👪

Inheritance

1

Autosomal recessive HP:0000007

autosomal recessive inheritance

Show evidence (1 reference)

PMID:21174000 SUPPORT Human Clinical

"Homozygous or compound-heterozygous mutations in the plasminogen (PLG) gene were found in 16 of 23 patients (70%), three of which were novel mutations reported here for the first time (C166Y, Y264S, IVS10-7T/G)."

The patient series identifies biallelic PLG genotypes in most severe hypoplasminogenemia cases, supporting recessive inheritance.

⚙

Pathophysiology

3

PLG-Related Plasminogen Deficiency

Biallelic pathogenic PLG variants reduce plasminogen antigen and activity, limiting the substrate available for plasmin generation.

plasminogen activation link ↓ DECREASED

Downstream

Impaired Fibrinolysis

Show evidence (2 references)

PMID:21174000 SUPPORT Human Clinical

"Here we report the molecular genetic and clinical findings on 23 new cases with severe hypoplasminogenaemia."

This case series directly studies severe hypoplasminogenemia and its PLG molecular basis.

PMID:27976734 SUPPORT Human Clinical

"Although plasminogen is a key protein in fibrinolysis and several mutations in the plasminogen gene (PLG) have been identified that result in plasminogen deficiency, there are conflicting reports to associate it with the risk of thrombosis."

This supports PLG variants as the genetic cause of plasminogen deficiency while distinguishing fibrinolysis biology from uncertain thrombosis risk.

Impaired Fibrinolysis

Reduced plasmin activity impairs fibrin degradation and extravascular wound repair, so fibrin persists after mucosal injury or inflammation.

fibrinolysis link ↓ DECREASED

Downstream

Ligneous Mucosal Pseudomembrane Formation

Show evidence (1 reference)

PMID:21174000 SUPPORT Human Clinical

"Inherited severe hypoplasminogenaemia is a multisystemic disorder leading to deficient extravascular fibrinolysis."

The abstract directly states that inherited severe hypoplasminogenemia causes deficient extravascular fibrinolysis.

Ligneous Mucosal Pseudomembrane Formation

Persistent fibrin-rich deposits form thick pseudomembranes on mucosal surfaces. The conjunctiva is the hallmark site, but airway, oral, genitourinary, gastrointestinal, and tympanic mucosa can also be involved.

conjunctival epithelial cell link

wound healing link ↓ DECREASED

Show evidence (1 reference)

PMID:39372655 SUPPORT Human Clinical

"Plasminogen deficiency type 1 (PLGD-1, hypoplasminogenemia) is an ultra-rare, lifelong disease associated with development of fibrinous lesions in multiple organ systems."

This recent clinical case series supports multisystem fibrinous lesion formation as a core disease mechanism.

⬡

Pathograph

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●

Phenotypes

7

Nervous System 1

Hydrocephalus Hydrocephalus (HP:0000238)

Show evidence (1 reference)

PMID:21174000 SUPPORT Human Clinical

"Compared to 79 previously published cases, clinical manifestations of the current group of patients showed higher percentages of ligneous periodontitis, congenital hydrocephalus, and involvement of the female genital tract."

The 23-patient series identifies congenital hydrocephalus among clinical manifestations enriched in the cohort.

Respiratory 1

Respiratory Insufficiency Respiratory insufficiency (HP:0002093)

Show evidence (1 reference)

PMID:39372655 SUPPORT Human Clinical

"Early recognition and effective treatment of airway obstruction caused by fibrinous lesions are critical to prevent morbidity due to respiratory compromise."

This supports respiratory compromise as a consequence of airway fibrinous lesions.

Other 5

Ligneous Conjunctivitis Conjunctival membrane (HP:0034814)

Show evidence (1 reference)

PMID:37612758 SUPPORT Human Clinical

"Ligneous Conjunctivitis (LC) is the most common clinical manifestation of Type I Plasminogen deficiency (T1PD; OMIM# 217090), and it is characterized by the formation of pseudomembranes (due to deposition of fibrin) on the conjunctivae leading to progressive vision loss."

This directly supports conjunctival pseudomembranes as the most common manifestation and links them to vision loss.

Severe Periodontitis Severe periodontitis (HP:0000166)

Show evidence (1 reference)

PMID:37506226 SUPPORT Human Clinical

"We reason that the role of fibrin in periodontitis becomes most evident in individuals with the Mendelian genetic defect, congenital plasminogen (PLG) deficiency, who are predisposed to severe periodontitis in childhood due to a defect in fibrinolysis."

This supports childhood severe periodontitis as a mucosal consequence of PLG deficiency.

Premature Loss of Teeth Premature loss of teeth (HP:0006480)

Show evidence (1 reference)

PMID:37506226 PARTIAL Human Clinical

"We reason that the role of fibrin in periodontitis becomes most evident in individuals with the Mendelian genetic defect, congenital plasminogen (PLG) deficiency, who are predisposed to severe periodontitis in childhood due to a defect in fibrinolysis."

The abstract supports severe childhood periodontitis; tooth loss is a downstream clinical consequence of severe periodontal destruction, so this is marked partial rather than direct support.

Airway Obstruction Airway obstruction (HP:0006536)

Show evidence (1 reference)

PMID:39372655 SUPPORT Human Clinical

"Depending on lesion location, clinical manifestations of PLGD-1 can result in acute and/or chronic respiratory airway disease which can compromise respiratory function leading to life-threatening events."

This supports clinically important respiratory tract involvement and airway compromise in PLGD-1.

Female Genital Tract Involvement Abnormality of the female genitalia (HP:0010460)

Show evidence (1 reference)

PMID:21174000 SUPPORT Human Clinical

"Compared to 79 previously published cases, clinical manifestations of the current group of patients showed higher percentages of ligneous periodontitis, congenital hydrocephalus, and involvement of the female genital tract."

This supports female genital tract involvement as a documented clinical manifestation.

🧬

Genetic Associations

1

PLG (Biallelic Pathogenic Variant)

Show evidence (3 references)

PMID:21174000 SUPPORT Human Clinical

"Homozygous or compound-heterozygous mutations in the plasminogen (PLG) gene were found in 16 of 23 patients (70%), three of which were novel mutations reported here for the first time (C166Y, Y264S, IVS10-7T/G)."

The cohort directly supports PLG as the causal gene and documents the biallelic variant pattern.

PMID:27976734 SUPPORT Human Clinical

"The whole PLG was tested using Next Generation Sequencing (NGS) and 5 putative pathogenic mutations were found (after in silico predictions) and associated with plasminogen deficiency."

Independent family sequencing supports pathogenic PLG variants as the genetic basis of plasminogen deficiency.

CGGV:assertion_2c9320e7-9f02-4b54-beba-0ca781a442eb-2019-10-23T160000.000Z SUPPORT Other

ClinGen classifies the PLG-hypoplasminogenemia gene-disease relationship as definitive with autosomal recessive inheritance.

💊

Treatments

3

Intravenous Plasminogen Replacement

Action: infusion procedure MAXO:0000757

Agent: plasminogen

Plasminogen, human-tvmh replacement restores circulating plasminogen activity and is disease-targeted therapy for visible and non-visible lesions in type 1 plasminogen deficiency.

Mechanism Target:

RESTORES PLG-Related Plasminogen Deficiency — Replacement therapy restores plasminogen substrate for plasmin generation.

RESTORES Impaired Fibrinolysis — Increased plasminogen activity supports restoration of fibrinolytic capacity.

Show evidence (2 references)

DOI:10.1111/hae.14849 SUPPORT Human Clinical

"The primary efficacy endpoint was achieved, as 100% of subjects (n = 11) with visible and assessable non‐visible lesions at baseline demonstrated ≥ 50% improvement after 48 weeks of study drug treatment with plasminogen, human‐tvmh."

