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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 12  |  Issue : 4  |  Page : 195-202

Platelets derived microparticles in COVID-19: Correlation to inflammatory and coagulation State


1 Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
3 Department of Chest Diseases, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission16-Jul-2021
Date of Acceptance12-Aug-2021
Date of Web Publication18-Jan-2022

Correspondence Address:
Dr. Mervat Abdalhameed Alfeky
Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_102_21

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  Abstract 


BACKGROUND: Evidences indicate that COVID-19 infection causes hypercoagulable state with micro and macrovascular thrombosis. Platelet-derived microparticles (PDMPs) have inflammatory and diverse coagulant roles.
AIM: The aim of the study was to assess PDMPs in patients with active and convalescent post COVID-19 infection and correlate PDMPs with clinical, radiological and laboratory findings used in follow up.
PATIENTS AND METHODS: The study enrolled 25 patients during active COVID-19 (Group A), of them five patients had thromboembolic events (TEE); and Group B including 32 patients during post COVID-19 stages. Clinical and radiological assessment, routine biomarkers, and detection of PDMPs levels, using enzyme-linked immunosorbent assay method, were done for all patients.
RESULTS: In addition to significant differences detected regarding hemoglobin level, total leukocyte count, absolute neutrophil count, absolute lymphocyte count, C-reactive protein level, D-dimer, and serum ferritin, and high significant differences in PDMPs levels were elicited between groups A and B (mean ± standard deviation: 38.7 ± 10.6 IU/mL, and 18.9 ± 15.3 IU/mL) respectively, with discriminative level at 20.5 IU/mL. PDMPs showed nonsignificant difference between patients with and without TEE and no correlation was detected between PDMPs and clinical or radiological severity in post-COVID-19 patients.
CONCLUSION: In COVID-19 infection, PDMPs are related to viral activity, and their major role is inflammatory associated.

Keywords: COVID-19, coagulopathy, inflammation, microparticles


How to cite this article:
Abdelmaksoud MF, Abdelmaksoud SS, Abdelsamee HF, Ezzelregal HG, Alfeky MA. Platelets derived microparticles in COVID-19: Correlation to inflammatory and coagulation State. J Appl Hematol 2021;12:195-202

How to cite this URL:
Abdelmaksoud MF, Abdelmaksoud SS, Abdelsamee HF, Ezzelregal HG, Alfeky MA. Platelets derived microparticles in COVID-19: Correlation to inflammatory and coagulation State. J Appl Hematol [serial online] 2021 [cited 2022 Sep 25];12:195-202. Available from: https://www.jahjournal.org/text.asp?2021/12/4/195/335935




  Introduction Top


A current worldwide pandemic of viral pneumonia, coronavirus disease (COVID-19), due to the virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions of people and continues a risk to many more.[1] While most critically ill patients with COVID-19 have isolated respiratory failure, often acute respiratory distress syndrome (ARDS), multiple organ dysfunction affects 20%–30% of patients with critical illness and more often in fatal cases.[2] Coagulopathy gained interest in patients with COVID-19 as abnormal coagulation parameters, most consistently elevations in D-dimer and fibrin degradation products, are associated with disease severity.[3],[4]

Published pathologic reports of histopathology for lung specimens from patients with early COVID-19 disease showed characteristic findings of ARDS and evidence of small-vessel occlusion.[5],[6] Infection with SARS-CoV-2 may result in microvascular and macrovascular thrombosis by several mechanisms including cytokine storm with activation of leukocytes, endothelium, and platelets resulting in upregulation of tissue factor (TF).[7]

