RARE DISEASE
Hypoplasminogenemia
Hypoplasminogenemia
Hypoplasminogenemia
Synonyms: Plasminogen deficiency type 1
Synonyms: Plasminogen deficiency type 1
Synonyms: Plasminogen deficiency type 1
Drug discovery
5
drugs
With orphan designations
Overview
Hypoplasminogenemia (type 1 plasminogen deficiency) is an ultra-rare autosomal recessive disorder caused by PLG mutations, leading to impaired fibrinolysis. Characterized by fibrin-rich pseudomembranes on mucous membranes, it manifests as ligneous conjunctivitis (60-85% of cases) and systemic lesions affecting respiratory, genitourinary, and gastrointestinal systems. Left untreated, it causes organ dysfunction, vision loss, and life-threatening complications. Diagnosis requires plasminogen activity/antigen testing (<45% activity typical) and genetic confirmation. Plasminogen replacement therapy (Ryplazim®) is FDA-approved and achieves ≥50% lesion resolution in 100% of treated patients [1][7][10].
Categories: rare genetic diseases, rare ophthalmic disorders, rare systemic and rheumatological diseases
Research Papers
138 drug discovery papers about Hypoplasminogenemia, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
138 drug discovery papers about Hypoplasminogenemia, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-02-10 | [Compound heterozygous plasminogen mutations causing hereditary plasminogen deficiency: a family study and mechanistic analysis].
Objective: To investigate the molecular mechanisms underlying compound heterozygous mutations in a patient with hereditary plasminogen (PLG) deficiency. Methods: The proband presented to the First Affiliated Hospital of Wenzhou Medical University with a 2-day history of left-sided limb weakness. Plasminogen activity (PLG∶A) and plasminogen antigen (PLG∶Ag) were measured by chromogenic substrate and enzyme-linked immunosorbent assays, respectively, in the proband and family members (eight individuals across three generations). Sanger sequencing was performed to identify the PLG mutation sites. Bioinformatic analyses were conducted to assess evolutionary conservation and to predict pathogenicity of the mutation sites. Mutant protein models were constructed to examine mutation-induced structural changes. Recombinant plasmid expression vectors were constructed, and in vitro expression of recombinant PLG protein was studied using quantitative real-time PCR (qRT-PCR), ELISA, and Western blot analysis. Results: The proband's PLG∶A was 27% (reference range, 80%-120%) and PLG∶Ag was 103% (reference range, 50%-150%), consistent with type Ⅱ plasminogen deficiency. Genetic analysis revealed compound heterozygous missense mutations in the proband: c.1702G>A (p. Gly568Arg) in exon 14 and c.1858G>A (p. Ala620Thr) in exon 15. The c.1702G>A site is highly conserved across seven species, and is predicted to be pathogenic by bioinformatic tools. Protein modeling showed that p. Gly568Arg introduces a longer side chain and forms a new hydrogen bond with Leu686. In vitro expression showed that neither mutation caused abnormalities in PLG transcript levels, protein expression, or secretion; however, the PLG∶A/PLG∶Ag ratios in the culture supernatants were significantly lower than wild-type for both variants (Ala620Thr: 0.598 ± 0.114 vs 1.000, P=0.013; Gly568Arg: 0.412 ± 0.079 vs 1.000, P=0.022) . Conclusion: The heterozygous missense mutations p.Gly568Arg and p. Ala620Thr are associated with decreased PLG∶A in the family proband and may cause functional impairment by altering protein conformation.
2025-11-07 | Human plasma-derived plasminogen replacement in type 1 plasminogen deficiency: a pediatric case with multisystemic manifestation
The article by D€onmez-Demir et al., ‘Novel plasminogen gene mutations in Turkish patients with type I plasminogen deficiency’, recently published in Blood Coagulation and Fibrinolysis[1], was read with great interest. The study’s authors expanded the mutational spectrum of the PLG gene in the Turkish population and emphasized the clinical heterogeneity and the timely recognition of this rare disorder. As highlighted in the discussion, treatment options for type 1 plasminogen deficiency remain limited, and management strategies, including plasminogen replacement therapy, are of particular clinical relevance. In this context, we wish to present our paediatric case demonstrating a multisystemic phenotype and favourable clinical response to human plasma-derived plasminogen replacement.
