Plasminogen deficiency

INTRODUCTION — Plasminogen deficiency (PLGD; also called hypoplasminogenemia [HPG]) is an autosomal recessive, multisystem disorder characterized by formation of fibrinous pseudomembranes on mucous membranes throughout the body.

The most commonly recognized manifestations of PLGD are lesions on the conjunctiva of the eye, termed ligneous conjunctivitis. These lesions can cause significant morbidity, and pseudomembranes affecting the respiratory system and central nervous system can cause fatal complications. Treatment with plasminogen replacement therapy can cause the lesions to regress and resolve; a plasminogen concentrate was approved by the US Food and Drug Administration (FDA) in 2021. However, diagnosis is often delayed for months, or even years or decades, as the condition is extremely rare and the spectrum of presenting findings is broad.

This topic discusses diagnosis, evaluation, and management of PLGD. Other disorders of the fibrinolytic system and the role of plasmin and plasminogen in hemostasis are discussed separately. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis" and "Overview of hemostasis".)

PATHOPHYSIOLOGY

PLG gene — The PLG gene encodes plasminogen. The gene has structural similarity to apolipoprotein(a) and an internal sequence that encodes angiostatin, a suppressor of metastasis. PLG was identified as disease gene for ligneous conjunctivitis in 1997 [1]. Some PLG variants cause a form of hereditary angioedema. (See "Hereditary angioedema with normal C1 inhibitor", section on 'Plasminogen'.)

PLGD is an autosomal recessive condition with variable penetrance (disease severity can differ in individuals with the same genotype, even within families). (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Penetrance and expressivity'.)

The spectrum of disease variants in PLG that cause PLGD has not been comprehensively described, as the disease is rare and underdiagnosed. Case reports and small studies have described point mutations in various regions of the gene, some leading to amino acid substitutions and premature stop codons [1,2].

A clinical distinction is made between PLG variants that cause hypoplasminogenemia (reduced levels of plasminogen, type I disease) versus those that cause a dysfunctional protein (type II disease). (See 'Type I versus type II' below.)

●The K19E mutation appears to be most common; accounting for approximately one-fourth to one-third of individuals in small studies [3]. It appears to be associated with higher plasminogen levels and milder disease, but this requires confirmation with further clinical studies, wider diagnosis, and additional genetic analysis.

●Mutations that create a dysfunctional protein (type II PLGD) appear to be more common than those that reduce protein levels; this disease differs from PLGD as discussed herein, in that individuals with dysfunctional plasminogen protein are generally asymptomatic and do not require replacement therapy.

Genotype-phenotype associations have not been well documented; however, across a large range of plasminogen levels, more severe deficiency appears to correlate with greater likelihood of significant clinical findings [4]. (See 'Clinical features' below.)

A database registry has been established to further characterize disease variants and explore genotype-phenotype correlations. (See 'Referral and coordination of care' below.)

Plasminogen function — Plasminogen is the precursor to plasmin, a serine protease that cleaves fibrin and other proteins to restore blood vessel patency and maintain the extracellular matrix following establishment of hemostasis. (See "Overview of hemostasis", section on 'Clot dissolution and fibrinolysis' and "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'Overview of the fibrinolytic system'.)

Plasmin contributes to wound healing, regulation of the inflammatory response, and tissue remodeling [5]. It degrades fibrin and other matrix glycoproteins, activates matrix metalloproteinases (MMPs), and stimulates release of the transforming growth factor (TGF)-beta [6]. Plasminogen-deficient mice have extensive deposits of fibrin and neutrophils at sites of wounds late in the recovery process, indicating that clearance of inflammatory mediators in the area of the wound is diminished [7]. Correction of the deficiency leads to faster wound healing and epithelialization; plasminogen appears to be recruited to the wound site by inflammatory cells [8].

Endogenous plasminogen has two forms, one with a glutamic acid at the amino terminus (Glu-plasminogen) and one with a lysine at the amino terminus (Lys-plasminogen), created upon cleavage/removal of the glutamic acid [9].

●Glu-plasminogen – Glu-plasminogen has a longer half-life (2.0 to 2.5 days, versus <1 day for Lys-plasminogen) and is the predominant form in the circulation. Glu-plasminogen is the main component of plasma-derived plasminogen replacement therapy [9]. (See 'Plasminogen replacement' below.)

