Abstract Number: PB0146
Meeting: ISTH 2021 Congress
Background: Severe COVID-19 leads to inflammation and coagulopathy with progression to multiple organ failure. Several prothrombotic mechanisms have been proposed, including platelet hyperactivation, elevation in procoagulant microvesicles and tissue factor (TF), and NETosis with release of citrullinated histones. The contribution of these factors to enhanced thrombin generation in COVID-19 remains elusive.
Aims: We hypothesized that plasma from COVID-19 patients enhances thrombin generation through both platelet-dependent and -independent mechanisms.
Methods: Platelet poor plasma (PPP) was isolated from 136 COVID-19 patients enrolled in a multicenter randomized clinical trial comparing standard prophylactic dose to intermediate dose enoxaparin in hospitalized patients with severe COVID-19 (NCT04360824). Samples were also collected from healthy control subjects (n=33). Thrombin generation was triggered by either tissue factor (TF), phospholipids, or both, and was measured in a calibrated automated thrombogram. Citrullinated histone H3 (H3Cit) and tissue factor pathway inhibitor (TFPI) were measured by immunoassay.
Results: When thrombin generation in PPP was triggered with TF and phospholipids, samples from COVID-19 patients exhibited higher endogenous thrombin potential (ETP), peak thrombin, and velocity index, and a delayed lag time compared to controls. The delayed lag time correlated with increased levels of TFPI in COVID-19 samples (P=0.01). Significant increases in thrombin generation in COVID-19 samples also occurred in response to phospholipids or TF alone, suggesting the presence of endogenous TF-positive microvesicles in COVID-19 plasma. To examine platelet-dependent thrombin generation, control platelets were incubated with PPP prior to measurement of thrombin generation triggered by TF. Significantly higher peak thrombin was observed with platelets incubated with plasma from COVID-19 patients; this effect was decreased by the histone aptamer KU7, suggesting histone-mediated platelet-dependent thrombin generation.
Conclusions: These findings suggest that in COVID-19, histones mechanistically drive increased thrombin generation via platelets; and microvesicles and TF contributes to thrombin generation in a platelet-independent manner.
To cite this abstract in AMA style:Eustes AS, Swamy J, Kudchadkar S, Jensen M, Wilson KM, Perepu U, Miller F, Lentz SR, Dayal S. Increased Thrombin Generation in COVID-19 is Mediated by Platelet-dependent and -Independent Mechanisms [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 1). https://abstracts.isth.org/abstract/increased-thrombin-generation-in-covid-19-is-mediated-by-platelet-dependent-and-independent-mechanisms/. Accessed September 16, 2021.
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