2025-10-01 | Podocyte Cytoskeletal Stabilization Through RhoA-Cofilin Signaling by Suppressing PAI-1
Background: Plasminogen activator inhibitor-1 (PAI-1) is upregulated in various fibrotic kidney diseases. Our previous studies demonstrated that systemic PAI-1 knockout (KO) mitigates glomerulosclerosis and decreases proteinuria by protecting podocytes in chronic kidney disease models. In this study, we investigated whether PAI-1 has direct podocyte effects and explored the underlying mechanisms. Methods: We generated inducible podocyte-specific PAI-1 knockdown mice (PAI-1 KD, PAI-1floxed/podocin Cre+) and wild type control (WT, PAI-1floxed/podocin Cre-). We crossed them with Nphs1-hCD25 mice (Nep25), which express human CD25 specifically in podocytes, and develop primary podocyte injury upon injection with immunotoxin (LMB2). These mice were then assessed at 3 wks after LMB2 for podocyte injury and urine albumin/creatinine ratio (ACR). For in vitro studies, primary podocytes were isolated from WT and PAI-1 KO mice and exposed to puromycin to induce injury. RNA sequencing was performed. RhoA activity was measured using G-LISA assay and phosphorylated cofilin (p-cofilin) levels were quantified by Western Blot. Actin cytoskeleton organization was evaluated by immunofluorescent staining. Results: PAI-1 KD/Nep25 vs Nep25 mice injected with LMB2 showed reduced ACR, less glomerulosclerosis and glomerular collagen IV deposition, with increased WT-1 positive cell density, a marker of mature podocytes. RNA sequencing of cultured PAI-1 KO vs WT podocytes after injury revealed upregulation of 3,387 genes and downregulation of 1,617 genes in the PAI-1 KO. Gene Ontology enrichment and KEGG pathway analyses revealed significant changes in genes involved in cytoskeletal organization. The activity of RhoA, a key regulator of the actin dynamics, was elevated in injured PAI-1 KO compared to WT podocytes. p-cofilin, a downstream target of RhoA that inhibits actin polymerization, was less in PAI-1 KO podocytes, thereby promoting the formation of actin filaments. WT podocytes displayed cell retraction and F-actin disorganization in response to puromycin-induced injury, while PAI-1 KO podocytes maintained intracellular F-actin but had comparable cell retraction. Conclusion: PAI-1 deficiency in podocytes enhances RhoA activity, reduces p-cofilin levels and stabilizes the actin cytoskeleton, thereby improving podocyte structural integrity and protecting against injury. Funding: NIDDK Support
2025-09-10 | Advancing Understanding of Ligneous Conjunctivitis: Bridging Pathogenesis, Diagnosis, and Therapy.
This review and case report address ligneous conjunctivitis (LC), a rare ocular condition caused by plasminogen deficiency type 1 (PLGD-1), which manifests as wood-like fibrin-rich membranes on the palpebral conjunctiva. The goal is to provide ophthalmologists-often the first physicians to encounter the condition-with a robust understanding of its systemic manifestations and to highlight current therapeutic strategies, with particular emphasis on the administration of intravenous plasminogen concentrate. We present a clinical LC case alongside a narrative review of published cases, etiology, and treatment approaches. LC initially manifests as erythematous lesions on the palpebral conjunctiva, eventually developing into fibrinous, wood-like membranes. It is typically associated with PLGD-1, a genetic disorder of the plasminogen gene ( PLG ), which results in impaired fibrinolysis and the formation of fibrin deposits. LC often appears within the first year of life, but patients may experience a prolonged period before diagnosis. PLGD-1 is also associated with the development of mucosal lesions in many other organ systems. Contributing factors include chronic inflammation, allergens, infections, and trauma. There have been many proposed treatment approaches for LC, but the recent approval of intravenous plasma-derived human plasminogen concentrate replacement has been an important advance. LC is an ocular disorder with potential vision- and life-threatening complications. The treatment of LC has historically been challenging; however, recognition of its association with PLGD-1 has led to more effective therapies, particularly intravenous plasminogen concentrate. Early diagnosis and coordinated care between ophthalmologists and other specialists, such as hematologists, are crucial to prevent complications, including vision loss.
