scoring system in identifying high-risk patients may possibly extend beyond our study to other highly inflammatory settings.