Serum fibrinogen may be a universal biomarker for MG: Study

The plasma protein was observed in all 31 MG patients in study

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by Andrea Lobo |

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High levels of serum fibrinogen were found to be a sensitive and specific biomarker to identify people with myasthenia gravis (MG), according to a recent study.

Fibrinogen is a plasma protein that participates in blood clotting and is usually not present in the serum. In MG patients, residual fibrinogen was found in the serum at higher levels than in patients with rheumatoid arthritis (RA), which was used as a reference disease, and healthy controls. Plasma is the liquid component of blood that remains after blood (red blood cells, white blood cells, and platelets) has been removed. Serum is similar to plasma but is obtained after letting blood clot, which results in the removal of clotting factors, such as fibrinogen.

This was observed in all MG patients, despite disease severity and their type of self-reactive antibodies or received treatments, indicating fibrinogen may be a universal MG biomarker.

“Our unanticipated discovery of high levels of residual serum fibrinogen in all MG patients can secure rapid bedside diagnosis of MG,” the researchers wrote in “Residual serum fibrinogen as a universal biomarker for all serotypes of Myasthenia gravis,” which was published in Scientific Reports.

MG is driven by self-reactive antibodies that attack proteins required for the normal function of the neuromuscular junction, the site where nerve cells and muscles communicate to coordinate voluntary movements, leading to muscle weakness and fatigue.

In about 85% of patients, these auto-antibodies target the acetylcholine receptors (AChRs) at the surface of muscle cells. A small proportion of patients develop antibodies against other neuromuscular junction proteins, including the muscle specific tyrosine kinase (MuSK). Some patients don’t have any of the two antibodies. That’s called seronegative.

If MG symptoms are present, a blood test to measure the levels of MG-causing antibodies may diagnose the condition and determine the specific MG type. Antibody levels aren’t associated with disease course or treatment outcomes, however.

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Identifying a universal blood biomarker in MG

“Despite recent advances in the understanding and treatment of MG1, challenges remain with the timely diagnosis of this autoimmune disease, as a result of its heterogeneous nature, nonspecific symptoms and lack of availability of a universal biomarker,” wrote the researchers, whose study sought to identify a blood biomarker that could detect all MG types associated with the presence of any reactive antibodies and with a high specificity to distinguish MG from related disorders. A total of 79 patients were recruited, including 31 with MG, 18 with RA, and 30 healthy people who served as controls. RA was selected because it’s also caused by self-reactive antibodies and a small percentage of people with MG have coexistent RA.

Regarding the type of MG, patients were classified according to the Myasthenia Gravis Foundation of America scale into Class I (25.8%), Class II (32.3%), and Class III (41.9%). Class I includes patients with only ocular muscle weakness. Class II refers to those with mild muscle weakness that extends beyond the ocular muscles, while Class III includes patients with moderate muscle weakness not limited to ocular muscles. Ocular muscle weakness may also present in classes II and III.

A pilot study was conducted to identify proteins specifically associated with MG by analyzing the serum samples of 18 patients, six from each group, using a proteomics approach, a large-scale study of the protein content in a sample.

Overall, 502 proteins were identified, of which 103 were unique to the MG group. Of these, six proteins had a significantly higher abundance in MG patients, with all three fibrinogen subunits (alpha, beta, and gamma) showing the largest abundance. This result was validated with analysis that used antibody-based testing.

“This observed high abundance of fibrinogen is peculiar, as to our knowledge there have been no previous reports of high fibrinogen in MG patients, nor is there any clotting disorder typically associated with the disease,” the researchers wrote.

Fibrinogen in MG

Subsequently, a blinded study of 10 independent samples to reveal the presence of fibrinogen identified 100% of MG patients, distinguishing them from controls.

Considering the promising data of the pilot analysis, the correlation of fibrinogen with MG was validated in the 31 MG patients — 27 positives for anti-AChR antibodies, one positive for anti-MUSK antibodies, and three seronegative — the 18 RA patients, and the 30 controls.

A more targeted quantitative proteomics method, called mass spectrometry, revealed an equally high abundance of all three fibrinogen subunits in MG patients over RA patients and controls. Fibrinogen levels were 28 to 54 times higher than in RA patients, and 250-4,000 times higher than in controls, being highly specific and 100% sensitive for MG. A test’s sensitivity reflects how well it can spot people with a specific condition, avoiding false negatives. Specificity indicates a test’s ability to identify those without the condition, excluding false positives.

The high specificity and sensitivity of fibrinogen levels in detecting MG patients suggest it may be superior to current diagnostic methods.

There were no differences between the three types of MG patients regarding fibrinogen abundance or between patients who received different treatments.

Considering that fibrinogen may rise in response to inflammation, “the observation that [its] levels were increased in all types of MG … regardless of the severity of disease, suggests an ongoing subclinical [asymptomatic] inflammatory process at the [neuromuscular junction],” the researchers wrote. “We anticipate our findings to provide the foundation for further studies and potentially the development of a routine approach for early MG diagnosis.”