2025-07-15 | CO48 | Gynecological involvement in females with congenital plasminogen deficiency type 1
Background and Aims: Congenital plasminogen deficiency type 1 (PLGD1) is an ultrarare disease characterized by the development of fibrin-rich pseudomembranes on mucosal surfaces of several organs and systems, mainly involving the conjunctiva. In affected females, ligneous lesions may occur on the vaginal and cervical surfaces, ovaries, Fallopian tubes and endometrium. Our aim was to conduct a review of the literature on clinical manifestations and therapeutic approaches of genital involvement in females with PLGD1, including our three cases. Methods: A review of the literature was conducted including terms such as ligneous cervicitis, ligneous vaginitis, ligneous endometritis, ligneous conjunctivitis and plasminogen deficiency type 1. Three patients with congenital plasminogen deficiency and genital involvement followed at our center were included in the analysis. Results: Fifty-seven cases of genital ligneous pseudomembranes, consistent with the typical clinical, histological, and laboratory findings of PLGD1, have been described in the literature. These are predominantly case reports and case series, while a number of patients were included in a phase 2-3 clinical study. Nine of these cases were documented before the correlation with plasminogen deficiency was identified. Reported plasminogen activity levels ranged from <2% to 50%. The pseudomembranous lesions have been described in the vagina, cervix, endometrium, ovaries and Fallopian tubes. Including our cases, genital lesions represented the sole clinical manifestation of the disease in 12 of 60 patients (20%), with extragenital involvement, primarily the conjunctiva, observed in the remaining patients. Main symptoms included dysmenorrhea, vaginal discharge, post-coital bleeding, and infertility (15 of 52 reported cases, 28.8%). Histological findings of pseudomembranes require a differential diagnosis with neoplasia, sometimes coexisting with the ligneous lesions. Simple excision of the pseudomembranes was associated with recurrence of the lesions. Data on the specific treatment of the gynecological area were scarce and often empirical: topical and systemic treatments included steroids, cyclosporine, estroprogestins and fresh frozen plasma. The only effective treatment was a replacement therapy with human Glu-plasminogen concentrate, already approved by the FDA. No data were found regarding the quality of life and psychological impact caused by gynecological involvement in patients with PLGD1. Conclusions: In patients with PLGD1, involvement of the genital apparatus is not uncommon, it can represent the sole clinical manifestation of the disease and can lead to infertility. There are very encouraging results from replacement therapy with human plasminogen concentrate, the use of which is still limited worldwide.
2026-02-10 | [Compound heterozygous plasminogen mutations causing hereditary plasminogen deficiency: a family study and mechanistic analysis].
Objective: To investigate the molecular mechanisms underlying compound heterozygous mutations in a patient with hereditary plasminogen (PLG) deficiency. Methods: The proband presented to the First Affiliated Hospital of Wenzhou Medical University with a 2-day history of left-sided limb weakness. Plasminogen activity (PLG∶A) and plasminogen antigen (PLG∶Ag) were measured by chromogenic substrate and enzyme-linked immunosorbent assays, respectively, in the proband and family members (eight individuals across three generations). Sanger sequencing was performed to identify the PLG mutation sites. Bioinformatic analyses were conducted to assess evolutionary conservation and to predict pathogenicity of the mutation sites. Mutant protein models were constructed to examine mutation-induced structural changes. Recombinant plasmid expression vectors were constructed, and in vitro expression of recombinant PLG protein was studied using quantitative real-time PCR (qRT-PCR), ELISA, and Western blot analysis. Results: The proband's PLG∶A was 27% (reference range, 80%-120%) and PLG∶Ag was 103% (reference range, 50%-150%), consistent with type Ⅱ plasminogen deficiency. Genetic analysis revealed compound heterozygous missense mutations in the proband: c.1702G>A (p. Gly568Arg) in exon 14 and c.1858G>A (p. Ala620Thr) in exon 15. The c.1702G>A site is highly conserved across seven species, and is predicted to be pathogenic by bioinformatic tools. Protein modeling showed that p. Gly568Arg introduces a longer side chain and forms a new hydrogen bond with Leu686. In vitro expression showed that neither mutation caused abnormalities in PLG transcript levels, protein expression, or secretion; however, the PLG∶A/PLG∶Ag ratios in the culture supernatants were significantly lower than wild-type for both variants (Ala620Thr: 0.598 ± 0.114 vs 1.000, P=0.013; Gly568Arg: 0.412 ± 0.079 vs 1.000, P=0.022) . Conclusion: The heterozygous missense mutations p.Gly568Arg and p. Ala620Thr are associated with decreased PLG∶A in the family proband and may cause functional impairment by altering protein conformation.
