Original Article
Brief Report
Therapy with a Purified Plasminogen Concentrate in an Infant with Ligneous Conjunctivitis and Homozygous Plasminogen Deficiency
N Engl J Med 1998; 339:1679-1686December 3, 1998
- Article
Ligneous conjunctivitis is a rare disease characterized by acute or chronic recurrent conjunctivitis in which the conjunctival membranes acquire a wood-like consistency, due primarily to deposits of fibrin.1,2 Corneal involvement and chronic obstruction of the eye may lead to blindness. The disease is frequently associated with nasopharyngitis, tracheobronchial obstruction, otitis media, vulvovaginitis, and defective wound healing.2-9 Pseudomembranous conjunctivitis was first described in 1847 by Bouisson,10 and the term “conjunctivitis lignosa” was introduced by Borel in 1933.11 More than 100 cases have been reported in the literature, but no satisfactory treatment has yet been found. The results of therapy with hyaluronidase eye drops, corticosteroids, cyclosporine, and antiviral agents are generally disappointing.6,7,12-14 Surgical treatment often causes accelerated recurrence of pseudomembranes.2,4-6,14
Family studies have suggested that the disorder is caused by a genetic defect with an autosomal recessive pattern of inheritance.3 A case of ligneous conjunctivitis with gingival and peritoneal lesions was reported after treatment with the antifibrinolytic agent tranexamic acid,15 suggesting a relation between ligneous conjunctivitis and impaired fibrinolysis. Although the syndrome may have more than one cause, it has recently been linked to severe plasminogen deficiency.16-18 Plasminogen-deficient mice generated by targeted gene disruption show signs of ligneous conjunctivitis, defective wound healing, and internal hydrocephalus.19,20
In this report, we describe a patient with homozygous plasminogen deficiency in whom ligneous conjunctivitis developed soon after birth. Other symptoms included hyperviscosity of tracheobronchial and nasopharyngeal secretions, impaired wound healing, and internal hydrocephalus. Replacement therapy with lys-plasminogen (lysine-conjugated plasminogen) led to rapid regression of the pseudomembranes and normalization of respiratory tract secretions and wound healing.
Case Report
The child was the second son of parents of Turkish origin, who were first cousins. Progressive internal hydrocephalus was diagnosed by prenatal ultrasound examination, and the child was delivered by elective cesarean section at a gestational age of 35 weeks. The findings on physical examination were normal except for a bulging fontanelle and macrocephalus (head circumference, 36.5 cm, above the 97th percentile). Bilateral inflammation of the palpebral portion of the conjunctiva, with hypersecretion and formation of pseudomembranes, was noticed three days after birth. Within two weeks, a thick, yellowish-white, fibrous, woody pseudomembranous layer of conjunctival proliferation had developed, spreading from the inner side of the upper and lower eyelids and completely closing both eyes (Figure 1Figure 1
Initial Appearance of a Child with Homozygous Plasminogen Deficiency, Showing the Typical Features of Ligneous Conjunctivitis.). The pseudomembranes were removed surgically several times but regrew rapidly. Local treatment with antibiotics, corticosteroids, and cyclosporine did not result in improvement, and there was a risk of complete loss of vision.Computed tomography and magnetic resonance tomography of the head and ultrasound examination showed an extended, symmetric internal hydrocephalus with a Dandy–Walker malformation, hypoplasia of the cerebellum, and a hypoplastic corpus callosum. The hydrocephalus was drained by ventriculoperitoneal shunting three weeks after birth. Wound-healing complications subsequently developed, with wound dehiscence and markedly retarded regeneration of the skin, which was generally dry and eczematous. Furthermore, recurrent airway infections developed, with hyperviscosity of the nasopharyngeal and tracheobronchial secretions. Visual evoked potentials on an electroencephalogram were normal; the results of hearing tests, including auditory evoked potentials, were abnormal, indicating a hearing deficiency at the middle-ear level.
Family studies showed that the patient's parents and older brother had decreased levels of plasminogen antigen and activity, suggesting heterozygous plasminogen deficiency. None of the family members had signs of venous or arterial disease, ligneous conjunctivitis, or other symptoms. In the patient, the level of functional plasminogen was below the limit of detection (<1 percent on chromogenic assay), as was that of plasminogen antigen (<1 percent on laser nephelometry, and <0.5 percent on immunoblotting). A diagnosis of homozygous plasminogen deficiency was therefore proposed. After written informed consent from the parents and approval from the local ethics committee of Mannheim University Hospital were obtained, replacement therapy was started (the patient was six months old at the time), with continuous intravenous infusion of 1000 caseinolytic units (CU) of lys-plasminogen (corresponding to 180 CU per kilogram of body weight) per 24 hours. One CU is defined as the activity of enzyme that liberates 450 μg of trichloroacetic acid–soluble tyrosine from casein in one hour under defined conditions.21 After two weeks of continuous infusion, lys-plasminogen was given as bolus injections of 2000 CU (corresponding to approximately 350 CU per kilogram) every 48 hours for two weeks. Maintenance therapy with daily bolus injections of 1000 CU (corresponding to 180 CU per kilogram at first, decreasing to 125 CU per kilogram as the child's weight increased) was then initiated and has been continued up to the present.
