Source: COVID-19 Severity  Jul 29, 2020  2 years ago
COVID-19 Severity: Irish Research Reveals High Presence Of Circulating Platelets With Unique Hyperactive Phenotype In COVID-19 Patients
COVID-19 Severity: Irish Research Reveals High Presence Of Circulating Platelets With Unique Hyperactive Phenotype In COVID-19 Patients
Source: COVID-19 Severity  Jul 29, 2020  2 years ago
COVID-19 Severity: A new Irish study led by researchers from University College Dublin and with other institutions involved have discovered the presence of circulating platelets with a unique hyperactive phenotype in COVID-19 patients.

The research findings published on a preprint server and yet to be peer-reviewed reports a bidirectional relationship between COVID-19 and coagulation abnormalities.
One of the disturbing uncertainties of the disease is the difficulty of predicting which patient will develop progressive severe symptoms ending in respiratory failure and death. COVID-19 disease, caused by the SARS-CoV02 coronavirus, is marked by a hyperinflammatory response and severe pneumonitis.
Past research has indicated that this inflammatory pathway interacts with abnormal coagulation activity, and this is a driver of severe illness in these patients.
It has now been known that patients with severe COVID-19 have shown an unexpected propensity to thromboembolism in the deep vein, and high D-dimer levels are also reported. This is a marker of hypercoagulability of blood and seems to indicate both more severe disease as well as a higher rate of mortality. The patients with a history of hypertension and diabetes, and other cardiovascular risk factors, are at higher risk of thrombosis. Moreover, autopsy studies of COVID-19 patients show the presence of clots throughout the lung blood vessels as well as in other organs.
Significantly, another important observation is the strange lack of usefulness of antiplatelet drugs like aspirin, and anticoagulant drug like low molecular weight heparin in COVID-19, though they are normally expected to play a starring role in preventing such venous thrombosis.
It was observed that in COVID-19, instead, the rates of venous thromboembolism (VTE) remain high, and arterial clots are also reported.

Considering the severe outcomes of such clots, it is vital to unravel the mechanisms at work to cause the hypercoagulable state in this disease to develop the right preventive and treatment regimens.
This Irish study focuses on the role of platelets in this abnormally coagulable condition. Platelets are vital to clotting as well as in inflammation, wound healing, and the growth of new blood vessels into restorative tissue. Platelets have been shown to respond to viral infections as part of the immune response. Moreover, COVID-19 patients appear to have alterations in the expression of platelet genes and the way platelets respond to various stimuli.
For instance, low platelets in COVID-19 patients may also herald death during hospitalization, as they may increase mean platelet volume (MPV), which is a sensitive indicator that circulating platelets are activated, as well as helping determine the outcome in clot-related inflammatory processes. MPV is also found to increase in particular viral infections.
The research included 54 patients with confirmed COVID-19, of which 34 patients were in intensive care units on ventilators. The rest of them remained stable. Platelets were tested for their ATP secretion, as well as for their expression of thrombopoietin (TPO), P-selectin and platelet factor 4 (PF4).
The study team found that D-dimer levels were higher at admission among those who developed progressive disease. This subset of patients also had higher MPV and a higher neutrophil count, while the ratio of platelets to neutrophils was lower at admission. These differences were still obvious after they entered ICUs.
Interestingly at initial stages, platelet counts were comparable between both groups but subsequently decreased among the severe group at the point of ICU admission, in addition to a higher ratio of neutrophils to lymphocytes, findings that agree with earlier studies.
Similar to other researchers, the current study shows that platelet aggregation increases with exposure to low-dose thrombin and U46619 (a thromboxane A2 receptor agonist), activators of dense granule release. Platelets respond more sensitively with ADP secretion to such activating doses within the blood of COVID-19.
It was observed that ADP release increased three times with low doses of thrombin, but 28 and 89 times with U46619 compared to healthy and hospitalized controls. With high doses, the dense granule secretion increased two and ten times in COVID-19 patients and controls, respectively.
In brief, platelets in COVID-19 patients respond more readily and highly to low doses of activators ie they have a lower threshold for activation.
Such a pattern has been previously reported concerning low-level agonist-induced platelet reactivity in patients with dengue virus nonstructural proteins.
Hence the study findings could imply “a virus-induced sensitization of platelets.”
Importantly, the autocrine role of ADP, ATP and thromboxane A2 causes further amplification of platelet activation and granule release. This further indicates that COVID-19 is a condition in which platelet reactivity is increased, promoting the occurrence of clotting.
Also it was observed that in COVID-19 patients, TPO, PF4, and soluble P-selectin were all higher compared to controls. The latter could also discriminate severe from mild COVID-19, as could TPO to a lesser extent.
More importantly, COVID-19 appears to be related to higher than normal platelet responsiveness to activators, which could indicate a push towards higher platelet production as signaled by the increase in TPO in COVID-19 patients uniformly.
The observed raised MPV at admission in those who went on to develop severe disease also indicates the expression of more activation markers, on platelets with a higher dense granule density. When these granules release their contents such as ADP, thromboxane, and Beta-thromboglobulin, this can act as a powerful stimulant to further activation of platelet reserves.
One past study has found that mRNA encoding ACE2 is found in platelets. Still, it is not known if the virus infects platelets, either via ACE2 or other receptors like FcγRIIA, to promote hyper-responsiveness.
Dr Barry Kevane the corresponding author and a Professor from the Department of Haematology, Mater Misericordiae University Hospital and also at University College Dublin told Thailand Medical News, “It has been apparent since the early stages of the COVID-19 pandemic that derangements of hemostasis represent a hallmark of this disease and appear to be associated with significant morbidity. The etiology of hypercoagulability in COVID-19 is likely multi-factorial but it is presumed to be driven by the marked inflammatory response which arises following infection. Further understanding of how platelet dysfunction occurs and how to counter it successfully in COVID-19 is crucial to reducing the number of deaths that occur following a progressive illness.”
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