Type I plasminogen deficiency with unexpected clinical aspects: Could be more than coexistence?

Altıner, Şule; Klammt, J; Bernhard, Matthias K.; Schuster, Volker; Karabulut, Halil Gürhan

doi:10.1080/2331205x.2017.1334317

Cited by 3 publications

(5 citation statements)

References 14 publications

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“…Overall, PDI can result in severe consequences, including blindness, tooth loss, and infertility in both males and females ( 25 , 100 ). This debilitating illness significantly impacts quality of life ( 101 ).…”

Section: Clinical Manifestations Of Pdimentioning

confidence: 99%

Plasminogen missense variants and their involvement in cardiovascular and inflammatory disease

Brito-Robinson,

Ayinuola,

Ploplis

et al. 2024

Front. Cardiovasc. Med.

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Human plasminogen (PLG), the zymogen of the fibrinolytic protease, plasmin, is a polymorphic protein with two widely distributed codominant alleles, PLG/Asp453 and PLG/Asn453. About 15 other missense or non-synonymous single nucleotide polymorphisms (nsSNPs) of PLG show major, yet different, relative abundances in world populations. Although the existence of these relatively abundant allelic variants is generally acknowledged, they are often overlooked or assumed to be non-pathogenic. In fact, at least half of those major variants are classified as having conflicting pathogenicity, and it is unclear if they contribute to different molecular phenotypes. From those, PLG/K19E and PLG/A601T are examples of two relatively abundant PLG variants that have been associated with PLG deficiencies (PD), but their pathogenic mechanisms are unclear. On the other hand, approximately 50 rare and ultra-rare PLG missense variants have been reported to cause PD as homozygous or compound heterozygous variants, often leading to a debilitating disease known as ligneous conjunctivitis. The true abundance of PD-associated nsSNPs is unknown since they can remain undetected in heterozygous carriers. However, PD variants may also contribute to other diseases. Recently, the ultra-rare autosomal dominant PLG/K311E has been found to be causative of hereditary angioedema (HAE) with normal C1 inhibitor. Two other rare pathogenic PLG missense variants, PLG/R153G and PLG/V709E, appear to affect platelet function and lead to HAE, respectively. Herein, PLG missense variants that are abundant and/or clinically relevant due to association with disease are examined along with their world distribution. Proposed molecular mechanisms are discussed when known or can be reasonably assumed.

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Section: Clinical Manifestations Of Pdimentioning

confidence: 99%

Plasminogen missense variants and their involvement in cardiovascular and inflammatory disease

Brito-Robinson,

Ayinuola,

Ploplis

et al. 2024

Front. Cardiovasc. Med.

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“…Ligneous cervicitis is another common place for the growth of the pseudomembranes among other structures of the female genital tract where they present with dysmenorrhea in addition to infertility due to growth on fallopian tubes, ovary, and endometrium [11]. The male genital tract is not spared from ligneous growth, and male infertility has been reported [12].…”

Section: Figure 3: Plasminogen Activation Pathwaysmentioning

confidence: 99%

Plasminogen Deficiency: A Case Report and Review

Nasiri,

Nassar,

Alzahrani

2023

Cureus

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Plasminogen deficiency, a rare disorder characterized by impaired fibrinolysis, frequently results in ligneous conjunctivitis. In this report, we report a case of a Saudi girl manifesting both conjunctivitis and hydrocephalus. Her initial symptoms at 1 month of age were recurring eye redness, which was inaccurately diagnosed as simple conjunctivitis. Surgical intervention for her ocular lesions revealed underlying membrane deposition. She later exhibited signs of increased intracranial pressure, resulting in a hydrocephalus diagnosis and subsequent surgery. Genetic analysis confirmed the presence of plasminogen deficiency. Clinical evaluations highlighted ligneous conjunctivitis, variations in visual acuity, and facial acne. Laboratory assessments demonstrated diminished plasminogen levels. The therapeutic approach encompassed plasminogen replacement, administered intravenously (1000 units, thrice weekly) and as eye drops, with the potential addition of fresh frozen plasma. Notably, this replacement therapy led to a significant reduction in hospital admissions and the severity of her conjunctivitis. Given the challenges in procuring consistent plasminogen supplies, the viability of hepatic transplantation is currently under investigation.