●Lys-plasminogen – Lys-plasminogen is generated at the site of a clot and is more easily converted to the active form of the enzyme, plasmin. The active enzyme plasmin is generated at the site of fibrin clot formation by endogenous tissue plasminogen activator (tPA) and urinary-type plasminogen activator (uPA), which cleave plasminogen to plasmin. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'Roles of specific proteins'.)

The plasminogen molecule contains specific lysine-binding sites that mediate interaction with its targets (fibrin and plasminogen receptors) and its major inhibitor, alpha-2-antiplasmin. Thrombin activatable fibrinolysis inhibitor (TAFI) is another inhibitor of plasmin activity.

Control of plasminogen levels — Plasminogen circulates in plasma at a concentration of approximately 2 micromolar. Plasminogen levels and functional activity appear to be lower in infants; these ultimately become relatively stable, likely within the first year of life [10,11]. It has been stated that levels are higher in females and with tobacco smoking, but some studies have found similar levels in males and females during adulthood, with a greater decline in older males [12]. Other regulators of plasminogen levels are under study [13].

Plasminogen is primarily produced by the liver, although other tissues contribute to synthesis [9]. Other tissues besides the liver that produce plasminogen include the brain, kidney, heart, lungs, intestines, uterus, spleen, and thymus [3]. These overlap substantially with the locations in which pseudomembranous lesions form in individuals with PLGD. (See 'Clinical features' below.)

Like many of the clotting proteins, plasminogen levels can vary among individuals, and clinical findings are rarely significant unless deficiency is severe. (See 'Laboratory and genetic testing' below.)

The amount of plasminogen needed to prevent symptoms of PLGD may vary by individual. Due to disease rarity, it is challenging to determine a cutoff above which symptoms will not occur. In a series of 23 patients with severe PLGD, plasminogen levels ranged from <5 to 57 percent (normal range, 75 to 120 percent) [2].

Type I versus type II — PLGD has been subclassified as type I versus type II disease.

●Type I – Type I is reduced protein production (quantitative deficiency, also called hypoplasminogenemia). Plasminogen protein levels and functional activity are both reduced.

●Type II – Type II is a dysfunctional protein (qualitative deficiency, also called dysplasminogenemia). Plasminogen protein levels may be normal but activity is reduced. Type II appears to be more common than type I.

These distinctions have major clinical implications, with type I disease causing symptoms (see 'Clinical features' below) and type II disease being asymptomatic. Both are autosomal recessive.

EPIDEMIOLOGY — PLGD due to homozygosity or compound heterozygosity for a PLG disease variant is considered an "ultra-rare" disorder, with a reported prevalence of approximately 1.6 per million population [14]. This would translate to approximately 12,000 individuals with the disorder worldwide. However, delayed, incorrect, and/or missed diagnoses are common, and the reported prevalence may be inaccurately low.

Heterozygosity for a PLG disease variant appears to be an asymptomatic carrier state with an estimated prevalence of approximately 1 in 400 individuals (0.26 percent) in the United Kingdom [14]. Because PLGD is autosomal recessive, the prevalence may be higher in areas of the world with greater frequencies of endogamous (from the same social group) and consanguineous (from the same genetic ancestor) unions or founder mutations. The prevalence is higher in the Kurdish population in Turkey than in other regions of the world.

CLINICAL FEATURES

Typical presentation — Presentations vary, and many individuals remain undiagnosed for months, years, or even decades. In small case series, the median age of onset has been approximately nine months to one year, but presentations in older adults have also been documented [2,3,14].

PLGD is a multisystem disorder. Patients generally present for medical attention when they develop clinical symptoms and associated sequelae of pseudomembrane formation. Pseudomembranes are fibrin-rich lesions that form on mucous membranes and are described as "woody" (ligneous). The table summarizes clinical manifestations (table 1).

●Ligneous conjunctivitis (pseudomembrane formation in the conjunctiva of the eye) is the most easily recognizable and the most common presentation. (See 'Ligneous conjunctivitis' below.)

●Other common sites include:

•Ear and mouth (gingiva, tonsils) – (See 'Ears, nose, and mouth' below.)

•Respiratory tract – (See 'Respiratory tract' below.)

•Gastrointestinal – (See 'Gastrointestinal' below.)

•Urogenital – (See 'Urogenital tract' below.)

●Involvement can also affect the central nervous system (CNS; cerebral ventricles, leading to occlusive hydrocephalus) [2,15]. Skin lesions have been reported in areas of sun exposure, including juvenile colloid milium (JCM), a lesion with degenerative papules on sun-exposed skin [16].

