Plasminogen deficiency

SummaryPlasminogen (plg) deficiency has been classified as (i) hypoplasminogenemia or ‘true’ type I plg deficiency, and (ii) dysplasminogenemia, also called type II plg deficiency. Both forms, severe hypoplasminogenemia and dysplasminogenemia, are not causally linked to venous thrombosis. Dysplasminogenemia does not lead to a specific clinical manifestation and probably represents only a polymorphic variation in the general population, mainly in Asian countries. Severe hypoplasminogenemia is associated with compromised extracellular fibrin clearance during wound healing, leading to pseudomembraneous (ligneous) lesions on affected mucous membranes (eye, middle ear, mouth, pharynx, duodenum, upper and lower respiratory tract and female genital tract). Ligneous conjunctivitis is by far the most common clinical manifestation. More than 12% of patients with severe hypoplasminogenemia exhibit congenital occlusive hydrocephalus. In milder cases of ligneous conjunctivitis, topical application of plg‐containing eye drops, fresh frozen plasma, heparin, corticosteroids or certain immunosuppressive agents (such as azathioprine) may be more or less effective. Oral treatment with sex hormones was successful in two female patients with ligneous conjunctivitis. In severe cases with possibly life‐threatening multi‐organ involvement, true therapeutic options are not available at present. The plg‐knockout mouse is a useful tool to study the many different properties of plg in a variety of settings, such as wound healing, tissue repair and tissue remodeling, virulence and invasiveness of certain bacteria in the human host, tumor growth and dissemination, as well as arteriosclerosis. Plasminogen (plg) deficiency has been classified as (i) hypoplasminogenemia or ‘true’ type I plg deficiency, and (ii) dysplasminogenemia, also called type II plg deficiency. Both forms, severe hypoplasminogenemia and dysplasminogenemia, are not causally linked to venous thrombosis. Dysplasminogenemia does not lead to a specific clinical manifestation and probably represents only a polymorphic variation in the general population, mainly in Asian countries. Severe hypoplasminogenemia is associated with compromised extracellular fibrin clearance during wound healing, leading to pseudomembraneous (ligneous) lesions on affected mucous membranes (eye, middle ear, mouth, pharynx, duodenum, upper and lower respiratory tract and female genital tract). Ligneous conjunctivitis is by far the most common clinical manifestation. More than 12% of patients with severe hypoplasminogenemia exhibit congenital occlusive hydrocephalus. In milder cases of ligneous conjunctivitis, topical application of plg‐containing eye drops, fresh frozen plasma, heparin, corticosteroids or certain immunosuppressive agents (such as azathioprine) may be more or less effective. Oral treatment with sex hormones was successful in two female patients with ligneous conjunctivitis. In severe cases with possibly life‐threatening multi‐organ involvement, true therapeutic options are not available at present. The plg‐knockout mouse is a useful tool to study the many different properties of plg in a variety of settings, such as wound healing, tissue repair and tissue remodeling, virulence and invasiveness of certain bacteria in the human host, tumor growth and dissemination, as well as arteriosclerosis. Plasminogen (plg) plays an important role in intravascular and extravascular fibrinolysis, wound healing, cell migration, tissue remodeling, angiogenesis, and embryogenesis [1Castellino F.J. Ploplis V.A. Structure and function of the plasminogen/plasmin system.Thromb Haemost. 