2025-11-07 | Human plasma-derived plasminogen replacement in type 1 plasminogen deficiency: a pediatric case with multisystemic manifestation
The article by D€onmez-Demir et al., ‘Novel plasminogen gene mutations in Turkish patients with type I plasminogen deficiency’, recently published in Blood Coagulation and Fibrinolysis[1], was read with great interest. The study’s authors expanded the mutational spectrum of the PLG gene in the Turkish population and emphasized the clinical heterogeneity and the timely recognition of this rare disorder. As highlighted in the discussion, treatment options for type 1 plasminogen deficiency remain limited, and management strategies, including plasminogen replacement therapy, are of particular clinical relevance. In this context, we wish to present our paediatric case demonstrating a multisystemic phenotype and favourable clinical response to human plasma-derived plasminogen replacement.
2025-10-01 | Podocyte Cytoskeletal Stabilization Through RhoA-Cofilin Signaling by Suppressing PAI-1
Background: Plasminogen activator inhibitor-1 (PAI-1) is upregulated in various fibrotic kidney diseases. Our previous studies demonstrated that systemic PAI-1 knockout (KO) mitigates glomerulosclerosis and decreases proteinuria by protecting podocytes in chronic kidney disease models. In this study, we investigated whether PAI-1 has direct podocyte effects and explored the underlying mechanisms. Methods: We generated inducible podocyte-specific PAI-1 knockdown mice (PAI-1 KD, PAI-1floxed/podocin Cre+) and wild type control (WT, PAI-1floxed/podocin Cre-). We crossed them with Nphs1-hCD25 mice (Nep25), which express human CD25 specifically in podocytes, and develop primary podocyte injury upon injection with immunotoxin (LMB2). These mice were then assessed at 3 wks after LMB2 for podocyte injury and urine albumin/creatinine ratio (ACR). For in vitro studies, primary podocytes were isolated from WT and PAI-1 KO mice and exposed to puromycin to induce injury. RNA sequencing was performed. RhoA activity was measured using G-LISA assay and phosphorylated cofilin (p-cofilin) levels were quantified by Western Blot. Actin cytoskeleton organization was evaluated by immunofluorescent staining. Results: PAI-1 KD/Nep25 vs Nep25 mice injected with LMB2 showed reduced ACR, less glomerulosclerosis and glomerular collagen IV deposition, with increased WT-1 positive cell density, a marker of mature podocytes. RNA sequencing of cultured PAI-1 KO vs WT podocytes after injury revealed upregulation of 3,387 genes and downregulation of 1,617 genes in the PAI-1 KO. Gene Ontology enrichment and KEGG pathway analyses revealed significant changes in genes involved in cytoskeletal organization. The activity of RhoA, a key regulator of the actin dynamics, was elevated in injured PAI-1 KO compared to WT podocytes. p-cofilin, a downstream target of RhoA that inhibits actin polymerization, was less in PAI-1 KO podocytes, thereby promoting the formation of actin filaments. WT podocytes displayed cell retraction and F-actin disorganization in response to puromycin-induced injury, while PAI-1 KO podocytes maintained intracellular F-actin but had comparable cell retraction. Conclusion: PAI-1 deficiency in podocytes enhances RhoA activity, reduces p-cofilin levels and stabilizes the actin cytoskeleton, thereby improving podocyte structural integrity and protecting against injury. Funding: NIDDK Support
2025-09-10 | Advancing Understanding of Ligneous Conjunctivitis: Bridging Pathogenesis, Diagnosis, and Therapy.