Phase 2/3 clinical evidence supports systemic plasminogen replacement for lesion improvement in type 1 plasminogen deficiency.

DOI:10.1111/hae.14849 SUPPORT Human Clinical

"All subjects achieved the targeted ≥ 10% increase in trough plasminogen activity above baseline through Week 12."

This supports the biochemical restoration mechanism of intravenous plasminogen replacement.

Plasminogen Replacement for Respiratory Lesions

Action: infusion procedure MAXO:0000757

Agent: plasminogen

Intravenous plasminogen, human-tvmh can resolve or greatly improve severe respiratory complications due to airway fibrinous lesions.

Mechanism Target:

MODULATES Ligneous Mucosal Pseudomembrane Formation — Replacement therapy can clear or reduce fibrinous airway lesions.

Target Phenotypes: airway obstruction ↗ respiratory insufficiency ↗

Show evidence (2 references)

PMID:39372655 SUPPORT Human Clinical

"Presented here is a case series of one adult and three pediatric patients with severe respiratory complications of PLGD-1 successfully managed by infusions of plasminogen, human-tvmh replacement therapy."

This directly supports systemic replacement therapy for severe airway complications.

PMID:39372655 SUPPORT Human Clinical

"Patients' respiratory symptoms were resolved or greatly improved, and treatment was generally well tolerated."

The case series reports clinical improvement of respiratory symptoms with replacement therapy.

Topical Plasminogen Eye Drops

Action: Pharmacotherapy NCIT:C15986

Agent: plasminogen

Topical plasminogen has been used to prevent recurrent conjunctival pseudomembranes in ligneous conjunctivitis, including long-term pediatric follow-up after ocular surgery.

Mechanism Target:

MODULATES Ligneous Mucosal Pseudomembrane Formation — Topical replacement targets local fibrin-rich membrane recurrence.

Target Phenotypes: conjunctival membrane ↗

Show evidence (2 references)

PMID:37612758 SUPPORT Human Clinical

"Treatment with topical purified plasminogen is used to prevent pseudomembranes formation (Blood 108:3021-3026, 2006, Ophthalmology 129:955-957, 2022)."

This supports topical plasminogen as a local treatment strategy for conjunctival pseudomembrane prevention.

PMID:37612758 SUPPORT Human Clinical

"The patient showed a progressive response to the topical plasminogen, with a complete absence of pseudomembrane formation at a twelve-year follow-up, despite using an ocular prosthesis."

Long-term follow-up supports durable control of conjunctival membranes in one pediatric case.

🔬

Biochemical Markers

1

Low Plasminogen Activity (PRESENT)

Show evidence (1 reference)

DOI:10.1111/hae.14849 SUPPORT Human Clinical

"All subjects achieved the targeted ≥ 10% increase in trough plasminogen activity above baseline through Week 12."

The replacement-therapy trial uses trough plasminogen activity as a biochemical endpoint in subjects with type 1 plasminogen deficiency.

🔬

Clinical Trials

2

NCT02690714 PHASE_II COMPLETED

Phase 2/3 open-label repeat-dose trial evaluating pharmacokinetics, efficacy, and safety of intravenous Prometic plasminogen in pediatric and adult subjects with hypoplasminogenemia.

Target Phenotypes: conjunctival membrane ↗ airway obstruction ↗

Show evidence (1 reference)

clinicaltrials:NCT02690714 SUPPORT Human Clinical

"This is a Phase 2/3 pivotal study to evaluate pharmacokinetics (PK), efficacy, and safety of Prometic Plasminogen (Human) Intravenous Lyophilized Solution, the investigational medicinal product (IMP), in pediatric and adult subjects with hypoplasminogenemia."

ClinicalTrials.gov identifies this pivotal intravenous plasminogen study in pediatric and adult hypoplasminogenemia.

NCT01554956 PHASE_II COMPLETED

Historically controlled phase 2/3 clinical trial evaluating topical human plasminogen eye drops in patients diagnosed with ligneous conjunctivitis.

Target Phenotypes: conjunctival membrane ↗

Show evidence (1 reference)

clinicaltrials:NCT01554956 SUPPORT Human Clinical

"Kedrion Human Plasminogen, a sterile human plasma-derived plasminogen preparation for topical ocular use will be evaluated for the indication of treatment of ligneous conjunctivitis."

ClinicalTrials.gov supports topical plasminogen eye drops as a clinical trial intervention for ligneous conjunctivitis.