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“…1,2 Patients with severe hypoplasminogenemia display clinical symptoms of a persistent inflammatory state with defective wound healing, lower body weight, and reduced fertility. [3][4][5][6][7] The etiology behind these clinical symptoms is linked to the formation of persistent fibrin deposits in mucous pseudomembranes. 3,4,7 The prognosis is highly variable, and managing the disorder is challenging due to varying clinical symptoms, the multisystem manifestations, and the lack of effective treatments.…”

Section: Introductionmentioning

confidence: 99%

“…[3][4][5][6][7] The etiology behind these clinical symptoms is linked to the formation of persistent fibrin deposits in mucous pseudomembranes. 3,4,7 The prognosis is highly variable, and managing the disorder is challenging due to varying clinical symptoms, the multisystem manifestations, and the lack of effective treatments. [6][7][8][9][10] Genetically modified mice with complete plasminogen deficiency have been used to study the disorder.…”

Section: Introductionmentioning

confidence: 99%

“…3,4,7 The prognosis is highly variable, and managing the disorder is challenging due to varying clinical symptoms, the multisystem manifestations, and the lack of effective treatments. [6][7][8][9][10] Genetically modified mice with complete plasminogen deficiency have been used to study the disorder. [3][4][5][11][12][13][14] Similar to the patients, plasminogen-deficient mice (Plg 2/2 ) exhibit spontaneous and persistent extravascular fibrin deposits in multiple organ systems.…”

Section: Introductionmentioning

confidence: 99%

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Absence of functional compensation between coagulation factor VIII and plasminogen in double-knockout mice

et al. 2018

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Plasminogen deficiency is associated with severely compromised fibrinolysis and extravascular deposition of fibrin. In contrast, coagulation factor VIII (FVIII) deficiency leads to prolonged and excessive bleeding. Based on opposing biological functions of plasminogen and FVIII deficiencies, we hypothesized that genetic elimination of FVIII would alleviate the systemic formation of fibrin deposits associated with plasminogen deficiency and, in turn, elimination of plasminogen would limit bleeding symptoms associated with FVIII deficiency. Mice with single and combined deficiencies of FVIII (F8−/−) and plasminogen (Plg−/−) were evaluated for phenotypic characteristics of plasminogen deficiency, including wasting disease, shortened lifespan, rectal prolapse, and multiorgan fibrin deposition. Conversely, to specifically examine the role of plasmin-mediated fibrinolysis on bleeding caused by FVIII deficiency, F8−/− and F8−/−/Plg−/− mice were subjected to a bleeding challenge. Mice with a combined deficiency in FVIII and plasminogen displayed no phenotypic differences relative to mice with single FVIII or plasminogen deficiency. Plg−/− and F8−/−/Plg−/− mice exhibited the same penetrance and severity of wasting disease, rectal prolapse, extravascular fibrin deposits, and reduced viability. Furthermore, following a tail vein–bleeding challenge, no significant differences in bleeding times or total blood loss could be detected between F8−/− and F8−/−/Plg−/− mice. Moreover, F8−/− and F8−/−/Plg−/− mice responded similarly to recombinant FVIII (rFVIII) therapy. In summary, the pathological phenotype of Plg−/− mice developed independently of FVIII-dependent coagulation, and elimination of plasmin-driven fibrinolysis did not play a significant role in a nonmucosal bleeding model in hemophilia A mice.

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Type I plasminogen deficiency with unexpected clinical aspects: Could be more than coexistence?

Cited by 3 publications

References 14 publications

Plasminogen missense variants and their involvement in cardiovascular and inflammatory disease

Plasminogen missense variants and their involvement in cardiovascular and inflammatory disease

Plasminogen Deficiency: A Case Report and Review

Absence of functional compensation between coagulation factor VIII and plasminogen in double-knockout mice

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