Abnormal Plasminogen Research Articles

Clinical and functional assessment after anticoagulant therapy of acute deep vein thrombosis involving the lower limb.

We assessed the clinical status after anticoagulant therapy in acute deep vein thrombosis (DVT) involving the lower limbs. Between 1994 and 2001, 139 patients suffering from acute DVT were treated with heparin therapy followed by oral anticoagulant therapy. The coagulation factor assay was done prior to any anticoagulation therapy. The duplex scan was checked serially. The mean follow-up periods was 32 +/- 19 months. There were 32 (23.0%)cases of protein C deficiency, 12 (8.6%) cases of protein S deficiency, 13 (9.4%) cases of AT-III deficiency and 11 (7.9%) cases of abnormal plasminogen level. Fourteen cases had coagulation factor abnormalities within the family. The initial lung scan showed 29 (20.9%) cases with high, 13 (9.4%) cases with intermediate and 70 (50.4%) cases with a low probability of pulmonary embolism (PE) developing. During the follow-up periods, there were 3 cases of non-fatal PE documented with chest CT scan. The patients were divided according to the extent of the thrombus; Group I (38 cases) was limited to the infrainguinal deep vein, Group II (70 cases) extended to the iliac vein and Group III (9 cases) extended to the vena cava. Partial lysis occurred in 20/35/3 (52.6/50.0/33.3%) cases and no change in 10/24/6 (26.3/ 34.3/ 66.7%) cases in Groups I/ II/ III, respectively. Deep vein valvular reflux occurred in 15/25/5 (39.5/35.7/55.6%) cases in Groups I/ II/ III, respectively. With anticoagulation therapy, most of the thrombi remained in unresolved states and there was a high rate of deep vein valvular reflux. However, there was no serious complications which affected the patients' quality of life.

245 Rapid genetic diagnosis for abnormal plasminogen by multiple amplification refractory mutation system (MARMS) and automated capillary electrophoresis

245 Rapid genetic diagnosis for abnormal plasminogen by multiple amplification refractory mutation system (MARMS) and automated capillary electrophoresis

407 Abnormal and unbalanced plasma plasminogen and Lp(a) lipoprotein levels in children with the nephrotic syndrome: Possible relation to thrombosis

407 Abnormal and unbalanced plasma plasminogen and Lp(a) lipoprotein levels in children with the nephrotic syndrome: Possible relation to thrombosis

84 Identification of a new Asn676 mutation and screening for four types of abnormal plasminogen genes in normal individuals

84 Identification of a new Asn676 mutation and screening for four types of abnormal plasminogen genes in normal individuals

5 Characterization of the 5′-regulatory region in normal and abnormal plasminogen genes and their related genes

5 Characterization of the 5′-regulatory region in normal and abnormal plasminogen genes and their related genes

Expanded Spectrum of Coagulopathy in the Etiology of Cerebral Infarction in Younger Adults in Japan

To clarify the role of coagulopathy in cerebral infarction (CI) in adults with onset before age 45, we performed comprehensive and repeated hemostatic analyses in 77 consecutive young adult patients with CI. Coagulopathy was found in 24% (9% in older adults, n = 241); inherited coagulopathy was observed in 14 patients, including protein-S deficiency in 6, abnormal plasminogen (genetically confirmed) in 5, and protein-C deficiency in 2. Acquired coagulopathy confined to the acute stage was observed in 6 patients, including siently present anticardiolipin antibody in 3, and transiently present lupus anticoagulant in 2. Of 20 patients who did not have any risk factor for atherosclerosis, acquired coagulopathy was observed in 6. We conclude that protein-S deficiency and abnormal plasminogen are frequent and might be critical causes of CI in younger adults; transient coagulopathy is also a possible cause.

Cyclosporine A inhibits tPA mRNA transcription in A431 cell line.

