New light on the role fibrinogen has in regulating a natural defence mechanism in the body


A finding from University of Alberta researchers is shining new light on the role fibrinogen has in regulating a natural defence mechanism in the body.

The discovery is hoped to contribute to improved diagnosis and treatments for patients in a variety of diseases ranging from inflammation, to heart failure, to cancer.

Fibrinogen is a well-known protein that is essential for wound healing and blood clotting in the body.

But a study published in Scientific Reports shows it is also a natural inhibitor of an enzyme named MMP2 that is important for normal organ development and repair.

MMP2 is typically found in increased levels in the blood in disease conditions.

The researchers believe a vital function of fibrinogen is to allow or disallow the enzyme to carry out its normal functions.

However, high levels of fibrinogen may excessively inhibit MMP2, which could result in arthritic and cardiac disorders similar to those seen in patients with MMP2 gene deficiency.

“Whenever there’s an infection or there’s an injury, fibrinogen can go up by tenfold in the blood.

So at that concentration it would excessively inhibit MMP2,” said Hassan Sarker, a Ph.D. candidate at the U of A and study lead author.

“Binding of fibrinogen in the circulation to MMP2 enzymes prevents them from docking to target tissues,” added Carlos Fernandez-Patron, a professor of biochemistry at the U of A, who directed this research.

“It affects their activity and we don’t know exactly whether that results in a beneficial or deleterious effect.

It’s something we need to investigate.”

The finding opens a new window into the inner workings of the MMP family of enzymes.

The researchers say having a greater understanding of how MMPs are regulated creates opportunities for future treatments.

They also suspect that abnormal MMP2 activity could be an undesirable side effect of important common medications such as the cholesterol-lowering drug known as statins and the antibiotic doxycycline, both of which are known to inhibit MMPs.

The researchers emphasize that future therapeutic developments must strike a balance between the levels of MMPs and their inhibitors, such as fibrinogen, so that net MMP activity in the body remains at nearly normal levels.

“We don’t want to inhibit them more than needed and we don’t want to cause their expression to be higher than it should,” said Fernandez-Patron.

“Knowing how those enzymes are regulated is key to improving diagnosis, prognosis and treatment of patients experiencing abnormal levels of either MMP2 or fibrinogen.”

The blood coagulation system and immune system of higher organisms are thought to have a common ancestral origin.

During infections, the blood coagulation system is activated and components of the hemostatic system are directly involved in the immune response and immune system modulations.

The current view is that the activation of coagulation is beneficial for infections with bacteria and viruses.

It limits pathogen dissemination and supports pathogen killing and tissue repair.

On the other hand, over‐activation can lead to thrombosis with subsequent depletion of hemostatic factors and secondary bleeding.

This review will summarize the current knowledge on blood coagulation and pathogen infection with focus on most recent studies of the role of the different parts of the blood coagulation system in selected bacterial and viral infections.

 Infections and the activation of coagulation

The coagulation system is activated in response to infection by a variety of different pathogens, including bacteria and viruses (Tables 1 and ​and22).1418202324 

This response appears to have developed as a host defense system to limit the spread of the pathogen.

During infections, there is an interplay between blood coagulation, immune cells, and platelets to restrict dissemination of pathogens within the body.91425 

Activation of coagulation coincides with the recruitment of leukocytes where clot components, such as fibrin, serve as a scaffold for adherence and migration of cells. Leukocytes themselves can enhance coagulation by expressing TF and by releasing TF+MV. More importantly, neutrophils release neutrophil extracellular traps (NETs) after activation.926 NETs are composed of nuclear DNA, histones, and several neutrophil enzymes including elastase.

NETs were shown to have important antibacterial and potential antiviral functions and, due to their negative charge, also a coagulation‐enhancing activity.92627 

Thus, leukocytes are thought to be a major player in the cross‐communication between blood coagulation and the immune response.

Sepsis is a clinical condition as response to an acute bacterial or viral infection in the blood, with ongoing activation of the immune and coagulation system.

Unfortunately, overactivation of the coagulation system in acute bacteremia and viremia can lead to disseminated intravascular coagulation (DIC), microvascular thrombosis–induced hypoxia that contributes to multiorgan failure, septic shock, and death.2425 

Hemorrhages occur due to consumption of coagulation factors and platelets, resulting from ongoing intravascular activation of the hemostatic system.28

Fibrin(ogen) has a central role in hemostasis and thrombosis but it also contributes to multiple physiologic and pathologic processes beyond blood coagulation.2930 

Reduced fibrin(ogen) levels are a predictor for hemorrhagic complications.31 

In addition, fibrin clots were shown to be a strong inducer of a proinflammatory response of in clot‐embedded monocytes and timely degradation via fibrinolysis can dampen this inflammatory response.