Methods
Histologic Findings
Specimens of conjunctival pseudomembranes were snap-frozen in liquid nitrogen, and 4-to-5-μm-thick sections were cut and processed for staining with hematoxylin and eosin and for immunohistologic analysis. Immunofluorescence staining for plasmin and plasminogen deposits in the granulation tissue was performed with use of previously described murine antihuman antibodies to plasmin and plasminogen22 and fluorescein isothiocyanate–labeled antimouse IgG antibodies.23
Analysis of Mutations
Genomic DNA was prepared from blood samples drawn from the patient and from healthy family members (his parents and elder brother). The DNA samples were amplified by the polymerase chain reaction (PCR) with use of a set of primer pairs flanking all 19 exons that include intron boundaries of the human plasminogen gene,24 with primer sequences and PCR conditions as previously described.25 To screen for mutations in the plasminogen gene, we used single-strand conformation polymorphism analysis.26 Amplified and subsequently denatured PCR segments underwent electrophoresis for seven hours at 10 W with a nondenaturing 5 percent polyacrylamide gel (Roth, Karlsruhe, Germany) containing 5 percent glycerol at room temperature. The gel was dried and exposed to Kodak XAR-S films (Eastman Kodak, Rochester, N.Y.). Variant bands of single-stranded DNA fragments that differed in their migration patterns were excised from dried gels, dissolved in buffer, purified with MicroSpin columns (Pharmacia, Freiburg, Germany), and reamplified. These PCR products were again purified with MicroSpin columns and were directly cycle-sequenced by the dideoxy chain-termination method with use of [35S]deoxyadenosine triphosphate and the Exo(–)Pfu Cyclist DNA Sequencing Kit (Stratagene, Heidelberg, Germany). Samples were electrophoresed on 6 percent polyacrylamide–8.3 M urea sequencing gels (Roth), dried, and exposed to Kodak XAR-S films.
Direct Detection of Mutations
To detect the Glu460Stop mutation directly, once it had been identified in the patient, amplified PCR products of exon 11 of the plasminogen gene (263-bp fragments) were digested with MboII (New England Biolabs, Beverly, Mass.) according to the manufacturer's recommendations and electrophoresed on a 2 percent agarose gel for analysis of the restriction-fragment–length pattern.
Laboratory Analyses
The functional activity of plasminogen was measured by chromogenic assay (Boehringer Mannheim, Mannheim, Germany). Plasminogen antigen was measured by laser nephelometry with use of polyclonal rabbit antiserum and reagents (Behring Diagnostics, Marburg, Germany). Plasminogen antigen was also detected by immunoblotting after sodium dodecyl sulfate–polyacrylamide-gel electrophoresis of whole plasma with use of polyclonal rabbit antiserum against human plasminogen (Behring) and an alkaline phosphatase–labeled monoclonal antibody against rabbit IgG (Sigma, Deisenhofen, Germany). A solution containing nitroblue tetrazolium chloride and 5-bromo-4-chloro-3-indolylphosphate substrate was used for visualization of enzyme-labeled antibodies.
Thrombin–antithrombin complex was measured by enzyme immunoassay (Enzygnost TAT, Behring). Tests for fibrin monomers (Enzymun-Test FM), d-dimer antigen (TINAquant), and fibrinogen were performed with use of reagents from Boehringer Mannheim. The functional activity of antithrombin was measured by chromogenic assay (Boehringer Mannheim).
Lys-Plasminogen
A sterile, freeze-dried concentrate of lys-plasminogen purified from human plasma was obtained from Immuno (Vienna, Austria). The product was supplied in vials containing 1000 CU for reconstitution with 10 ml of sterile water. Per milliliter, the reconstituted solution contains 100±20 CU of lys-plasminogen, 4 to 6 mg of total protein, 7.2 to 10.8 mg of sodium chloride, 0.8 to 1.2 mg of trisodium citrate, 0.14 to 0.26 mg of lysine, and 0.8 mg of dibasic sodium citrate. This concentrate has been used in other clinical studies27 and is not licensed in Germany. The safety of the vapor heating process used for inactivation of virus was demonstrated in an international study in which no cases of product-related transmission of hepatitis viruses or human immunodeficiency virus occurred.28
Results
Histologic Evaluation
The hematoxylin–eosin staining of parts of the conjunctival pseudomembranes revealed fibrin-rich granulation tissue with a mixed neutrophil-rich perivascular infiltrate. Immunophenotyping confirmed the mixed character of the infiltrate, with predominantly neutrophilic granulocytes (which are elastase-positive), monocytes and macrophages (CD68-positive), and a few scattered T cells (CD3-positive). Staining with an antibody specific for fibrin and fibrinogen revealed diffuse fibrin deposits; no staining was evident when antibodies against plasmin and plasminogen were used.
