Learn About Plasminogen Deficiency (PLGD)
In all patients with plasminogen deficiency, plasma plasminogen levels are markedly reduced.1 Plasminogen is a naturally occurring protein that is synthesized by the liver and circulates in the blood.
Activated plasminogen, known as plasmin, is an enzymatic component of the fibrinolytic system and the main enzyme involved in the lysis of clots and clearance of extravasated fibrin.2 Activated plasminogen is also involved in wound healing, cell migration, tissue remodeling, angiogenesis, and embryogenesis.3
Plasminogen deficiency has been classified as hypoplasminogenemia, or true type I plasminogen deficiency, and as dysplasminogenemia, or type II plasminogen deficiency. Dysplasminogenemia does not lead to a specific clinical manifestation and probably represents only a polymorphic variation in the general population, mainly in Asian countries.4
Type I plasminogen deficiency is a rare autosomal recessive disorder that leads to severe clinical manifestations primarily related to the formation of fibrous depositions on mucous membranes throughout the body.5 The prevalence of type I plasminogen deficiency has been theoretically estimated at 1.6 cases per million population.1 There is no effective therapy currently available for this disease.
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Native PLG is produced in two main forms, Glu-PLG and Lys-PLG, named for the N-terminal amino acid of either glutamic acid or lysine. Glu-PLG is composed of the entire amino acid sequence designated by the gene sequence (excluding the activation peptide), while Lys-PLG is the result of a cleavage of the Glu-PLG between Lys-77 and Lys-78. The circulating half-life of Lys-PLG is considerably shorter than Glu-PLG (2-2.5 days for Glu-PLG, 0.8 days for Lys-PLG). Glu-PLG is the dominant form of PLG present in plasma with very little Lys- PLG detected in circulation (Violand, 1978; Collen, 1975).2, 6
PLG is a zymogen of plasmin (Figure 1). It contains 791 amino acids with a molecular weight of about 90 kD and a pI (isoelectric point) of approximately 7.0, although differential glycosylation and/or removal of the N-terminal activation peptide can result in a pI range of 6.2 to 8.0. It is a single-chain protein with 24 intra-chain disulfide bridges, 5 kringle domains (involved in the binding to fibrin and to the inhibitor α2-antiplasmin), a serine protease domain (P), and an activation peptide (AP) consisting of the first 77 amino acids.
There is one N-linked glycosylation site and one O-linked site, although a second O-linked site has been identified (Goldberg, 2006).7 Approximately 70% of the PLG in circulation contains only O-linked glycosylation while the rest contains both N- and O-linked sugars.
PLG is synthesized in the liver and secreted into plasma. PLG is distributed throughout the body, and when conditions are present for activation, the PLG pro-enzyme is converted to the active enzyme, plasmin, by tissue-type plasminogen activator (t-PA) or by urokinase plasminogen activator (u-PA). Plasmin then degrades fibrin and converts latent matrix metalloproteinases (pro-MMPs) into active MMPs, which in turn further degrade extracellular matrix (ECM) as part of the tissue healing/remodeling process. PLG activation mediated by t-PA is primarily involved in fibrin homeostasis, while plasmin generation via u-PA, forming a complex with its receptor u-PAR, plays a role in tissue remodeling.
Figure 1: Schematic of the kringle domains of plasminogen
1. Tefs K, Gueorguieva M, Klammt J, et al. Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients. Blood. 2006;108(9):3021-3026.
2. Collen D, Ong EB, Johnson AJ. Human plasminogen in vitro and in vivo evidence for the biological integrity of NH2-terminal glutamic acid plasminogen. hromb Res. 1975;7(4):515-529.
3. Castellino FJ, Ploplis VA. Structure and function of the plasminogen/plasmin system. Thromb Haemost. 2005;93(4):647-654.
4. Shoseyov D. Congenital plasminogen deificiency with respiratory complication. PowerPoint presentation at Hadassah Medical Center Jerusalem: Jerusalem, Israel.
5. Schott D, Dempfle C-E, Beck P, et al. Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency. N Engl J Med. 1998;339(23):1679-1686.
6. Violand BN, Byrne R, Castellino FJ. The effect of a-w-amino acids on human plasminogen structure and activation. J Biol Chem. 1978;253(15):5395-5401.
7. Goldberg HJ, Whiteside CI, Hart GW, Fantus IG. Posttranslational, reversible O-glycosylation is stimulated by high glucose and mediates plasminogen activator inhibitor-1 gene expression and Sp1 transcriptional activity in glomerular mesangial cells. Endocrinology. 2006;147(1):222-231.