Fibrinogen a key player in health and disease, says new study

By Dr. Liji Thomas, MDJun 12 2019

A new study from the University of Alberta demonstrated that the blood clotting protein called fibrinogen also regulates MMP-2, an enzyme involved in immunity and in clot formation inside blood vessels. Prolonged MMP-2 inhibition could potentially produce a deficiency state with severe consequences.

The study, published in the journal Scientific Reports, reports on the role of abnormally high fibrinogen levels in non-genetic MMP-2 deficiency.

Human fibrinogen blood clot (factor I) protein, chemical structure. Fibrinogen is a soluble plasma enzyme that is converted to fibrin by thrombin. Image Credit: molekuul_be / Shutterstock

MMP-2, or matrix metalloproteinase-2, is also called gelatinase or type IV collagenase, and belongs to a family of enzymes that break down collagens and other proteins in the extracellular matrix, as well as certain immune cell signaling molecules or cytokines that attract white blood cells. Its activity is carefully regulated at multiple levels.

Both low and high levels of MMP-2 are associated with inflammation and cardiovascular disease.

A high MMP-2 level increases the risk of hypertension, heart disease and heart failure, and for diabetic/ arthritic conditions in these patients, as well as the risk of death. Rheumatoid arthritis, in particular, is linked to high MMP-2 expression.  Natural inhibitors reduce MMP-2 activity even when it is present at high concentrations. But too much of these inhibitors may not be a good thing, producing MMP-2 deficiency as in pancreatitis and hepatic cirrhosis.

The genetic deficiency of MMP-2 is linked to bone and cardiac disorders, as well as inflammation.

The current study began with the accidental finding that in a certain blood sample, gelatin failed to bind to pro MMP-2 as expected. Pro-MMP-2 is the inactive form of MMP-2. Researchers found that the serum contained extremely high fibrinogen levels. They repeated the experiment using serum from rheumatoid arthritis patients, who typically have elevated fibrinogen levels. Again, it inhibited gelatin binding by MMP-2 in both active and precursor form.

Fibrinogen is thus a natural and selective MMP-2 inhibitor, acting through a mixed mechanism, using both competitive and non-competitive pathways. Fibrinogen is elevated by up to ten times in response to inflammation. It is thus high in a host of conditions like arthritis, atherosclerosis, heart failure and renal failure. Fibrinogen also attracts white blood cells in infective states and can cause thrombosis.

MMP-2 is a protein-cleaving enzyme, but it has no significant effect on fibrinogen. Thus fibrinogen inhibition of MMP-2 is a physiologically important phenomenon, and its effect increases with its concentration.

Fibrinogen binds competitively to the catalytic site of MMP-2, preventing other substrates like collagen from gaining access to the enzyme. Another non-competitive mechanism by which fibrinogen inhibits MMP-2 involves its binding to another site, which causes a conformational change in the fibrinogen molecule. This blocks MMP-2 activity despite high enzyme levels.

The addition of anti-fibrinogen antibody reverses MMP-2 inactivation, resulting in cleavage of gelatin. Other molecules that naturally modulate MMP-2 activity include tissue inhibitors of matrix metalloproteinases (TIMPs) and alpha-2-macroglobulin.
The current study found proof that fibrinogen at normal levels in the bloodstream inhibits MMP-2 in the blood by 40% to 70%. Platelets release MMP-2 at sites of vascular injury, where fibrinogen is also high. MMP-2 increases platelet activation, and also promotes the platelet clumping caused by molecules like collagen, thrombin or adenosine diphosphate (ADP).

In this situation, fibrinogen competes with MMP-2 for its platelet surface binding site, where it stabilizes the platelet clot. In the process, fibrinogen reduces MMP-2 mediated platelet activation and clumping. On the other hand, it does not inhibit MMP-9 which is a natural antagonist to MMP-2 induced platelet aggregation. Thus its overall effect could be to regulate further platelet aggregation while stabilizing already formed platelet clumps.

Extremely high fibrinogen levels could cause excessive MMP-2 inhibition even in the presence of normal enzyme levels, preventing the enzyme’s normal physiological functions in target tissues. This could possibly trigger inflammation similar to genetic MMP-2 deficiency if it persists too long.

Of course, it could be that MMP-2 is the real culprit behind the pathological inflammation, and the rise in fibrinogen levels is an attempt to counteract it. Carlos Fernandez-Patron who directed this study commented: “Binding of fibrinogen in the circulation to MMP2 enzymes prevents them from docking to target tissues. We don’t know exactly whether that results in a beneficial or deleterious effect. It’s something we need to investigate.”

Many adverse drug reactions linked to drugs like statins, used to lower cholesterol, and antibiotics like doxycycline, could be due to their ability to inhibit MMPs. This should direct research into therapeutic drugs that maintain the balance between MMPs and their inhibitors in the body. As Fernandez-Patron adds, “Knowing how those enzymes are regulated is key to improving diagnosis, prognosis and treatment of patients experiencing abnormal levels of either MMP2 or fibrinogen.”