Skip to main content
. 2021 Feb 11;7(1):e001549. doi: 10.1136/rmdopen-2020-001549

Table 7.

Endothelial dysfunction, thrombosis and SARS-CoV-2 infection

Author Methods Population Description of result Rob
Platelet gene expression
Manne et al58 RNA Seq 10 COVID-19
vs
5 HD

  • Non-ICU and ICU COVID-19 patients clustered together, but separately from healthy controls

  • In COVID-19 enriched pathways associated with protein ubiquitination, antigen presentation and mitochondrial dysfunction

  • One of the top significantly overexpressed genes in COVID-19 is IFITM3, coding for an antiviral protein normally absent in HD and overexpressed in dengue and H1N1

  • No expression of ACE2 mRNA in COVID-19 and HD (nor of ACE2 protein by WB)

  • In 2 ICU COVID-19 mRNA expression of the SARS-CoV-2 N1 was detected

  • A comparison with existing RNA-Seq data in H1N1 and sepsis revealed that numerous gene expression differences between both condition. Of the shared gene expression,>96% changed in the same direction.

 Low
Zaid et al60 PCR 49 COVID-19
vs
17 HD		 SARS-CoV-2 RNA was detected in 11 COVID-19 (9/38 mild and 2/11 severe) and in no HD. Individuals with positive platelets for SARS-CoV-2 RNA were significantly older but otherwise similar to the negative patients. Unclear
Platelet activation
Manne et al58 In vitro assays 41 COVID-19
vs
17 HD

  • Higher basal expression of P-sel vs HD

  • Increasing doses of 2MeSADP and PAR1 peptide (SFLLRN or TRAP) induced significantly greater activation (P-sel expression) vs HD

  • P-sel expression in response to low-dose 2MeSADP significantly correlated with COVID-19 severity based on SOFA scores

  • 2MeSADP, SFLLRN (TRAP) and collagen-related peptide resulted in decreased PAC-1 binding vs HD (not due to altered expression of αIIb which was similar in the 2 groups)

 Low
Hottz et al59 In vitro assays 37 COVID-19
vs
11 HD

  • Higher basal expression of P-sel vs HD

  • Higher basal expression of P-sel in severe vs mild/asymptomatic COVID-19

  • Similar expression of P-sel in mild/asymptomatic vs HD

  • TXA2 synthesis was increased in platelets from severe but not mild/asymptomatic COVID-19

  • Platelet-derived factors are present in tracheal aspirates from COVID-19 patients

  • P-selectin elevations above HD median was predictive of in-hospital mortality (OR=9.6 (95% CI 1.02 to 90.35); p=0.045).

 Low
Zaid et al60 PCR 49 COVID-19
vs
17 HD		 Suboptimal concentrations of α-thrombin induced higher expression of p-PCKδ vs HD, with higher concentration no difference between groups Unclear
Platelet aggregation
Manne et al58 In vitro assays 41 COVID-19
vs
17 HD

  • In vitro platelet aggregation in response to low-dose agonists (2MeSADP, thrombin and collagen) was significantly increased vs HD

  • Aggregation was more pronounced in ICU COVID-19, especially at lower doses of thrombin

  • Aggregation is associated with increased MAPK pathway in ICU COVID-19

  • PLA2 in upregulated at baseline vs HD and further increases on stimulation with low-dose agonists

  • TXA2 was increases by 2MeSADP in platelets from COVID-19 ICU

  • In vitro aggregation of platelets from COVID-19 ICU could be reduced by pretreatment with high-dose aspirin

 Low
Denorme et al61 In vitro assays 11 COVID-19
vs
11 HD

  • In vitro generation of procoagulant platelets in response to dual agonist stimulation with thrombin and convulxin was significantly lower vs HD

  • Procoagulant platelet responses were similarly reduced in non-ICU and ICU COVID-19

  • Dysregulated procoagulant platelet responses in COVID‐19 are due to higher mitochondrial ROS levels at baseline and dual agonist stimulation of platelets from COVID‐19 patients did not elicit further increases in mitochondrial ROS generation

  • In vitro generation of procoagulant platelets in response to agonist stimulation with Ca2+ ionophore A23187 was similar to HD

 Unclear
Platelets adhesion
Manne et al58 In vitro assays 41 COVID-19
vs 17 HD		 Greater adhesion and spreading on fibrinogen and collagen vs HD Low
Zaid et al60 PCR 49 COVID-19
vs 17 HD		 The number of adherent platelets on a collagen-coated surface under flow conditions was significantly higher in severe vs mild Unclear
Platelets and monocytes interactions
Hottz et al59 In vitro assays 37 COVID-19
VS
11 HD

  • Platelets formed higher numbers of aggregates with monocytes in severe COVID-19

  • While aggregated, platelets induced monocyte expression of tissue factor (TF) via P-sel and integrin αIIb/β3 and TF expression was maximal at 2 hour of interaction

  • Only P-selectin, but not αIIb/β3, neutralisation was able to reduce platelet-monocyte aggregate formation

  • Abciximab pre-treatment did not affect P-sel expression on platelets from COVID-19 patients that were aggregated with monocytes

  • Aspirin or clopidogrel failed to modify platelet-monocyte aggregate formation or platelet-induced TF expression

  • TF expression in monocytes was increased among non-survivors

  • Platelet-monocyte aggregates did not associate with mortality

 Low
Circulating endothelial cells
Mancuso et al64 Flow cytometry 27 active COVID‐19 vs
9 recovered COVID-19 vs
8 HD

  • CECs/mL were similar to HD

  • Less apoptotic CECs/mL vs HD

  • Less apoptotic CECs/mL in recovered COVID-19 vs HD, vs mild COVID-19 vs severe COVID-19

  • Apoptotic CECs/mL inversely correlated with viral RNA copies

 Unclear
Nizzoli et al63 Flow cytometry 30 COVID
vs
6 HD

  • CECs/mL higher vs HD

  • CECs/mL higher in early phase of disease

 High
Guervilly et al65 Immuno magnetic separation 80 no ICU COVID-19
vs
19 ICU COVID-19

  • CECs/mL higher in ICU vs non-ICU COVID-19 independently of all comorbidities

  • CECs/mL directly correlated with length of hospital stay

  • CECs/mL independently associated with CKD

 Unclear
Khider et al62 Immuno magnetic separation 66 COVID-19
vs 30 clinically suspected non COVID-19

  • CECs/mL higher vs HD

  • CECs/mL lower in COVID-19 treated with anticoagulation (for any reason) vs untreated

  • In patients treated with ACEi or ARBs the effect of curative anticoagulation on the CEC level was more pronounced

 Unclear
Circulating precursors endothelial cells
Mancuso et al64 Flow cytometry 27 active COVID‐19 vs
nine recovered COVID-19
vs 8 HD

  • Viable and apoptotic CEPs/ml higher in acute and recovered COVID-19 vs HD

  • No difference between mild and severe COVID-19

  • Apoptotic CEPs/ml positively correlated with the copies of SARS-CoV-2 RNA in severe COVID-19

 Unclear

HD, healthy donor; ICU, intensive care unit; RoB, risk of bias.