Cyclosporine A (CyA), a well established treatment of psoriasis, is a highly lipophilic cyclic undecapeptide mainly used for its immunosuppressive properties and exerting a wide spectrum of biological activities including fungicidal antiproliferative and anti-inflammatory effects. Plasminogen activators (PA), urokinase (UK, M(r) 55,000) and tissue type plasminogen activators (tPA, M(r) 74,000), physiologically catalyze the conversion of the plasminogen to the wide spectrum proteinase plasmin. UK and tPA are involved in cell growth, differentiation and migration. It has recently been shown that psoriatic epidermis is provided with abnormal tPA-dependent PA activity and that in lesional epidermis elevated tPA mRNA levels are present. It has been suggested that the tPA-dependent PA activity is a marker of disease activity and is reversible with different topical and systemic treatments. In this preliminary study we investigate the effect of CyA on the tPA mRNA transcription on A431 keratinocytes cell line. Subconfluent A431 cell cultures have been treated with CyA at in vivo relevant concentrations (10, 7.5, 5 micrograms/ml) for 48 h. Northern blot analysis of total RNA extracted from cultured A431 cell line has been performed for detecting tPA mRNA. mRNA for tPA has been detected in the control samples whereas an evident decrease of tPA mRNA expression has been detected in the CyA-treated samples. These data suggest that CyA could have an effect in clearing psoriatic lesions also modulating the abnormal plasminogen activation i.e. tPA-dependent serinoproteinase activity.

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

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.

Congenital abnormal plasminogen chicago IV: A dysplasminogenemia with 50% potential active sites with active centre, charge mutations and kinetics of activation defects

Summary Plasma plasminogen levels, both functional activity and antigen, were determined in a family with a history of coronary artery disease. The propositus suffered a myocardial infarct at the age of 40 years, followed by an episode of deep vein thrombosis. The propositus has a ratio of functional plasma plasminogen to antigen of 0.45:1, indicating a Type 1 dysplasminogenemia. His asymptomatic mother, age 60 years, has high levels of functional plasma plasminogen with a functional to antigen ratio of 1.38:1. His asymptomatic youngest brother, age 25 years, has normal functional plasminogen activity. A second brother died of a myocardial infarct at age 30 years. His three children have a plasma plasminogen functional to antigen ratio of 0.8:1 to 0.75:1, also indicating a Type 1 dysplasminogenemia. Plasminogen was isolated from the propositus and his mother. The yield of plasminogen recovered by a ffinity chromatography reflected the antigen levels. Characterization of the plasminogen by SDS-PAGE showed Glu-plasminogen forms, while isoelectric focusing showed fewer isoelectric forms than found in normal Glu-plasminogen with the addition of a few forms with a more basic pI. The specific activity of the purified plasminogen was 13.9 and 13.6 IU/mg protein for the propositus and his mother, respectively. This represents 50% of the normal specific activity of 27.4±2.2 IU/mg protein for highly purified Glu-plasminogen prepared in our laboratory. Generation of the active site in the equimolar plasminogen.streptokinase complex followed over time shows a slow generation of active site reaching a maximum of 50% of normal for the propositus plasminogen, but only 37% of normal for his mother's plasminogen. Plasmin generation in the soluble phase is low with three different plasminogen activators, streptokinase, plasmin light (B) chain.streptokinase complex and urokinase. Analysis of the assembly of the propositus and mother's purified plasminogens on the surface of U937 cells showed a good binding affinity with a K d of 0.9 M compared with a K d of 2.25 M for normal Glu-Plg with a B max of about 1.7 million for the propositus and mother's Plg's versus a B max of 3.5 million for normal. Despite the good affinity for the cell surface, neither the propositus or mother's plasminogen was activated by a high molecular weight urokinase on the cell surface. These plasminogen's were also unable to activate single chain urokinase on the cell surface. Plasmin generation in a noncrosslinked fibrin clot was evaluated using three direct plasminogen activators (plasminogen.streptokinase complex, urokinase, and tissue plasminogen activator) by determining the amount of time required to lyse 50% of a standard fibrin clot with a fixed concentration of purified plasminogen. Clot lysis times were prolonged for the propositus and mother's plasminogen compared to normal plasminogen with the three activators. Analysis of the kinetics of plasminogen activation parameters in this clot lysis assay with increasing concentrations of plasminogen gave normal Michaelis constants (K plg ) for the propositus and mother's plasminogen's with the plasminogen.streptokinase complex and urokinase, with lowered catalytic rate constants (k plg ). With tissue plasminogen activator as the activator, the Michaelis constants (K plg ) for the variant plasminogens were higher than normal showing a reduced affinity for tissue plasminogen activator with normal catalytic rate constants (k plg ). The second order rate constants (k plg /K plg ) were lower for the propositus and mother's plasminogens than for normal Glu-plasminogen showing a reduced catalytic efficiency for all three activators. Studies with the purified plasminogens show that the propositus (heterozygote) and his asymptomatic mother (heterozygote) have a dysplasminogenemia with 50% potential active sites, with an active centre defect, a charge mutation, and a kinetic defect.

