Patients with coronavirus disease 19 (COVID-19) are at high risk for thrombotic arterial and venous occlusions; however, in a subset of patients, there is also a risk of bleeding complications, according to a study published in Scientific Reports.
“While the prothrombotic risk associated with COVID-19 is well recognised, the risk of bleeding should not be ignored,” wrote Yu Zuo, MD, University of Michigan Medicine, Ann Arbor, Michigan, and colleagues. “Understanding the balance between coagulation and fibrinolysis will help inform optimal approaches to thrombosis prophylaxis and potential utility of fibrinolytic-targeted therapies.”
For the study, the researchers measured plasma antigen levels of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), and performed spontaneous clot-lysis assays in 118 hospitalised patients with COVID-19 and 30 healthy controls. In the cohort, 42% of patients were supported by mechanical ventilation, 8% were receiving high-flow oxygen, 27% were supported by standard nasal cannula, and 24% were breathing ambient air.
Patients hospitalised with COVID-19 had markedly elevated tPA (mean, 78 vs 2.4 ng/mL, P < 0.0001) and PAI-1 (mean, 75 vs 40 ng/mL, P < 0.0001) than controls. High levels of both tPA (r = -0.19, P = 0.04) and PAI-1 (r = -0.35, P = 0.0002) were also associated with worse respiratory status.
Among the 118 patients, 24 died, 92 were discharged, and two remained hospitalised at the time of the analysis. Significantly higher levels of both PAI-1 (P = 0.04) and tPA (P = 0.0003) were observed among patients who died compared with those who were discharged, with the authors noting that the difference was especially “robust” for tPA.
A spontaneous fibrinolysis assay was performed on the plasma samples of 10 patients with COVID-19 with high tPA (>100 ng/mL) and 10 patients with COVID-19 with low tPA (< 20 ng/mL), as well as 10 healthy controls. The high-tPA COVID-19 samples significantly enhanced spontaneous fibrinolysis compared with low-tPA and healthy control plasma samples.
“Consistent with this observation, we found that tPA levels were on average 2.2-fold higher than PAI-1 in the high tPA group,” the authors wrote. “This was in contrast to the ratio in control plasma samples or in patients with COVID-19 with tPA <20 ng/mL.”
“While both tPA and PAI-1 are elevated among patients with COVID-19, extremely high levels of tPA enhance spontaneous fibrinolysis and are significantly associated with mortality in some patients,” the authors wrote. “These data indicate that fibrinolytic homeostasis in COVID-19 is complex with a subset of patients expressing a balance of factors that may favour fibrinolysis. Further study of tPA as a biomarker is warranted.”
“Because the COVID-19 associated prothrombotic risk is known, prophylactic anticoagulation has become part of standard COVID-19 treatment. High rates of thromboembolic events from early studies prompted some experts to recommend a more intensive dose of anticoagulation among COVID-19 patients,” the authors noted. “We would urge caution regarding this recommendation (pending randomised studies) as the coagulopathy of COVID-19 is complex and potentially dynamic.”
“Profibrinolytic therapy has been suggested as a potential beneficial therapy in COVID-19 patients suffering from acute respiratory distress syndrome and is currently being tested in multiple clinical trials,” the authors added. “We have now found that a hyperfibrinolytic state exists in some COVID-19 patients. Targeted therapies that promote fibrinolysis therefore need to be selective and cautious to minimise bleeding risk.”