2005; 93: 647-54Crossref PubMed Scopus (353) Google Scholar]. Plg is converted to plasmin by cleavage of the Arg561–Val562 peptide bond by either tissue‐type plg activator (tPA) or urokinase‐type plg activator (uPA; Fig. 1). The resulting N‐terminal α (‘heavy’) chain consists mainly of five kringles harboring lysine‐binding sites, whereas the β (‘light’) chain, Arg561‐plasmin, contains the catalytic triad of His603, Asp646 and Ser741 (Fig. 1). Activation of plg by tPA is the major pathway that leads to efficient lysis of fibrin clots in the blood stream, whereas activation of plg by uPA seems to be mainly responsible for mediating plg activation in association with cell surfaces (wound healing, tissue remodeling) [2Bugge T.H. Flick M.J. Danton M.J. Daugherty C.C. Romer J. Dano K. Carmeliet P. Collen D. Degen J.L. Urokinase‐type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue‐type plasminogen activator.Proc Natl Acad Sci USA. 1996; 93: 5899-904Crossref PubMed Scopus (231) Google Scholar]. The main substrate for plasmin is fibrin. Dissolution of fibrin is pivotal for prevention of pathological blood clot formation [3Collen D. Lijnen H.R. Basic and clinical aspects of fibrinolysis and thrombolysis.Blood. 1991; 78: 3114-24Crossref PubMed Google Scholar]. Plasmin also has substrate specificities for several other components of the extracellular matrix (ECM), including fibronectin, proteoglycans and gelatin, indicating that plasmin also plays an important role in ECM remodeling. Indirectly, plasmin also degrades additional components of the ECM via its ability to convert some pro‐matrix metalloproteinases (pro‐MMPs) to active MMPs. The plg gene maps to chromosome 6q26‐q27. It spans about 52.5 kilobases (kb) of DNA and consists of 19 exons and 18 introns. The plg cDNA of 2.7 kb encodes a protein consisting of 791 amino acid residues [4Petersen T.E. Martzen M.R. Ichinose A. Davie E.W. Characterization of the gene for human plasminogen, a key proenzyme in the fibrinolytic system.J Biol Chem. 1990; 265: 6104-11Abstract Full Text PDF PubMed Google Scholar] (Fig. 1). In hypoplasminogenemia, or type I plg deficiency, the level of immunoreactive plg is reduced in parallel with its functional activity. The specific plg activity is normal. Congenital heterozygous hypoplasminogenemia is a rare event and was first described in 1982 in a patient with thromboembolic disease [5Hasegawa D. Tyler B. Edson J.R. Thrombotic disease in three families with inherited plasminogen deficiency.Blood. 1982; 60: 213aPubMed Google Scholar]. Some further case reports and family studies had originally suggested that heterozygous hypoplasminogenemia might be a risk factor for venous thrombosis [6Dolan G. Greaves M. Cooper P. Preston F.E. Thrombovascular disease and familial plasminogen deficiency: a report of three kindreds.Br J Haematol. 1988; 70: 417-21Crossref PubMed Scopus (34) Google Scholar, 7Leebeek F.W. Knot E.A. Ten Cate J.W. Traas D.W. Severe thrombotic tendency associated with a type I plasminogen deficiency.Am J Hematol. 1989; 30: 32-5Crossref PubMed Scopus (18) Google Scholar, 8Lottenberg R. Dolly F.R. Kitchens C.S. Recurring thromboembolic disease and pulmonary hypertension associated with severe hypoplasminogenemia.Am J Hematol. 1985; 19: 181-93Crossref PubMed Scopus (40) Google Scholar, 9Sartori M.T. Patrassi G.M. Theodoridis P. Perin A. Pietrogrande F. Girolami A. Heterozygous type I plasminogen deficiency is associated with an increased risk for thrombosis: a statistical analysis in 20 kindreds.Blood Coagul Fibrinolysis. 