Molecular Genetic Findings
In single-strand conformation polymorphism analysis, a sequence difference of only a single base (point mutation) alters the secondary structure of DNA and thus its mobility in electrophoresis. Altered single-strand band patterns were found in the patient's genomic DNA only when primers specific for exon 11 of the plasminogen gene were used (Figure 2Figure 2
Results of Single-Strand Conformation Polymorphism Analysis of Exon 11 of the Plasminogen Gene in the Patient, His Parents, and His Brother., lane 2).Direct sequencing of fragments of exon 11 from the patient (Figure 3Figure 3
Sequence Analysis of Exon 11 of the Plasminogen Gene in the Patient and a Healthy Control Subject., right) demonstrated a homozygous point mutation at position 1511 (G→T), leading to a stop codon (TAA) at position 460 (Glu460Stop). This mutation abolishes the catalytic domain of plasmin. The healthy brother (Figure 2, lane 5) and the healthy parents (Figure 2, lanes 3 and 4) were shown to be heterozygous for this mutation, whereas it was not present in a healthy control (Figure 2, lane 1). The healthy control had a homozygous single-base-pair substitution (Figure 3, left) at position 1490 (A→G), leading to an amino acid substitution at position 453 (Asn453Asp), which probably represents only a polymorphism in the normal population.24 We found the Asn453Asp substitution in four additional healthy subjects, all of whom had normal plasminogen antigen concentrations and functional plasminogen activity (data not shown).Restriction-Fragment–Length Analysis
The Glu460Stop mutation disrupts a restriction site for the restriction enzyme MboII (GAAGA) in exon 11 of the plasminogen gene (Figure 4AFigure 4
Detection of the Glu460Stop Mutation at Exon 11 of the Plasminogen Gene by Digestion with the Restriction Enzyme MboII.). Therefore, subjects who are homozygous or heterozygous for the Glu460Stop mutation can be identified with use of agarose-gel electrophoresis to detect differences in the restriction-fragment–length pattern of their MboII-digested PCR fragments (Figure 4B). The patient had only one band of 263 bp, a finding that was compatible with both alleles' containing the Glu460Stop mutation and that indicated homozygosity. The mother, the elder brother, and the father each had both the mutant allele (263 bp) and the shorter normal allele (236 bp), indicating heterozygosity. The healthy control, as well as 50 other unrelated healthy subjects (data not shown), had only the normal allele. These data indicate that the Glu460Stop mutation does not represent a polymorphism.Recovery and Half-Life of Lys-Plasminogen
The patient's plasminogen level began to increase within 3 hours after the start of the initial continuous intravenous infusion of lys-plasminogen (1000 CU per 24 hours); the level approached the normal value within 24 hours, fluctuated, and then leveled off at between 40 percent and 50 percent of normal after one week (Figure 5Figure 5
Levels of Plasminogen, Thrombin–Antithrombin Complex (TAT), Fibrin Monomer, d-Dimer, Fibrinogen, and Antithrombin III during the Initial 340 Hours of Continuous Intravenous Lys-Plasminogen–Replacement Therapy in a Patient with Homozygous Plasminogen Deficiency.).For the evaluation of the in vivo half-life of lys-plasminogen, serial blood samples were obtained from the patient before and 30 minutes and 1, 3, 6, and 24 hours after bolus injection of lys-plasminogen on three separate occasions (a sample was also obtained after 48 hours on the first occasion). Early during the course of therapy, the administration of 2000 CU of lys-plasminogen increased the plasminogen level from 0 to 150 percent of normal within 30 minutes, with 7 percent residual activity after 24 hours and 1 percent after 48 hours (data not shown). After approximately five months of replacement therapy, the administration of 1000 CU of lys-plasminogen increased the plasminogen level on one occasion to 74 percent of normal after 30 minutes, with 4 percent residual activity after 24 hours, and on another occasion to 80 percent of normal, with 6 percent residual activity after 24 hours. The half-life of lys-plasminogen was approximately five hours.
Effect of Lys-Plasminogen on Measures of Fibrinolysis and Coagulation
Whereas d-dimer antigen was absent in pretreatment blood samples, indicating the absence of endogenous plasmin-dependent fibrinolysis, the levels rose sharply after the start of treatment, peaking at six hours and then decreasing gradually (Figure 5). This pattern showed that fibrinolytic activity had resulted in the release of fibrin split products.
The level of thrombin–antithrombin complex increased three hours after the start of the continuous infusion of lys-plasminogen and reached maximal levels after six hours (Figure 5); this pattern indicated that thrombin, which is inhibited by covalent binding to antithrombin, had been formed or released. Thrombin–antithrombin complex levels returned to normal within 24 hours. Fibrin monomers (measured with the Enzymun Test FM) were absent in pretreatment samples, indicating the absence of an activation state of coagulation; their level paralleled the rise in thrombin–antithrombin complex, but decreased only slowly over the following 10 to 12 days (Figure 5). Fibrinogen and antithrombin activity remained virtually within the normal range throughout treatment, indicating the absence of consumption coagulopathy (Figure 5). Thus, coagulation appeared to be somewhat activated as a result of fibrinolysis, without the consumption of fibrinogen or measurable antithrombin activity.
Similarly, in the pharmacokinetic study with the administration of a bolus of 2000 CU of lys-plasminogen during the initial phase of therapy, d-dimer and thrombin–antithrombin complex levels showed slight increases, suggesting fibrinolytic activation and the release of small amounts of thrombin. However, no effects were seen after the administration of 1000 CU of lys-plasminogen later in the course of therapy.
