Maywood II: A congenitally abnormal plasminogen with defective lysine-binding sites associated with stroke in a 16-year-old male

Abstract

Summary A 16-year-old male with a right-sided cerebral infarct was found to have low levels of functional plasminogen. Plasma was obtained from his mother, brother and sister for analysis. Both the propositus and his mother have a lowered ratio of plasma plasminogen functional to antigen levels of 0.47 and 0.77, respectively, indicating a dysplasminogenemia. The brother and sister have normal levels of plasminogen, both functional and antigen, with a functional to antigen ratio of about 1:1. An ELISA that measures the concentration of plasminogen kringles-1,2,3 (lysine-binding sites) gave values that did not agree with a conventional nephelometric assay for plasminogen; the propositus and his mother have very low levels of Plg by this assay, less than 60%. The yield of plasminogen recovered by affinity chromatography of the plasma on L-lysine-substituted Sepharose was low for the propositus and his mother, and correlated with the concentration of plasminogen determined by the ELISA. All four of the highly purified plasminogens from the four family members had low specific activities, low active site generation in the equimolar plasminogen.streptokinase complex, and low plasmin generation in solution. Isoelectric focusing gels showed that these plasminogens had fewer isoelectric forms than normal plasminogen and had several bands with a more basic pI than normal. All four of these plasminogens bound to the surface of U937 cells, but the binding was not inhibitable by 10 mM lysine, suggesting that the mode of interaction with the cell surface was not through the lysine-binding sites, as is normally the case. The propositus's plasminogen could not be activated to plasmin on the cell surface, but the other three family members' plasminogens did generate plasmin on the cell surface, however, greater than normal. Fibrinolytic activity determined in a purified system with a noncrosslinked fibrin clot and three direct plasminogen activators gave normal clot lysis times for the propositus with all three activators. The sister had prolonged clot lysis times when the equimolar plasminogen.streptokinase complex and urokinase were used as the activators; while the mother and brother had prolonged clot lysis times only when tissue plasminogen activator was used. However, all four family members had abnormal kinetics of plasminogen activation parameters with at least two of the activators used. The propositus had a Type 1 dysplasminogenemia with an active centre defect, charge mutation, kinetic defect and abnormal lysine binding sites. This defect is present in the other, asymptomatic, three family members, but is expressed differently and to a different extent in each individual.