Although the initial description of PLGD was in an individual with venous thromboembolism (VTE), and despite reports of recurrent VTE in individuals with biallelic PLG disease variants, the bulk of the evidence, including a population study of over 4000 individuals, suggests that isolated PLGD is not a risk factor for thrombosis [3,12,17-19]. (See "Overview of the causes of venous thrombosis".)

Ligneous conjunctivitis — Ligneous conjunctivitis (formation of a membrane affecting the eye or eyelid conjunctiva) occurs in 80 to 90 percent of individuals with PLGD and is often the presenting finding [3,14]. The prevalence was even higher (96 percent) in a series of 23 individuals with severe disease [2]. The pseudomembranes typically are white, yellow-white, or red; they can develop a wood-like consistency (picture 1).

Approximately two-thirds of individuals have bilateral disease, and one-third have only one eye affected. Formation can be triggered by minor infection or injury to the eye, which may contribute to the explanation of why lesions are sometimes unilateral.

The lesions usually affect the upper eyelid (primarily on the upper tarsal conjunctiva). The lesions can be inflamed and painful and can continue to enlarge, threatening vision [20,21]. Approximately one-third of individuals also have corneal involvement with the potential for blindness [14].

Ears, nose, and mouth — Approximately one-third of patients develop ligneous gingivitis (gum involvement) (picture 2) with periodontitis [3]. Loss of bone and eventually teeth may occur.

Ligneous tonsillitis has also been reported and may cause tonsillar involvement to a degree that swallowing or breathing is impaired.

Viscous secretions also affect the nasopharynx and the middle ear, leading to otitis media or to a misdiagnosis as isolated otitis media or cholesteatoma. Hearing loss may result from chronic lesions.

The nose may also be affected with lesions that lead to irritation, epistaxis, and obstruction.

Respiratory tract — Involvement of the upper and lower respiratory tract have been described [15]. Laryngeal and bronchial lesions can cause life-threatening tracheobronchial obstruction. Lesions of the vocal cords may result in hoarseness or loss of voice, which may last for prolonged periods.

Gastrointestinal — Lesions in the gastrointestinal tract have been reported. Some lesions are misdiagnosed as ulcers and/or inflammatory bowel disease.

Urogenital tract — Various areas of urogenital involvement have been described, including:

●Collecting system of the kidney

●Fallopian tubes and ovaries

●Endometrium

●Cervix and vagina

Infertility and dysmenorrhea are common [22]. Some individuals pass viscous or fibrous tissue vaginally (during menses or without menses), and some report dysmenorrhea and/or dyspareunia.

Central nervous system — CNS manifestations can include Dandy-Walker malformation and occlusive hydrocephalus. (See "Hydrocephalus in children: Physiology, pathogenesis, and etiology", section on 'CNS malformations'.)

Hydrocephalus may be present at birth, suggesting a congenital malformation, or it may become apparent in childhood [2,23].

Skin — Skin manifestations include impaired wound healing, which can be severe, and juvenile colloid milium (JCM). JCM lesions are small yellow/brown papules in sun-exposed areas, usually seen in children. The figure illustrates the appearance in an adult (picture 3).

EVALUATION

Clinical assessment — PLGD may be suspected in an individual of any age who has one or more of the following:

●Unexplained pseudomembrane formation in one or more of the sites listed above (see 'Clinical features' above)

●Impaired wound healing (see "Basic principles of wound healing")

●A first-degree relative with PLGD (see 'Counseling and testing of family members' below)

Clinical evaluation of first-degree relatives is important even if they are apparently unaffected, as some affected individuals may be identified this way and can be assured to have appropriate long-term care. (See 'Management' below.)

Laboratory and genetic testing — Laboratory testing involves measurement of plasminogen levels (both activity and antigen) [20]; both tests are performed on citrated plasma.

The figure provides a diagnostic algorithm based on these results (algorithm 1).

●Activity – Plasminogen activity is measured using a chromogenic assay; the typical normal range is approximately 70 to 130 (or 75 to 120) percent. Activity level <40 percent is consistent with deficiency, although an absolute cutoff has not been established, and some individuals with clinical manifestations of disease may have higher levels [2]. (See 'Diagnostic confirmation' below.)