Clinical Course
Both the viscosity of the nasopharyngeal and tracheobronchial secretions and wound healing improved markedly within three days after the start of replacement therapy and subsequently became normal. After approximately two weeks, the conjunctival pseudomembranes softened and could easily be drawn off, although slight bleeding was observed on two occasions after removal. After four weeks of treatment, both eyes were largely free of membranes except for a small remnant, and vision was restored. Symptoms and fibrin deposits on the cornea reappeared when therapy was interrupted for more than 48 hours and disappeared again when plasminogen treatment was reinstated. After seven months of treatment (through a central venous catheter), only minor residues of ligneous conjunctivitis remained (Figure 6Figure 6
Patient with Homozygous Plasminogen Deficiency and Ligneous Conjunctivitis after Seven Months of Replacement Therapy with Lys-Plasminogen.).Discussion
The fibrinolytic activity of all body fluids clears fibrin deposits. In the tear fluid of the eye, plasminogen activators released by the cornea30 convert the zymogen plasminogen into the fibrinolytic enzyme plasmin, which rapidly clears the cornea of fibrin deposits. The absence of plasmin activity results in the formation of the fibrin-rich viscous or membranous material typically seen in patients with ligneous conjunctivitis and in mice with targeted disruption of the plasminogen gene.19,20,31 An inflammatory reaction combined with activation of inflammatory cells and fibroblasts, with a drying out of the fibrin, results in the wood-like appearance of the conjunctival lesions. In a double-gene knockout-mouse model, the combination of plasminogen deficiency and fibrinogen deficiency prevents corneal fibrin deposits and associated inflammatory reactions and restores normal wound healing.19,20,32 Tracheobronchial fibrin deposition has been observed in our patient, in others with ligneous conjunctivitis,2,5,13,33 and in plasminogen-deficient mice.34 The fibrin deposits impair the ciliary system of the tracheobronchial tree and support bacterial growth, predisposing the patient to multiple sinobronchial infections. The ear involvement in our patient and others8 is attributable to fibrin deposition in the middle ear. The internal hydrocephalus reported in patients with ligneous conjunctivitis4,12,13,16 and in plasminogen-deficient mice19 appears to be related to plasminogen deficiency. The pathophysiologic mechanism may be fibrin deposition in the cerebral ventricular system, causing impaired circulation of the fluid in the aqueduct region.
It is striking that no intravascular thromboembolic episodes occur in ligneous conjunctivitis,17 despite a severe deficiency of the key zymogen of the fibrinolytic system. Heterozygous plasminogen deficiency also appears not to be a risk factor for thrombosis,35,36 despite several reports to the contrary.37-40 It remains a matter of speculation which mechanisms are involved in keeping the vasculature free of thrombosis even with virtually complete plasminogen deficiency. Experiments with plasminogen-deficient mice have shown a 10 percent rate of spontaneous clot lysis after eight hours,41 suggesting the action of fibrinolytic proteases other than plasmin. Electrophoretic analysis of plasma obtained from our patient before treatment with lys-plasminogen concentrate showed the presence of small amounts of fibrin derivatives that did not react with antibodies against epitopes exposed by plasmin cleavage of fibrin.42 This suggests the presence of an alternative system for the dissolution of intravascular fibrin, which apparently is not active in the extravascular compartments.
Our patient had a homozygous inactivating mutation of the plasminogen gene that abolished the catalytic domain of plasmin and caused severe type I plasminogen deficiency. Because of this mutation, messenger RNA transcription, the half-life of messenger RNA of the mutant plasminogen allele, or both may be markedly decreased. As a result, the liver may synthesize a truncated plasminogen molecule that is rapidly cleared from the circulation, or secretion of the mutant plasminogen molecules may be impaired. In a recent study using genetic engineering techniques, the latter mechanism has been demonstrated in vitro for type I plasminogen deficiency caused by a Ser572Pro mutation.43 In addition to the Glu460Stop plasminogen mutation, two other homozygous mutations (Arg216→His and Trp597Stop) have recently been identified in two unrelated Turkish girls with ligneous conjunctivitis and severe type I plasminogen deficiency.17 These molecular genetic findings confirm assumptions by others4,23,29 that ligneous conjunctivitis is inherited, probably in an autosomal recessive manner.
Mingers et al.18 were the first to try low-dose lys-plasminogen concentrate for the short-term treatment of patients with homozygous plasminogen deficiency, but they did not observe any definite effect on clinical symptoms. In our patient, long-term plasminogen-replacement therapy at a dose 2 to 10 times as high as that used by Mingers et al. led to complete regression of the ligneous conjunctivitis and normalized both the hyperviscous secretions in the respiratory tract and wound healing. The regression of symptoms with replacement therapy and their reappearance when therapy was interrupted demonstrate the pivotal role of plasminogen in extravascular fibrinolysis and confirm that severe plasminogen deficiency causes ligneous conjunctivitis.
Presented in part at the 41st Annual Meeting of the Gesellschaft für Thrombose- und Hämostaseforschung, Vienna, Austria, February 22–26, 1997, and at the 39th Annual Meeting of the American Society of Hematology, San Diego, Calif., December 5, 1997.