1994; 5: 889-93Crossref PubMed Scopus (34) Google Scholar]. The relationship between hypoplasminogenemia and venous thrombosis has more recently been called into question, mainly based on two lines of evidence. Firstly, three large, recent epidemiological studies have demonstrated that isolated heterozygous hypoplasminogenemia is not a risk factor for thrombosis [10Demarmels Biasiutti F. Sulzer I. Stucki B. Wuillemin W.A. Furlan M. Lammle B. Is plasminogen deficiency a thrombotic risk factor? A study on 23 thrombophilic patients and their family members.Thromb Haemost. 1998; 80: 167-70Crossref PubMed Scopus (43) Google Scholar, 11Shigekiyo T. Uno Y. Tomonari A. Satoh K. Hondo H. Ueda S. Saito S. Type I congenital plasminogen deficiency is not a risk factor for thrombosis.Thromb Haemost. 1992; 67: 189-92Crossref PubMed Scopus (47) Google Scholar, 12Tait R.C. Walker I.D. Conkie J.A. Islam S.I. McCall F. Isolated familial plasminogen deficiency may not be a risk factor for thrombosis.Thromb Haemost. 1996; 76: 1004-8Crossref PubMed Scopus (52) Google Scholar]. Summarizing five studies [6Dolan G. Greaves M. Cooper P. Preston F.E. Thrombovascular disease and familial plasminogen deficiency: a report of three kindreds.Br J Haematol. 1988; 70: 417-21Crossref PubMed Scopus (34) Google Scholar, 9Sartori M.T. Patrassi G.M. Theodoridis P. Perin A. Pietrogrande F. Girolami A. Heterozygous type I plasminogen deficiency is associated with an increased risk for thrombosis: a statistical analysis in 20 kindreds.Blood Coagul Fibrinolysis. 1994; 5: 889-93Crossref PubMed Scopus (34) Google Scholar, 11Shigekiyo T. Uno Y. Tomonari A. Satoh K. Hondo H. Ueda S. Saito S. Type I congenital plasminogen deficiency is not a risk factor for thrombosis.Thromb Haemost. 1992; 67: 189-92Crossref PubMed Scopus (47) Google Scholar, 12Tait R.C. Walker I.D. Conkie J.A. Islam S.I. McCall F. Isolated familial plasminogen deficiency may not be a risk factor for thrombosis.Thromb Haemost. 1996; 76: 1004-8Crossref PubMed Scopus (52) Google Scholar, 13Biasiutti F.D. Stucki B. Solenthaler M. Tobler A. Furlan M. Lammle B. Venous thrombosis after caesarean section in a young woman with homozygous APC resistance and type I protein S deficiency.Eur J Haematol. 1997; 58: 127-9Crossref PubMed Scopus (4) Google Scholar], the overall (total) incidence of a history of thrombosis in family members with heterozygous plg deficiency was 6.8% (18/265) compared with an incidence of 3.5% (6/170) in family members without plg deficiency. This difference is not statistically significant [14Brandt J.T. Plasminogen and tissue‐type plasminogen activator deficiency as risk factors for thromboembolic disease.Arch Pathol Lab Med. 2002; 126: 1376-81Crossref PubMed Google Scholar]. The second line of evidence supporting the hypothesis that hypoplasminogenemia is not a significant risk factor for venous thrombosis in larger vessels is the observation that no deep vein thrombosis has ever been reported in at least 63 patients with severe homozygous or compound‐heterozygous hypoplasminogenemia studied so far [15Schott D. Dempfle C.E. Beck P. Liermann A. Mohr‐Pennert A. Goldner M. Mehlem P. Azuma H. Schuster V. Mingers A.M. Schwarz H.P. Kramer M.D. Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency.N Engl J Med. 1998; 339: 1679-86Crossref PubMed Scopus (127) Google Scholar, 16Schuster V. Mingers A.M. Seidenspinner S. Nüssgens Z. Pukrop T. Kreth W. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis.Blood. 