Extreme γ′ fibrinogen levels in COVID-19 patients, 2024, Hudkins et al.

SNT Gatchaman · May 21, 2024

Extreme γ′ fibrinogen levels in COVID-19 patients
Hudkins; Hamilton; Underwood; Kazmierczak; Dewey; Kazmierczak; Messer; Khan; Schreiber; Farrell

COVID-19 disease progression can be accompanied by a “cytokine storm” that leads to secondary sequelae such as acute respiratory distress syndrome. Several inflammatory cytokines have been associated with COVID-19 disease progression, but have high daily intra-individual variability. In contrast, we have shown that the inflammatory biomarker γ’ fibrinogen (GPF) has a 6-fold lower coefficient of variability compared to other inflammatory markers such as hs-CRP.

The aims of the study were to measure GPF in serial blood samples from COVID-19 patients at a tertiary care medical center in order to investigate its association with clinical measures of disease progression. COVID-19 patients were retrospectively enrolled between 3/16/2020 and 8/1/ 2020. GPF was measured using a commercial ELISA.

We found that COVID-19 patients can develop extraordinarily high levels of GPF. Our results showed that ten out of the eighteen patients with COVID-19 had the highest levels of GPF ever recorded. The previous highest GPF level of 80.3 mg/dL was found in a study of 10,601 participants in the ARIC study. GPF levels were significantly associated with the need for ECMO and mortality. These findings have potential implications regarding prophylactic anticoagulation of COVID-19 patients.

Link | PDF (Blood Cells, Molecules, and Diseases)

SNT Gatchaman · May 21, 2024

Several inflammatory cytokines, including high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6), have been associated with COVID-19 progression, but have far too much daily intra-individual variability to be useful in tracking the course of the disease. In contrast, we have shown that the inflammatory biomarker gamma prime fibrinogen (GPF) has a 6-fold lower coefficient of variability compared to other inflammatory markers such as hs-CRP. The mRNA for the γ chain of GPF, expressed from the FGG gene, is upregulated 8.3-fold by IL-6 in vitro, so that GPF may be a more stable and therefore superior surrogate marker to IL-6 as well.
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GPF arises from alternative mRNA processing that results in the substitution of the carboxyl terminal four amino acids with a different twenty-amino acid sequence. The γ’ chain pairs with the more common γA chain to form γA/γ’ fibrinogen, whereas the majority of fibrinogen is γA/γA fibrinogen. γ’ fibrinogen typically constitutes ~7–10% of total fibrinogen in plasma, although this varies widely among individuals. The normal range of total fibrinogen is 150–300 mg/ dL, whereas GPF has a wide reference interval in healthy individuals from 8.8 to 55.1 mg/dL.
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GPF has several biochemical and biophysical properties that distinguish it from the more common γA isoform. Clots made from GPF in the presence of coagulation factor XIII (a.k.a. “fibrin-stabilizing factor” in earlier nomenclature) are highly resistant to fibrinolysis. In addition, the γ’ chain contains a high affinity binding site for thrombin, and clots made from GPF have an altered clot architecture.
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Importantly, thrombin that is bound to the γ’ chain remains bound in the growing fibrin clot and is resistant to inactivation by antithrombin and heparin. This is due to the fact that the γ’ chain binds to the heparin binding site on thrombin.
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The finding that COVID-19 patients can develop extraordinarily high levels of GPF has several important clinical implications. GPF contains a high affinity binding site for thrombin. This binds to anion binding exosite II on thrombin and protects it from inactivation by heparin. The mechanism behind the heparin resistance stems from the fact that unfractionated heparin also binds to exosite II; therefore, heparin cannot bind to thrombin that is bound to GPF. High levels of GPF therefore provide a reservoir of heparin-resistant clotbound thrombin when the GPF is clotted. Furthermore, recent in vitro evidence provides a mechanistic explanation for the thrombotic properties of GPF. Increasing plasma levels of GPF accelerate clot formation and increase fibrin clot size, both at venous and arterial shear.
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The rapid decrease in GPF levels following the administration of methylprednisolone (Fig. 3) was unexpected, given the reported half-life of fibrinogen antigen of 88 h.
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These findings have potential clinical implications regarding prophylactic anticoagulation of COVID-19 patients. The resistance of GPFbound thrombin to heparin suggests that heparin prophylaxis may be less effective than treatment with other anticoagulants, particularly direct thrombin inhibitors.
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It is possible that inhibition of factor Xa by current DOACs may also reduce the levels of active thrombin and thereby prevent activation of thrombin substrates by GPFbound thrombin, including factor V, factor VIII, factor XI, factor XIII, and fibrinogen
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SNT Gatchaman · May 21, 2024

Some of their references —

The presence of γ′ chain impairs fibrin polymerization (2009, Thrombosis Research)

Fibrinogen gamma-chain splice variant γ′ alters fibrin formation and structure (2003, Blood)

Crystal structure of thrombin in complex with fibrinogen γ′ peptide (2007, Biophysical Chemistry)

Evidence that fibrinogen γ′ regulates plasma clot structure and lysis and relationship to cardiovascular risk factors in black Africans (2013, Blood)

Studies on the basis for the properties of fibrin produced from fibrinogen-containing γ′ chains (2005, Blood)

Resistance of γA/γ′ Fibrin Clots to Fibrinolysis (1997, Journal of Biological Chemistry)

SNT Gatchaman · May 21, 2024

GPF LoCov Study (Perth)

Perth Blood Institute are partnering with Gamma Diagnostics to study the role that Gamma Prime Fibrinogen (GPF) plays in various inflammatory disease states. The Long COVID Syndrome Study (GPF LoCov Study) will be investigating if a certain coagulation factor, Gamma Prime Fibrinogen (GPF) is elevated in patients with acute and long COVID. As GPF is also an inflammatory marker associated with cardiovascular disease (Appiah et al. 2015), a secondary aim of the study is to see if there is a correlation between GPF and other coagulation, inflammatory and endothelial markers.
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https://www.pbi.org.au/gpf-locov-study

https://www.pbi.org.au/news/long-covid

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Extreme γ′ fibrinogen levels in COVID-19 patients, 2024, Hudkins et al.

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Extreme γ′ fibrinogen levels in COVID-19 patients, 2024, Hudkins et al.

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