Thrombin generation in patients with COVID-19 with and without thromboprophylaxis

Abstract

Objectives 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. Methods We enrolled consecutive patients with confirmed diagnosis of COVID-19 admitted to Medical Departments (MD) or Intensive Care Units (ICU), and 54 healthy controls. Results 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 dose thromboprophylaxis. 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. Conclusions 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.

Dynamic Hemostasis and Fibrinolysis Assays in Intensive Care COVID-19 Patients and Association with Thrombosis and Bleeding—A Systematic Review and a Cohort Study

“…Thrombin generation assays showed variable results but revealed normal 34 to prolonged lag time. 3,35,37 The ETP was comparable to healthy controls 25,34,35 or within reference range, 37 while when compared with non-ICU COVID-19 patients it was found to be increased 36 or even reduced. 3 However, the latter two studies differed in timing of blood sampling, as Canzano et al obtained blood samples on hospital admission, while de la Morena-Barrio et al sampled within median 2 (IQR: 1-7) days following admission.…”

Viscoelastometric Testing to Assess Hemostasis of COVID-19: A Systematic Review

“…So far, some in vitro studies have reported that there was a heparin concentration dependent decrease in thrombin generation [120,121]. Studies showed that COVID-19 patients had a higher endogenous thrombin potential [31,39,48,66,[122][123][124][125][126][127]] than manufacturer's reference range, healthy controls or patients with sepsis, sometimes despite UFH or LMWH anticoagulation at a minimum of prophylactic dosing. Few studies found a heparin dose-dependent decrease in thrombin generation [125,127] as described in vitro.…”

“…Studies showed that COVID-19 patients had a higher endogenous thrombin potential [31,39,48,66,[122][123][124][125][126][127]] than manufacturer's reference range, healthy controls or patients with sepsis, sometimes despite UFH or LMWH anticoagulation at a minimum of prophylactic dosing. Few studies found a heparin dose-dependent decrease in thrombin generation [125,127] as described in vitro. Interestingly, one study showed that a persisting thrombin burst despite anticoagulation correlated with non-survival [123], whereas another found no difference between noncritical and critically ill COVID-19 patients [124].…”

Incidence and Predictors of Thrombotic Complications in 4742 Patients with COVID-19 or Other Acute Infectious Respiratory Diseases: A Propensity Score-Matched Study

“…Alternatively, endothelial cells can be directly infected through the ACE-2 receptor, leading to platelet receptor activation and local coagulation [34][35][36][37]. Thus, due to the possible relationship between COVID-19 and hypercoagulability, and also to the obvious increased thrombotic risk in hypoxic patients, even in the absence of a high level of evidence, most centers have consequently modified their pharmacological thromboprophylaxis strategy toward therapeutic anticoagulation for routine care of COVID-19 patients [38][39][40].…”