COVID-19 Diagnostics: University of Manchester Study Finds That Platelet Size Can Be Used To Predict COVID-19 Severity And Mortality
: A new study by researchers from the University of Manchester-UK has found that platelet size can be used to predict COVID-19 severity and mortality.
According to the researchers, parameters reflecting platelet size can be sensitive indicators that circulating platelets are activated and COVID-19 patients are at increased risk of thrombosis.
The team attempted to assess the association of mean platelet volume (MPV), platelet distribution width (PDW) and platelet-large cell ratio (P-LCR) with disease severity and mortality in COVID-19 patients.
Various English and Chinese databases were searched electronically to identify studies reporting data on MPV, PDW or P-LCR in COVID-19 patients. Included articles underwent a quality rating. A meta-analysis was performed using the standard mean difference and interpreted as the common language effect size (CLES).
In all twenty-two studies (11,906 patients) were included in the meta-analysis. Of these, 14 were rated poor and eight were fair.
The study finding showed that the MPV and P-LCR was significantly higher at hospital admission in severe patients compared to non-severe patients. The MPV, PDW and P-LCR were significantly higher at hospital admission in non-survivors compared to survivors. There was a marked increase in the probability of a severe COVID-19 patient presenting with higher P-LCR at hospital admission than a non-severe patient (CLES: 68.7% [95% CI: 59.8%, 76.5%]), when compared with MPV and PDW ((CLES: 59.2% [95% CI: 53.1%, 65.1%]) and (CLES: 55.9% [95% CI: 50.6%, 62.2%]), respectively).
The study findings concluded that severe COVID-19 disease is associated with the increased production of larger, younger platelets. When comparing MPV, PDW and P-LCR, P-LCR is the most important biomarker for evaluating platelet activity. P-LCR testing at hospital admission could identify COVID-19 patients with increased risk for thrombotic events, allowing preventative treatment.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2021.07.15.21260576v1
The current COVID-19 pandemic caused by the SARS-CoV-2 has baffled researchers with its propensity to cause symptoms of largely unpredictable severity in the affected individuals.
Though most patients have mild or no symptoms, a significant minority develop severe or critical symptoms, and some have a fatal outcome.
Excitingly this new study finding shows the potential predictive value of platelet size
in this situation. COVID-19 patients with severe disease often develop clots in vital organs, which leads to further complications. It is known that platelet size is a good indicator of activation.
The study shows that platelet-large cell ratio (P-LCR) is a key signal of platelet activity in COVID-19, detectable at the point of admission, and could well triage high-risk patients before they develop thrombotic complications.
Further detailed research will be required both to ratify this finding, and to de
termine reliable thresholds with clinical utility.
Typically platelets are tiny bits of cells containing coagulation granules that play a key role in both clotting and in the immune response. As such, they take part in sealing bleeding vessels, but also in abnormal clot formation. During viral infection, the platelets take part in immunothrombosis, involving both these processes.
It has been found that COVID-19 patients show evidence of platelet activation, with high P-selectin expression even in resting platelets, and clumps of platelets associated with leukocytes in circulation.
Platelet aggregation is also increased, with elevated levels of thromboxane, a pro-inflammatory procoagulant molecule.
Importantly this state of platelet hyperreactivity is considered by some scientists to be the cause of immunothrombosis in COVID-19, especially since platelet counts are slightly decreased in these patients. In fact, a consistent fall in platelets is linked to higher mortality in this condition.
A majority of COVID-19 patients with acute lung injury (ALI) show increased pulmonary megakaryocytes. This may indicate compensatory megakaryocyte production in this organ, a prominent site of production, due to platelet consumption in the activated state triggered by COVID-19.
The study team used platelet activation markers to assess the activation status of the platelets in COVID-19 patients. However, they used inexpensive point-of-care techniques that would yield rapid results, thus making them suitable for clinical practice. One such is platelet size, which can be determined using automated analyzers commonly used in hematology.