One of the features of viral infection is the formation of inflammatory environment around infected cells which is closely related to cell activation or initiation of apoptosis and necrosis in these infected cells resulting in shedding of microparticles (MPs).[8] The MPs are small membrane vesicles derived from activated and apoptotic cells, the diameter of which ranges from 100 to 1000 nm,[9] and they are generated by many types of body cells such as platelets, endothelial cells, leukocytes, smooth muscle cells, and erythrocytes.[10] They can be detected in blood of healthy individuals and increase in various diseases including cardiovascular diseases, diabetes, sepsis, and cancer.[10],[11],[12],[13],[14] The MPs have been suggested to play roles in thrombosis, inflammation, and angiogenesis.[15],[16] Platelet-derived MPs (PDMPs) have claimed to have diverse coagulant role. While some studies reported that they are strongly procoagulant because they contain the anionic phospholipid (PS), being the major source of PS + MPs in blood and represent 70-90% of all circulating MPs;[12],[13],[14],[15] others reported anticoagulant activities for PDMPs.[16],[17],[18],[19]

Beyond haemostasis, PDMPs convey diverse of materials and can include lipids, proteins, nucleic acids, and organelles involved in many other biological processes.[20]

Although flow cytometry is the most widely used method for detecting MPs, TF-dependent procoagulant assay and enzyme-linked immunosorbent assay (ELISA) methods, have been used as well.[21]

Aim of the study

This observational study aims to assess the levels of PDMPs in patients with active and post COVID-19 convalescent stages and to correlate their levels with clinical and radiological findings as well as other routine biological markers currently used in follow up of COVID-19 patients.


  Patients and Methods Top


The study included 57 patients in two groups; Group A including 25 patients during the active COVID-19 stage as evidenced by polymerase chain reaction (PCR) positivity, and Group B that included 32 patients during the post-COVID-19 convalescent stage after up to 4 weeks of being PCR negative for the virus. Patients were recruited from the attendants of Obour Isolation Hospital, Ain Shams University, Cairo, Egypt.

An informed verbal consent was obtained from each patient or concerned relative, for patients in intensive care unit (ICU), before participation. The procedures applied in this study were approved by the Ethical Committee of Human Experimentation of Ain Shams University and are in accordance with the Helsinki Declaration of 1975.

All included patients were subjected to:

  1. Detailed medical history and through clinical examination excluding patients with other comorbidities as diabetes, chronic renal diseases, hypertension, or cancer
  2. Laboratory investigations:


    • Real-time reverse transcriptase-PCR assay (NAAT) for SARS-CoV-2 RNA using Viasure SARS-COV2 detection kit (Cer Test, Biotec, Spain) after viral RNA extraction using magnetic beads on Chemagic 360 (Perkin Elmer, Germany)
    • Complete blood count with differential count was done using Advia 560 and 560 AL Hematology System, Siemens Healthineers, Germany
    • Chemistry biomarkers and C-reactive protein (CRP) were done using Biolis 24i Chemistry Analyzer, Tokyo Boeki, Japan
    • D-dimer was done by immunoassay using VIDAS PC, Biomerieux, France
    • Prothrombin time and activated partial thromboplastin time were assayed using STA compact, STAGO, France
    • Measurement of PDMPs.


Quantitative assay of PDMPs concentration was done using ELISA kit supplied by SinoGeneClon Biotech Co., China. The kit adopts purified PDMP antibodies (anti-CD42a/GP-IX and anti-CD42b/GPIb antibodies) to coat microtiter plate and form the solid phase antibody. Standards and samples containing PDMPs were added to the microtiter wells. If PDMPs were present, they would bind to the antibody on the well. The PDMP antibodies were combined with labeled horseradish peroxidase enzyme (HRP) (the conjugate) and added to form antibody-antigen-enzyme-antibody complex. Tetramethylbenzidine substrate was added to produce a change in color with HRP catalysis. The enzyme-substrate reaction was terminated by adding a stop solution and the color change was measured spectrophotometrically at a wavelength of 450 nm. A standard curve was constructed by plotting the absorbance value (i.e., the intensity of the color) against the concentration of standards. The PDMPs concentration in the samples was determined by comparing the optical density (O.D.) of the samples to the standard curve.

For used kit, intra-assay precision is mentioned as, CV: <8%; inter-assay is mentioned as, CV: <10%.

