Mingers A-M, Philapitsch A, Zeitler P, Schuster V, Schwarz HP & Kreth HW. Human homozygous type I plasminogen deficiency and ligneous conjunctivitis. APMIS 1999: 107:62-72.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 1 1 parents tested, and levels were higher in homozygotes than in heterozygotes. 2) Hereditary factor XI1 deficiency was found in 3 of 6 patients tested. 3) CI-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. C 1 -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.We diagnosed homozygous type I plasminogen deficiency for the first time in 1994. This defect of the fibrinolytic system had not previously been seen in humans. The patient was an 18-month-old female infant who had ligneous conjunctivitis ( 1 4 ) as well as congenital hydrocephalus. Occlusions had repeatedly occurred at the tips of shunts inserted for drainage, but there was no other evidence of thrombus formation. The etiology of ligneous conjunctivitis was unclear at that time (5-17), and we hypothesized that it was related to the severe plasminogen deficiency. We therefore decided to study this condition in more detail.A questionnaire focusing on genetic aspects was

SummaryTransient procoagulant states resulting in failure of recanalization or rethrombosis of the reperfused artery during thrombolytic therapy might be due to an inhibitory effect of plasmin on the anticoagulant properties of protein C. We therefore studied the effect of plasmin on protein C (PC) and activated protein C (APC) using purified human proteins.Incubation of 70 nM purified human PC with 40-400 nM human plasmin resulted in rapid activation and subsequent inactivation of PC as measured by amidolytic and anticoagulant assays. The rates of activation and inactivation were dependent on the concentration of plasmin. Lower concentrations of plasmin resulted in higher peaks of generated APC and more sustained activity, while at higher concentrations, both activation and inactivation were more rapid. Anticoagulant activity appeared more sensitive to inactivation by plasmin than amidolytic activity; e. g., while amidolytic activity reached a maximum of 13.8 nM in 6 min and declined to approximately 6 nM after 30 min, anticoagulant activity reached its maximum of only 1.4 nM within 30 s and completely disappeared within 90 s.Plasmin rapidly destroyed both the anticoagulant and amidolytic activity of purified APC, with second order rate constants of 2.8 × 105 M−1 s−1 and 1.2 × 104 M−1 −1, respectively, for 70 nM APC. The rates of activation and subsequent inactivation were slowed by the presence of CaCl2. The second order rate constant of inactivation of APC amidolytic activity decreased to 6.6 × 103 M−1 s−1 in the presence of 5 mM CaCl2. Proteolytic degradation of both PC and APC corresponding to the loss of amidolytic activity was demonstrated on SDS-PAGE using 125I-labelled proteins. When normal human plasma was incubated with plasmin or streptokinase a substantial loss of PC anticoagulant activity was observed.These results in vitro suggest that plasmin modulates the anticoagulant properties of protein C in a way that might be of relevance for the success of fibrinolytic therapy.

To improve the efficacy of local intraarterial fibrinolysis (LIF), we compared different fibrinolytic drugs in a cerebral circulation model in the laboratory. The technical efficacy of fibrinolysis, defined as the clot volume lysed per unit time, was found to be optimal with r-tissue plasminogen activator (TPA) activated lys-plasminogen (= plasmin). Subsequently, 20 patients with stroke due to carotid artery territory occlusion were treated by local intraarterial fibrinolysis using the plasmin regimen. The angiographic data and clinical outcome of these patients were compared with those of 40 patients who received plasminogen activators (urokinase or r-TPA) only. Laboratory and clinical data confirmed that plasmin lysis is superior to treatment using only plasminogen activators.

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.

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