The reported inflammatory response was thrombin‐independent but fibrin‐dependent.32 Innate immune cells responding via the integrin receptor αMβ2 (CD11b/CD18, Mac‐1) to the γ chain of fibrin(ogen) by phagocytosis, generation of reactive oxygen species and NFκB–mediated gene expression of proinflammatory mediators.33 

Interestingly, a report showed that soluble fibrin(ogen) can bind and induce signaling in neutrophils independently of Mac‐1 in vitro which suggests an additional fibrin(ogen) receptor.34 

Mac‐1 was further identified as a surface receptor for dsRNA on macrophages mediating TLR3‐dependent and ‐independent immune responses.35 The dsRNA:Mac‐1 interaction was blocked by treatment of cells with fibrin(ogen).35

 This observation suggests that high levels of soluble fibrin(ogen) might saturate Mac‐1 and therefore reduce the innate immune response to dsRNA in viral infection. Finally, fibrin degradation products (FDP) are potent chemotactic signals for neutrophils and other leukocytes.3637 

In addition, FDP are able to enhance as well as inhibit platelet function/aggregation.38

In the past, research was focused on the effect of endotoxemia and bacteremia/sepsis on the coagulation system with regards to DIC, septic shock, and bleeding complications. Newer studies have tried to understand its protective role in viral infections, such as H1N1 influenza A virus (IAV), Ebola virus, and emerging viral pathogens including Dengue and Zika virus.14232539404142

Studies showed that vascular TF expression can be induced by pathogen‐associated molecular patterns, including bacterial lipopolysaccharides (LPS) and viral dsRNA which leads to activation of coagulation in vitro and in vivo.4344 

TF expressed by monocytes/macrophages is the major source of pathologic TF in bacteremia/sepsis and endotoxemia that leads to aberrant coagulation and inflammation.2044 

The contribution of endothelial cells to activation of coagulation through expression of TF in vivo is controversial.12 

In addition, TF is associated with NETs suggesting a direct link between NETs and the extrinsic pathway.145 

Neutrophil elastase, which is released during sepsis, can degrade tissue factor pathway inhibitor, the inhibitor of the TF pathway, which may further enhance coagulation.26 

Furthermore, case studies reported that FVII consumption and uncontrolled bleeding during sepsis can be reduced and survival improved by systemic administration of additional FVIIa.4647 Occurrence of diffuse pulmonary bleeding can be reduced by local administration of FVIIa into the airspace of the lung.48

The role of the intrinsic pathway of coagulation in inflammatory responses was recently summarized in detail by others.1049 

However, there are only limited data available on the role of the intrinsic coagulation pathway and its members FIX, FXI, and FXII in immune responses to viral infections. Studies proposed that depending on the mode of activation, FXII can either trigger blood coagulation via activation of FXI or activate the kallikrein‐kinin system (KKS).

When FXII is bound to an activating surface, the classic activation, FXII is cleaved and activated by plasma prekallikrein/kallikrein in complexing with high molecular weight kininogen (HK) which subsequently leads to FXIa generation.1050 In addition, enveloped viruses were shown to enhance intrinsic pathway activation in vitro.51 

However, FXII can also be activated by an alternative mechanism via proteases, including elastase and plasmin.50 Certain bacteria were shown to express specific LPS, polyphosphates, elastase, or plasminogen activators to trigger bradykinin production via FXII activation.505253 

The alternative activation mechanism of FXII results in a significant reduced activation of coagulation and shifting FXIIa towards its pro‐inflammatory role.50

The remainder of this review will focus on the role of the coagulation cascade in infections with selected pathogens with particular attention paid to the intersection of the hemostatic system with antibacterial and antiviral immune responses (Tables 1 and ​and22).

More information: Hassan Sarker et al, Identification of fibrinogen as a natural inhibitor of MMP-2, Scientific Reports (2019). DOI: 10.1038/s41598-019-40983-y

Journal information: Scientific Reports
Provided by University of Alberta Faculty of Medicine & Dentistry


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