Multiorgan Clotting in COVID-19 Hints at Platelets’ Role in Inflammatory Response

A small series of autopsies from COVID-19 patients in New York confirms prior observations about severe hypercoagulability and shows the presence of platelet-rich blood clots in major organs, including the heart. The findings also suggest that physicians have pivoted in response to what they are learning from pathology data about thrombotic risk.

Compared with just a few months ago, current autopsies show that more and more patients battling COVID-19 are being anticoagulated, said Amy V. Rapkiewicz, MD (New York University Long Island School of Medicine, Mineola, NY).

“I think it just goes to show how the rapid distribution of this information, although sometimes it may not be peer reviewed, has actually been a relatively positive thing in the sense that we all have undivided attention towards this disease, and we are making relatively informed changes to better outcomes in these patients,” she told TCTMD.

In her study of seven autopsies, published online today in Lancet eClinicalMedicine, Rapkiewicz and colleagues further the pathological picture by confirming that platelet-rich thrombi could be found in the pulmonary, hepatic, renal, and cardiac microvasculature regardless of anticoagulation status before death.

“I think what it adds is that the degree of small-vessel thrombi, or microvascular thrombosis, is more widespread than just the lungs,” Rapkiewicz noted.

Autopsy studies of COVID-19 patients have been slowly trickling into the medical literature over the last few months. As TCTMD previously reported, a German pathology study of 12 patients found that many had mortality-related pulmonary embolism (PE) despite no preclinical evidence of pulmonary embolism or deep venous thrombosis (DVT). Similarly, a series from Texas clarified suggestions that endothelial damage from the virus leads to a clotting disorder in the capillaries of the lungs of COVID-19 patients.

Commenting on the new data for TCTMD, Sahil Parikh, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), said while the findings regarding platelets and their distribution are interesting and potentially novel, they should not be misconstrued as suggesting the need for aggressive antiplatelet therapy given that the bleeding hazard in these patients is not inconsequential.

“It does give us another clue that inflammation is important. Platelet-rich thrombi may be a unifying feature, which would sort of tie together inflammation, as well as thrombosis, in a mechanism different than what has been targeted by treatment so far,” he noted. While there may be implications for treatment, Parikh reiterated that a cautious approach is needed to balance the thrombosis and bleeding risks and not make assumptions, especially based on very small autopsy studies, about the mortality benefits of anticoagulation.

“If it were true, we would be seeing reports from every institution saying anticoagulation saves lives,” he added. “We can’t be quick to pull the trigger on anticoagulation as the answer.”

Focusing on Platelets

Among the new clues imparted by Rapkiewicz’s study is the importance of megakaryocytes, the parent cells that create platelets. In addition to being found at increased numbers in the lung, megakaryocytes and platelet-fibrin microthrombi were found in the cardiac microvasculature in every patient. She and her colleagues say the finding is both suspicious and provocative, noting that there are only rare reports in the literature of megakaryocytes being found within the heart. Together, the megakaryocytes and the platelet-fibrin microthrombi may provide a window into furthering understanding of the underlying mechanisms that propel COVID-19.

Platelet-rich thrombi may be a unifying feature, which would sort of tie together inflammation, as well as thrombosis, in a mechanism different than what has been targeted by treatment so far. Sahil Parikh

To TCTMD, Rapkiewicz said it is “a very interesting observation that seems to be consistent across multiple COVID cases.” Importantly, she added, it suggests the need to look to what is known about other contagious viruses that affect the coagulation system. While COVID-19’s thrombotic pattern is at the opposite end of the spectrum from hemorrhagic viruses like Dengue fever and Ebola, Rapkiewicz said now is the time for researchers to be diligent and “learn from our history.”

Studying platelets, she added, could help tease out whether levels of proteins in the blood that normally stimulate platelet production are different in symptomatic versus asymptomatic COVID-19 patients. Emerging clues in the blood also may enable scientists to figuratively “walk backwards” from death to severe disease and focus on ways to identify high-risk patients and intervene earlier.

Another finding of the study was that four of seven patients had pulmonary arterial thrombi, which is in agreement with other COVID-19 autopsy studies showing that patients who die from the virus have a high prevalence of that type of thrombi. The appearance suggested that the thrombi were formed in situ in pulmonary arteries and not as a result of embolization from elsewhere in the body, which also aligns with other autopsy reports.

“However, it remains possible that the large thrombi progressed rapidly, originating from smaller emboli without time for development of organization and adherence to the vessel wall,” Rapkiewicz and colleagues write, adding that dissection of extremities could not be performed due to infection-control policies.

Anticoagulation Trials ‘All Over the Map’

Despite the fact that autopsy studies are limited by various factors, including being based on referral for autopsy rather than prespecified clinical parameters, Rapkiewicz said she believes it is important that postmortems continue in COVID-19 patients to help inform physicians as much as possible. Data from her group’s autopsies, of which there have now been 18, spurred creation by study co-author Jeffrey Berger, MD (NYU Langone Health, New York, NY), of a randomized trial comparing high-dose enoxaparin and lower-dose prophylactic anticoagulation in COVID-19 patients. The study is one of at least eight ongoing trials that are testing a host of anticoagulation strategies and timing of interventions.

Parikh is a primary investigator of one of those trials, IMPROVE, which is examining prophylactic enoxaparin at standard or intermediate dose based on indications that standard doses may be ineffective for blood thinning in COVID-19 patients.

“The strategies are all over the map,” he said. One problem with this is that the rate of COVID-19 infections is slowing in New York, where several of these trials are based: some of them may not fulfill their enrollment. Since multicenter studies are needed to confirm a consistent finding, the multiple efforts and trial designs are hampering progress.

“If we don't have the same protocols, you're comparing apples to oranges,” Parikh said. “So, if anything, it's a call for action for us as a community to get on the same page and try to run the same trial at multiple centers so we can then meta-analyze the data.”