Plasminogen Deficiency

Disease Overview

Plasminogen deficiency is a disorder that results in unusual and significant clinical sequelae characterized by development of fibrin rich pseudomembranes that impair normal tissue and organ function. The lesions are commonly described as ligneous membranes. Most commonly, ophthalmologic lesions have been described, however, other physiologic systems are affected including the gingiva, otic, renal collecting system, respiratory tract, and female genitourinary system.1 Interestingly, affected individuals do not appear to have an increased incidence of arterial or venous thromboembolic disease; however as the number of affected individuals is small and longitudinal follow-up is lacking, available data is limited from which to draw such conclusions.

These lesions were first described in 1847 by Bouisson in a young patient who developed pseudomembranes that covered the eye.1 In 1933, the term ligneous conjunctivitis was introduced to describe the wood-like appearance of these pseudomembranes. Thereafter, similar lesions were noted to affect the gingiva, ear, respiratory tract, and female genitourinary tract.1 In 1958, Verhoeff reviewed the literature after encountering a case of ligneous conjunctivitis and hypothesized that these lesions were due to an infectious agent as they were often reported in association with a nasopharyngitis.2,3 In 1969, a case report of two patients with this condition was published where an evaluation for an associated infectious and/or autoimmune condition was performed without a demonstrable relationship. Therefore, the authors postulated that their information pointed towards an inherited etiology.3

The recognition of substances in blood that dissolved thrombi once formed began in the 19th century, however isolation of plasminogen/plasmin did not occur until the 1940’s.4 In 1978 a group from Japan were the first to report a case of dysplasminogenemia with decreased plasminogen activity in the face of a normal antigenic level in a patient with recurrent thrombosis.5

It was not until the 1990’s that a clear correlation between decreased plasminogen levels and development of ligneous conjunctivitis was firmly established in a young female with both ligneous conjunctivitis and congenital hydrocephalus.1 Subsequently, two further cases firmly established this relationship.6

While the plasminogen-plasmin system has a well-established pivotal role in clot dissolution, it also plays other physiologic roles including being critical to normal wound healing. Two mammalian enzymes, tissue-Plasminogen Activator (t-PA) and urokinase-Plasminogen Activator (u-PA) convert the zymogen, plasminogen, to the active enzyme, plasmin. This tightly regulated system is controlled by Plasminogen Activator Inhibitors (PAI’s), which inhibit t-PA and u-PA, and alpha-2-antiplasmin, the main plasmin inhibitor (see Figure 1).

The gene for plasminogen is encoded on the long arm of Chromosome 6, 6q26, and contains 19 exons and 18 introns.7,8 Plasminogen is predominantly made in the liver; however, other organs have been documented to produce plasminogen including the brain, kidney, heart, lungs, uterus, spleen, thymus, and intestines.7,8 Two forms of plasminogen are produced, Glu- and Lys-Plasminogen. A glutamic acid residue on the N-Terminus results in the Glu-Plasminogen, with an associated plasma half-life of 2.2 days. Lys-Plasminogen with a lysine residue at the N-terminus has a plasma half-life of 0.8 days.9 The plasminogen activators, t-PA and u-PA, are able to convert either form of plasminogen to plasmin, however, due to conformational differences, the Lys-Plasminogen is more rapidly converted. Interestingly, plasmin converts Glu-Plasminogen to the Lys form. Therefore, Glu-Plasminogen is initially converted to Glu-Plasmin by plasminogen activators, which once generated, converts other Glu-Plasminogen proteins to Lys-Plasminogen, which accelerates subsequent plasmin generation (see Figure 1).9

As mentioned, the plasminogen/plasmin system plays an important role in normal wound healing.7,10 An initial step in wound healing is generation of a fibrin-rich material, critical to temporarily halt bleeding and provide a foundation for the initiation of tissue repair. Plasmin and other matrix metalloproteases are required to break down this fibrin-rich material and allow generation of granulation tissue, with the fibrin-rich clot eventually degraded in the process of repair. However, both cellular migration and the generation of active metalloproteases appear to be a direct result of plasminogen and plasmin.10 More recently, a role for plasminogen in intracellular signaling as part of the proinflammatory response has been described.11 Therefore, a deficiency of plasminogen results in a diminished capacity to break down fibrinous material, both directly and indirectly through the inability to effectively activate metalloproteases, and to down regulate this process at the granulation stage. The inability to progress past this stage in wound healing, particularly in mucous membranes, results in development of observed ligneous lesions seen in plasminogen deficiency. Plasminogen knockout mice develop similar ligneous conjunctival lesions as those seen in humans.12

Plasminogen deficiency is divided in two main categories, Type 1 and Type 2 deficiency, both of which are autosomal recessive conditions. Affected patients may either be homozygous for a specific mutation or be compound heterozygotes with each gene having a different mutation. Type 1 deficiency is present when there is a quantitative defect of protein product with concordant levels of plasminogen activity and antigen. Several studies have reported numerous mutations within the plasminogen gene that result in a Type 1 deficiency state.13,14 Of these, the K19E mutation appears to be most common; it was found in 17 of 50 subjects in one study, and 6 of 23 subjects in another.13,14 In a Scottish blood donor study, 13 of 15 patients with known low plasminogen levels had this K19E mutation.15 This mutation has a variable clinical phenotype with a range of plasminogen levels. Interestingly, other mutations also do not necessarily confer a predictable clinical expression.  One family with the W597C mutation included three siblings, homozygotes for this mutation, where one presented with ligneous gingivitis, one with ligneous conjunctivitis, and one without clinical symptoms.14 Therefore, the mutation does not always predict clinical phenotypic expression.

Mutations resulting in a dysfunctional protein have been well documented and are associated with Type II deficiency.16-19 The mutations that lead to a dysfunctional plasminogen protein appear more commonly than type I mutations.  Heterozygous Type I mutations are found in <1% of the populations studied.15,17 However, Type 2 Plasminogen gene mutations have been documented in separate reports from Japan, China and Korea with a heterozygous prevalence of 3.8%, 1.5% and 1.6%, respectively.18,19 Interestingly, while initial reports suggested that inherited dysplasminogenemia was associated with an increased risk of venous thrombosis, a large population study has not supported this association.18 In fact, people with Type II deficiency may be asymptomatic, which would explain the higher prevalence of these mutations.17

Plasminogen deficiency is extremely rare, and the true prevalence is unknown. A study of blood donors from Scotland revealed 25 of 9,611 tested subjects with a heterozygous plasminogen deficiency.15 Based on this data, a predicted prevalence of homozygous or compound heterozygous plasminogen deficiency would approximate 1.6 per 1,000,000 people.1 Patients from many countries throughout the world have had documented mutations in the plasminogen gene, thereby demonstrating no specific ethnic predilection. However, in areas where consanguineous unions are more common, an increased number of patients have been documented including populations from Turkey and the Middle East. Of 50 patients reported from 11 countries, 21 were of Turkish descent.13 In a subsequent study from this same group, 10 of 23 subjects were of Turkish descent.14

A review of documented cases reveals an increase number of affected females as compared to males with a ratio of approximately 1.5:1.14 An autosomal recessive inheritance would predict equal distribution among cases; the increased number of identified females may be due to an increased risk of disease expression in a particular sex and therefore reporting bias. Clinical age of symptom expression is quite variable, with a median age of 1 year, and a mean age of ~5 years.14

The lack of international ongoing efforts to pool longitudinal follow-up and outcome data in plasminogen deficient patients prevents accurate conclusions about the true extent of morbidity and mortality associated with this disorder.