{ }

Source YAML

click to show

name: Hypoplasminogenemia
creation_date: "2026-05-07T12:56:42Z"
updated_date: "2026-05-07T12:56:42Z"
category: Mendelian
disease_term:
  preferred_term: hypoplasminogenemia
  term:
    id: MONDO:0009009
    label: hypoplasminogenemia
synonyms:
- plasminogen deficiency type 1
- congenital plasminogen deficiency type I
- type 1 plasminogen deficiency
- PLGD-1
parents:
- Coagulation Disorder
- Hereditary Hematologic Disorder
description: >-
  Hypoplasminogenemia is an autosomal recessive PLG-related disorder in which
  low plasminogen antigen and activity impair plasmin-mediated fibrinolysis and
  wound healing on mucosal surfaces. The disease produces fibrin-rich ligneous
  pseudomembranes, most often ligneous conjunctivitis, and can involve the
  periodontium, respiratory tract, genitourinary tract, gastrointestinal tract,
  and central nervous system.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:21174000
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous or compound-heterozygous mutations in the plasminogen (PLG) gene were found in 16 of 23 patients (70%), three of which were novel mutations reported here for the first time (C166Y, Y264S, IVS10-7T/G)."
    explanation: >-
      The patient series identifies biallelic PLG genotypes in most severe
      hypoplasminogenemia cases, supporting recessive inheritance.
pathophysiology:
- name: PLG-Related Plasminogen Deficiency
  description: >-
    Biallelic pathogenic PLG variants reduce plasminogen antigen and activity,
    limiting the substrate available for plasmin generation.
  gene:
    preferred_term: PLG
    term:
      id: hgnc:9071
      label: PLG
  biological_processes:
  - preferred_term: plasminogen activation
    term:
      id: GO:0031639
      label: plasminogen activation
    modifier: DECREASED
  evidence:
  - reference: PMID:21174000
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report the molecular genetic and clinical findings on 23 new cases with severe hypoplasminogenaemia."
    explanation: >-
      This case series directly studies severe hypoplasminogenemia and its PLG
      molecular basis.
  - reference: PMID:27976734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although plasminogen is a key protein in fibrinolysis and several mutations in the plasminogen gene (PLG) have been identified that result in plasminogen deficiency, there are conflicting reports to associate it with the risk of thrombosis."
    explanation: >-
      This supports PLG variants as the genetic cause of plasminogen deficiency
      while distinguishing fibrinolysis biology from uncertain thrombosis risk.
  downstream:
  - target: Impaired Fibrinolysis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37506226
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We reason that the role of fibrin in periodontitis becomes most evident in individuals with the Mendelian genetic defect, congenital plasminogen (PLG) deficiency, who are predisposed to severe periodontitis in childhood due to a defect in fibrinolysis."
      explanation: >-
        This review links congenital PLG deficiency to defective fibrinolysis in
        a clinically affected mucosal tissue.
- name: Impaired Fibrinolysis
  description: >-
    Reduced plasmin activity impairs fibrin degradation and extravascular wound
    repair, so fibrin persists after mucosal injury or inflammation.
  biological_processes:
  - preferred_term: fibrinolysis
    term:
      id: GO:0042730
      label: fibrinolysis
    modifier: DECREASED
  evidence:
  - reference: PMID:21174000
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inherited severe hypoplasminogenaemia is a multisystemic disorder leading to deficient extravascular fibrinolysis."
    explanation: >-
      The abstract directly states that inherited severe hypoplasminogenemia
      causes deficient extravascular fibrinolysis.
  downstream:
  - target: Ligneous Mucosal Pseudomembrane Formation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired fibrin degradation
    - defective mucosal wound healing
    evidence:
    - reference: PMID:21174000
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As a clinical consequence wound healing capacity of mucous membranes is markedly impaired leading to ligneous conjunctivitis and several other manifestations."
      explanation: >-
        This connects deficient extravascular fibrinolysis to impaired mucosal
        wound healing and ligneous lesions.
- name: Ligneous Mucosal Pseudomembrane Formation
  description: >-
    Persistent fibrin-rich deposits form thick pseudomembranes on mucosal
    surfaces. The conjunctiva is the hallmark site, but airway, oral,
    genitourinary, gastrointestinal, and tympanic mucosa can also be involved.
  cell_types:
  - preferred_term: conjunctival epithelial cell
    term:
      id: CL:1000432
      label: conjunctival epithelial cell
  biological_processes:
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: DECREASED
  evidence:
  - reference: PMID:39372655
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasminogen deficiency type 1 (PLGD-1, hypoplasminogenemia) is an ultra-rare, lifelong disease associated with development of fibrinous lesions in multiple organ systems."
    explanation: >-
      This recent clinical case series supports multisystem fibrinous lesion
      formation as a core disease mechanism.
phenotypes:
- category: Ophthalmologic
  name: Ligneous Conjunctivitis
  description: >-
    Chronic or recurrent conjunctival pseudomembranes are the hallmark clinical
    manifestation and can cause progressive visual morbidity.
  phenotype_term:
    preferred_term: conjunctival membrane
    term:
      id: HP:0034814
      label: Conjunctival membrane
  evidence:
  - reference: PMID:37612758
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ligneous Conjunctivitis (LC) is the most common clinical manifestation of Type I Plasminogen deficiency (T1PD; OMIM# 217090), and it is characterized by the formation of pseudomembranes (due to deposition of fibrin) on the conjunctivae leading to progressive vision loss."
    explanation: >-
      This directly supports conjunctival pseudomembranes as the most common
      manifestation and links them to vision loss.
- category: Dental
  name: Severe Periodontitis
  description: >-
    Mucosal fibrin persistence predisposes affected children to severe
    periodontitis and early tooth loss.
  phenotype_term:
    preferred_term: severe periodontitis
    term:
      id: HP:0000166
      label: Severe periodontitis
  evidence:
  - reference: PMID:37506226
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We reason that the role of fibrin in periodontitis becomes most evident in individuals with the Mendelian genetic defect, congenital plasminogen (PLG) deficiency, who are predisposed to severe periodontitis in childhood due to a defect in fibrinolysis."
    explanation: >-
      This supports childhood severe periodontitis as a mucosal consequence of
      PLG deficiency.
- category: Dental
  name: Premature Loss of Teeth
  description: >-
    Severe ligneous periodontal disease can lead to premature tooth loss.
  phenotype_term:
    preferred_term: premature loss of teeth
    term:
      id: HP:0006480
      label: Premature loss of teeth
  evidence:
  - reference: PMID:37506226
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "We reason that the role of fibrin in periodontitis becomes most evident in individuals with the Mendelian genetic defect, congenital plasminogen (PLG) deficiency, who are predisposed to severe periodontitis in childhood due to a defect in fibrinolysis."
    explanation: >-
      The abstract supports severe childhood periodontitis; tooth loss is a
      downstream clinical consequence of severe periodontal destruction, so this
      is marked partial rather than direct support.
- category: Respiratory
  name: Airway Obstruction
  description: >-
    Fibrinous lesions can develop in the respiratory tract and compromise
    respiratory function, sometimes producing life-threatening airway disease.
  phenotype_term:
    preferred_term: airway obstruction
    term:
      id: HP:0006536
      label: Airway obstruction
  evidence:
  - reference: PMID:39372655
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Depending on lesion location, clinical manifestations of PLGD-1 can result in acute and/or chronic respiratory airway disease which can compromise respiratory function leading to life-threatening events."
    explanation: >-
      This supports clinically important respiratory tract involvement and
      airway compromise in PLGD-1.
- category: Respiratory
  name: Respiratory Insufficiency
  description: >-
    Severe respiratory lesions can impair respiratory function and may require
    disease-targeted replacement therapy.
  phenotype_term:
    preferred_term: respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:39372655
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early recognition and effective treatment of airway obstruction caused by fibrinous lesions are critical to prevent morbidity due to respiratory compromise."
    explanation: >-
      This supports respiratory compromise as a consequence of airway fibrinous
      lesions.
- category: Neurologic
  name: Hydrocephalus
  description: >-
    Congenital or occlusive hydrocephalus is reported in a subset of severe
    hypoplasminogenemia cases.
  phenotype_term:
    preferred_term: hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:21174000
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared to 79 previously published cases, clinical manifestations of the current group of patients showed higher percentages of ligneous periodontitis, congenital hydrocephalus, and involvement of the female genital tract."
    explanation: >-
      The 23-patient series identifies congenital hydrocephalus among clinical
      manifestations enriched in the cohort.
- category: Reproductive
  name: Female Genital Tract Involvement
  description: >-
    Ligneous lesions can involve the female genital tract and contribute to
    reproductive morbidity in affected individuals.
  phenotype_term:
    preferred_term: abnormality of the female genitalia
    term:
      id: HP:0010460
      label: Abnormality of the female genitalia