Supported in part by a grant from the Deutsche Forschungsgemeinschaft (Schu 560/4-1, to Dr. Schuster).
We are indebted to Kathryn Nelson, E.L.S., for editorial assistance.
Source Information
From the Department of Pediatrics (D.S., P.B., M.G., P.M.), the First Department of Medicine (C.-E.D.), and the Department of Ophthalmology (A.L.), Klinikum Mannheim, University of Heidelberg, Mannheim, Germany; the Hyland-Immuno Division of Baxter Healthcare, Heidelberg, Germany (A.M.-P.), and Vienna, Austria (H.P.S.); the First Department of Internal Medicine, University of Tokushima, Tokushima, Japan (H.A.); the Department of Pediatrics, University of Wuerzburg, Wuerzburg, Germany (V.S., A.-M.M.); and the Department of Immunology, University of Heidelberg, Heidelberg, Germany (M.D.K.).
Address reprint requests to Dr. Schott at the Klinikum Mannheim Kinderklinik, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany.
Other authors were Hans Liesenhoff, M.D., Department of Ophthalmology, and Karl Heinz Niessen, M.D., Department of Pediatrics, Klinikum Mannheim, University of Heidelberg, Mannheim, Germany.
- References
References
1
Eagle RC Jr ,Brooks JS ,Katowitz JA ,Weinberg JC ,Perry HD . Fibrin as a major constituent of ligneous conjunctivitis. Am J Ophthalmol 1986;101:493-494
Web of Science | Medline2
Hidayat AA ,Riddle PJ . Ligneous conjunctivitis: a clinicopathologic study of 17 cases. Ophthalmology 1987;94:949-959
Web of Science | Medline3
Bateman JB ,Pettit TH ,Isenberg SJ ,Simons KB . Ligneous conjunctivitis: an autosomal recessive disorder. J Pediatr Ophthalmol Strabismus 1986;23:137-140
Medline4
Chambers JD ,Blodi FC ,Golden B ,McKee AP . Ligneous conjunctivitis. Trans Am Acad Ophthalmol Otolaryngol 1969;73:996-1004
Medline5
Cooper TJ ,Kazdan JJ ,Cutz E . Ligneous conjunctivitis with tracheal obstruction: a case report with light and electron microscopy findings. Can J Ophthalmol 1979;14:57-62
Web of Science | Medline6
Firat T . Ligneous conjunctivitis. Am J Ophthalmol 1974;78:679-688
Web of Science | Medline7
Francois J ,Victoria-Troncoso V . Treatment of ligneous conjunctivitis. Am J Ophthalmol 1968;65:674-678
Web of Science | Medline8
Marcus DM ,Walton D ,Donshik P ,Choo L ,Newman RA ,Albert DM . Ligneous conjunctivitis with ear involvement. Arch Ophthalmol 1990;108:514-519
Web of Science | Medline9
Scurry J ,Planner R ,Fortune DW ,Lee CS ,Rode J . Ligneous (pseudomembranous) inflammation of the female genital tract: a report of two cases. J Reprod Med 1993;38:407-412
Web of Science | Medline10
Bouisson M . Ophthalmie sur-aigue avec formation de pseudomembranes à la surface de la conjonctive. Ann Ocul 1847;17:100-10411
Borel MG . Un nouveau syndrome palpébral. Bull Soc Ophtalmol Fr 1933;46:168-18012
Nussgens Z ,Roggenkamper P . Ligneous conjunctivitis: ten years follow-up. Ophthalmic Paediatr Genet 1993;14:137-140
CrossRef | Medline13
Babcock MF ,Bedford RF ,Berry FA . Ligneous tracheobronchitis: an unusual cause of airway obstruction. Anesthesiology 1987;67:819-821
CrossRef | Web of Science | Medline14
Schwartz GS ,Holland EJ . Induction of ligneous conjunctivitis by conjunctival surgery. Am J Ophthalmol 1995;120:253-254
Web of Science | Medline15
Diamond JP ,Chandna A ,Williams C , et al. Tranexamic acid-associated ligneous conjunctivitis with gingival and peritoneal lesions. Br J Ophthalmol 1991;75:753-754
CrossRef | Web of Science | Medline16
Mingers AM ,Heimburger N ,Zeitler P ,Kreth HW ,Schuster V . Homozygous type I plasminogen deficiency. Semin Thromb Hemost 1997;23:259-269
CrossRef | Web of Science | Medline17
Schuster V ,Mingers AM ,Seidenspinner S ,Nussgens Z ,Pukrop T ,Kreth HW . Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis. Blood 1997;90:958-966
Web of Science | Medline18
Mingers AM, Heimburger N, Lutz E. Familiärer homozygoter und heterozygoter Typ I-Plasminogenmangel. In: Scharrer I, Schramm W, eds. 25: Hämophilie-Symposium Hamburg 1994. Berlin, Germany: Springer-Verlag, 1996:96-104.