●Antigen – Plasminogen antigen (protein levels) are measured using an immunologic assay; the normal range is approximately 6 to 25 mg/dL. Discordance between activity and antigen levels suggests type II PLGD, which is generally asymptomatic despite very low activity levels. (See 'Type I versus type II' above.)

As noted above, normal ranges for activity and antigen levels are lower in neonates and infants; age-specific reference ranges should be consulted. (See 'Control of plasminogen levels' above.)

Standard coagulation testing is normal in PLGD and is not a routine component of the evaluation, as the phenotype does not include bleeding or thrombotic manifestations.

In a study of 14 individuals with PLGD undergoing therapy with plasminogen concentrate, baseline plasminogen activity levels ranged between 0 and 30 percent [9]. Individuals with levels <1 percent (below limits of detection) are also described [15].

Laboratories conducting genetic testing of the PLG gene can be found via the Genetic Testing Registry website [24]. (See 'Referral and coordination of care' below.)

Histopathology — Biopsy is not required for diagnosis. However, lesions may be sent for histopathology during the evaluation, before PLGD has been considered, and pathologic examination may be useful in suggesting PLGD when the diagnosis is unknown or confusing.

Histopathology in PLGD may show ulceration, fibrin-containing membranes, and inflammatory cells [25,26]. Histologic analysis has demonstrated hyaline-positive material in the stroma and fibrinogen deposits in the dermis [27].

Diagnostic confirmation — The diagnostic threshold for PLGD is not well-established. Both clinical features and laboratory results should be considered when making the diagnosis (algorithm 1).

The diagnosis is considered confirmed in individuals with plasminogen activity and antigen levels <45 percent. Levels <30 percent are common [9]. In our experience, some symptomatic individuals may have higher plasminogen activity levels (in the range of 45 to 55 percent).

Genetic testing that reveals biallelic pathogenic variants in PLG (known or predicted to cause type I PLGD) can also provide diagnostic confirmation. This may be especially useful for individuals with borderline plasminogen levels who appear to be asymptomatic. (See 'PLG gene' above.)

Individuals with very low plasminogen activity who do not have symptoms may have type II PLGD, a different disorder that generally does not require treatment. Plasminogen antigen levels are normal in these individuals. (See 'Type I versus type II' above.)

Differential diagnosis — The differential diagnosis depends on the site(s) of involvement. Unlike these other disorders, individuals with PLGD have reduced plasminogen activity and antigen levels, and the lesions respond to plasminogen replacement therapy. Examples include the following:

●Ocular – Other causes of ocular findings include infectious conjunctivitis, either viral (herpes simplex virus [HSV], adenovirus) or bacterial. Rare cases of ligneous conjunctivitis have been reported in individuals treated with the antifibrinolytic agent tranexamic acid (TXA) [28,29]. (See "Conjunctivitis", section on 'Causes and clinical manifestations'.)

●Ears, mouth, nose – Other considerations include otitis media, cholesteatoma, sensorineural hearing loss; nasal polyps, seasonal allergies; periodontitis, Cowden's disease, oral fibromas, and other causes of gingival hypertrophy. (See "Chronic suppurative otitis media (CSOM): Clinical features and diagnosis" and "Etiologies of nasal obstruction: An overview" and "An overview of rhinitis" and "Gingivitis and periodontitis in children and adolescents".)

●Respiratory – Other possible diagnoses include reactive airways disease, seasonal allergies, gastroesophageal reflux disease (GERD), tonsillitis, strep throat, vocal cord polyps, recurrent pneumonia, and cystic fibrosis. (See "Asthma in adolescents and adults: Evaluation and diagnosis" and "Evaluation of wheezing illnesses other than asthma in adults" and "Gastroesophageal reflux and asthma" and "Hoarseness in adults" and "Cystic fibrosis: Clinical manifestations and diagnosis".)

●Gastrointestinal tract – Other considerations include other causes of GERD, ulcer disease, irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD). (See "Clinical manifestations and diagnosis of gastroesophageal reflux disease in children and adolescents" and "Clinical presentation and diagnosis of inflammatory bowel disease in children" and "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents".)

●Urogenital tract – Other disorders that may be considered include kidney stones, cervical polyps, vaginitis/cervicitis, endometriosis, cervical polyps, polycystic ovary disease, and primary infertility. (See "Evaluation of gross hematuria in children" and "Etiology and evaluation of hematuria in adults" and "Overview of infertility".)