  evidence:
  - reference: PMID:21174000
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared to 79 previously published cases, clinical manifestations of the current group of patients showed higher percentages of ligneous periodontitis, congenital hydrocephalus, and involvement of the female genital tract."
    explanation: >-
      This supports female genital tract involvement as a documented clinical
      manifestation.
biochemical:
- name: Low Plasminogen Activity
  presence: PRESENT
  notes: >-
    Type 1 plasminogen deficiency is characterized clinically by low functional
    plasminogen activity together with low plasminogen antigen; routine PT/aPTT
    testing may be unrevealing, so targeted plasminogen assays are diagnostic.
  evidence:
  - reference: DOI:10.1111/hae.14849
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All subjects achieved the targeted ≥ 10% increase in trough plasminogen activity above baseline through Week 12."
    explanation: >-
      The replacement-therapy trial uses trough plasminogen activity as a
      biochemical endpoint in subjects with type 1 plasminogen deficiency.
genetic:
- name: PLG
  gene_term:
    preferred_term: PLG
    term:
      id: hgnc:9071
      label: PLG
  association: Biallelic Pathogenic Variant
  features: >-
    PLG encodes plasminogen. Reported pathogenic alleles include homozygous and
    compound-heterozygous variants that reduce plasminogen activity and antigen.
  evidence:
  - reference: PMID:21174000
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous or compound-heterozygous mutations in the plasminogen (PLG) gene were found in 16 of 23 patients (70%), three of which were novel mutations reported here for the first time (C166Y, Y264S, IVS10-7T/G)."
    explanation: >-
      The cohort directly supports PLG as the causal gene and documents the
      biallelic variant pattern.
  - reference: PMID:27976734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The whole PLG was tested using Next Generation Sequencing (NGS) and 5 putative pathogenic mutations were found (after in silico predictions) and associated with plasminogen deficiency."
    explanation: >-
      Independent family sequencing supports pathogenic PLG variants as the
      genetic basis of plasminogen deficiency.
  - reference: CGGV:assertion_2c9320e7-9f02-4b54-beba-0ca781a442eb-2019-10-23T160000.000Z
    reference_title: "PLG / hypoplasminogenemia (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PLG | HGNC:9071 | hypoplasminogenemia | MONDO:0009009 | AR | Definitive"
    explanation: ClinGen classifies the PLG-hypoplasminogenemia gene-disease relationship as definitive with autosomal recessive inheritance.
treatments:
- name: Intravenous Plasminogen Replacement
  description: >-
    Plasminogen, human-tvmh replacement restores circulating plasminogen
    activity and is disease-targeted therapy for visible and non-visible lesions
    in type 1 plasminogen deficiency.
  treatment_term:
    preferred_term: infusion procedure
    term:
      id: MAXO:0000757
      label: infusion procedure
    therapeutic_agent:
    - preferred_term: plasminogen
  target_mechanisms:
  - target: PLG-Related Plasminogen Deficiency
    treatment_effect: RESTORES
    description: Replacement therapy restores plasminogen substrate for plasmin generation.
  - target: Impaired Fibrinolysis
    treatment_effect: RESTORES
    description: Increased plasminogen activity supports restoration of fibrinolytic capacity.
  evidence:
  - reference: DOI:10.1111/hae.14849
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The primary efficacy endpoint was achieved, as 100% of subjects (n = 11) with visible and assessable non‐visible lesions at baseline demonstrated ≥ 50% improvement after 48 weeks of study drug treatment with plasminogen, human‐tvmh."
    explanation: >-
      Phase 2/3 clinical evidence supports systemic plasminogen replacement for
      lesion improvement in type 1 plasminogen deficiency.
  - reference: DOI:10.1111/hae.14849
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All subjects achieved the targeted ≥ 10% increase in trough plasminogen activity above baseline through Week 12."
    explanation: >-
      This supports the biochemical restoration mechanism of intravenous
      plasminogen replacement.
- name: Plasminogen Replacement for Respiratory Lesions
  description: >-
    Intravenous plasminogen, human-tvmh can resolve or greatly improve severe
    respiratory complications due to airway fibrinous lesions.
  treatment_term:
    preferred_term: infusion procedure
    term:
      id: MAXO:0000757
      label: infusion procedure
    therapeutic_agent:
    - preferred_term: plasminogen
  target_phenotypes:
  - preferred_term: airway obstruction
    term:
      id: HP:0006536
      label: Airway obstruction
  - preferred_term: respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  target_mechanisms:
  - target: Ligneous Mucosal Pseudomembrane Formation
    treatment_effect: MODULATES
    description: Replacement therapy can clear or reduce fibrinous airway lesions.
  evidence:
  - reference: PMID:39372655
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Presented here is a case series of one adult and three pediatric patients with severe respiratory complications of PLGD-1 successfully managed by infusions of plasminogen, human-tvmh replacement therapy."
    explanation: >-
      This directly supports systemic replacement therapy for severe airway
      complications.
  - reference: PMID:39372655
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients' respiratory symptoms were resolved or greatly improved, and treatment was generally well tolerated."
    explanation: >-
      The case series reports clinical improvement of respiratory symptoms with
      replacement therapy.
- name: Topical Plasminogen Eye Drops
  description: >-
    Topical plasminogen has been used to prevent recurrent conjunctival
    pseudomembranes in ligneous conjunctivitis, including long-term pediatric
    follow-up after ocular surgery.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: plasminogen
  target_phenotypes:
  - preferred_term: conjunctival membrane
    term:
      id: HP:0034814
      label: Conjunctival membrane
  target_mechanisms:
  - target: Ligneous Mucosal Pseudomembrane Formation
    treatment_effect: MODULATES
    description: Topical replacement targets local fibrin-rich membrane recurrence.
  evidence:
  - reference: PMID:37612758
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with topical purified plasminogen is used to prevent pseudomembranes formation (Blood 108:3021-3026, 2006, Ophthalmology 129:955-957, 2022)."
    explanation: >-
      This supports topical plasminogen as a local treatment strategy for
      conjunctival pseudomembrane prevention.
  - reference: PMID:37612758
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient showed a progressive response to the topical plasminogen, with a complete absence of pseudomembrane formation at a twelve-year follow-up, despite using an ocular prosthesis."
    explanation: >-
      Long-term follow-up supports durable control of conjunctival membranes in
      one pediatric case.
clinical_trials:
- name: NCT02690714
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Phase 2/3 open-label repeat-dose trial evaluating pharmacokinetics,
    efficacy, and safety of intravenous Prometic plasminogen in pediatric and
    adult subjects with hypoplasminogenemia.
  target_phenotypes:
  - preferred_term: conjunctival membrane
    term:
      id: HP:0034814
      label: Conjunctival membrane
  - preferred_term: airway obstruction
    term:
      id: HP:0006536
      label: Airway obstruction
  evidence:
  - reference: clinicaltrials:NCT02690714
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a Phase 2/3 pivotal study to evaluate pharmacokinetics (PK), efficacy, and safety of Prometic Plasminogen (Human) Intravenous Lyophilized Solution, the investigational medicinal product (IMP), in pediatric and adult subjects with hypoplasminogenemia."
    explanation: >-
      ClinicalTrials.gov identifies this pivotal intravenous plasminogen study
      in pediatric and adult hypoplasminogenemia.
- name: NCT01554956
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Historically controlled phase 2/3 clinical trial evaluating topical human
    plasminogen eye drops in patients diagnosed with ligneous conjunctivitis.
  target_phenotypes:
  - preferred_term: conjunctival membrane
    term:
      id: HP:0034814
      label: Conjunctival membrane
  evidence:
  - reference: clinicaltrials:NCT01554956
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kedrion Human Plasminogen, a sterile human plasma-derived plasminogen preparation for topical ocular use will be evaluated for the indication of treatment of ligneous conjunctivitis."
    explanation: >-
      ClinicalTrials.gov supports topical plasminogen eye drops as a clinical
      trial intervention for ligneous conjunctivitis.
animal_models:
- species: dog
  genotype: PLG exon 1 deletion
  category: NATURAL
  description: >-
    A Maltese dog with a large PLG deletion and absent plasminogen activity has
    been reported as a spontaneous comparative model of ligneous membranitis.
  evidence:
  - reference: PMID:34370320
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This study provides a spontaneous animal model for LM associated with complete plasminogen deficiency and provides a method for detecting affected or carrier dogs."
    explanation: >-
      The Falcon report identified a natural canine PLG-deficiency case as a
      comparative animal model; this title-level abstract cache supports the
      model relationship after reference fetch.
diagnosis:
- name: Plasminogen Activity and Antigen Testing
  description: >-
    Diagnosis is supported by targeted measurement of plasminogen activity and
    antigen, with type 1 disease showing low activity and low antigen.
  evidence:
  - reference: PMID:27976734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In type I, both plasminogen activity and antigen levels are decreased."
    explanation: >-
      This directly supports the diagnostic distinction that type 1
      plasminogen deficiency has both low activity and low antigen.
datasets:

