Fibrinogen and Clotting Characterization in COVID-19 Patients Restricted; Files Only

Obertone, Carys (Spring 2022)

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The usual pathogenesis of COVID-19 patients sparks interest due to high levels of inflammatory markers. Despite prophylactic anticoagulation efforts, patients infected with SARS-CoV-2 are at a greater risk for developing blood clots. Hyperfibrinogenemia and hyperviscosity in said patients and clots with increased resistance to fibrinolysis prompt an exploration of the fibrinogen pathway and its effects on the coagulation cascade as a target for mediating COVID-19 symptoms. Fibrinogen is an acute phase reactant that is cleaved by thrombin to generate fibrin, which serves as a building block of fibrous clots. Fibrinogen circulates as a hexamer consisting of three pairs of polypeptide chains termed A𝛼, B𝛽, and 𝛾. The 𝛾 chain fibrinogen has a minor isoform, denoted 𝛾A/𝛾’ or 𝛾’, that accounts for around 10% of the total fibrinogen. This variant, produced by alternative mRNA processing, has a different carboxyl terminus that has been previously shown to create abnormal clots that are more resistant to fibrinolysis. The 𝛾’chain’s thrombin binding site has both antithrombotic and prothrombotic effects, explaining COVID symptoms of severe clotting alongside instances of bleeding out. With no previous exploration of 𝛾’ in regards to SARS-CoV-2, identifying whether it was 𝛾’ concentrations alone or the ratio of 𝛾’ to total fibrinogen causing clotting dysfunction is essential for assisting in new therapies. Enzyme-linked immunosorbent assay (ELISA) to quantify 𝛾’ fibrinogen was utilized, showing that total 𝛾’ fibrinogen concentrations are elevated in COVID-19 patients and 𝛾’ concentrations are positively correlated with total fibrinogen levels. Scanning electron microscopy provided efficient visual analysis and comparisons of the clot architecture, binding of spike proteins, and fibers of COVID plasma samples as well as blood clots for COVID patients and controls. Through our exploratory project providing preliminary results, we aim to assist in new therapies for lowering fibrinogen in COVID patients that have hyperviscosity and/or refractory hypercoagulability to address coagulation complications. 

Table of Contents

Introduction 1

Background 2

 Figure 1: Overall simplified structure of fibrinogen 4

 Figure 2: Simplified view of coagulation and fibrinolysis process 8

 Figure 3: Alternative mRNA processing leads to the formation of the γ’ chain 9

 Figure 4: Falls and Farrell show decreased fibrinolysis rates of γA/ γ’ clots 11

Methods 17

Results 20

 Figure 5: Total 𝛾’ fibrinogen levels are elevated in patients infected with SARS-CoV-2 21

 Figure 6: COVID-19 patient γ’/total fibrinogen ratios 22

 Figure 7: SEM images of blood clots removed during brain surgery 23

 Figure 8: SEM images of plasma clot 24

Discussion and Future Directions 25

 Table 1: COVID-19 patient plasma samples selected for SEM analysis 27

Conclusion 28

References 30

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