●Central nervous system – Other considerations include other causes of Dandy-Walker malformation or occlusive hydrocephalus. (See "Hydrocephalus in children: Clinical features and diagnosis" and "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Dandy-Walker malformation'.)

●Skin – Other considerations include skin disorders that may present with colloid milium and/or poor wound healing, such as Ehlers-Danlos syndrome. (See "Risk factors for impaired wound healing and wound complications" and "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes".)

●Multisystem – Other multisystem disorders that may present with abnormalities similar to those seen in PLGD include:

•Cystic fibrosis – (See "Cystic fibrosis: Clinical manifestations and diagnosis".)

•IgG4-related disease – (See "Clinical manifestations and diagnosis of IgG4-related disease".)

•Sjögren's disease – (See "Diagnosis and classification of Sjögren’s disease".)

•Amyloidosis – (See "Overview of amyloidosis".)

•Lipoid proteinosis – (See "Lipoid proteinosis".)

Prenatal diagnosis — Prenatal diagnosis can be made using fetal-free DNA in the maternal circulation, chorionic villus sampling, or amniocentesis if there has been a previously affected child from the same pair of parents and the responsible pathogenic variant(s) in PLG have been identified. (See 'PLG gene' above.)

However, many individuals do not pursue prenatal genetic testing, since identifying that a fetus is homozygous or compound heterozygous for pathogenic variants in PLG cannot determine the spectrum and severity of symptoms. Variability has been observed even in individuals with the same genotype and within the same family. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Penetrance and expressivity'.)

MANAGEMENT

Plasminogen replacement — Restoration of normal plasminogen corrects the deficiency and leads to resolution of pseudomembranes. A human plasma-derived plasminogen (Ryplazim) was approved by the US Food and Drug Administration (FDA) in June 2021 [30]. Prior to this, an ophthalmic preparation of plasminogen was used and was effective local therapy for the ocular pseudomembranes. (See 'Ligneous conjunctivitis' above.)

The figure presents an approach to management (algorithm 2).

●Indications – Treatment with plasminogen is appropriate for individuals with symptomatic lesions including ligneous conjunctivitis or gingivitis, as well as other sites of involvement [9]. Plasminogen concentrate may also be appropriate prior to invasive procedures that could cause or contribute to development of lesions due to local trauma.

●Dose and dose frequency – The dose is 6.6 mg/kg body weight administered intravenously every two to four days, with the actual dose calculated by obtaining a trough level of at least 10 percent above the documented baseline plasminogen activity level.

The frequency of administration depends on the disease burden and organ compromise. More intensive dosing (daily dosing) may be required initially for one or more of the following:

•High disease burden

•Significantly impaired organ function

•Respiratory lesions, especially if lesions compromise the work of breathing or oxygenation or resulting in hypercapnia

•Obstructive hydrocephalous that requires shunt placement

•Need for an invasive procedure

Once lesions are healed and stable, dosing intervals may be lengthened and a maintenance schedule established.

A plasminogen trough level of at least 10 percent over the patient's baseline should be targeted during maintenance therapy [9]. Peak levels >50 percent appear to be sufficient to completely restore normal function [15]. Individuals undergoing surgery or other invasive procedures may require dose modification with higher trough levels than used for standard maintenance therapy.

●Duration – The optimal duration of therapy is under study and is likely to vary depending on clinical manifestations. It is possible that some individuals will be able to discontinue therapy and restart if lesions recur, while others may require continuous therapy to prevent life-threatening complications, vision-threatening lesions, or disability from developing. It is likely that individuals with a high burden of respiratory or central nervous system disease will require long-term therapy. Consultation with a Hemophilia Treatment Center (HTC) or other national center of excellence is advised. (See 'Referral and coordination of care' below.)

●Monitoring – Bleeding and/or tissue sloughing may occur as plasminogen activity is initially restored and lesions are lysed. Most individuals begin to see benefit within days to weeks of therapy.

Monitoring is challenging and depends on the severity and location of lesions. Individuals with respiratory lesions may require intensive monitoring in a hospital setting. Individuals with kidney lesions may develop hematuria and pain as fibrous tissue is passed or obstructs urinary outflow.

Plasminogen trough levels are measured more frequently during initial therapy and with dosage changes; the monitoring interval can be extended during maintenance therapy.