19
Drew AF ,Kaufman AH ,Kombrinck KW , et al. Ligneous conjunctivitis in plasminogen-deficient mice. Blood 1998;91:1616-1624
Web of Science | Medline20
Kao WW ,Kao CW ,Kaufman AH , et al. Healing of corneal epithelial defects in plasminogen- and fibrinogen-deficient mice. Invest Ophthalmol Vis Sci 1998;39:502-508
Web of Science | Medline21
Robbins KC ,Summaria L . Human plasminogen and plasmin. Methods Enzymol 1970;19:184-199
CrossRef22
Gissler HM ,Simon MM ,Kramer MD . Enhanced association of plasminogen/plasmin with lesional epidermis of bullous pemphigoid. Br J Dermatol 1992;127:272-277
CrossRef | Web of Science | Medline23
Schafer BM ,Maier K ,Eickhoff U ,Todd RF ,Kramer MD . Plasminogen activation in healing human wounds. Am J Pathol 1994;144:1269-1280
Web of Science | Medline24
Petersen TE ,Martzen MR ,Ichinose A ,Davie EW . Characterization of the gene for human plasminogen, a key proenzyme in the fibrinolytic system. J Biol Chem 1990;265:6104-6111
Web of Science | Medline25
Azuma H ,Uno Y ,Shigekiyo T ,Saito S . Congenital plasminogen deficiency caused by a Ser572 to Pro mutation. Blood 1993;82:475-480
Web of Science | Medline26
Schuster V ,Seidenspinner S ,Kreth HW . Detection of a novel mutation in the SRC homology domain 2 (SH2) of Bruton's tyrosine kinase and direct female carrier evaluation in a family with X-linked agammaglobulinemia. Am J Med Genet 1996;63:318-322
CrossRef | Web of Science | Medline27
Freitag HJ ,Becker VU ,Thie A , et al. Lys-plasminogen as an adjunct to local intra-arterial fibrinolysis for carotid territory stroke: laboratory and clinical findings. Neuroradiology 1996;38:181-185
CrossRef | Web of Science | Medline28
Shapiro A ,Abe T ,Aledort LM , et al. Low risk of viral infection after administration of vapor-heated factor VII concentrate or factor IX complex in first-time recipients of blood components. Transfusion 1995;35:204-208
CrossRef | Web of Science | Medline29
Forsgren M ,Raden B ,Israelsson M ,Larsson M ,Heden LO . Molecular cloning and characterization of a full-length cDNA clone for human plasminogen. FEBS Lett 1987;213:254-260
CrossRef | Web of Science | Medline30
Mirshahi S ,Soria J ,Nelles I , et al. Plasminogen activators in human corneal fibroblasts: secretion, cellular localization and regulation. Fibrinolysis Proteolysis 1996;10:255-26231
Carmeliet P ,Moons L ,Ploplis V ,Plow E ,Collen D . Impaired arterial neointima formation in mice with disruption of the plasminogen gene. J Clin Invest 1997;99:200-208
CrossRef | Web of Science | Medline32
Bugge TH ,Kombrinck KW ,Flick MJ ,Daugherty CC ,Danton MJ ,Degen JL . Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell 1996;87:709-719
CrossRef | Web of Science | Medline33
Cohen SR . Ligneous conjunctivitis: an ophthalmic disease with potentially fatal tracheobronchial obstruction: laryngeal and tracheobronchial features. Ann Otol Rhinol Laryngol 1990;99:509-512
Web of Science | Medline34
Ploplis VA ,Carmeliet P ,Vazirzadeh S , et al. Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice. Circulation 1995;92:2585-2593
Web of Science | Medline35
Tait RC ,Walker ID ,Conkie JA ,Islam SI ,McCall F . Isolated familial plasminogen deficiency may not be a risk factor for thrombosis. Thromb Haemost 1996;76:1004-1008
Web of Science | Medline36
Shigekiyo T ,Uno Y ,Tomonari A , et al. Type I congenital plasminogen deficiency is not a risk factor for thrombosis. Thromb Haemost 1992;67:189-192
Web of Science | Medline37
Sartori MT ,Patrassi GM ,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;5:889-893
CrossRef | Web of Science | Medline38
Leebeek FW ,Knot EA ,Ten Cate JW ,Traas DW . Severe thrombotic tendency associated with a type I plasminogen deficiency. Am J Hematol 1989;30:32-35
CrossRef | Web of Science | Medline39
Dolan G ,Greaves M ,Cooper P ,Preston FE . Thrombovascular disease and familial plasminogen deficiency: a report of three kindreds. Br J Haematol 1988;70:417-421
CrossRef | Web of Science | Medline40
Girolami A ,Marafioti F ,Rubertelli M ,Cappellato MG . Congenital heterozygous plasminogen deficiency associated with a severe thrombotic tendency. Acta Haematol 1986;75:54-57
CrossRef | Web of Science | Medline41
Lijnen HR ,Carmeliet P ,Bouche A , et al. Restoration of thrombolytic potential in plasminogen-deficient mice by bolus administration of plasminogen. Blood 1996;88:870-876
Web of Science | Medline42
