Homozygous and compound-heterozygous type I plasminogen deficiency is a common cause of ligneous conjunctivitis.

Severe type I plasminogen deficiency has been recently linked to ligneous conjunctivitis, a rare and uncommon form of chronic conjunctivitis. In this study, eight unrelated ligneous conjunctivitis patients living in different parts of the world were examined. All affected subjects from which plasma was available displayed absent or markedly reduced plasminogen antigen and plasminogen functional activity. Molecular genetic studies of seven patients identified a Lys19-->Glu mutation in two boys in a homozygous state, and in two girls in a compound-heterozygous state in which the second plasminogen gene carried a missense (Arg134-->Lys) and a nonsense mutation (Cys133--> Stop), respectively. A fifth patient was shown to be homozygous for a frameshift mutation in plasminogen exon 14 (Gly565ins-G). In two unrelated subjects with ligneous conjunctivitis no mutations in the plasminogen gene were identified. Our results suggest that the Lys19-->Glu mutation is the most prevalent mutation in the plasminogen gene of patients with ligneous conjunctivitis.

Compound-heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis.

Homozygous type I plasminogen deficiency has been identified as a cause of ligneous conjunctivitis. In this study, 5 additional patients with ligneous conjunctivitis are examined. Three unrelated patients (1 boy, 1 elderly woman, and 1 man) had plasminogen antigen levels of less than 0.4, less than 0.4, and 2.4 mg/dL, respectively, but had plasminogen functional residual activity of 17%, 18%, and 17%, respectively. These subjects were compound-heterozygotes for different missense mutations in the plasminogen gene: Lys19 --> Glu/Arg513 --> His, Lys19 --> Glu/Arg216 --> His, and Lys19 --> Glu/Leu128 --> Pro, respectively. The other 2 patients, a 14-year-old boy and his 19-year-old sister, who both presented with a severe course of the disease, exhibited plasminogen antigen and functional activity levels below the detection limit (<0.4 mg/dL and <5%, respectively). These subjects were compound-heterozygotes for a deletion mutation (del Lys212) and a splice site mutation in intron Q (Ex17 + 1del-g) in the plasminogen gene. These findings show that certain compound-heterozygous mutations in the plasminogen gene may be associated with ligneous conjunctivitis. Our findings also suggest that the severity of clinical symptoms of ligneous conjunctivitis and its associated complications may depend on the amount of plasminogen functional residual activity.

Human homozygous type I plasminogen deficiency and ligneous conjunctivitis.

On the basis of a questionnaire sent to the ophthalmology departments of hospitals throughout Germany, 10 patients with ligneous conjunctivitis or pseudomembranous disease, ranging in age from 1 to 71 years were identified. All 10 patients had severely reduced plasminogen levels. Genetic analysis revealed homozygous type I plasminogen deficiency (which had not previously been described in humans) in 7 patients and compound heterozygous plasminogen deficiency in 1 patient. Clear differentiation was not possible in 2 patients. Most of the parents had heterozygous plasminogen deficiency. None of the patients had experienced any episodes of thrombosis. Additionally, the following observations were made: 1) Levels of polymorphonuclear (PMN)-elastase protein were markedly elevated in 6 of 6 patients and 10 of 11 parents tested, and levels were higher in homozygotes than in heterozygotes. 2) Hereditary factor XII deficiency was found in 3 of 6 patients tested. 3) C1-inhibitor was elevated in 2 of 4 patients, prekallikrein was elevated in 1 of 4 patients, and plasminogen activator inhibitor type 1 was elevated in 1 of 4 patients. Infusions of lys-plasminogen concentrate induced pronounced fibrinolytic activity as indicated by high levels of D-dimer, increases in plasmin-antiplasmin complex and decreases in polymorphonuclear elastase. C1-inhibitor, prekallikrein and PAI-1 normalized after repeated infusions of lys-plasminogen. In contrast to dysplasminogenemia, severe type I plasminogen deficiency might be seen as a problem of extravascular space, in particular of the mucous membranes, possibly triggered by mechanically induced or inflammatory lesions of the vessels supplying the tissue.