1997; 90: 958-66Crossref PubMed Google Scholar, 17Schuster V. Seidenspinner S. Zeitler P. Escher C. Pleyer U. Bernauer W. Stiehm E.R. Isenberg S. Seregard S. Olsson T. Mingers A.M. Schambeck C. Kreth H.W. Compound‐heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis.Blood. 1999; 93: 3457-66Crossref PubMed Google Scholar, 18Schuster V. Zeitler P. Seregard S. Ozcelik U. Anadol D. Luchtman‐Jones L. Meire F. Mingers A.M. Schambeck C. Kreth H.W. Homozygous and compound‐heterozygous type I plasminogen deficiency is a common cause of ligneous conjunctivitis.Thromb Haemost. 2001; 85: 1004-10Crossref PubMed Scopus (52) Google Scholar, 19Tefs K. Gueorguieva M. Klammt J. Allen C.M. Aktas D. Anlar F.Y. Aydogdu S.D. Brown D. Ciftci E. Contarini P. Dempfle C.E. Dostalek M. Eisert S. Gokbuget A. Gunhan O. Hidayat A.A. Hugle B. Isikoglu M. Irkec M. Joss S.K. et al.Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients.Blood. 2006; 108: 3021-6Crossref PubMed Scopus (108) Google Scholar, unpubl. results]. In addition, plg‐knockout (plg−/−) mice also do not develop thrombosis of larger vessels [20Drew A.F. Kaufman A.H. Kombrinck K.W. Danton M.J. Daugherty C.C. Degen J.L. Bugge T.H. Ligneous conjunctivitis in plasminogen‐deficient mice.Blood. 1998; 91: 1616-24Crossref PubMed Google Scholar]. Similar to a suspected mechanism in plg−/− mice, in patients with homozygous or compound‐heterozygous hypoplasminogenemia deficient plg‐mediated intravascular fibrinolysis also might be compensated by plg‐independent mechanisms (e.g. by cathepsins, elastases or matrix metalloproteinases). The data suggest that isolated heterozygous or homozygous/compound‐heterozygous hypoplasminogenemia by itself is not a risk factor for deep venous thrombosis. Thus, at the 36th College of American Pathologists Consensus Conference in 2001, it was recommended that determination of plg concentration (activity or antigen) should not be part of the routine evaluation of patients with thrombophilia (evidence level 1) [14Brandt J.T. Plasminogen and tissue‐type plasminogen activator deficiency as risk factors for thromboembolic disease.Arch Pathol Lab Med. 2002; 126: 1376-81Crossref PubMed Google Scholar]. However, similar to observations in plg−/− mice, the thrombotic risk in small vessels and capillaries might also be increased in humans with severe hypoplasminogenemia [20Drew A.F. Kaufman A.H. Kombrinck K.W. Danton M.J. Daugherty C.C. Degen J.L. Bugge T.H. Ligneous conjunctivitis in plasminogen‐deficient mice.Blood. 1998; 91: 1616-24Crossref PubMed Google Scholar, 21Bugge T.H. Flick M.J. Daugherty C.C. Degen J.L. Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction.Genes Dev. 1995; 9: 794-807Crossref PubMed Scopus (373) Google Scholar, 22Bugge T.H. Kombrinck K.W. Flick M.J. Daugherty C.C. Danton M.J. Degen J.L. Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency.Cell. 1996; 87: 709-19Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar, 23Ploplis V.A. Carmeliet P. Vazirzadeh S. Van Vlaenderen I. Moons L. Plow E.F. Collen D. Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice.Circulation. 1995; 92: 2585-93Crossref PubMed Scopus (309) Google Scholar]. These findings in mice have not been confirmed in humans to date. Furthermore, it should be noted that the risk of fibrin‐rich thrombotic occlusions of implanted catheters, such as cerebrospinal fluid (CSF) shunts (ventriculo‐atrial, ventriculo‐peritoneal, CSF shunt from the ventricles into the gallbladder) may be markedly increased in severely hypoplasminogenic patients (for an example, see patient 2 in Schuster et al. [16Schuster V. Mingers A.M. Seidenspinner S. Nüssgens Z. Pukrop T. Kreth W. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis.Blood. 1997; 90: 958-66Crossref PubMed Google Scholar]). The incidence rate of (heterozygous) hypoplasminogenemia has roughly been estimated in different geographic regions at 0.35% (only in white subjects) in Minnesota, USA [24Dykes D. Polesky H. Incindence of the PLG *Q0 allele in human populations.in: Mayr W Advanced in Forensic Haemogenetics. Springer, 1988: 261-4Crossref Google Scholar], at 0.13% in Southern Germany [25Weidinger S. Patutschnick W. Schwarzfischer F. Further evidence of a silent plasminogen (PLG) allele in two paternity cases.Z Rechtsmed. 1988; 101: 99-104Crossref PubMed Scopus (6) Google Scholar], at 0.26% in Scotland [12Tait R.C. Walker I.D. Conkie J.A. Islam S.I. McCall F. Isolated familial plasminogen deficiency may not be a risk factor for thrombosis.Thromb Haemost. 1996; 76: 1004-8Crossref PubMed Scopus (52) Google Scholar] and at 0.42% in Japan [26Okamoto A. Sakata T. Mannami T. Baba S. Katayama Y. Matsuo H. Yasaka M. Minematsu K. Tomoike H. Miyata T. Population‐based distribution of plasminogen activity and estimated prevalence and relevance to thrombotic diseases of plasminogen deficiency in the Japanese: the Suita Study.J Thromb Haemost. 2003; 1: 2397-403Crossref PubMed Scopus (29) Google Scholar]. In 9611 Scottish blood donors studied so far, a K19E plg gene missense mutation was demonstrated in 0.14% [27Tefs K. Tait C.R. Walker I.D. Pietzsch N. Ziegler M. Schuster V. A K19E missense mutation in the plasminogen gene is a common cause of familial hypoplasminogenaemia.Blood Coagul Fibrinolysis. 2003; 14: 411-6Crossref PubMed Scopus (17) Google Scholar]. Several further studies suggest the K19E mutation to be the most common molecular genetic defect in patients with hypoplasminogenemia worldwide [19Tefs K. Gueorguieva M. Klammt J. Allen C.M. Aktas D. Anlar F.Y. Aydogdu S.D. Brown D. Ciftci E. Contarini P. Dempfle C.E. Dostalek M. Eisert S. Gokbuget A. Gunhan O. Hidayat A.A. Hugle B. Isikoglu M. Irkec M. Joss S.K. et al.Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients.Blood. 2006; 108: 3021-6Crossref PubMed Scopus (108) Google Scholar]. Besides this K19E mutation, a variety of other genetic abnormalities have been identified in the plg gene in subjects with heterozygous, homozygous and compound‐heterozygous hypoplasminogenemia (Fig. 1, blue circles or blue arrows): missense mutations T9N, L128P, R134K, G142R, G176D, T181P, R216H, D219N, R234H, P285A, P285T, R306H, N307I, T352I, P353A, P491R, A505V, R513H, S575P, W597C, A675T, P744S, C765G, R776H; nonsense mutations C133X, K378X, Q380X, E460X, R471X, Q540X, W597X; frameshift mutations W417fsX432, E455fsX493, V563fsX580, L650fsX652; splice site mutations IVS11‐2A/G, IVS11‐7T/G, IVS11 + 1G/A, IVS17 + 1delG as well as an amino acid deletion mutation K212del, and an amino acid insertion mutation T319_N320insN [15Schott D. Dempfle C.E. Beck P. Liermann A. Mohr‐Pennert A. Goldner M. Mehlem P. Azuma H. Schuster V. Mingers A.M. Schwarz H.P. Kramer M.D. Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency.N Engl J Med. 1998; 339: 1679-86Crossref PubMed Scopus (127) Google Scholar, 16Schuster V. Mingers A.M. Seidenspinner S. Nüssgens Z. Pukrop T. Kreth W. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis.Blood. 1997; 90: 958-66Crossref PubMed Google Scholar, 17Schuster V. Seidenspinner S. Zeitler P. Escher C. Pleyer U. Bernauer W. Stiehm E.R. Isenberg S. Seregard S. Olsson T. Mingers A.M. Schambeck C. Kreth H.W. Compound‐heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis.Blood. 