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 42 citations 2026-05-07T09:31:19.148794

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Hypoplasminogenemia
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Hypoplasminogenemia covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Disease Characteristics Report: Hypoplasminogenemia (Type 1 Plasminogen Deficiency)

Executive summary

Hypoplasminogenemia—also called type 1 plasminogen deficiency (PLGD-1)—is an ultra-rare, autosomal recessive disorder caused by biallelic pathogenic variants in PLG that reduce plasminogen antigen and activity and thereby impair fibrinolysis and tissue remodeling. The hallmark phenotype is ligneous disease, i.e., fibrin-rich “wood-like” pseudomembranes on mucosal surfaces (most commonly the conjunctiva), with potentially life-threatening airway involvement. Since 2021, intravenous plasma-derived human plasminogen (plasminogen, human‑tvmh; Ryplazim) has become a disease-targeted replacement therapy with evidence for durable lesion control in a phase 2/3 study and post-approval case series. (shapiro2023plasminogenhuman‐tvmhfor pages 1-2, nakar2024casereportrespiratory pages 1-2)

1. Disease information

1.1 Overview (what is the disease?)

Type 1 congenital plasminogen deficiency (hypoplasminogenemia) is defined by low plasminogen antigen and low functional plasminogen activity, leading to impaired fibrin clearance and accumulation of fibrin-rich pseudomembranes on mucosal surfaces (“ligneous” lesions). A 2023 review summarizes that type I disease is autosomal recessive and results in decreased antigenic and functional plasminogen with mucosal fibrin deposition. (silva2023plasminmediatedfibrinolysisin pages 1-2)

Abstract-supported key concept quote (2023 review): “The hemostatic and inflammatory systems work hand in hand to maintain homeostasis at mucosal barrier sites… fibrin is well recognized for its role in mucosal homeostasis, wound healing, and inflammation.” (silva2023plasminmediatedfibrinolysisin pages 1-2)

1.2 Key identifiers

MONDO: MONDO_0009009 (hypoplasminogenemia) (OpenTargets). (OpenTargets Search: plasminogen deficiency,hypoplasminogenemia-PLG)
OMIM disease: Type 1 plasminogen deficiency / hypoplasminogenemia = OMIM #217090. (panfili2023longtermfollowupin pages 1-3)
OMIM gene: PLG = OMIM #173350. (panfili2023longtermfollowupin pages 1-3)

Not retrieved in the current tool evidence (therefore not reported here to avoid guessing): Orphanet ID, ICD-10/ICD-11 codes, MeSH descriptor.

1.3 Synonyms / alternative names

Type 1 plasminogen deficiency; congenital plasminogen deficiency type I; PLGD‑1; “true plasminogen deficiency”; ligneous disease due to plasminogen deficiency. (panfili2023longtermfollowupin pages 1-3, nakar2024casereportrespiratory pages 1-2)

1.4 Evidence sources

The information in this report is derived from peer-reviewed reviews and case reports/series, plus ClinicalTrials.gov trial records and OpenTargets disease–gene association. (OpenTargets Search: plasminogen deficiency,hypoplasminogenemia-PLG, NCT02690714 chunk 1, nakar2024casereportrespiratory pages 1-2)

2. Etiology

2.1 Disease causal factors

Genetic cause (primary): biallelic pathogenic variants in PLG (chromosome 6q26) that reduce plasminogen antigen and activity (type I). (panfili2023longtermfollowupin pages 1-3, martinfernandez2016theunravellingof pages 1-2)

2.2 Risk factors

Genetic risk factors

Autosomal recessive inheritance for severe PLGD‑1 (homozygous/compound heterozygous), supported by multiple series. (klammt2011identificationofthree pages 3-4, klammt2011identificationofthree pages 1-2)
Consanguinity is commonly reported in case series enriched from certain regions (e.g., Turkey in one series). (klammt2011identificationofthree pages 1-2)

Environmental/clinical triggers (non-genetic)

Local triggers for mucosal lesion development/worsening (especially in oral disease) include irritation, infection, poor hygiene, and surgery in a 2023 review of ligneous periodontitis. (bektaskayhan2023ligneousperiodontitisassociated pages 1-2)

2.3 Protective factors

Not established in the retrieved sources.

2.4 Gene–environment interactions

Evidence in retrieved texts is suggestive (trauma/infection/surgery as triggers), but no quantitative gene–environment interaction studies were retrieved. (bektaskayhan2023ligneousperiodontitisassociated pages 1-2)

3. Phenotypes

3.1 Core phenotype: ligneous conjunctivitis / keratoconjunctivitis

Most frequent manifestation: ligneous conjunctivitis (LC) affects >80% of symptomatic PLGD‑1 patients in a 2024 case series background and is 80% in a large cited cohort summarized in a 2023 review. (nakar2024casereportrespiratory pages 1-2, silva2023plasminmediatedfibrinolysisin pages 1-2)
LC lesions are described as fibrin-rich, “woody” pseudomembranes on tarsal/palpebral conjunctiva; can bleed and threaten vision through corneal scarring/perforation. (alghubaishi2023recurrentmeningitisand pages 2-4, nasiri2023plasminogendeficiencya pages 3-4)

Suggested HPO terms (not tool-validated here): - Ligneous conjunctivitis / membranous conjunctivitis; conjunctival pseudomembrane; corneal scarring; vision impairment.

3.2 Oral/periodontal phenotypes

Ligneous gingivitis reported as 34% in a large study summarized by a 2023 review; type I deficiency predisposes to early-onset severe periodontitis in childhood. (silva2023plasminmediatedfibrinolysisin pages 1-2)
In a 2023 gingival-lesion literature review, ages for gingival cases spanned 1–66 years, with a strong female predominance in reported cases (74.3% female in that review). (bektaskayhan2023ligneousperiodontitisassociated pages 2-3)

Suggested HPO terms: gingival enlargement; periodontitis; early tooth loss.

3.3 Respiratory tract involvement

Frequency: respiratory lesions in ~20–30% of PLGD‑1 patients (2024 case series background). (nakar2024casereportrespiratory pages 1-2)
Can involve the tracheobronchial tree causing cough/stridor/wheeze/dyspnea and life‑threatening airway obstruction; severe manifestations often in infants/young children. (nakar2024casereportrespiratory pages 1-2)

Image-based evidence (real-world implementation): bronchoscopy shows obstructing ligneous plaques pre-treatment and resolution after 10 days of IV plasminogen replacement. (nakar2024casereportrespiratory media f6ed748e)

Suggested HPO terms: airway obstruction; stridor; bronchial obstruction; recurrent pneumonia.

3.4 Genitourinary and gastrointestinal mucosal lesions

Mucosal lesions can occur in urinary and genital systems and gastrointestinal tract, described across reviews and clinical trial background. (silva2023plasminmediatedfibrinolysisin pages 1-2, shapiro2023plasminogenhuman‐tvmhfor pages 2-2)

Suggested HPO terms: cervicitis; infertility; gastrointestinal pseudomembranes.

3.5 Ear involvement

Middle ear/tympanic membrane involvement (e.g., otitis media/hearing loss) is described in a 2023 case review. (nasiri2023plasminogendeficiencya pages 3-4)

Suggested HPO terms: otitis media; hearing impairment.

3.6 Central nervous system (CNS) involvement

Congenital/occlusive hydrocephalus is repeatedly reported in type I disease, including 2023 case reviews and a 2023 pediatric case report background. (nasiri2023plasminogendeficiencya pages 1-3, panfili2023longtermfollowupin pages 1-3)
Recurrent meningitis has been described in association with severe disease in a 2023 case report. (alghubaishi2023recurrentmeningitisand pages 2-4)

Suggested HPO terms: hydrocephalus; meningitis.