Polymorphonuclear elastase in patients with homozygous type I plasminogen deficiency and ligneous conjunctivitis.

Laboratory studies were performed on six female patients (ranging in age from 1 to 31 years) with ligneous conjunctivitis, which we regard as a systemic condition consisting of ligneous conjunctivitis and other pseudomembranous lesions. Plasminogen levels were severely reduced in all six patients; five patients were homozygous, and one patient was double heterozygous for type I plasminogen deficiency. Of family members tested, 11 of 12 parents and two of six siblings tested were diagnosed as heterozygous. No thrombotic episodes had occurred in any of the patients. Polymorphonuclear (PMN) elastase protein levels were markedly elevated in all, significantly more so in the homozygous patients (range 88 to 335 ng/mL; normal range, 20+/-10 ng/mL) than in the heterozygous patient (58 ng/mL). Of 11 parents examined, only 1 mother had normal PMN elastase (27 ng/mL, with plasminogen antigen 60% and plasminogen functional activity 86%), whereas values were moderately elevated (range 42 to 110 ng/mL) in the other 10 parents examined. After plasminogen substitution, PMN elastase levels consistently decreased but did not reach normal values. We interpret our findings as indicating that non-plasmin-induced fibrinolytic processes, possibly mediated via elastase, may be intensified in patients with plasminogen deficiency.

Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis.

Ligneous conjunctivitis is a rare and unusual form of chronic pseudomembranous conjunctivitis that usually starts in early infancy. The disease may be associated with pseudomembranous lesions of other mucous membranes in the mouth, nasopharynx, trachea, and female genital tract. We examined two unrelated Turkish girls both suffering from ligneous conjunctivitis and occlusive hydrocephalus. Both children exhibited a severe plasminogen deficiency. Genomic DNA from both patients as well as from clinically healthy family members were screened for mutations in the plasminogen gene by polymerase chain reaction, single-strand conformation polymorphism (SSCP) analysis, and DNA sequencing. In the first girl with ligneous conjunctivitis a homozygous G-->A point mutation was identified in plasminogen exon 7 at position 780 leading to an amino acid exchange (Arg216-->His). Her healthy sister and her healthy parents were heterozygous for this mutation. The second patient revealed a homozygous G-->A point mutation in plasminogen exon 15 at position 1924 which leads to a stop-codon (Trp597-->Stop). The healthy parents were shown to be heterozygous for this mutation. In addition, the father's second allele revealed another mutation in the same codon (Trp597-->Cys) (compound heterozygosity). In conclusion, certain homozygous mutations in the plasminogen gene may cause ligneous conjunctivitis.

Homozygous type I plasminogen deficiency.

Homozygous type I plasminogen (Plg) deficiency has not been described in human subjects so far. Ligneous conjunctivitis is a rare and unusual form of chronic pseudomembranous conjunctivitis of unknown etiology. Here we report for the first time on homozygous type I Plg deficiency in three unrelated female patients who suffered from ligneous conjunctivitis and additional pseudomembranous lesions of other mucous membranes. The disease is caused by massive fibrin depositions within the "extravascular space" of mucous membranes because of absent clearance by plasmin. Infusions of albumin, fresh frozen plasma, or Lys-plasminogen (Lys-Plg) into two of the three patients revealed normal Plg activation capacity in these patients. The absence of fibrinolytic activity could therefore be shown to be due to Plg deficiency. Similar studies in the third patient have not been completed. In the two patients studied so far, infusions of Lys-Plg resulted in prompt and adequate Plg recovery with a short half-life and high amounts of plasmin-antiplasmin complexes and D-dimer. One patient additionally revealed an inherited partial factor XII deficiency. Functionally, this factor XII deficiency did not interfere with Plg activation. However, there may be a pathway of Plg activation in this patient via the prekallikrein C1-INH system.

[Perioperative hemostatic problems in children]. / Perioperative Gerinnungsprobleme bei Kindern.

