The role of carboxypeptidase U in severe COVID-19
The role of carboxypeptidase U in severe COVID-19

The role of carboxypeptidase U in severe COVID-19

Corona disease 2019 (COVID-19), which is caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), primarily affects the lower respiratory tract. However, the majority of individuals infected with SARS-CoV-2 either develop no symptoms or experience very mild symptoms.

Examination: Activation of the Carboxypeptidase U (CPU, TAFIa, CPB2) system in patients with SARS-CoV-2 infection may contribute to COVID-19 hypofibrinolytic status and prognosis of disease severity. Image Credit: MattLphotography /


Approximately 15% of COVID-19 patients develop viral pneumonia and requires oxygen support, of which about 5% of patients may develop sepsis, severe acute respiratory distress syndrome (ARDS) and / or multiorgan failure.

Along with respiratory failure, systemic thromboembolic complications are frequently observed in COVID-19 patients due to dysregulation of the hemostatic balance. These patients are characterized by low antithrombin concentrations, prolonged prothrombin time, mild thrombocytopenia and elevated fibrinogen.

Elevated levels of plasminogen activator inhibitor 1 (PAI-1) and significantly reduced clot light indicate hypofibrinolysis in COVID-19 patients. Increased plasma D-dimer concentrations also indicate plasmin-mediated fibrinolysis due to the activation of the coagulation cascade.

The enzyme carboxypeptidase U (CPU) is a potent inhibitor of fibrinolysis. After thrombin or plasmin activates zymogenic procarboxypeptidase U (proCPU), CPU effectively delays plasminogen activation and helps counteract the progression of fibrinolysis.

A new study published in Jural for clinical medicine measured both proCPU and CPU + CPUi over time to determine the impact of SARS-CoV-2 infection on the CPU system. These results may help determine whether CPU plays a role in the hypofibrinolytic state observed in COVID-19 patients.

About the study

The current study involved hospitalized patients who were at least 18 years old and with confirmed SARS-CoV-2 infection. Clinical data, recorded interventions and information on the severity of the disease were collected. Clinically healthy individuals were also included in the study to serve as controls.

Blood samples were collected from the inpatients shortly after admission, who were also monitored periodically until their discharge. For controls, two blood samples were taken at four-week intervals.

Plasma proCPU concentrations, as well antigen levels of both enabled and disabled CPU (CPU + CPUi) were determined from the samples collected. Routine laboratory parameters for the COVID-19 positive cohort were also determined.

Survey results

A total of 56 SARS-CoV-2-positive patients were included in the current study, of which 38 were men and 18 were women. The average length of hospitalization was three to 61 days, while the mean age ranged from 29 to 84 years. A total of 32 healthy controls were included in the study, of which 14 had a history of previous SARS-CoV-2 infection, while 18 had no previous SARS-CoV-2 exposure.

The results indicated that proCPU or CPU + CPUi antigen levels did not differ between the two control groups. For COVID-19 patients, proCPU levels were lower compared to controls shortly after hospitalization, whereas CPU + CPUi antigen levels were significantly higher.

However, ProCPU levels increased during the first week of hospitalization and were significantly higher around day 14 compared to healthy controls. Thereafter, proCPU levels decreased and were almost comparable between COVID-19 positive patients and healthy controls at discharge.

CPU + CPUi antigen levels also increased over time after hospitalization and until day 14. This was followed by a significant reduction in CPU + CPUi antigen levels at discharge that were comparable to levels shortly after hospitalization.

However, CPU + CPUi antigen levels at discharge were higher in COVID-19 patients compared to controls. Both proCPU and CPU + CPUi antigen levels remained stable for 28 days.

The secondary increase in proCPU levels was higher for critical illness compared to non-critical illness. Furthermore, the normalization of CPU + CPUi antigen levels was slower in patients with critical illness.

High levels of C-reactive protein (CRP) were observed in patients with reduced proCPU levels. A positive correlation between baseline CPU + CPUi antigen levels and the duration of hospital stays was observed. CPU + CPUi antigen levels shortly after admission were also reported to correlate positively with disease severity.


The current study found that an increase in both proCPU and CPU + CPUi antigen levels occurs after hospitalization for COVID-19 patients. These CPU changes may lead to closure of fibrinolysis and increase the risk of thrombosis in COVID-19 patients.

Therefore, CPU inhibitors can be used as therapeutic agents to potentially increase fibrinolytic capacity in COVID-19 patients. In addition, CPU + CPUi antigen levels can serve as a biomarker with prognostic value as they correlate with the severity of the disease and the duration of hospitalization.


Follow-up of additional hemostasis parameters was not performed over time. A further limitation was that patients with asymptomatic SARS-CoV-2 infection were not included in the current study. Finally, correlations of fibrinolytic activity and CPU-related parameters in patients with severe SARS-CoV-2 infections were not determined.

Journal reference:

  • Claesen, K., Sim, Y., Bracke, A., et al. (2022). Activation of the Carboxypeptidase U system (CPU, TAFIa, CPB2) in patients with SARS-CoV-2 infection may contribute to COVID-19 hypofibrinolytic status and prognosis of disease severity. Journal of Clinical Medicine. doi: 10.3390 / jcm11061494.

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