Abnormal plasminogen genes in patients with myocaridal infarction and venous thrombosis

Abnormal plasminogen genes in patients with myocaridal infarction and venous thrombosis

Congenitally abnormal plasminogen in juvenile ischemic cerebrovascular disease.

Congenitally abnormal plasminogen is characterized by markedly decreased fibrinolytic activity and has been reported mainly in association with venous occlusive disease. We found three young adult patients (34, 45, and 27 years old at onset) with ischemic cerebrovascular disease, all of whom had congenital plasminogen abnormalities but no other known risk factors. Hemostatic tests of all three patients revealed plasma plasminogen activities at almost one half of the normal level despite normal plasma plasminogen antigen levels. They were found to be heterozygotes with abnormal plasminogen (normal Ala-601[GCT] to abnormal Thr-601[ACT]) by DNA sequence analysis after polymerase chain reaction. Congenital plasminogen abnormalities could be one of the risk factors of juvenile ischemic cerebrovascular disease of the arterial as well as venous type.

Stroke in a young adult with familial plasminogen disorder.

We report a new plasminogen disorder detected in a 29-year-old man with a cerebellar infarct. To our knowledge, plasminogen disorders have not been previously linked with stroke. Tests for well-recognized causes of stroke were negative. However, a screening hypercoagulation profile indicated low functional levels of plasminogen activity. Immunologic plasminogen (Laurell technique) was 64% of normal (normal level, 80-130%). The rate of plasmin generation induced by adding urokinase to plasma was also low. Plasminogen activator, free protease, and alpha 2-plasmin inhibitor levels were normal. Family studies detected a similar plasminogen abnormality in the patient's mother and 9-year-old son, both of whom are asymptomatic. Our patient shows a congenital, heterozygous, functionally abnormal plasminogen. Although the exact relationship to stroke is unclear, we suggest screening young patients with unexplained stroke for plasminogen defects using commercially available assay systems.

Congenital Protein C Deficiency Combined with a Congenital Abnormal Plasminogen with Deep Venous Thrombosis

Two cases of congenital protein C deficiency combined with a congenital abnormal plasminogen with deep venous thrombosis were reported. First case (AA) was a 41 year-old male who had a suprasaggital venous thrombosis and left femoral venous thrombosis. Hemostatic tests of the family revealed that his elder daughter and a son had a molecular abnormality of plasminogen, and his younger daughter had the same hemostatic abnormalities (protein C deficiency and abnormal plasminogen). None of them showed thrombotic symptom. Second case (YO) was a 33 year-old male who had recurrent right femoral venous thrombosis. His father had an abnormal plasmionogen but normal level of protein C activity and antigen. The mode of inheritance was not clear because of unavailability of tests of their relatives. Although two proposita were found to be heterozygotes with abnormal plasminogen (normal Ala-601 [GCT] to abnormal Thr-601 [ACT]) by the analysis of DNA sequencing, molecular analysis of protein C deficiency remained to be cleared.

Cumulative Irritant Dermatitis and Abnormal Epidermal Plasminogen Activator Activity: What Connection?

Cumulative Irritant Dermatitis and Abnormal Epidermal Plasminogen Activator Activity: What Connection?