Dempfle CE ,Pfitzner SA ,Schott D ,Niessen KH ,Heene DL . Fibrinogen heterogeneity in homozygous plasminogen deficiency type I: further evidence that plasmin is not involved in formation of LMW- and LMW'-fibrinogen. Thromb Haemost 1997;77:879-883
Web of Science | Medline43
Azuma H ,Mima N ,Shirakawa M , et al. Molecular pathogenesis of type I congenital plasminogen deficiency: expression of recombinant human mutant plasminogens in mammalian cells. Blood 1997;89:183-190
Web of Science | Medline
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T. IWAKI, C. MALINVERNO, D. SMITH, Z. XU, Z. LIANG, V. A. PLOPLIS, F. J. CASTELLINO. (2010) The generation and characterization of mice expressing a plasmin-inactivating active site mutation. Journal of Thrombosis and Haemostasis 8:10, 2341-2344
CrossRef7
B. M. Connolly, E. Y. Choi, H. Gardsvoll, A. L. Bey, B. M. Currie, T. Chavakis, S. Liu, A. Molinolo, M. Ploug, S. H. Leppla, T. H. Bugge. (2010) Selective abrogation of the uPA-uPAR interaction in vivo reveals a novel role in suppression of fibrin-associated inflammation. Blood 116:9, 1593-1603
CrossRef8
María-Dolores Torres, Marta Leiva, María-Dolores Tabar, Carolina Naranjo, Josep Pastor, Teresa Peña. (2009) Ligneous conjunctivitis in a plasminogen-deficient dog: clinical management and 2-year follow-up. Veterinary Ophthalmology 12:4, 248-253
CrossRef9
Angela C. Chi, Elizabeth Prichard, Mary S. Richardson, Kenneth P. Rasenberger, Dwight R. Weathers, Brad W. Neville. (2009) Pseudomembranous disease (ligneous inflammation) of the female genital tract, peritoneum, gingiva, and paranasal sinuses associated with plasminogen deficiency. Annals of Diagnostic Pathology 13:2, 132-139
CrossRef10
Sophia L. Yohe, Marcos Reyes, Daniel A. Johnson, Constance L. Fry, Frank W. Scribbick, Marsha C. Kinney. (2009) Plasminogen Deficiency as a Rare Cause of Conjunctivitis and Lymphadenopathy. The American Journal of Surgical Pathology 33:2, 313-319
CrossRef11
Gregg Fine, Kenneth Bauer, Maha Al-Mohaya, Sook-Bin Woo. (2009) Successful treatment of ligneous gingivitis with warfarin. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 107:1, 77-80
CrossRef12
J. Biswas, K. Billingham, S. Biswas, L. Hirschowitz, D. Bisson. (2009) Ligneous cervicitis: An unusual cause of post-coital bleeding in a postmenopausal woman. Journal of Obstetrics & Gynaecology 29:2, 163-165
CrossRef13
R. MEHTA, A. D. SHAPIRO. (2008) Plasminogen deficiency. Haemophilia 14:6, 1261-1268
CrossRef14
Vuslat Pelitli Gürlü, Muzaffer Demir, M Levent Alimgil, Sait Erda. (2008) Systemic and Topical Fresh-Frozen Plasma Treatment in a Newborn With Ligneous Conjunctivitis. Cornea 27:4, 501-503
CrossRef15
Nancy S. Johnstone McLean, Daniel A. Ward, Diane V. H. Hendrix, Robert L. Donnell, Marcia R. S. Ilha. (2008) Ligneous conjunctivitis secondary to a congenital plasminogen deficiency in a dog. Journal of the American Veterinary Medical Association 232:5, 715-721
CrossRef16
V. SCHUSTER, B. HÜGLE, K. TEFS. (2007) Plasminogen deficiency. Journal of Thrombosis and Haemostasis 5:12, 2315-2322
CrossRef17
C Scully, A Gokbuget, I Kurtulus. (2007) Hypoplasminogenaemia, gingival swelling and ulceration. Oral Diseases 13:6, 515-518
CrossRef18
Tamara L. Lotan, Katrin Tefs, Volker Schuster, Jonathan Miller, Jose Manaligod, Amy Filstead, Seiko Diane Yamada, Thomas Krausz. (2007) Inherited plasminogen deficiency presenting as ligneous vaginitis: a case report with molecular correlation and review of the literature. Human Pathology 38:10, 1569-1575
CrossRef19
M. Teresa Rodríguez-Ares, Ihab Abdulkader, Ana Blanco, Rosario Touriño-Peralba, Clara Ruiz-Ponte, Ana Vega, José Cameselle-Teijeiro. (2007) Ligneous conjunctivitis: a clinicopathological, immunohistochemical, and genetic study including the treatment of two sisters with multiorgan involvement. Virchows Archiv 451:4, 815-821
CrossRef20
A. GUTIÉRREZ-FERNÁNDEZ, R. J. PARMER, L. A. MILES. (2007) Plasminogen gene expression is regulated by nerve growth factor. Journal of Thrombosis and Haemostasis 5:8, 1715-1725
CrossRef21
Idil Kurtulus, Aslan Gokbuget, Ahmet Efeoglu, Serdar Cintan, Katrin Tefs, Volker Schuster, Crispian Scully. (2007) Hypoplasminogenemia With Ligneous Periodontitis: A Failed Local Therapeutic Approach. Journal of Periodontology 78:6, 1164-1175
CrossRef22
K McCullough, H Nguyen, D Stechschulte, O Tawfik. (2007) Ligneous conjunctivitis: a case report with multiorgan involvement. Histopathology 50:4, 511-513
CrossRef23
John A. Heit. 2007. Thrombophilia: Clinical and Laboratory Assessment and Management. , 211-244.
