Investigation of a Congenital Abnormal Plasminogen, Frankfurt I, and Its Relationship to Thrombosis

Abstract

SummaryA new abnormal plasminogen, Frankfurt I, has been identified in the plasma of a 42 year-old male patient who has recurrent deep vein thrombosis. Clinical laboratory data showed normal hemostasis test results. Since plasma plasmin generation rates gave low values, the fibrinolytic system was analyzed for a possible fibrinolytic system defect. Functional and antigen plasminogen concentrations both in the plasma and with the isolated, purified plasminogen showed that only 49% of the antigen concentration had potential functional active sites. Also, a reduced antigen concentration was found in both the propositus, and his mother (46% active sites).Sodium dodecyl sulfate polyacrylamide gel electrophoresis of the purified Frankfurt I plasminogen showed a normal native Glu-plasminogen band. Crossed-immunoelectrophoresis revealed a peak with normal size and shape, but displaced with respect to normal Glu-plasminogen toward the anode, i. e., was, as a whole, more negatively charged. Isoelectric focusing followed by zymog-raphy on a agarose-fibrin plate proved this observation, but did not indicate a separation of the normal from the abnormal plasminogen molecular species, also, fewer bands were found in the abnormal plasminogen isozyme pattern.Kinetic studies of Frankfurt I Glu-plasminogen and plasmin led to the conclusion that most of the functional abnormality is related to absence of active sites in half of the molecules. The plasmin generated was very unstable in the absence of stabilizing ligands and/or substrates. After reduction, the plasmin was completely converted to the typical two plasmin chains, A and B.

Reference Values and Variability of Plasminogen in Healthy Blood Donors and Its Relation to Parameters of the Fibrinolytic System

“…A comparison of the data obtained in this study with those published in the current literature (3,12,13,14,15,16,17,18,19) did not indicate marked differences. The values of t-PA activity and concentration, measured during the survey, tended to be higher than in most of the already published data (5,6,7,8,9).…”

Hereditary Defects in Fibrinolysis Associated with Thrombosis

“…There have since been additional reports of patients with dysfunctional plasminogen variants presenting with venous thrombosis at a relatively young age. [87][88][89] The variant plasminogens form a heterogeneous group and can be classified on the basis of their defect (Table 1; see Robbins for review 90 ). To date, three distinct types of abnormalities have been described.…”

Classification of Abnormal Plasminogens: Dysplasminogenemias

“…Twelve abnormal Plgs have been reported in patients with a history of thromboembolic diseases. [5][6][7][8][9][10][11][12][13][14][15] Eight of these variant Plgs are found in patients with normal Plg antigen levels; two in patients with low antigen levels. Tochigi I and II and Nagoya with normal Plg antigen levels are members of the same family with the same molecular defect, an Ala 600 to Thr substitution in the active site.…”

“…An attempt will be made tentatively to classify variant, abnormal plasminogens. This classification is based on only 12 reported patients in which studies were carried out on the isolated Plgs after identification of the dysplasminogenemias in plasma; included are four patients with hypoplasminogenemia, [12][13][14][15] with dysplasminogenemia. Since not all published reports have the same data, the classification will be general, rather than all-inclusive, since some of the variants differ by single properties, such as charge mutation, which is not common to most variants.…”