This review and case report address ligneous conjunctivitis (LC), a rare ocular condition caused by plasminogen deficiency type 1 (PLGD-1), which manifests as wood-like fibrin-rich membranes on the palpebral conjunctiva. The goal is to provide ophthalmologists-often the first physicians to encounter the condition-with a robust understanding of its systemic manifestations and to highlight current therapeutic strategies, with particular emphasis on the administration of intravenous plasminogen concentrate. We present a clinical LC case alongside a narrative review of published cases, etiology, and treatment approaches. LC initially manifests as erythematous lesions on the palpebral conjunctiva, eventually developing into fibrinous, wood-like membranes. It is typically associated with PLGD-1, a genetic disorder of the plasminogen gene ( PLG ), which results in impaired fibrinolysis and the formation of fibrin deposits. LC often appears within the first year of life, but patients may experience a prolonged period before diagnosis. PLGD-1 is also associated with the development of mucosal lesions in many other organ systems. Contributing factors include chronic inflammation, allergens, infections, and trauma. There have been many proposed treatment approaches for LC, but the recent approval of intravenous plasma-derived human plasminogen concentrate replacement has been an important advance. LC is an ocular disorder with potential vision- and life-threatening complications. The treatment of LC has historically been challenging; however, recognition of its association with PLGD-1 has led to more effective therapies, particularly intravenous plasminogen concentrate. Early diagnosis and coordinated care between ophthalmologists and other specialists, such as hematologists, are crucial to prevent complications, including vision loss.
2025-07-15 | CO48 | Gynecological involvement in females with congenital plasminogen deficiency type 1
Background and Aims: Congenital plasminogen deficiency type 1 (PLGD1) is an ultrarare disease characterized by the development of fibrin-rich pseudomembranes on mucosal surfaces of several organs and systems, mainly involving the conjunctiva. In affected females, ligneous lesions may occur on the vaginal and cervical surfaces, ovaries, Fallopian tubes and endometrium. Our aim was to conduct a review of the literature on clinical manifestations and therapeutic approaches of genital involvement in females with PLGD1, including our three cases. Methods: A review of the literature was conducted including terms such as ligneous cervicitis, ligneous vaginitis, ligneous endometritis, ligneous conjunctivitis and plasminogen deficiency type 1. Three patients with congenital plasminogen deficiency and genital involvement followed at our center were included in the analysis. Results: Fifty-seven cases of genital ligneous pseudomembranes, consistent with the typical clinical, histological, and laboratory findings of PLGD1, have been described in the literature. These are predominantly case reports and case series, while a number of patients were included in a phase 2-3 clinical study. Nine of these cases were documented before the correlation with plasminogen deficiency was identified. Reported plasminogen activity levels ranged from <2% to 50%. The pseudomembranous lesions have been described in the vagina, cervix, endometrium, ovaries and Fallopian tubes. Including our cases, genital lesions represented the sole clinical manifestation of the disease in 12 of 60 patients (20%), with extragenital involvement, primarily the conjunctiva, observed in the remaining patients. Main symptoms included dysmenorrhea, vaginal discharge, post-coital bleeding, and infertility (15 of 52 reported cases, 28.8%). Histological findings of pseudomembranes require a differential diagnosis with neoplasia, sometimes coexisting with the ligneous lesions. Simple excision of the pseudomembranes was associated with recurrence of the lesions. Data on the specific treatment of the gynecological area were scarce and often empirical: topical and systemic treatments included steroids, cyclosporine, estroprogestins and fresh frozen plasma. The only effective treatment was a replacement therapy with human Glu-plasminogen concentrate, already approved by the FDA. No data were found regarding the quality of life and psychological impact caused by gynecological involvement in patients with PLGD1. Conclusions: In patients with PLGD1, involvement of the genital apparatus is not uncommon, it can represent the sole clinical manifestation of the disease and can lead to infertility. There are very encouraging results from replacement therapy with human plasminogen concentrate, the use of which is still limited worldwide.
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Drug Discovery Landscape
5 orphan drug designations for Hypoplasminogenemia, including 1 approved therapy.
5 orphan drug designations for Hypoplasminogenemia, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Human plasminogen | proteins | EMA | 2015-07-28 | — | Kedrion S.p.A. |
plasminogen, human-tvmh [Ryplazim] | proteins | FDA | 2013-03-05 | 2021-06-04 | ProMetic BioTherapeutics, Inc. |
human plasminogen | proteins | FDA | 2010-06-07 | — | Kedrion, S.p.A. |
Human plasminogen | proteins | EMA | 2007-08-03 | — | Kedrion S.p.A. |
taberminogene vadenovec | — | FDA | 2000-10-24 | — | Finvector Vision Therapies, Ltd. |
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