During childhood preoperative coagulation diagnosis is performed to prove or to rule out an inborn coagulation disorder or an acquired v. Willebrand disease. The coagulation system of the newborns differs considerably from that of the adults as well as the time in which the single parameters reach adult values. Reducing the coagulation screening to the determination of aPTT and Quicktest neglects severe hemostaseological disorders easily, e.g. v. Willebrand disease which often in childhood is to be observed and often combined with normal aPTT values. Probably sometimes children affected with hypertrophy of the adenoids have temporary aPTT prolongations combined with normal values for the other coagulation parameters possibly due to lupus inhibitors. When children with deficiencies of coagulation factors need high doses of coagulation concentrates the number of laboratory controls may be reduced by determination on recovery and half-life period some times before.

[Perioperative blood coagulation problems in children]. / Perioperative Gerinnungsprobleme bei Kindern.

During childhood preoperative coagulation diagnosis is performed to prove or to rule out an inborn coagulation disorder or an acquired von Willebrand disease. The coagulation system of the newborn differs considerably from that of the adults as well as the time in which the single parameters reach adult values. Reducing the coagulation screening to the determination of aPTT and Quick test neglects severe hemostaseological disorders easily, such as von Willebrand disease which is often observed in childhood and often combined with normal aPTT values. Sometimes children affected with hypertrophy of the adenoids have temporary aPTT prolongations combined with normal values for the other coagulation parameters possibly due to lupus inhibitors. When children with deficiencies of coagulation factors need high doses of coagulation concentrates, the number of laboratory controls may be reduced by determination of recovery and the half-life period some time before.

[Pellagra in anticonvulsive therapy]. / Pellagra unter antikonvulsiver Behandlung.

The case of a mentally handicapped female patient is presented who developed typical pellagra with dermatitis, diarrhoea and mental alteration following a long-term antiepileptic treatment with phenytoin, ethosuximide and valproic acid. In addition, she had a deficient meat intake. A course of treatment with multivitamins proved successful in resolving the symptoms within 2 weeks.

[Influence of hypocaloric diet on the platelets of overweight children (author's transl)]. / Einfluss hypokalorischer Kost auf die Thrombocyten übergewichtiger Kinder.

20 overweight, otherwise healthy children aged 8--15 years received a hypocaloric mixed diet. Platelet counts and qualities were examined. Before dieting in relation to the weight platelet counts were elevated, their spreading capacity diminished, but the values were still within the normal range. Some tests of platelet qualities were abnormal. During the first weeks of dieting platelet counts decreased continuously while some of their qualities worsened.

[Influence of hypocaloric diet on blood coagulation of overweight children (author's transl)]. / Einfluss hypokalorischer Kost auf die Blutgerinnung übergewichtiger Kinder.

32 overweight otherwise healthy children aged 8-15 years received a hypocaloric mixed diet for some weeks. Their blood coagulation was studied with regard to possible changes. Before dieting the levels of fibrinogen were markedly increased, also maximal amplitude (ma) of the thrombelastograms. The other values were within the normal range. During the diet statistically significant changes were found in the values of the following coagulatin parameters: ma of the thrombelastograms as well as the activities of the coagulation factors I, II, VII, VIII, IX, and X.

[Studies of metabolism of overweight children before and during weight reducing diet applied some weeks (author's transl)]. / Stoffwechselstudien bei übergewichtigen Kindern vor und während einer mehrwöchigen Kur zur Gewichtsreduktion.

32 overweight and otherwise healthy children aged 8--15 years received a hypocaloric assorted diet for some weeks. Their weight loss was satisfactory, and as expected most considerable in the beginning. Before and during dieting a great number of investigations were carried out concerning the changes of metabolism and blood counts. This was done in weekly intervals. By means of the resulting parameters the changes of metabolism during dieting are discussed.

Thrombocyte functions, thrombelastograms and fibrinogen of healthy children in different age groups.

Platelet counts, adhesiveness, aggregation and spreading capacity, as well as the thrombopoiesis index, thrombelastogram and fibrinogen were examined in 74 healthy children aged from 2 to 14 years. Sex-linked differences were only found in the thrombopoiesis index. Age-linked differences showed in practically all the parameters, especially in the platelet counts, fibrinogen and thrombelastograms.