CrossRef24
Kenn Holmbeck, Ludmila Szabova. (2006) Aspects of extracellular matrix remodeling in development and disease. Birth Defects Research Part C: Embryo Today: Reviews 78:1, 11-23
CrossRef25
L. D. CURTIS, A. BROWN, M. B. COMER, J. M. SENIOR, S. WARRINGTON, K. M. DAWSON. (2005) Pharmacokinetics and pharmacodynamics of BB-101531, a thrombin-activatable plasminogen, in healthy volunteers. Journal of Thrombosis and Haemostasis 3:6, 1180-1186
CrossRef26
Gabriela Cesarman-Maus, Katherine A. Hajjar. (2005) Molecular mechanisms of fibrinolysis. British Journal of Haematology 129:3, 307-321
CrossRef27
M. B. COMER, K. S. CACKETT, S. GLADWELL, L. M. WOOD, K. M. DAWSON. (2005) Thrombolytic activity of BB-10153, a thrombin-activatable plasminogen. Journal of Thrombosis and Haemostasis 3:1, 146-153
CrossRef28
Stefano Barabino, Maurizio Rolando. (2004) Author reply. American Journal of Ophthalmology 138:4, 699-700
CrossRef29
Khalid F. Tabbara. (2004) Prevention of ligneous conjunctivitis by topical and subconjunctival fresh frozen plasma. American Journal of Ophthalmology 138:2, 299-300
CrossRef30
Qi Ling, Andrew T. Jacovina, Arunkumar Deora, Maria Febbraio, Ronit Simantov, Roy L. Silverstein, Barbara Hempstead, Willie H. Mark, Katherine A. Hajjar. (2004) Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo. Journal of Clinical Investigation 113:1, 38-48
CrossRef31
David G. Heidemann, George A. Williams, Michael Hartzer, Alexandra Ohanian, Matthew E. Citron. (2003) Treatment of Ligneous Conjunctivitis with Topical Plasmin and Topical Plasminogen. Cornea 22:8, 760-762
CrossRef32
Lakshmanan Suresh, Alfredo Aguirre, Vijay Kumar, Lynn W. Solomon, Edward A. Sielski, Mirdza E. Neiders. (2003) Recurrent Recalcitrant Gingival Hyperplasia and Plasminogen Deficiency: A Case Report. Journal of Periodontology 74:10, 1508-1513
CrossRef33
Volker Schuster, Stefan Seregard. (2003) Ligneous conjunctivitis. Survey of Ophthalmology 48:4, 369-388
CrossRef34
Katrin Tefs, Campbell R Tait, Isobel D Walker, Nicole Pietzsch, Maike Ziegler, Volker Schuster. (2003) A K19E missense mutation in the plasminogen gene is a common cause of familial hypoplasminogenaemia. Blood Coagulation & Fibrinolysis 14:4, 411-416
CrossRef35
Patrick Watts, Palanisamy Suresh, Eedy Mezer, Anna Ells, Manuela Albisetti, Lazlo Bajzar, Velma Marzinotto, Maureen Andrew, Patricia Massicotle, David Rootman. (2002) Effective treatment of ligneous conjunctivitis with topical plasminogen. American Journal of Ophthalmology 133:4, 451-455
CrossRef36
Troels Wind, Martin Hansen, Jan K. Jensen, Peter A. Andreasen. (2002) The Molecular Basis for Anti-Proteolytic and Non-Proteolytic Functions of Plasminogen Activator Inhibitor Type-1: Roles of the Reactive Centre Loop, the Shutter Region, the Flexible Joint Region and the Small Serpin Fragment. Biological Chemistry 383:1, 21-36
CrossRef37
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CrossRef38
Evelyn Braungart, Viktor Magdolen, Klaus Degitz. (2001) Retinoic Acid Upregulates the Plasminogen Activator System in Human Epidermal Keratinocytes. Journal of Investigative Dermatology 116:5, 778-784
CrossRef39
George B Segel, Charles A Francis. (2000) Anticoagulant Proteins in Childhood Venous and Arterial Thrombosis: A Review. Blood Cells, Molecules, and Diseases 26:5, 540-560
CrossRef40
Victoria A. Ploplis, Francis J. Castellino. (2000) Nonfibrinolytic Functions of Plasminogen. Methods 21:2, 103-110
CrossRef41
Volker Schuster, Silvia Seidenspinner, Clemens Müller, Andreas Rempen. (1999) Prenatal diagnosis in a family with severe type I plasminogen deficiency, ligneous conjunctivitis and congenital hydrocephalus. Prenatal Diagnosis 19:5, 483-487
CrossRef42
ANNE-MARIE MINGERS, ANTON PHILAPITSCH, PETRA ZEITLER, VOLKER SCHUSTER, HANS PETER SCHWARZ, HANS WOLFGANG KRETH. (1999) Human homozygous type I plasminogen deficiency and ligneous conjunctivitis. APMIS 107:1-6, 62-72
CrossRef