3.7 Quality of life impact

The phase 2/3 plasminogen replacement study reported quality of life (0–10 scale) was improved or maintained in 93% through week 48. (shapiro2023plasminogenhuman‐tvmhfor pages 5-6)

4. Genetic / molecular information

4.1 Causal gene(s)

Primary causal gene: PLG (plasminogen). (klammt2011identificationofthree pages 3-4, martinfernandez2016theunravellingof pages 1-2)

4.2 Variant spectrum and molecular consequences

Variant types causing type I deficiency include missense, splice-site, frameshift, nonsense, and larger deletions/structural variants; allelic heterogeneity is substantial. (klammt2011identificationofthree pages 3-4, martinfernandez2016theunravellingof pages 1-2)
In a 23‑patient series, 16/23 (70%) carried homozygous or compound-heterozygous PLG mutations, supporting recessive inheritance for severe hypoplasminogenemia. (klammt2011identificationofthree pages 3-4)
Functional impact includes reduced plasminogen activity (e.g., <5% to 57% in one series; normal ~75–120%). (klammt2011identificationofthree pages 3-4)

Examples (variant + functional correlation): - PLG c.763G>A (p.Glu255Lys) homozygous: proband activity 2.50%; heterozygous parents 41.02% and 54.07%. (xu2021novelhomozygousmutation pages 1-3) - PLG c.2095T>C (p.Cys699Arg) homozygous: plasminogen level 15% (normal 75–150% in that report). (alghubaishi2023recurrentmeningitisand pages 2-4) - Review tables summarize many missense variants with measured antigen/activity and predicted pathogenicity; reference ranges cited include antigen 6–25 mg/dL and activity 70–140%. (britorobinson2024plasminogenmissensevariants pages 14-15)

4.3 Modifier genes

No definitive modifier genes for ligneous disease penetrance/severity were established in retrieved sources. Some studies consider other thrombosis-risk loci (e.g., F12, F13A1) in families with thrombotic events, but this is not established as a modifier of ligneous disease itself. (martinfernandez2016theunravellingof pages 4-5)

4.4 Epigenetics / chromosomal abnormalities

Not established in the retrieved sources.

4.5 Suggested GO (biological process) and CL (cell type) terms

Based on disease mechanism described in reviews (defective fibrinolysis and mucosal wound healing) (silva2023plasminmediatedfibrinolysisin pages 1-2): - GO processes (suggested): fibrinolysis; wound healing; extracellular matrix organization; inflammatory response. - CL terms (suggested): mucosal epithelial cell; neutrophil (given discussion of fibrin–neutrophil activation in periodontal homeostasis). (silva2023plasminmediatedfibrinolysisin pages 1-2)

5. Environmental information

Not a primary driver in Mendelian PLGD‑1. Local environmental/clinical factors (infection, irritation, surgery) may precipitate lesions in mucosa, especially oral tissues. (bektaskayhan2023ligneousperiodontitisassociated pages 1-2)

6. Mechanism / pathophysiology

6.1 Current understanding (causal chain)

Biallelic PLG pathogenic variants → reduced plasminogen antigen/activity (type I). (martinfernandez2016theunravellingof pages 1-2, klammt2011identificationofthree pages 3-4)
Defective plasmin-mediated fibrinolysis → impaired fibrin clearance and abnormal wound healing. (silva2023plasminmediatedfibrinolysisin pages 1-2, nasiri2023plasminogendeficiencya pages 3-4)
Accumulation of amorphous fibrin-rich material in lamina propria → pseudomembranous “ligneous” lesions on mucosal surfaces. (silva2023plasminmediatedfibrinolysisin pages 1-2)
Site-specific lesion burden (conjunctiva, gingiva, airway, GU/GI mucosa) → organ dysfunction (vision loss, tooth loss, airway obstruction, infertility, etc.). (shapiro2023plasminogenhuman‐tvmhfor pages 2-2, nakar2024casereportrespiratory pages 1-2)

6.2 Tissue/cell processes highlighted in recent reviews

A 2023 review emphasizes interplay of hemostasis and inflammation at mucosal barriers and highlights fibrin’s role in mucosal homeostasis and periodontitis susceptibility in PLG deficiency. (silva2023plasminmediatedfibrinolysisin pages 1-2)

7. Anatomical structures affected

Organ/system level (representative)

Eye/conjunctiva: ligneous conjunctivitis (most common). (silva2023plasminmediatedfibrinolysisin pages 1-2)
Oral cavity/periodontium: ligneous gingivitis/periodontitis; early tooth loss. (silva2023plasminmediatedfibrinolysisin pages 1-2, bektaskayhan2023ligneousperiodontitisassociated pages 1-2)
Respiratory tract (larynx/trachea/bronchi): obstructive ligneous lesions. (nakar2024casereportrespiratory pages 1-2)
Genitourinary tract: cervix/uterus/vagina and other mucosa. (silva2023plasminmediatedfibrinolysisin pages 1-2, alghubaishi2023recurrentmeningitisand pages 2-4)
GI tract: mucosal lesions. (silva2023plasminmediatedfibrinolysisin pages 1-2)
CNS: hydrocephalus (subset). (panfili2023longtermfollowupin pages 1-3, alghubaishi2023recurrentmeningitisand pages 2-4)

Suggested UBERON terms (not tool-validated): conjunctiva; gingiva; trachea/bronchus; uterine cervix; gastrointestinal tract.

8. Temporal development

Onset: typically infancy/childhood; mean reported onset 13–16 years in an ophthalmology case series report; <20% present in the 4th–5th decades. (almeida2024ligneousconjunctivitisfreshfrozen pages 1-3)
Course: often chronic/relapsing with recurrence after surgical excision when replacement is not provided; spontaneous remission has been described in a minority. (alghubaishi2023recurrentmeningitisand pages 2-4, panfili2023longtermfollowupin pages 1-3)

9. Inheritance and population

9.1 Inheritance

Autosomal recessive for severe type I PLGD‑1 (homozygous or compound heterozygous). (klammt2011identificationofthree pages 3-4, alghubaishi2023recurrentmeningitisand pages 2-4)

9.2 Epidemiology (statistics)

Severe type I PLGD (homozygous/compound heterozygous): estimated ~1.6 per 1,000,000 in Europe. (silva2023plasminmediatedfibrinolysisin pages 1-2)
Heterozygous carrier frequency: ~0.3–0.4% in the general population (as summarized in a 2023 review). (silva2023plasminmediatedfibrinolysisin pages 1-2)

Note: Some papers repeat the 0.3–0.4% figure ambiguously; the 2023 J Dent Res review explicitly applies 0.3–0.4% to heterozygous mutations. (silva2023plasminmediatedfibrinolysisin pages 1-2)

10. Diagnostics

10.1 Clinical tests

Key laboratory confirmation: measure both
plasminogen activity (commonly chromogenic assay; e.g., tPA-activated assays), and
plasminogen antigen to classify type I vs type II. (martinfernandez2016theunravellingof pages 1-2, alghafry2025inheriteddisordersof pages 5-6)

10.2 Distinguishing type I vs type II

Type I (hypoplasminogenemia): low activity + low antigen. (martinfernandez2016theunravellingof pages 1-2, alghafry2025inheriteddisordersof pages 5-6)
Type II (dysplasminogenemia): low activity with normal antigen; rarely symptomatic. (silva2023plasminmediatedfibrinolysisin pages 1-2, martinfernandez2016theunravellingof pages 1-2)

10.3 Routine labs often normal / non-diagnostic

Conventional coagulation tests (e.g., platelet count, PT, aPTT, factor levels, fibrinogen, vWF) can be normal and are not diagnostic; targeted plasminogen assays are needed. (alghafry2025inheriteddisordersof pages 5-6)

10.4 Genetic testing

Confirmatory genetic testing via sequencing of PLG (Sanger, WES/WGS, NGS; long-range PCR approaches may help avoid homology/pseudogene issues) is used for definitive diagnosis and family studies. (xu2021novelhomozygousmutation pages 1-3, martinfernandez2016theunravellingof pages 2-3)

10.5 Suggested differential diagnosis

Not comprehensively enumerated in retrieved texts. Clinically, LC can be misdiagnosed as nonspecific conjunctivitis early; persistent/recurrent pseudomembranes plus low plasminogen support PLGD‑1. (nasiri2023plasminogendeficiencya pages 3-4)

11. Outcome / prognosis

Severity varies with lesion location and burden. Untreated disease can cause major morbidity (blindness, airway obstruction, complications of hydrocephalus) and can be fatal, as emphasized in clinical trial background and case literature. (shapiro2023plasminogenhuman‐tvmhfor pages 2-2, alghubaishi2023recurrentmeningitisand pages 2-4)
Replacement therapy can produce rapid resolution of life-threatening airway disease in reported cases. (nakar2024casereportrespiratory pages 1-2, nakar2024casereportrespiratory media f6ed748e)

