Hypofibrinolytic state and high thrombin generation may play a major role in SARS-COV2 associated thrombosis

Abstract

Background: Thirty percent of Covid-19 patients admitted to intensive care units present with thrombotic complications despite thromboprophylaxis. Bed rest, obesity, hypoxia, coagulopathy, and acute excessive inflammation are potential mechanisms reported by previous studies. Better understanding of the underlying mechanisms leading to thrombosis is crucial for developing more appropriate prophylaxis and treatment strategies.

Objective: We aimed to assess fibrinolytic activity and thrombin generation in 78 Covid-19 patients.

Patients and methods: Forty-eight patients admitted to the intensive care unit and 30 patients admitted to the internal medicine department were included in the study. All patients received thromboprophylaxis. We measured fibrinolytic parameters (tissue plasminogen activator, PAI-1, thrombin activatable fibrinolysis inhibitor, alpha2 anti-plasmin, and tissue plasminogen activator-modified ROTEM device), thrombin generation, and other coagulation tests (D-dimer, fibrinogen, factor VIII, antithrombin).

Results and conclusions: We observed two key findings: a high thrombin generation capacity that remained within normal values despite heparin therapy and a hypofibrinolysis mainly associated with increased PAI-1 levels. A modified ROTEM is able to detect both hypercoagulability and hypofibrinolysis simultaneously in Covid-19 patients with thrombosis.

Keywords: Covid-19; TAFI; fibrinolysis; plasminogen activator inhibitor 1; thrombin generation; tissue plasminogen activator.

Figure 1

Thrombin generation and TEM‐tPA results in Covid‐19 patients. A, Representative thrombin generation curves of a Covid‐19 patient receiving high‐dose LMWH prophylaxis (subcutaneous enoxaparin 40 mg BID, anti‐Xa activity 0.4 U/mL, red curve), and an obese patient without Covid‐19 infection at high risk of thrombosis, receiving the same treatment (subcutaneous enoxaparin 40 mg BID, anti‐Xa activity 0.4 U/mL, blue curve). The normal range of thrombin generation is represented in gray (mean ± 1 SD). Despite an overall correlation between anti‐Xa and ETP levels (P = .02; Spearman correlation test), the majority of Covid‐19 patients on prophylaxis with LMWH had normal or increased ETP (1670 ± 554 nmol/L/min [mean ± 2 SD]). Among 78 patients included in the study, 30 (38.5%) had an ETP above the reference range, 37 (47.4%) in the reference range, and 11 (14.1%) below the reference range. In vitro spiking of a plasma sample of a Covid‐19 patient with increasing concentrations of LMWH showed effective anticoagulation with expected anti‐Xa and ETP levels with high doses of LMWH (1 anti‐Xa U/mL). Taking together these results strongly suggests that patients with Covid‐19 infection were profoundly hypercoagulable at baseline. B, Representative TEM‐tPA curves from a normal control (green curve), a Covid‐19 patient with thrombosis (red curve), and a Covid‐19 patient without thrombosis (black curve). MCF corresponds to the maximal amplitude and reflects coagulation capacity of the patient. In Covid‐19 patients, MCF is increased. Ly30 is the lysis index at 30 minutes, which is very high in Covid‐19 patients with thrombosis and lower in other Covid patients. C, Ly30 results in Covid‐19 patients with and without thrombosis, compared with controls