Statistical methods

Data were analyzed using Stata© version 14.2 (StataCorp LLC, College Station, TX, USA) and MedCalc© Statistical Software version 18.11.3 (MedCalc© Software bvba, Ostend, Belgium). Categorical variables are presented as number and percentage and numerical variables as mean, standard deviation (SD) range, percentiles, median, and range. Point-biserial correlation (rpb) is used to test the strength of association between continuous variables and nominal variables on two levels. Correlations between continuous variables are tested using the Pearson correlation ®. The correlation coefficients (rpb or Pearson r) are interpreted as follows: <0.2 = very weak association, 0.2–0.39 = weak association, 0.4–0.59 = moderate association, 0.6–-0.79 = strong association, and ≥0.8 = very strong association. Mann–Whitney U Test was used to compare the differences in various parameters between patients with and without thromboembolic events (TEE) (number is five).

Receiver-operating characteristic (ROC) curve analysis is used to examine the value of PDMPs or alternative biomarkers for discrimination between PCR-positive (COVID-19) and PCR-negative (post-COVID-19) patients. The area under the ROC curve is interpreted as follows: <0.6 = fail, 0.6–0.69 = poor, 0.7–0.79 = fair, 0.8–0.89 = good, and ≥0.9 = excellent. Areas under different ROC curves are compared sing the DeLong method. Two-sided P < 0.05 are considered statistically significant.


  Results Top


This study was conducted on 57 patients in two groups; Group A included 25 patients during active COVID-19 infection stage; they were 12/25 females (48%) and 13/25 males (52%), and all were admitted to ICU. TEE were manifested in 5/25 (20%) of patients in the form of deep vein thrombosis and myocardial infarction, in two patients for each and pulmonary embolism in one patient.

And group B included 32 patients during the post COVID-19 convalescent stage; they were 25/32 (78.1%) females and 7/32 (21.9%) males. Their CT chest showed no infiltrates in 19/32 (59.4%) of them, while mild and moderate infiltrates were detected in 9/32 (28.1%), and 4/32 (12.5%), respectively. Twenty of them (62.5%) were home managed, while inpatients were 10/32 (31.3%), with 4/32 (12.5%) needed oxygen supplementation, and ICU admission was needed in 2/32 (6.3%).

The most common residual symptoms manifested in post COVID-19 patients were anosmia (29/32, 90.6%), muscle weakness and fatigue (27/32, 84.4%), dyspnea (15/32, 46.9%), and cough (15/32, 46.9%).

Comparison of the hematological and biochemical variables in active COVID-19 and post COVID-19 patients

By comparing the hematological and biochemical variables in group A and B patients, a high significant difference was elicited between both groups regarding the PDMPs levels (mean ± SD: 38.7 ± 10.6 IU/mL and 18.9 ± 15.3 IU/mL) respectively. Furthermore, high significant differences between both groups were detected regarding hemoglobin (Hb) level, total leukocyte count (TLC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), CRP level, D-dimer, and serum ferritin [Table 1].
Table 1: Comparison of haematological and biochemical variables in acute COVID-19 and post-COVID-19 patients

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Among group A patients, we found that levels of PDMPs were higher in patients with TEE than that in patients with no TEE, however the level did not reach a statistically significant difference. Also, levels of D-dimer, TLC, ANC, and CRP showed non-significant differences. The ALC was the only significantly different parameter between patients with and without TEE [Table 2].
Table 2: Comparison between Group A patients with and without thrombo-embolic events regarding platelets derived microparticles

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Correlations of platelet-derived microparticles with hematological and biochemical variables in group A patients

Significant positive correlations were found between PDMPs and TLC and ANC, and a highly significant positive correlation was found between PDMPs and lactate dehydrogenase (LDH) enzyme [Table 3].
Table 3: Correlations of platelets derived microparticles with other patients' hematological and biochemical variables in Group A patients

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Correlations of platelet-derived microparticles with hematological, biochemical, and clinical variables in group B patients

Highly significant positive correlations were detected between PDMPs and both CRP and serum ferritin, and a significant correlation was detected between PDMPs and LDH [Table 4].
Table 4: Correlations of platelets derived microparticles with other patients' hematological and biochemical variables in Group B patients