1999; 93: 3457-66Crossref PubMed Google Scholar, 18Schuster V. Zeitler P. Seregard S. Ozcelik U. Anadol D. Luchtman‐Jones L. Meire F. Mingers A.M. Schambeck C. Kreth H.W. Homozygous and compound‐heterozygous type I plasminogen deficiency is a common cause of ligneous conjunctivitis.Thromb Haemost. 2001; 85: 1004-10Crossref PubMed Scopus (52) Google Scholar, 19Tefs K. Gueorguieva M. Klammt J. Allen C.M. Aktas D. Anlar F.Y. Aydogdu S.D. Brown D. Ciftci E. Contarini P. Dempfle C.E. Dostalek M. Eisert S. Gokbuget A. Gunhan O. Hidayat A.A. Hugle B. Isikoglu M. Irkec M. Joss S.K. et al.Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients.Blood. 2006; 108: 3021-6Crossref PubMed Scopus (108) Google Scholar, 28Azuma H. Uno Y. Shigekiyo T. Saito S. Congenital plasminogen deficiency caused by a Ser572 to Pro mutation.Blood. 1993; 82: 475-80Crossref PubMed Google Scholar, unpubl. data]. Ligneous conjunctivitis (McKusick #217090) is an unusual and rare form of chronic ‘idiopathic membraneous’ conjunctivitis characterized by initial chronic tearing and redness of the conjunctivae and the subsequent formation of pseudomembranes mostly on the palpebral surfaces that progress to white, yellow‐white, or red thick masses with a wood‐like consistency that replace the normal mucosa [29Schuster V. Seregard S. Ligneous conjunctivitis.Surv Ophthalmol. 2003; 48: 369-88Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. Most affected cases are infants and children. In predisposed subjects, ligneous conjunctivitis may be triggered by local injuries, local and systemic infections, and various surgical interventions at the eye [29Schuster V. Seregard S. Ligneous conjunctivitis.Surv Ophthalmol. 2003; 48: 369-88Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. In 1994, an 18‐month‐old Turkish girl with congenital occlusive hydrocephalus and ligneous conjunctivitis was admitted to hospital because of shunt occlusion and subsequent decompensation of hydrocephalus. Routine laboratory testing prior to necessary surgical revision of the occluded ventriculo‐peritoneal shunt included determination of plg levels. Surprisingly, both plg antigen levels and plg activity were shown to be undetectable in this child. This was the first report of a severe, probably homozygous hypoplasminogenemia [30Mingers A.M. Heimburger N. Zeitler P. Kreth H.W. Schuster V. Homozygous type I plasminogen deficiency.Semin Thromb Hemost. 1997; 23: 259-69Crossref PubMed Scopus (80) Google Scholar]. This finding was soon confirmed in two further patients with ligneous conjunctivitis, who both exhibited also severe hypoplasminogenemia [30Mingers A.M. Heimburger N. Zeitler P. Kreth H.W. Schuster V. Homozygous type I plasminogen deficiency.Semin Thromb Hemost. 1997; 23: 259-69Crossref PubMed Scopus (80) Google Scholar]. During the following years, distinct homozygous and compound‐heterozygous mutations in the plg gene were reported in patients with hypoplasminogenemia (Fig. 1) [15Schott D. Dempfle C.E. Beck P. Liermann A. Mohr‐Pennert A. Goldner M. Mehlem P. Azuma H. Schuster V. Mingers A.M. Schwarz H.P. Kramer M.D. Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency.N Engl J Med. 1998; 339: 1679-86Crossref PubMed Scopus (127) Google Scholar, 16Schuster V. Mingers A.M. Seidenspinner S. Nüssgens Z. Pukrop T. Kreth W. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis.Blood. 1997; 90: 958-66Crossref PubMed Google Scholar, 17Schuster V. Seidenspinner S. Zeitler P. Escher C. Pleyer U. Bernauer W. Stiehm E.R. Isenberg S. Seregard S. Olsson T. Mingers A.M. Schambeck C. Kreth H.W. Compound‐heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis.Blood. 