Abstract
Thrombin generation (TG) with and without thrombomodulin (TM) was evaluated in COVID-19 patients with different disease severity and thromboprophylaxis regimen, in order to understand the prothrombotic profile. We enrolled consecutive patients with confirmed diagnosis of COVID-19 admitted to Medical Departments (MD) or Intensive Care Units (ICU), and 54 healthy controls. Eighty-nine patients were included (mean age 60.4±16.1 years, 68.5% male); 33.7% admitted to ICU. Twenty-four patients (26.9%) were enrolled before thromboprophylaxis administration; 45 patients (50.6%) received standard and 20 (22.5%) intermediate sub-therapeutic dosethromboprophylaxis. Overall, patients with COVID-19 showed a TG profile comparable to that of healthy subjects (i.e. comparable peak height, endogenous thrombin potential [ETP] with and without TM). The only exception was lag time and time to peak, prolonged in COVID-19 patients vs. controls. MD patients showed a similar TG profile to healthy controls, and ICU patients showed significantly decrease ETP (p=0.030) compared to MD. As for thromboprophylaxis, TG profile was significantly increased in COVID-19 patients without thromboprophylaxis vs. controls and vs. those with thromboprophylaxis. In this latter group, ETP inhibition was significantly decreased (p=0.0003) and positively correlated with anti-Xa activity (r=0.49, p=0.0017). However, patients with thromboprophylaxis had similar TG profile vs. controls. Intermediate dose thromboprophylaxis more effectively inhibited TG in severe COVID-19 patients by increasing ETP inhibition via ETP with TM reduction vs. standard dose. COVID-19 patients showed increased TG at diagnosis. Standard thromboprophylaxis reduced TG to levels of healthy controls. Intermediate sub-therapeutic thromboprophylaxis more effectively inhibited TG by decreasing ETP with TM.
Highlights
The typical symptoms of pandemic SARS-CoV-2 infection (COVID-19) are fever, cough, dyspnea, enteric disorders; they can develop rapidly into interstitial pneumonia with severe respiratory distress requiring hospitalization, including mechanical ventilation in intensive care units (ICU) [1–4]
Thrombin generation assay (TGA), performed in the presence of thrombomodulin (TM) – the cofactor in the thrombin-induced activation of the anticoagulant protein C pathway – is increasingly recognized as a valuable tool to assess the haemostatic balance in platelet-poor plasma, for its ability to concomitantly evaluate the effect of plasma pro- and anticoagulant factors [18–20]
COVID-19 is characterized by an abnormal immune response and an exaggerated pro-inflammatory state, which compound to foster the development of a profound haemostasis disturbance - mainly hypercoagulability – resulting in venous thromboembolism (VTE) complications and poor outcomes [11–15, 17, 27, 28]
Summary
The typical symptoms of pandemic SARS-CoV-2 infection (COVID-19) are fever, cough, dyspnea, enteric disorders; they can develop rapidly into interstitial pneumonia with severe respiratory distress requiring hospitalization, including mechanical ventilation in intensive care units (ICU) [1–4]. In addition to respiratory complications, high incidence rates of venous thromboembolism (VTE) have been reported in critically ill COVID-19 patients [5–7]. Campello et al.: Thrombin generation and COVID-19 more pronounced in intensive care unit (ICU) patients with severe COVID-19 [13–15]. In patients with complex haemostatic disorders, TM-modified TGA provides more information than traditional coagulation tests such as prothrombin time or partial thromboplastin time which are sensitive to procoagulant proteins only [21–25]. TGA has the potential to better describe a COVID-19 patient’s coagulation status
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