12. Treatment

12.1 Pharmacotherapy / replacement therapy (current standard)

Intravenous plasminogen, human‑tvmh (Ryplazim)

Trial evidence: open-label phase 2/3 study (15 subjects) with treatment up to 124 weeks; dosing 6.6 mg/kg with individualized intervals. (shapiro2023plasminogenhuman‐tvmhfor pages 1-2)
Efficacy: in participants with visible assessable lesions, 100% (n=11) had ≥50% improvement at 48 weeks; all met the co-primary biochemical endpoint of ≥10% absolute trough plasminogen activity increase through week 12. (shapiro2023plasminogenhuman‐tvmhfor pages 1-2)
Non-visible lesions: high proportion resolved among assessed lesions during follow-up (table excerpt). (shapiro2023plasminogenhuman‐tvmhfor pages 4-5)
Safety: treatment-emergent bleeding AEs in 5/15 (33%), mild/short; no neutralizing antibodies detected. (shapiro2023plasminogenhuman‐tvmhfor pages 7-8)
QoL: improved/maintained in 93% through week 48. (shapiro2023plasminogenhuman‐tvmhfor pages 5-6)
Real-world application (respiratory lesions): case series of four patients with severe airway disease; rapid clinical improvement and lesion resolution documented, including bronchoscopy resolution by day 10 and durable outpatient/home infusion regimens. (nakar2024casereportrespiratory pages 2-3, nakar2024casereportrespiratory media f6ed748e)

MAXO (suggested): plasminogen replacement therapy; intravenous drug administration.

12.2 Topical/local approaches (when commercial plasminogen eyedrops unavailable)

Membrane excision + topical/subconjunctival FFP + topical heparin: 2024 report of two LC cases with no recurrence at 12 months; detailed preparation/storage protocol for FFP aliquots and intensive postoperative regimen. (almeida2024ligneousconjunctivitisfreshfrozen pages 1-3)
Topical plasminogen drops compounded from FFP: 2023 pediatric case report describes ethics-approved topical plasminogen formulation with durable absence of pseudomembranes at 12‑year follow-up, enabling prosthesis use after debulking surgery. (panfili2023longtermfollowupin pages 1-3)
Allogeneic donor plasma drops (clinical trial N-of-1): protocol NCT05404932 uses donor plasma drops 1–2 drops every 1–5 hours for 2–6 months with safety monitoring (Canada). (NCT05404932 chunk 1)

MAXO (suggested): topical plasma administration; conjunctival membrane excision.

12.3 Clinical trials and registries (real-world implementation)

NCT02690714: IV plasminogen 6.6 mg/kg, phase 2/3; endpoints include trough plasminogen activity and lesion improvement. (NCT02690714 chunk 1)
NCT01554956: plasminogen eye drops for LC, phase 2/3, enrollment 12; results posted 2023‑01‑25; endpoint includes prevention of pseudomembrane relapse. (NCT01554956 chunk 1)
NCT03797495 (HISTORY): observational registry/biobank planned 100 affected individuals to define natural history and correlate factors with disease expression/severity; includes centralized activity/antigen and genetic testing. (NCT03797495 chunk 1)

13. Prevention

No primary prevention is established for Mendelian PLGD‑1. Secondary/tertiary prevention is primarily via: - early recognition of characteristic mucosal lesions and - genetic counseling / family testing in autosomal recessive disease. (alghubaishi2023recurrentmeningitisand pages 2-4, xu2021novelhomozygousmutation pages 1-3)

14. Other species / natural disease

A naturally occurring canine ligneous membranitis/conjunctivitis case (Maltese dog) was linked to a large PLG rearrangement deleting exon 1 and complete lack of plasminogen activity; article frames this as a spontaneous animal model. (turba2021alargedeletion pages 1-2)
OMIA: canine ligneous membranitis is referenced as OMIA 002020‑9615 in the dog paper. (turba2021alargedeletion pages 1-2)

15. Model organisms

The retrieved evidence directly supports: - Spontaneous dog model (above). (turba2021alargedeletion pages 1-2) Additional model organism claims (e.g., engineered Plg−/− mice) are mentioned in case-report literature but were not retrieved as primary full-text evidence here; therefore not expanded to avoid overstatement. (xu2021novelhomozygousmutation pages 1-3)

Recent developments (2023–2024 highlights)

Mechanistic consolidation at mucosal barriers: 2023 review integrates fibrin biology with mucosal/periodontal homeostasis and emphasizes Mendelian PLG deficiency as a natural experiment for understanding severe early-onset periodontitis. (silva2023plasminmediatedfibrinolysisin pages 1-2)
Expanded therapeutic evidence for IV plasminogen replacement: 2023 phase 2/3 trial provides long-term (to 124 weeks) efficacy, safety, and QoL outcomes supporting replacement therapy as disease-modifying. (shapiro2023plasminogenhuman‐tvmhfor pages 1-2, shapiro2023plasminogenhuman‐tvmhfor pages 7-8)
Post-approval real-world respiratory rescue: 2024 case series documents rapid reversal of life-threatening airway lesions, supported by imaging/bronchoscopy and biomarker changes. (nakar2024casereportrespiratory pages 1-2, nakar2024casereportrespiratory media f6ed748e, nakar2024casereportrespiratory media 11094d94)
Continued innovation in topical/local therapy when commercial drops unavailable: 2024 ophthalmology case series reports standardized FFP/heparin perioperative protocol with 12-month recurrence-free follow-up; N-of-1 trial protocols formalize donor plasma drops. (almeida2024ligneousconjunctivitisfreshfrozen pages 1-3, NCT05404932 chunk 1)

Limitations of this report (evidence gaps in retrieved texts)

Orphanet/ICD/MeSH identifiers, and contemporary large prospective cohort statistics (beyond the commonly cited Tefs et al. frequencies summarized in 2023–2024 reviews) were not retrieved in the tool-accessible full texts for this run.
Formal differential diagnosis lists and validated ontology IDs for HPO/GO/UBERON/MAXO terms were not pulled from dedicated ontology databases in the available evidence; terms provided are suggestions based on phenotype descriptions.

Key source list (URLs and publication dates)

Silva LM et al. “Plasmin-Mediated Fibrinolysis in Periodontitis Pathogenesis.” Journal of Dental Research. 2023-07. https://doi.org/10.1177/00220345231171837 (silva2023plasminmediatedfibrinolysisin pages 1-2)
Shapiro AD et al. “Plasminogen, human‑tvmh for the treatment of children and adults with plasminogen deficiency type 1.” Haemophilia. 2023-09. https://doi.org/10.1111/hae.14849 (shapiro2023plasminogenhuman‐tvmhfor pages 1-2)
Nakar C et al. “Respiratory lesions successfully treated with intravenous plasminogen, human‑tvmh…” Frontiers in Pediatrics. 2024-09. https://doi.org/10.3389/fped.2024.1465166 (nakar2024casereportrespiratory pages 1-2)
de Almeida ICGB, Marback PMF. “Ligneous conjunctivitis: Fresh-frozen plasma and heparin…” Arq Bras Oftalmol. 2024-03. https://doi.org/10.5935/0004-2749.2022-0288 (almeida2024ligneousconjunctivitisfreshfrozen pages 1-3)
Brito-Robinson T et al. “Plasminogen missense variants…” Frontiers in Cardiovascular Medicine. 2024-06. https://doi.org/10.3389/fcvm.2024.1406953 (britorobinson2024plasminogenmissensevariants pages 15-16)
ClinicalTrials.gov NCT02690714 (2016; results posted 2021): https://clinicaltrials.gov/study/NCT02690714 (NCT02690714 chunk 1)
ClinicalTrials.gov NCT01554956 (2013; results posted 2023-01-25): https://clinicaltrials.gov/study/NCT01554956 (NCT01554956 chunk 1)
ClinicalTrials.gov NCT03797495 (2018): https://clinicaltrials.gov/study/NCT03797495 (NCT03797495 chunk 1)

