Plasminogen is a protein produced in the liver that plays a central role in the body’s process of breaking down blood clots. It circulates in the blood as an inactive precursor, known as a zymogen. When activated, plasminogen transforms into plasmin, also called fibrinolysin, which directly breaks down fibrin, the main protein component of blood clots. This process, called fibrinolysis, ensures that clots are dissolved once they are no longer needed, preventing blockages in blood vessels. Plasminogen deficiency is a rare condition where this natural clot-dissolving mechanism is impaired, leading to the accumulation of fibrin in various tissues.
The Genetic Basis of Plasminogen Deficiency
Plasminogen deficiency arises from changes in the PLG gene. This gene contains instructions for creating plasminogen, the protein responsible for breaking down fibrin clots. When mutations occur in the PLG gene, it can disrupt the normal production or function of plasminogen.
There are two primary forms of this deficiency. Type I, known as hypoplasminogenemia, occurs when the body produces an insufficient quantity of plasminogen. In contrast, Type II, called dysplasminogenemia, involves the production of plasminogen that is present in adequate amounts but does not function correctly. Both types are inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of the mutated PLG gene, one from each parent, to develop the condition.
Recognizing the Symptoms
The primary manifestation of plasminogen deficiency is the formation of “ligneous” growths, which are firm, woody-textured lesions that appear on mucous membranes. These growths result from the excessive accumulation of fibrin, which the body cannot properly break down. These growths can occur in various parts of the body, often causing significant discomfort and functional impairment.
One of the most common locations for these growths is the eyes, leading to a condition called ligneous conjunctivitis. This involves the formation of thick, pseudomembranous lesions on the conjunctiva, the membrane lining the eyelids and covering the white part of the eye. These lesions can cause chronic irritation, redness, pain, and may impair vision if left untreated. Recurrences are common even after surgical removal.
Growths can also affect the gums, a condition known as ligneous gingivitis. This involves the development of firm, fibrous lesions on the gingiva, potentially leading to bleeding, pain, and difficulty with oral hygiene.
Beyond the eyes and gums, ligneous growths can appear in other mucous membrane-lined areas. The respiratory tract, including the larynx, trachea, and bronchi, can be affected, leading to symptoms such as chronic cough, hoarseness, difficulty breathing, or recurrent infections. In severe cases, airway obstruction can occur, requiring urgent medical intervention. The genitourinary tract, including the kidneys, bladder, and female reproductive organs, may also develop these lesions, causing symptoms like recurrent infections, pain, or functional disturbances depending on the specific site of involvement.
How Plasminogen Deficiency is Diagnosed
Diagnosis begins with a medical evaluation, including a review of symptoms and history. Blood tests are then performed to assess plasminogen levels and activity. These tests measure both the amount of plasminogen protein (antigen level) and its ability to function (activity level).
These blood tests are crucial for differentiating between the two main types of plasminogen deficiency. In Type I (hypoplasminogenemia), both the plasminogen antigen level and its activity are found to be low. For Type II (dysplasminogenemia), the antigen level might be normal or near normal, but the plasminogen activity will be significantly reduced because the protein is not functioning properly. A definitive diagnosis is confirmed through genetic testing, which analyzes the PLG gene for specific mutations that cause the disorder.
Managing and Treating the Condition
Management focuses on replacing the missing or dysfunctional protein. Plasminogen replacement therapy is the only FDA-approved treatment, directly addressing the underlying cause by supplying human plasminogen. This therapy aims to restore normal fibrinolysis, preventing new ligneous growths and promoting the resolution of existing ones. Ryplazim (human plasminogen-tvmh) is an example of a plasma-derived plasminogen product used for Type 1 deficiency.
In addition to replacement therapy, other supportive treatments may manage specific symptoms or complications. Surgical removal of ligneous growths might be necessary, particularly if causing significant obstruction or discomfort in areas like the eyes or airways. However, surgical intervention alone does not address the underlying deficiency and growths may recur if the plasminogen levels are not adequately maintained. Topical treatments, such as eye drops containing plasminogen, may also be used for localized ocular lesions.