This scanning electron microscope image shows SARS-CoV-2 (yellow)—also known as 2019-nCoV, the virus that causes COVID-19—isolated from a patient in the United States, emerging from the surface of cells (blue/pink) cultured in the lab. [NIAID-RML]

A study in Ireland has found that some Caucasian patients hospitalized with severe COVID-19 develop a form of abnormal blood clotting that can contribute to death. The study, carried out by clinician scientists at the Irish Centre for Vascular Biology, RCSI, and St. James’s Hospital, Dublin, found that the abnormal blood clotting caused micro-clots within the lungs, and that patients with higher levels of blood clotting activity had a significantly worse prognosis and were more likely to require admission to an intensive care unit (ICU). The investigators say their results may also help to explain emerging evidence of differences in racial susceptible to COVID-19 mortality.

The study is published in the British Journal of Haematology. “Our novel findings demonstrate that COVID-19 is associated with a unique type of blood clotting disorder that is primarily focused within the lungs and which undoubtedly contributes to the high levels of mortality being seen in patients with COVID-19,” said James O’Donnell, MD, director of the Irish Centre for Vascular Biology, RCSI, and consultant hematologist at the National Coagulation Centre in St James’s Hospital, Dublin. O’Donnell and colleagues reported their findings in a paper titled, “COVID-19 Coagulopathy in Caucasian Patients.”

Severe COVID-19 infection is associated with marked lung alveolar inflammatory cell infiltrate, together with a systemic cytokine storm response, the authors wrote. Several studies have also reported evidence of COVID-19-associated clotting disorders, and post-mortem studies have indicated pathological changes to the lung microvasculature, including microthrombi and hemorrhagic necrosis. “Although the pathophysiology underlying severe COVID-19 remains poorly understood, accumulating data suggest that a lung-centric coagulopathy may plan an important role,” the team noted. “Moreover, emerging data suggest that severe COVID-19 is also associated with a significant risk for developing deep vein thrombosis and pulmonary embolism.”

Most published data on COVID-19-related coagulopathy have been derived from studies on Chinese patients, but race and ethnicity have major effects on thrombotic risk, the investigators continued. Epidemiological studies have found that the incidence of venous thromboembolism (VTE) is 3–4 fold lower in Chinese patients than it is in Caucasians, and is significantly higher in African-Americans than it is in Caucasians. The lower incidence of VTE in Chinese patients means that thromboprophylaxis is used less in Chinese hospitals. “Given these data, it is clearly important to determine whether there are differences in coagulopathic features in COVID-10-infected Caucasian compared to Chinese patients.”

The investigators’ study included 83 consecutive COVID-19 patients admitted to the hospital between March 13, 2020, and April 10, 2020. There were 55 male and 28 female patients, with an age range of 26–92 years. Sixty-seven patients (81%) were Caucasian, 10 (12%) were Asian, 5 (6%) were African, and 1 (1%) was of Latino/Hispanic ethnicity. Underlying comorbidities were identified in 67 (80.7%) patients. All patients tested positive for SARS-CoV-2 by PCR, and all received supportive care, including the use of supplemental oxygen where indicated, and low molecular weight heparin (LMWH) for thromboprophylaxis, unless contraindicated.

The patients underwent a range of tests at admission and throughout hospitalization, including measures of coagulation, D-dimer level, platelet counts, and fibrinogen testing. The cohort was also split into two groups based on whether they had to be admitted to the ICU for ventilator support or died due to COVID-19 infection, versus those who were discharged without requiring ICU support.

The researchers observed elevated D-dimer levels at admission, which remained higher in those patients who eventually needed ICU admission. “Similarly, fibrinogen and CRP levels were also both significantly elevated in the poor prognosis group,” the authors wrote. “The marked increase in D-dimer levels is consistent with progressive activation, along with concurrent activation of fibrinolysis within the lungs.” However, they noted that despite increased D-dimer levels, platelet counts were normal. “Thus, despite the fact that thrombotic risk is much higher in Caucasian patients and the significant elevated levels of D-dimers observed, overt DIC as defined according to the ISTH SSC DIC score was present in none of our COVID-19 patients at time of admission.”

James O’Donnell, MD, director of the Irish Centre for Vascular Biology, RCSI University of Medicine and Health Sciences, and consultant hematologist in the National Coagulation Centre in St James’s Hospital, Dublin. [Maxwell Photography]
Reporting on their findings, the investigators said that the observation that abnormal coagulation parameters on admission to hospital were linked with poorer prognosis in Caucasian patients with COVID-19 infection was in keeping with previous Chinese data.

“In addition to pneumonia affecting the small air sacs within the lungs, we are also finding hundreds of small blood clots throughout the lungs,” O’Donnell stated. “This scenario is not seen with other types of lung infection, and explains why blood oxygen levels fall dramatically in severe COVID-19 infection.”

“Cumulatively, these data support the hypothesis that COVID-19 associated coagulopathy probably contributes to the underlying pulmonary pathogenesis.” But critically, the investigators added, “despite the evidence of progressive COVID-19 coagulopathy over time, none of our cohort maintained on prophylactic LMWH developed systemic DIC.” In the rare cases that DIC did develop, it tended to be restricted to late-stage disease.

The investigators concluded that diffuse bilateral pulmonary inflammation observed in COVID-19 is associated with a novel pulmonary-specific vasculopathy, which is distinct from DIC, and which they’ve termed “pulmonary intravascular coagulopathy (PIC).”

“Understanding how these micro-clots are being formed within the lung is critical so that we can develop more effective treatments for our patients, particularly those in high-risk groups,” O’Donnell commented. “Further studies will be required to investigate whether different blood thinning treatments may have a role in selected high-risk patients in order to reduce the risk of clot formation.”

The authors suggest that larger, controlled studies will be needed to determine whether more intensive anticoagulation and/or targeted anti-inflammatory therapies might help reduce PIC in patients with severe COVID-19. The findings may also be relevant to growing evidence that some ethnicities are more likely to develop serious COVID-19 than others. “Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID-19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID-19 mortality,” they concluded.

O’Donnell led the cross-disciplinary study, with joint first authors Helen Fogarty, MD, and Liam Townsend, MD, together with consultants from multiple specialties within St. James’s Hospital and researchers at RCSI University of Medicine and Health Sciences and Trinity College Dublin.

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