References

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(martinfernandez2016theunravellingof pages 4-5): Laura Martin-Fernandez, Pascual Marco, Irene Corrales, Raquel Pérez, Lorena Ramírez, Sonia López, Francisco Vidal, and José Manuel Soria. The unravelling of the genetic architecture of plasminogen deficiency and its relation to thrombotic disease. Scientific Reports, Dec 2016. URL: https://doi.org/10.1038/srep39255, doi:10.1038/srep39255. This article has 24 citations and is from a peer-reviewed journal.
(almeida2024ligneousconjunctivitisfreshfrozen pages 1-3): Isabela Costa Guerra Barreto de Almeida and Patrícia Maria Fernandes Marback. Ligneous conjunctivitis: fresh-frozen plasma and heparin use intra-and postoperatively, a report of two cases. Arquivos Brasileiros de Oftalmologia, Mar 2024. URL: https://doi.org/10.5935/0004-2749.2022-0288, doi:10.5935/0004-2749.2022-0288. This article has 5 citations and is from a peer-reviewed journal.
(alghafry2025inheriteddisordersof pages 5-6): Maha Al-Ghafry, Mouhamed Yazan Abou-Ismail, and Suchitra S. Acharya. Inherited disorders of the fibrinolytic pathway: pathogenic phenotypes and diagnostic considerations of extremely rare disorders. Seminars in Thrombosis and Hemostasis, 51:227-235, Sep 2025. URL: https://doi.org/10.1055/s-0044-1789596, doi:10.1055/s-0044-1789596. This article has 12 citations and is from a peer-reviewed journal.
(martinfernandez2016theunravellingof pages 2-3): Laura Martin-Fernandez, Pascual Marco, Irene Corrales, Raquel Pérez, Lorena Ramírez, Sonia López, Francisco Vidal, and José Manuel Soria. The unravelling of the genetic architecture of plasminogen deficiency and its relation to thrombotic disease. Scientific Reports, Dec 2016. URL: https://doi.org/10.1038/srep39255, doi:10.1038/srep39255. This article has 24 citations and is from a peer-reviewed journal.
(shapiro2023plasminogenhuman‐tvmhfor pages 4-5): Amy D. Shapiro, Charles Nakar, Joseph M. Parker, Karen Thibaudeau, Roberto Crea, and Per Morten Sandset. Plasminogen, human‐tvmh for the treatment of children and adults with plasminogen deficiency type 1. Haemophilia, 29:1556-1564, Sep 2023. URL: https://doi.org/10.1111/hae.14849, doi:10.1111/hae.14849. This article has 15 citations and is from a peer-reviewed journal.
(shapiro2023plasminogenhuman‐tvmhfor pages 7-8): Amy D. Shapiro, Charles Nakar, Joseph M. Parker, Karen Thibaudeau, Roberto Crea, and Per Morten Sandset. Plasminogen, human‐tvmh for the treatment of children and adults with plasminogen deficiency type 1. Haemophilia, 29:1556-1564, Sep 2023. URL: https://doi.org/10.1111/hae.14849, doi:10.1111/hae.14849. This article has 15 citations and is from a peer-reviewed journal.
(nakar2024casereportrespiratory pages 2-3): Charles Nakar, Heather McDaniel, Joseph M. Parker, Karen Thibaudeau, Neelam Thukral, and Amy D. Shapiro. Case report: respiratory lesions successfully treated with intravenous plasminogen, human-tvmh, replacement therapy in four patients with plasminogen deficiency type 1. Frontiers in Pediatrics, Sep 2024. URL: https://doi.org/10.3389/fped.2024.1465166, doi:10.3389/fped.2024.1465166. This article has 2 citations.
(NCT05404932 chunk 1): Sarah Tehseen. Treatment of Ligneous Conjunctivitis in Children With Plasminogen Deficiency. University of Saskatchewan. 2022. ClinicalTrials.gov Identifier: NCT05404932
(NCT01554956 chunk 1): Efficacy/Safety of Human Plasminogen Eye Drop in Ligneous Conjunctivitis Patients. Kedrion S.p.A.. 2013. ClinicalTrials.gov Identifier: NCT01554956
(NCT03797495 chunk 1): Amy D Shapiro, MD. Study of Individuals Affected With Hypoplasminogenemia. Indiana Hemophilia &Thrombosis Center, Inc.. 2018. ClinicalTrials.gov Identifier: NCT03797495
(turba2021alargedeletion pages 1-2): M. E. Turba, P. C. Ostan, S. Ghetti, M. Dajbychova, F. Dondi, and F. Gentilini. A large deletion in the plasminogen gene is associated with ligneous membranitis in a maltese dog. Animal Genetics, 52:767-771, Aug 2021. URL: https://doi.org/10.1111/age.13130, doi:10.1111/age.13130. This article has 2 citations and is from a domain leading peer-reviewed journal.
(nakar2024casereportrespiratory media 11094d94): Charles Nakar, Heather McDaniel, Joseph M. Parker, Karen Thibaudeau, Neelam Thukral, and Amy D. Shapiro. Case report: respiratory lesions successfully treated with intravenous plasminogen, human-tvmh, replacement therapy in four patients with plasminogen deficiency type 1. Frontiers in Pediatrics, Sep 2024. URL: https://doi.org/10.3389/fped.2024.1465166, doi:10.3389/fped.2024.1465166. This article has 2 citations.
(britorobinson2024plasminogenmissensevariants pages 15-16): Teresa Brito-Robinson, Yetunde A. Ayinuola, Victoria A. Ploplis, and Francis J. Castellino. Plasminogen missense variants and their involvement in cardiovascular and inflammatory disease. Frontiers in Cardiovascular Medicine, Jun 2024. URL: https://doi.org/10.3389/fcvm.2024.1406953, doi:10.3389/fcvm.2024.1406953. This article has 6 citations and is from a peer-reviewed journal.

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Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Biochemical Markers

Clinical Trials

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References & Deep Research

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Comprehensive Disease Characteristics Report: Hypoplasminogenemia (Type 1 Plasminogen Deficiency)

Executive summary

1. Disease information

1.1 Overview (what is the disease?)

1.2 Key identifiers

1.3 Synonyms / alternative names

1.4 Evidence sources

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

Genetic risk factors

Environmental/clinical triggers (non-genetic)

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Core phenotype: ligneous conjunctivitis / keratoconjunctivitis

3.2 Oral/periodontal phenotypes

3.3 Respiratory tract involvement

3.4 Genitourinary and gastrointestinal mucosal lesions

3.5 Ear involvement

3.6 Central nervous system (CNS) involvement

3.7 Quality of life impact

4. Genetic / molecular information

4.1 Causal gene(s)

4.2 Variant spectrum and molecular consequences

4.3 Modifier genes

4.4 Epigenetics / chromosomal abnormalities

4.5 Suggested GO (biological process) and CL (cell type) terms

5. Environmental information

6. Mechanism / pathophysiology

6.1 Current understanding (causal chain)

6.2 Tissue/cell processes highlighted in recent reviews

7. Anatomical structures affected

Organ/system level (representative)

8. Temporal development

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology (statistics)

10. Diagnostics

10.1 Clinical tests

10.2 Distinguishing type I vs type II

10.3 Routine labs often normal / non-diagnostic

10.4 Genetic testing

10.5 Suggested differential diagnosis

11. Outcome / prognosis

12. Treatment

12.1 Pharmacotherapy / replacement therapy (current standard)