●Supporting evidence – Evidence for efficacy comes from small observational studies. In a study in 14 individuals with PLGD (age range, 5 to 42 years) who were treated with plasminogen for at least 12 weeks, all experienced clinical improvements, often rapidly (days to weeks) [9]. These included resolution or significant decrease in the size of visible lesions in the eye and mouth, as well as symptomatic improvement or other measures of improved function (eg, on pulmonary function testing) in nonvisible lesions. There were no new or recurrent lesions during the treatment period. Therapy was well tolerated, with no serious adverse events or drug discontinuations due to adverse events. However, many individuals experienced initial oozing or frank bleeding (epistaxis, hematuria) or sloughing of pseudomembranous tissues with therapy, likely due to healing, epithelialization, and resolution of the affected areas. Many of the individuals in the study had significantly better improvement in lesions than they had with previous therapies such as those mentioned below. (See 'Other therapies' below.)

Additional follow-up of 11 individuals in the above study who were monitored on therapy for up to 124 weeks demonstrated ≥50 percent improvement in all 11 with no additional safety concerns [31].

Other therapies — Other interventions may be appropriate in individuals who do not have access to plasminogen replacement (algorithm 2).

Often a combination of approaches is most effective. Examples include:

Systemic

●Plasma – Plasma is a source of plasminogen. It is preferred for individuals who require plasminogen replacement and do not have access to plasminogen concentrate. However, the concentration of plasminogen in plasma is low relative to concentrates, and it is difficult to achieve a therapeutic level without associated volume overload. Plasma takes a long time to administer and carries risks of infection and transfusion reactions. (See "Clinical use of plasma components", section on 'Risks'.)

●Estrogen – Oral estrogen-containing contraceptives have been reported to increase circulating plasminogen levels. One report described a female with severe PLGD (blindness due to ligneous conjunctivitis) who had a stable increase in plasminogen level from 15 to 40 percent after starting an oral contraceptive containing levonorgestrel 50 microg plus ethinylestradiol 30 microg, and the ligneous membrane on her eye stopped growing [4]. A meta-analysis of menopausal hormone therapy (unrelated to PLGD) also documented an increase in plasminogen levels [32].

●Immunosuppression – Immunosuppressive and antiinflammatory therapies have been used systemically or topically, including glucocorticoids, cyclosporin, and azathioprine. The optimal dose and schedule are unknown.

Ophthalmic and topical

●Ophthalmic

•Plasminogen concentrate eye drops – These provide plasminogen directly to the eye in individuals with ligneous conjunctivitis (algorithm 2). Efficacy has been demonstrated in case reports and small series [33-35]. In a 2023 series from Italy of six patients who used plasminogen eye drops for ligneous conjunctivitis, all six individuals had resolution of the lesions without recurrence [35]. Lesions regressed within a few weeks. There were no major safety concerns; one individual developed transient antiplasminogen antibodies, but none required modification or interruption of therapy.

•Dosing (in the above series) [35]:

-Patients not undergoing surgery – Two drops eight times per day for four weeks, followed by two drops six times per day for eight weeks.

-Patients requiring surgery for pseudomembrane removal – Preoperatively, two drops eight times per day for four weeks. Postoperatively, two drops 12 times per day for one week, followed by two drops eight times per day for three weeks, followed by two drops six times per day for four weeks.

•Maintenance therapy after lesions resolve – Two drops four to six times per day.

•Other drops – Other ophthalmologic drops have been used including eye drops with plasma, antibiotics, immunosuppressive drugs, heparin, and cromolyn [36]. (See "Allergic conjunctivitis: Management", section on 'Topical therapies' and "Conjunctivitis", section on 'Bacterial'.)

●Topical

•Thrombolytic agents – Topical thrombolytic agents have been used but are not particularly effective.

•Plasma – Topical plasma has also been used. It carries some of the same risks associated with systemic plasma but can be effective in some cases. (See 'Systemic' above.)

Invasive procedures — Some individuals with PLGD have undergone a high number of surgical procedures, especially for ocular and respiratory lesions.

Surgical excisions of pseudomembranes may be necessary in some cases, but clinicians should be aware that instrumentation often results in regrowth of the lesions if performed without adequate replacement therapy [14]. Plasmin is important in tissue remodeling and wound healing, and experts have suggested that repeated biopsies and surgical interventions should be avoided if at all possible [22]. This is especially important in individuals who are not receiving plasminogen replacement therapy.