1999; 93: 3457-66Crossref PubMed Google Scholar, 18Schuster V. Zeitler P. Seregard S. Ozcelik U. Anadol D. Luchtman‐Jones L. Meire F. Mingers A.M. Schambeck C. Kreth H.W. Homozygous and compound‐heterozygous type I plasminogen deficiency is a common cause of ligneous conjunctivitis.Thromb Haemost. 2001; 85: 1004-10Crossref PubMed Scopus (52) Google Scholar, 19Tefs K. Gueorguieva M. Klammt J. Allen C.M. Aktas D. Anlar F.Y. Aydogdu S.D. Brown D. Ciftci E. Contarini P. Dempfle C.E. Dostalek M. Eisert S. Gokbuget A. Gunhan O. Hidayat A.A. Hugle B. Isikoglu M. Irkec M. Joss S.K. et al.Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients.Blood. 2006; 108: 3021-6Crossref PubMed Scopus (108) Google Scholar]. It has become increasingly obvious that hypoplasminogenemia is a multisystemic disease that affects mainly the eyes (ligneous conjunctivitis), but more or less commonly also other mucous membranes of the body, the central nervous system (congenital occlusive hydrocephalus, Dandy–Walker malformation) and the skin (juvenile colloid milium). Clinical manifestations in a collection of 74 patients with severe (i.e. homozygous or compound‐heterozygous) hypoplasminogenemia [15Schott D. Dempfle C.E. Beck P. Liermann A. Mohr‐Pennert A. Goldner M. Mehlem P. Azuma H. Schuster V. Mingers A.M. Schwarz H.P. Kramer M.D. Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency.N Engl J Med. 1998; 339: 1679-86Crossref PubMed Scopus (127) Google Scholar, 16Schuster V. Mingers A.M. Seidenspinner S. Nüssgens Z. Pukrop T. Kreth W. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis.Blood. 1997; 90: 958-66Crossref PubMed Google Scholar, 17Schuster V. Seidenspinner S. Zeitler P. Escher C. Pleyer U. Bernauer W. Stiehm E.R. Isenberg S. Seregard S. Olsson T. Mingers A.M. Schambeck C. Kreth H.W. Compound‐heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis.Blood. 1999; 93: 3457-66Crossref PubMed Google Scholar, 18Schuster V. Zeitler P. Seregard S. Ozcelik U. Anadol D. Luchtman‐Jones L. Meire F. Mingers A.M. Schambeck C. Kreth H.W. Homozygous and compound‐heterozygous type I plasminogen deficiency is a common cause of ligneous conjunctivitis.Thromb Haemost. 2001; 85: 1004-10Crossref PubMed Scopus (52) Google Scholar, 19Tefs K. Gueorguieva M. Klammt J. Allen C.M. Aktas D. Anlar F.Y. Aydogdu S.D. Brown D. Ciftci E. Contarini P. Dempfle C.E. Dostalek M. Eisert S. Gokbuget A. Gunhan O. Hidayat A.A. Hugle B. Isikoglu M. Irkec M. Joss S.K. et al.Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients.Blood. 2006; 108: 3021-6Crossref PubMed Scopus (108) Google Scholar, unpubl. results] were as follows. The median age of first clinical manifestation was 9.54 months (range 3 days to 61 years). The female to male ratio was 1.43:1. The majority of affected subjects suffered from ligneous conjunctivitis (60/74 patients, 81%), followed by ligneous gingivitis (22/74 patients, 30%), a complication which may lead to complete loss of teeth. Further manifestations included involvement of the upper and lower respiratory tract (sinus, larynx, respiratory tract and alveolar tissue; 17/74 patients, 20%), the middle ear (11/74 patients, 15%), the female genital tract (vaginitis, cervicitis, involvement of the fallopian tube, ovary and endometrium, 7/74 patients, 9%), the gastrointestinal tract (duodenal ulcer; 2/74 patients, 2.7%), the kidneys (kidney stones; 3/74 patients, 4%) and the skin (juvenile colloid milium, 1/74 patients; 1%). Congenital occlusive hydrocephalus was found in at least nine of 74 patients (12%). At least four patients (5%) exhibited Dandy–Walker malformation, a congenital hypoplasia and upward rotation of the cerebellar vermis and cystic dilation of the fourth ventricle. Severely impaired skin wound healing was reported in a few plg‐deficient patients, mostly following surgical procedures [15Schott D. Dempfle C.E. Beck P. Liermann A. Mohr‐Pennert A. Goldner M. Mehlem P. Azuma H. Schuster V. Mingers A.M. Schwarz H.P. Kramer M.D. Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency.N Engl J Med. 1998; 339: 1679-86Crossref PubMed Scopus (127) Google Scholar]. Severe hypoplasminogenemia seems to be a cause of infertility caused by chronic fibrinous inflammation of the female genital tract and perhaps also by an impaired ovulation capacity. To the best of our knowledge, no affected woman with severe hypoplasminogenemia has become pregnant or has given birth [29Schuster V. Seregard S. Ligneous conjunctivitis.Surv Ophthalmol. 2003; 48: 369-88Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 31Pantanowitz L. Bauer K. Tefs K. Schuster V. Balogh K. Pilch B.Z. Adcock D. Cirovic C. Kocher O. Ligneous (pseudomembranous) inflammation involving the female genital tract associated with type‐1 plasminogen deficiency.Int J Gynecol Pathol. 2004; 23: 292-5Crossref PubMed Scopus (29) Google Scholar]. In our studies, plg values in patients with homozygous/compound‐heterozygous hypoplasminogenemia ranged from <1 to 9 mg dL−1 for plg antigen plasma level and <1%–51% for functional plg activity. These values might be a very rough threshold between symptomatic and asymptomatic hypoplasminogenemia. However, we have identified two unrelated subjects with homozygous K19E mutation (plg antigen 5 and 2 mg dL−1, respectively; plg activity 30% and 15%, respectively [19Tefs K. Gueorguieva M. Klammt J. Allen C.M. Aktas D. Anlar F.Y. Aydogdu S.D. Brown D. Ciftci E. Contarini P. Dempfle C.E. Dostalek M. Eisert S. Gokbuget A. Gunhan O. Hidayat A.A. Hugle B. Isikoglu M. Irkec M. Joss S.K. et al.Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients.Blood. 2006; 108: 3021-6Crossref PubMed Scopus (108) Google Scholar, 27Tefs K. Tait C.R. Walker I.D. Pietzsch N. Ziegler M. Schuster V. A K19E missense mutation in the plasminogen gene is a common cause of familial hypoplasminogenaemia.Blood Coagul Fibrinolysis. 2003; 14: 411-6Crossref PubMed Scopus (17) Google Scholar]) and two sisters of a patient with severe ligneous conjunctivitis who were also compound‐heterozygous for the plg gene mutation K378X/T319_N320insN and also had significantly decreased plg plasma levels (patient, 5% plg activity; healthy sisters <1%) [19Tefs K. Gueorguieva M. Klammt J. Allen C.M. Aktas D. Anlar F.Y. Aydogdu S.D. Brown D. Ciftci E. Contarini P. Dempfle C.E. Dostalek M. Eisert S. Gokbuget A. Gunhan O. Hidayat A.A. Hugle B. Isikoglu M. Irkec M. Joss S.K. et al.Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients.Blood. 2006; 108: 3021-6Crossref PubMed Scopus (108) Google Scholar]) who are all clinically healthy. It is quite possible that these subjects will develop clinical symptoms later in life. Inherited homozygous or compound‐heterozygous hypoplasminogenemia is a very rare disorder (with an incidence roughly estimated at below 1:106) which is associated with deficient extravascular plg‐dependent fibrin(ogen) clearance leading to impaired wound healing mainly of mucous membranes (ligneous conjunctivitis, ligneous gingivitis and other clinical manifestations). In affected patients, the wound‐healing capacity seems to be arrested at the stage of granulation tissue formation [29S