German Study Finds That SARS-CoV-2 Triggers Never Seen Before Altered Fibrin Clot Structures That Contributes To Thrombosis Risk In Severe COVID-19!
: A new study led by German researchers from the Center for Infection and Genomics of the Lung (CIGL), Universities of Giessen and Marburg Lung Center, Giessen-Germany along with scientist from numerous other German research institutions have shockingly found that the SARS-CoV-2 induces the formation of unique and different and fibrin clot structures never seen before in the human body and it is these altered fibrin clot structures that are contributing to thrombosis risk in severe COVID-19 patients.
According to the study abstract, “The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology.”
The study team demonstrated altered levels of factor XII (FXII) and its activation products in two independent cohorts of critically ill COVID-19 patients in comparison to patients suffering from severe acute respiratory distress syndrome due to influenza virus (ARDS-influenza).
The study team found rapid consumption of FXII in COVID-19, but not in ARDS-influenza, plasma.
Interestingly, the kaolin clotting time was not prolonged in COVID-19 as compared to ARDS-influenza.
Utilizing confocal and electron microscopy, the study team showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggers formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19.
The study team also observed clot lysis in 30% of COVID-19 patients and 84% of ARDS-influenza subjects. Analysis of lung tissue sections revealed wide-spread extra- and intra-vascular compact fibrin deposits in COVID-19.
The study findings indicate that elevated fibrinogen levels and increased FXII activation rate promote thrombosis and thrombolysis resistance via enhanced thrombus formation and stability in COVID-19.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.09.17.460777v1
The SARS-CoV-2 coronavirus causes the COVID-19 disease, which is a multisystem disease affecting the respiratory tract. Data available so far shows endothelial injury caused by hyperactivation of the immune system as a major underlying molecular mechanism for COVID-19 severity and mortality. In addition, this endothelial involvement leads to many hemostasis abnormalities in severe COVID-19 patients.
Besides elevated levels of pro- and anti-inflammatory mediators such as interleukin (IL)-6, IL-10, IL-2R, and tumor necrosis factor-α (TNF-α), increased levels of D-dimer, fibrinogen, and prolonged prothrombin time (PT) have also been found in severe COVID-19 patients.
The observation and monitoring of these elevated biomarkers are clinically relevant because abnormal levels of D-dimer are associated with 28-day mortality in COVID-19 patients.
Furthermore post-mortem studies show the presence of micro-thrombi and capillarostasis in the lungs of these severe COVID-1 patients. The high incidence of thrombotic events in severe COVID-19 patients in
dicates a possible role of the contact system pathway in COVID-19 pathology.
The COVID-19 Research
team demonstrated that altered levels of factor XII (FXII) and its activation products in 2 independent cohorts of critically ill patients with COVID-19 compared to patients suffering from severe acute respiratory distress syndrome caused by the influenza virus (acute respiratory distress syndrome (ARDS)-influenza).
Coagulation factor XII, also known as Hageman factor or simply FXII, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme (EC 18.104.22.168) of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the F12 gene. It typically circulates in plasma as a single-chain zymogen.
Upon coming into contact with anionic surfaces like kaolin, neutrophil extracellular traps, extracellular RNA from damaged cells, or polyphosphates from activated platelets, FXII is autoactivated to αFXIIa.
Importantly activation of the contact-phase system leads to increased thrombin and fibrin production, although FXIIa/PKa-mediated conversion of plasminogen to plasmin may have a mild effect on fibrinolysis.
The study team also reported rapid consumption of FXII in the plasma of COVID-19 patients, but not in plasma from ARDS-influenza, which is compatible with the above data. Interestingly, the kaolin clotting time was not prolonged in COVID-19 patients compared to that in ARDS-influenza patients.
Corresponding author Dr Malgorzata Wygrecka, PhD from the Center for Infection and Genomics of the Lung (CIGL) Universities of Giessen and Marburg Lung Center told Thailand Medical News, “Elevated levels of fibrinogen were reported to contribute to the faster fibrin formation and increased fibrin network density, strength, and stability.”
Utilizing confocal and electron microscopy, the study team showed that increased FXII activation rate, along with elevated fibrinogen levels, drives the formation of unique never seen before fibrinolysis-resistant clots with thin fibers and small pores in COVID-19 patients.
Dr Wygrecka commented, “Clots generated from COVID-19 plasma exhibited higher packing density, small pores and were built of thin fibers.”
The study findings revealed that clot lysis was observed in 30% of COVID-19 patients and 84% of ARDS influenza patients.
Importantly upon detailed analysis of lung tissue sections of COVID-19 patients, extensive but unique extra- and intra-vascular compact fibrin deposits were revealed.
The study findings help establish a model for future studies on the role of altered fibrin clot structure in COVID-19-related thrombosis.
According to the study team, on the basis of the findings, the uncontrolled response of defense mechanisms, including the immune and coagulation system, constitute the underlying mechanism for severe SARS-CoV-2 infection.
Importantly abnormalities in plasma composition, blood immune cells due to virus-mediated cell damage, and release of intracellular debris all favor the activation of FXII. Apart from high levels of fibrinogen, FXIIa leads to pathologic thrombus formation not only through thrombin generation but also via the formation of compact and lysis-resistant clots.
The study findings indicate that increased fibrinogen levels and increased FXII activation rate drive thrombosis and thrombolysis resistance through enhanced thrombus formation and stability in COVID-19 patients.
The study team concluded, “Thus, this study establishes a model for future studies on the role of altered fibrin clot structure in thrombosis and thrombolysis in severe COVID-19 patients. Whether the interaction of FXII/FXIIa with fibrinogen can interfere with the binding of t-PA to fibrin and thereby inhibits fibrinolysis warrants further investigation.”
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