Normally younger platelets are larger and more active, indicating a higher risk of thrombosis. The analyzers assess the size and count using methods such as impedance, optical scattering, and fluorescence.
Platelet morphology is described in terms of mean platelet volume (MPV), platelet distribution width (PDW) and platelet-large cell ratio (P-LCR).These morphological parameters were assessed as well for their association with adverse outcomes in severe COVID-19.
The study team reviewed numerous studies on this aspect of platelet morphology in COVID-19. They found 22 studies that fulfilled their criteria, of which 15 used MPV as a parameter.
The meta analysis showed higher MPV levels in severe COVID-19 relative to less severely ill patients, though the difference was slight. When only intensive care unit admission was used as a criterion to define severe COVID-19, the difference was greater.
Platelet distribution width or PDW, as assessed for correlation in seven studies, showed a higher value in the severe group. Still, when the time of testing was taken into account, the swelling of the platelets over time, following collection, was found to underlie the apparent increase in size.
Interestingly, the P-LCR was also found to be higher in severe cases, with a marked difference from less severe illness. The standard mean deviation of 0.60 was higher than that found with the other two parameters, which had SMDs hovering around 0.23.
The study team also found that the pooled MPV showed an SMD of 0.34 between severe and non-severe COVID-19 cases, while the PDW showed an SMD of 0.45 between the two.
The P-LCR however showed a very significant difference, with the SMD being 0.49.
The study team also found that the chances of the MPV being high in severe COVID-19 were almost 60%, vs. 56% for higher PDW. The probability was almost 70% that severely ill COVID-19 patients would have higher P-LCR values compared to non-severe COVID-19.
Utilizing only four studies, SMD data showed that the chances for a high MPV at admission, relative to survivors, were over 60% in patients with a fatal outcome. The probability that the PDW would be high in non-survivors was similar, at 59%, with the probability of a higher P-LCR being 62%.
The study findings indicate that platelet size could be a valid predictor of COVID-19 severity and mortality.
This is the first full-scale analysis of all studies based on this parameter in this area.
Importantly not only is the MPV much more likely to be higher in severe or non-survivor COVID-19 patients, but the association was even stronger when only studies that used clearly defined outcomes were included.
This sheds light on the need to describe outcomes as such in similar studies.
Interestingly the PDW is also linked to severe disease, but its significance is doubtful when the time of testing is accounted for. However, the homogeneity of the studies lends weight to the findings.
It should be also noted that high P-LCR values are also associated with severe disease and higher mortality in these patients, a finding reported in another earlier study.
In simple terms, despite modest increases, “it identified that there was a higher probability that a COVID-19 patient who does not survive, will have a higher MPV, PDW and P-LCR at hospital admission than a survivor.”
Hence the MPV and P-LCR could be biomarkers of severe or fatal outcomes in COVID-19.
The study team also pointed out that despite severe illness, with both immune and coagulation system activation, platelet counts remained more or less normal, indicating that platelet production increased to keep pace with the increased consumption.
It is also known that larger platelets, corresponding to younger platelets, have greater surface receptor expression and ATP content. They are also more transcriptionally active and bind fibrinogen to a greater extent.
In this research, larger platelet size was reported, indicating that severe COVID-19 is associated with mild decreases in the platelet count, which triggers compensatory megakaryopoiesis and the release of larger numbers of immature larger platelets.
Significantly this could be one mechanism explaining the higher rate of thrombosis in COVID-19.
The study findings, which come from routine automated hematology analyses, are extremely promising, since this association of platelet size with outcome could serve as a predictor of potentially severe or fatal disease. Both MPV and P-LCR predict a higher risk of severe or fatal outcomes when they are elevated at the time of admission. Also PDW is associated with a higher risk of death, but P-LCR most significantly with severe disease, in COVID-19.
Importantly further detailed studies are needed to validate and quantify these results before they can be used as clinical parameters.
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