Abstract
Coronavirus disease 2019 (COVID-19) is associated with an increased risk of thrombotic events. Ischemic stroke in COVID-19 patients entails high severity and mortality rates. Here we aimed to analyze cerebral thrombi of COVID-19 patients with large vessel occlusion (LVO) acute ischemic stroke to expose molecular evidence for SARS-CoV-2 in the thrombus and to unravel any peculiar immune-thrombotic features. We conducted a systematic pathological analysis of cerebral thrombi retrieved by endovascular thrombectomy in patients with LVO stroke infected with COVID-19 (n = 7 patients) and non-covid LVO controls (n = 23). In thrombi of COVID-19 patients, the SARS-CoV-2 docking receptor ACE2 was mainly expressed in monocytes/macrophages and showed higher expression levels compared to controls. Using polymerase chain reaction and sequencing, we detected SARS-CoV-2 Clade20A, in the thrombus of one COVID-19 patient. Comparing thrombus composition of COVID-19 and control patients, we noted no overt differences in terms of red blood cells, fibrin, neutrophil extracellular traps (NETs), von Willebrand Factor (vWF), platelets and complement complex C5b-9. However, thrombi of COVID-19 patients showed increased neutrophil density (MPO+ cells) and a three-fold higher Neutrophil-to-Lymphocyte Ratio (tNLR). In the ROC analysis both neutrophils and tNLR had a good discriminative ability to differentiate thrombi of COVID-19 patients from controls. In summary, cerebral thrombi of COVID-19 patients can harbor SARS-CoV2 and are characterized by an increased neutrophil number and tNLR and higher ACE2 expression. These findings suggest neutrophils as the possible culprit in COVID-19-related thrombosis.Graphical
Highlights
Coronavirus disease 2019 (COVID-19) is primarily characterized by pulmonary involvement but neurological manifestations [10, 11, 14, 30, 39] and thrombotic complications [17] are frequent
We could detect severe acute respiratory syndrome (SARS)-CoV-2 directly in one thrombus of a COVID-19 patient, and Angiotensin-converting enzyme 2 (ACE2) levels were higher in cerebral thrombi of COVID-19 patients compared to controls
Our findings suggest that the endothelial cells within our cohort of cerebral thrombi have a limited significance as a direct target for SARS-CoV-2
Summary
Coronavirus disease 2019 (COVID-19) is primarily characterized by pulmonary involvement but neurological manifestations [10, 11, 14, 30, 39] and thrombotic complications [17] are frequent. Diverse pathophysiological mechanisms have been hypothesized to explain the prothrombotic state in COVID-19, namely direct viral invasion of vascular structures (such as endothelial cells) [37] or of blood cells, or as a consequence of the organ’s immune response. High D-dimer levels and coagulation abnormalities have been frequently reported in COVID-19 patients suggesting that the activation of the coagulation system may be involved as an effector pathway of the immune response to the virus. Dysregulation of the angiotensin 2 (AngII)/angiotensin receptor type 1 (AT1R) pathway downstream of ACE2 could lead to cytokine release syndrome and severe endothelial dysfunction with consequent increased vascular permeability and uncontrolled inflammation, which could be implied in virus-specific thrombo-inflammatory mechanisms. A hyper-inflammatory state with macrophage activation, hyperactivation of the myeloid compartment and cytokine storm has been observed in severe COVID-19 patients [33]
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