Referral and coordination of care — Care through an HTC, other center of excellence, or hematologist with expertise in bleeding disorders is advised, as these individuals have the greatest experience in dosing and monitoring coagulation factor products. HTC involvement may also be the best way to ensure access to clinical trials and new therapies. A directory of HTCs in the United States is available through the Centers for Disease Control and Prevention (CDC) HTC directory [37].

Appropriate long-term care is important for assessing development of new lesions and/or need for change in therapy. This is true even for individuals who appear to be asymptomatic.

Enrollment in the HISTORY registry and participation in the HISTORY project will establish a database of clinical features by obtaining retrospective information and following patients prospectively. The registry can be accessed at plgdeficiency.com.

The plasminogen deficiency foundation (plasminogendeficiency.org) provides information about other clinical trials and patient support materials, as well as descriptions of patients' clinical courses [38].

Counseling and testing of family members — Biologic parents of an individual with PLGD are generally obligate heterozygotes. Full siblings have a 25 percent (1 in 4) chance of inheriting biallelic disease variants, a 50 percent (1 in 2) chance of being a carrier, and a 25 percent (1 in 4) chance of inheriting neither disease variant.

Genetic counseling should be offered to first-degree relatives of an affected individual and as part of reproductive counseling for individuals considering childbearing, especially if they have an affected child.

PROGNOSIS — Without plasminogen replacement, many individuals survive to adulthood with chronic complications [9]. However, lesions can progress to cause blindness, loss of hearing, complications of hydrocephalus, and/or bronchial obstruction, which can be fatal.

Information on prognosis with plasminogen replacement is limited as the replacement product was only approved in 2021, but preliminary experience suggests that the growth of lesions can be abated and existing lesions can regress and resolve.

SUMMARY AND RECOMMENDATIONS

●Disease definition – Plasminogen deficiency (PLGD) is an autosomal recessive disorder caused by biallelic pathogenic variants in the PLG gene. Plasminogen is the precursor to plasmin, which facilitates wound healing, resolution of inflammation, and epithelialization. Reduced plasminogen function causes fibrin-rich pseudomembranes on mucosal surfaces, often at sites of injury or irritation. (See 'Pathophysiology' above.)

●Prevalence – PLGD is an extremely rare disorder with an estimated 12,000 expected cases in the world; however, underdiagnosis is likely. Approximately 1 in 400 individuals are heterozygous carriers. (See 'Epidemiology' above.)

●Clinical findings – Presentations vary with different site(s) of involvement (table 1). (See 'Clinical features' above.)

•Ligneous conjunctivitis is the most common finding.

•Oral and respiratory lesions, gastrointestinal involvement, urogenital involvement, and central nervous system findings are also seen.

•Pseudomembranes can threaten vision and cause obstruction (respiratory, urogenital, central nervous system [CNS]), which can be life-threatening.

•Venous thromboembolism (VTE) does not appear to be increased.

●Evaluation

•The evaluation starts with a clinical assessment and family history. (See 'Evaluation' above.)

•Laboratory testing should include plasminogen activity and antigen (protein level) (algorithm 1). Standard coagulation testing is not helpful.

•The differential diagnosis is broad.

•Genetic testing can be confirmatory and may help with evaluation of first-degree relatives. (See 'Counseling and testing of family members' above.)

●Management – (See 'Management' above.)

•Plasminogen replacement therapy (plasma-derived plasminogen concentrate) can cause lesions to regress and resolve (algorithm 2). It may be life-saving, vision-sparing, or reduce morbidity in individuals with organ-threatening manifestations. Plasminogen concentrate eye drops are effective for ligneous conjunctivitis.

•The optimal regimen remains to be determined and may include either continuous prophylaxis or intermittent treatment, depending on the individual's disease severity and clinical course. Dosing intervals and duration are also individualized.

•Coordination of care via a Hemophilia Treatment Center (HTC) or other national center of excellence provides the opportunity for expert input, family testing, and enrollment in clinical trials. HTC resources are listed above.

•Ongoing expert management is also important for individuals with PLGD who do not have symptoms, so that symptomatic lesions can be identified and treated early should they arise.

●Prognosis – Individuals who are treated with plasminogen replacement can have remarkable and complete resolution of pseudomembranes over the course of weeks to months. Without replacement, pseudomembranes may continue to enlarge and can cause organ dysfunction; loss of vision, hearing, dentition; or other sequelae. (See 'Prognosis' above.)