Can platelet size predict severity and mortality in COVID-19?

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has baffled researchers with its propensity to cause symptoms of largely unpredictable severity in the affected individuals. While most patients have mild or no symptoms, a significant minority develop severe or critical symptoms, and some have a fatal outcome.

An exciting new study reports on 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.

Study: Platelet size as a predictor for severity and mortality in COVID-19 patients: a systematic review and meta-analysis. Image Credit: Christoph Burgstedt / Shutterstock

Recently released onto the medRxiv* preprint server, 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 prospective research will be required both to ratify this finding, and to determine reliable thresholds with clinical utility.

Background

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.

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.

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.

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.  

Study methods

The researchers 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. 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.

What were the findings?

The scientists 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 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.

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.

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.

Platelet size and COVID-19 mortality

The researchers 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.

However, the P-LCR showed a very significant difference, with the SMD being 0.49. The researchers 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.

Using 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%.

What are the implications?

These 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.

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.

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.

High P-LCR values are also associated with severe disease and higher mortality in these patients, a finding reported in another earlier study. In other words, 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.”

The MPV and P-LCR could therefore be biomarkers of severe or fatal outcomes in COVID-19.

The researchers 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.

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 study, 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.

This could be one mechanism explaining the higher rate of thrombosis in COVID-19.

These 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.

Meanwhile, PDW is associated with a higher risk of death, but P-LCR most significantly with severe disease, in COVID-19. Future prospective studies are needed to validate and quantify these results before they can be used as clinical parameters.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.