Click here to view


ROC curve analysis for discrimination between group A and group B patients using PDMPs and alternative markers was performed. It revealed that PDMPs showed area under the curve (AUC) 0.846, with sensitivity 96%, and specificity 78.1% at cut off >20.5 IU/mL, compared to CRP, D-Dimer, Ferritin, ALC, and relative lymphocyte count (RLC) showing AUC of 0.970, 0.860, 0.897, 0.842, and 0.913, respectively. Except for CRP, no significant difference was detected between AUC of PDMPs and other markers [Table 5], [Table 6] and [Figure 1].
Table 5: Receiver-operating characteristic curve analysis for discrimination between PCR-positive (COVID-19) and PCR-negative (post-COVID-19) patients using platelets derived microparticles or alternative markers

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Table 6: Comparison of the area under receiver-operating characteristic curves associated with platelets derived microparticles or alternative markers

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Figure 1: Receiver-operating characteristic (curves for discrimination between PCR-positive (COVID-19) or PCR-negative (post-COVID-19) patients using PDMPs or alternative markers. PDMPs = Platelets derived microparticles, CRP = C reactive protein, ALC = Absolute lymphocyte count, RLC = Relative lymphocyte count, ROC = Receiver-operating characteristic, PCR = Polymerase chain reaction

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  Discussion Top


Significant evidences indicate that COVID-19 is associated with a hypercoagulable state.[22] As MPs have been reported to have roles in thrombosis, inflammation, and angiogenesis, we aimed in this study to assess the levels of PDMPs in patients with active and post COVID-19 infection stages and to correlate their levels to clinical and radiological findings as well as other biological markers in current routine use.

Regarding clinical severity, this study was conducted on 57 patients in two groups; Group A included 25 patients during active COVID-19 infection stage and all were severe cases admitted to ICU, and five of them had TEE. Group B included 32 patients during the post-COVID-19 convalescent stage, within a period up to 4 weeks of turning PCR negative for COVID-19 virus. Although most of post-COVID-19 patients were home managed, CT chest showed mild to moderate infiltrates in about 40% of them. A study by Huang et al.[23] reported that more than 50% of post COVID-19 patients presented with residual chest imaging abnormalities and the disease severity during the acute phase was independently associated with the extent of lung diffusion impairment at follow-up.

It was reported that survivors of COVID-19 mostly had residual symptoms within 3 months of illness;[24] and a study on adult patients with COVID-19 in convalescence, showed that after 6 months of illness, about 76% of the patients reported at least one symptom that persisted, with fatigue or muscle weakness being the most frequently reported symptom.[23] In accordance, this study showed that residual symptoms were manifested in post-COVID-19 patients, with anosmia, muscle weakness and fatigue, dyspnea, and cough being the most frequent.

The inflammatory environment around viral infected cells is closely related to cell activation or the initiation of apoptosis and necrosis in these infected cells with subsequent shedding of MPs.[8] Studies have shown that MPs, including PDMPs, contain cellular receptors, cytoplasmic proteins, nucleic acids (RNA, microRNA, and DNA), and cytokines,[20] which may be the key factor mediating lung inflammation storms. The PDMPs can stimulate the production of inflammatory mediators as interleukin-1 (IL-1), IL-6, IL-8 and tumour necrosis factor-alpha. These cytokines, in turn, further activate inflammation, allowing cells to produce more MPs, which exacerbate inflammatory response.[25]

Our finding that PDMPs are significantly higher in active COVID-19 patients is consistent with a model, in which SARS-CoV and SARS-CoV-2 directly infect endothelial and epithelial cells, increasing levels of proinflammatory cytokines, causing immune-mediated damage to the vasculature and surrounding tissue releasing MPs.[26]

