Over 16.6 million people have been infected the world over with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) since the COVID-19 outbreak began in December 2020. The infection is a curious one, with many scientists comparing the confirmed cases to the tip of an iceberg.
Among the vexing 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 virus, is marked by a hyperinflammatory response and severe pneumonitis. Prior research has indicated that this inflammatory pathway interacts with abnormal coagulation activity, and this is a driver of severe illness in these patients.
Now, a new study by Irish researchers and published in the preprint server medRxiv* in July 2020 reports a bidirectional relationship between COVID-19 and coagulation abnormalities.
Hypercoagulability in COVID-19
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.
Still another indicator 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. In COVID-19, instead, the rates of venous thromboembolism (VTE) remain high, and arterial clots are also reported. Given 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.
The current 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.
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 Study: Hyperactive Platelets
The study 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 researchers 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.
Initially, 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.
Platelets Hyper-Responsive to Activators
Like 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.
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 short, platelets in COVID-19 patients respond more readily and highly to low doses of activators – they have a lower threshold for activation.
This pattern has been previously reported concerning low-level agonist-induced platelet reactivity in patients with dengue virus nonstructural proteins. This, the study says, could mean “a virus-induced sensitization of platelets.” 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.
Higher PF4, sP-Selectin, and TPO
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.
Platelet Activation Predicts Severe Disease
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 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 prior 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.
The study concludes, “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.
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.