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Clinical Context

COVID-19 is known to create a prothrombotic state, although thrombi in patients with COVID-19 are usually limited to small vessels. Nonetheless, there is a potential role for routine anticoagulation among patients with severe COVID-19. All patients hospitalized with COVID-19 should be strongly considered for routine thromboprophylaxis with drugs such as enoxaparin, but Lemos and colleagues compared prophylactic doses of enoxaparin with higher dosages used to treat active thrombosis in a cohort of patients with severe COVID-19. The results of their small, randomized trial were published in the December 2020 issue of Thrombosis Research.^[1]

Researchers randomly assigned 20 patients with severe COVID-19 receiving mechanical ventilation to prophylactic or therapeutic doses of enoxaparin. Over 14 days, the group receiving the higher dose of enoxaparin had improved partial pressure of arterial oxygen to fraction of inspired oxygen ratios, indicating improved pulmonary function. The cohort receiving the prophylactic dose of enoxaparin did not achieve this outcome. In addition, participants in the therapeutic dose group had a 4-fold increase in weaning off mechanical ventilation vs the prophylactic dose cohort, with a total of 15 fewer days on mechanical ventilation. There were no major bleeding events in either treatment group.

This study was too small to change current management protocols for severe COVID-19, but larger trials of anticoagulation are ongoing. A stronger understanding of the pathophysiology of thrombosis in COVID-19 can help to identify more therapeutic targets, and the current study by Canzano and colleagues addresses this issue.

Study Synopsis and Perspective

New evidence shows that patients with COVID-19 with severe disease have a high level of sustained platelet activation that is likely contributing to the thrombotic issues associated with the infection from SARS-CoV-2, the virus that causes COVID-19.

"We know that COVID-19 patients have an increased thrombotic risk, despite being treated with heparin. In this study, we found evidence of a huge platelet activation in patients hospitalized with COVID-19 infection, suggesting that we should be considering antiplatelet agents as well as anticoagulants as part of their treatment," lead author Marina Camera, PhD, told Medscape Medical News.

"Our data is important for the scientific community," she added. "Many trials are underway investigating antiplatelet agents in COVID patients but until this study, there was no hard scientific data supporting this."

Treating thrombotic complications in COVID-19 with anticoagulants is complicated by the high risk of bleeding if doses are increased too much, Camera noted.

"These data suggest we should be trying antiplatelet agents," she said.

Camera, who is professor of pharmacology at the University of Milan, Milan, Italy, pointed out that the findings are consistent with autopsy studies that have found platelet-rich thrombi in the microvessels of the lungs.

"These thrombi get stuck in the vessels and impair oxygen exchange," she explained.

She suggested that clinicians could consider treating patients who have worsening COVID-19 with an antiplatelet drug.

"Just a low-dose aspirin -- the dose used for cardiovascular prevention -- could be enough. The risk would be low as it would only be taken for a few weeks," she said and added that more information on this would be forthcoming from the ongoing clinical trials.

Still, commenting for Medscape Medical News, Prapa Kanagaratnam, PhD, professor of cardiology at Imperial College, London, United Kingdom, urged caution.

"This study is very interesting and contributes to the growing evidence to support treatment aimed at thromboprophylaxis," Kanagaratnam said.

"It highlights the importance of supporting and completing the randomized clinical trials that are currently underway and are targeting various aspects of the thrombosis cascade. But until these trials start publishing their outcomes, we would not recommend treatment with these agents," he added.

The study was published in the March issue of JACC: Basic to Translational Science.^[2]

The authors noted that it is now well-documented that severe COVID-19 predisposes patients to thrombotic disease, both in the venous and arterial vascular beds, which may develop despite standard pharmacologic prophylaxis with heparin.

Endothelial injury, a common feature of viral infection, can alter hemostasis directly or indirectly. Viral or bacterial infections and inflammatory stimuli can induce tissue factor (TF) expression (a key activator of the blood coagulation cascade) in endothelial and circulating monocytes and granulocytes; these cells upon activation also release procoagulant microvesicles into the bloodstream, the authors explained.

Platelets participate in inflammation and thrombotic responses in many viral infections, the researchers reported.

"The low platelet count often described in COVID-19 patients suggests increased consumption due to a massive platelet activation and thrombus formation. Activated platelets also express a functionally active [TF] so they are able themselves to trigger the coagulation cascade," they wrote.

Severe COVID-19 is also associated with a cytokine storm, but how this affects platelet and endothelial activation in this clinical setting is almost completely unknown, they noted.

"Whereas data are rapidly emerging about COVID-19--associated coagulopathy and thrombosis risk, there is little high-quality evidence to guide antithrombotic management," they added.

The current study involved analysis of blood from 46 consecutive patients with COVID-19 admitted to San Luca Hospital, Milan, Italy, in April 2020. The researchers assessed the level of TF expression among the circulating cells and microvesicles; the residual plasma thrombin generation capacity despite heparin treatment; and the extent of platelet and endothelial activation.

They reported "a massive cell activation with production of [TF], mainly by platelets, granulocytes, and microvesicles."

The median level of TF-positive platelets in patients with COVID-19 was significantly higher than that found in healthy participants, with a trend toward greater values in patients with COVID-19 needing ventilation compared with patients not needing ventilation.

Results also showed a sustained platelet activation in terms of P-selectin expression, platelet-leukocyte aggregate (PLA) formation, and altered nitric oxide/prostacyclin synthesis.

When plasma from the patients with COVID-19 was added to the blood of healthy participants, platelet activation similar to that observed in vivo was seen. This effect was blunted by pre-incubation with aspirin, a P2Y12 inhibitor or the interleukin (IL)-6 antibody tocilizumab.

"These observations give insights into the IL-6--mediated platelet activation that triggers the hypercoagulable state in COVID-19, suggesting the potential effectiveness of anti--IL-6 antibodies and antiplatelet drugs," the authors wrote.

"The present study provides, for the first time to our knowledge, evidence that the coagulopathy reported in COVID-19 patients is supported by: 1) a sustained [TF] expression by virtually all the cells in contact with blood and by the derived microvesicles; and 2) a massive platelet activation characterized by the formation of PLA that may be involved in the pulmonary microthrombi found in autoptic specimens," the researchers stated.

"Our data provide the bench-to-clinic rationale behind the ongoing clinical trials assessing the potential effectiveness of antiplatelet drugs and IL-6 receptor antagonists in the treatment of COVID-19 patients," they added.

This work was supported by a grant from Italian Ministry of Health. The authors have disclosed no relevant financial relationships.

Clinical Implications

• In a previous small trial, therapeutic dosages of enoxaparin improved pulmonary function and discontinuation of mechanical ventilation vs prophylactic dosages of enoxaparin in patients with severe COVID-19. There were no major bleeding events in either treatment group. Further research is ongoing and necessary to confirm the results of this trial.
• Multiple cell types contribute to a hypercoagulable state in cases of COVID-19, with microvesicles derived from platelets and erythrocytes of particular importance. Thrombin production was elevated in cases of COVID-19, although low-molecular-weight heparin blunted this effect. IL-6 was associated with increasing platelet aggregation, and tocilizumab reduced this effect in vitro.
• Implications for the healthcare team: The healthcare team should watch for results of ongoing trials and national recommendations in advising treatment to patients with severe cases of COVID-19.

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