As COVID-19 is a newly emergent infectious disease, only a few studies have been focused on extracellular vesicles (EVs), including MPs, in terms of their role in the pathogenesis of COVID-19.[27] A study by Zaid et al.;[28] revealed that phosphatidylserine-expressing platelet MPs, quantified by flow cytometry, were increased in nonsevere cases compared to that in healthy volunteers but not in severe cases of COVID-19. In the same way, a significant higher levels of PDMPs were reported in COVID-19 affected patients compared to healthy controls.[29] Another study has evaluated TF positive EVs in COVID-19 patients; revealed that the levels of TF activity of the EVs were significantly higher in patients with COVID-19 than in healthy controls; and their activity levels were related to disease severity and mortality.[30] We found that levels of PDMPs were nonsignificantly higher in active COVID-19 disease with TEE than those without TEE. Furthermore, nonsignificant correlation between levels of PDMPs and residual symptoms severity or radiological findings in post COVID patients was detected. We relate that finding to the method we used to measure PDMPs which is based on detection of platelets specific markers with no reflection of their TF activity and can be explained by previous studies that reported both procoagulant and anticoagulant properties of PDMPs.[12],[13],[14],[15],[16],[17],[18],[19] The increased PDMPs levels in active COVID-19 are mostly due to direct inflammatory environment secondary to virus activity, however, the small sample size included for patients with TEE make an enquiry about the role of PDMPs in COVID-19 hypercoagulability. Hence, we suggest further comprehensive studies including also mild and moderate cases with active COVID-19 infection for better assessment of the prognostic value and biological role of PDMPs in COVID-19 patients.

By comparing hematological and biochemical variables in active COVID-19 and post-COVID-19 patients, high significant differences were elicited between both groups regarding Hb level, TLC, ANC, ALC, CRP level, D-dimer, and serum ferritin. These findings are in accordance with previous reports those concluded the usefulness of these biomarkers in diagnosis and follow up as well as detection of recovery for COVID-19 patients.[31],[32],[33],[34],[35]

The highly significant positive correlation detected between PDMPs and LDH in active COVID-19 patients can be explained by the effect of inflammation and tissue damage caused by the active virus that increases the levels of both PDMPs and LDH.[8],[36] In the same way, the positive correlations between PDMPs and both TLC and ANC can be attributed to the role of MPs in initiation and propagation of inflammatory processes by stimulating their mediators those affect immune response including neutrophils. The ALC was the only marker showing a significant difference between patients with and without TEE; the prognostic value of ALC in sever COVID-19 infection is previously reported.[37]

In group B, significant positive correlations were found between PDMPs levels and CRP, serum ferritin, and LDH. As previously discussed, the mentioned biomarkers are upregulated with inflammation and tissue destruction and lower down with its subsequent decline. In addition, platelets PDMPs can affect CRP level by modifying the pentameric CRP into its inflammatory form.[38]

The finding that PDMPs levels are correlated to some of the known follow-up biomarkers, made suggestion that PDMPs can be used in follow–up, and discrimination between active and post-COVID-19 patients. To reveal that, ROC curve analysis was performed for discrimination between active COVID-19 and post-COVID-19 patients using PDMPs and alternative known markers including CRP. D-dimer, serum ferritin, ALC, and RLC. All these markers, including PDMPs at a cutoff level ≥20 IU/mL, could discriminate active from post-COVD-19 patients. Except for CRP, no significant difference was detected between AUC of PDMPs and other markers.

The findings that these known biomarkers can be used in follow-up of COVID-19 patients are in accordance of previous reports.[31],[32],[33],[34],[35] Regarding PDMPs, the result in this study is in agree with previous studies suggested the use of PDMPs in follow-up and severity assessment for other viral infected patients, for example, dengue fever and HIV.[39],[40],[41]


  Conclusion Top


Levels of PDMPs increase in patients with active COVID-19 infection as a part of the ongoing inflammatory process due to virus activity. Their correlation to TEE in active COVID-19 and severity of the disease or clinical outcome in post-COVID-19 could not be elicited. Comprehensive studies including mild and moderate cases of active COVID-19 are recommended for the better assessment of the prognostic value and biological role of PDMPs in COVID-19 infection.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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International Journal of Molecular Sciences. 2022; 23(14): 7837
[Pubmed] | [DOI]



 

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  In this article
Abstract
Introduction
Patients and Methods
Results
Discussion
Conclusion
References
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