Plasminogen phenotypes in a Japanese population. Four new variants including one with a functional defect.

Human plasminogen (PLG) phenotypes were investigated by polyacrylamide gel isoelectric focusing followed by immunoblotting. In 5,735 plasma samples from unrelated, healthy Japanese individuals, four new variants were detected and tentatively designated PLG AOsaka, PLG BOsaka, PLG MOsaka and PLG ANara. The plasminogen concentrations and activities of the PLG phenotypes were studied. In agreement with previous studies PLG M5 was found to have a decreased activity. The new variant PLG MOsaka had a very low activity and appears to be an abnormal plasminogen with a functional defect similar to that of PLG M5.

Abnormalities of the fibrinolytic system as a cause of upper extremity ischemia: A preliminary report

Abnormalities of the fibrinolytic system can result in unusual or unexplained clotting that occurs spontaneously or after minor trauma. We identified five patients with limb-threatening arterial thrombosis of the upper extremity associated with either a low level of plasminogen or an abnormal immunoreactive plasminogen. All patients had extensive thrombosis of the brachial, radial, and ulnar arteries. Two patients had concomitant thrombus of the subclavian artery, which in one patient was associated with distal embolization to the hand. There was no evidence of atherosclerosis in any patient. Detection of an abnormal plasminogen level was done by immunoelectrophoresis of the patient's serum with antiplasminogen sera. In these patients a separate immunoreactive band located near the anode and distinct from the normal single plasminogen band was detected. Because of extensive thrombosis of the arterial system, exploration of the brachial artery, as well as the origin of all the forearm vessels, was necessary for complete balloon catheter thrombectomy. Prompt diagnosis and treatment are necessary to prevent the catastrophic complication of arm or hand amputation. Patients with an abnormal plasminogen level should receive perioperative heparin therapy and long-term warfarin to prevent recurrent thrombotic episodes.

Abnormalities of the fibrinolytic system as a cause of upper extremity ischemia: a preliminary report.

Abnormalities of the fibrinolytic system can result in unusual or unexplained clotting that occurs spontaneously or after minor trauma. We identified five patients with limb-threatening arterial thrombosis of the upper extremity associated with either a low level of plasminogen or an abnormal immunoreactive plasminogen. All patients had extensive thrombosis of the brachial, radial, and ulnar arteries. Two patients had concomitant thrombus of the subclavian artery, which in one patient was associated with distal embolization to the hand. There was no evidence of atherosclerosis in any patient. Detection of an abnormal plasminogen level was done by immunoelectrophoresis of the patient's serum with antiplasminogen sera. In these patients a separate immunoreactive band located near the anode and distinct from the normal single plasminogen band was detected. Because of extensive thrombosis of the arterial system, exploration of the brachial artery, as well as the origin of all the forearm vessels, was necessary for complete balloon catheter thrombectomy. Prompt diagnosis and treatment are necessary to prevent the catastrophic complication of arm or hand amputation. Patients with an abnormal plasminogen level should receive perioperative heparin therapy and long-term warfarin to prevent recurrent thrombotic episodes.

Plasminogen San Antonio: An Abnormal Plasminogen with a More Cathodic Migration, Decreased Activation and Associated Thrombosis

An abnormal plasminogen (San Antonio) has been isolated from a patient with axillary vein thrombosis. A decreased level of fibrinolytic activity was detected in both plasma and a purified system. The molecular abnormalities were investigated with both functional and immunological tests. Slightly decreased antigen concentration was noted in plasma. By crossed immunoelectrophoresis, the patient and his two children had a second small arc and the primary arc migrated more cathodically. A distinct isozyme was detected in the abnormal plasminogen. Functionally, this abnormal plasminogen is characterized by failure to enhance maximal conversion to plasmin, especially by plasminogen activators, which are enhanced by fibrin or fibrin degradation products. The proband and his children are heterozygous for this abnormal plasminogen.

Incidence of abnormal plasminogen in healthy adults and in several diseases in Japanese population.

We examined 1, 479 pilot plasmas of blood donors, 171 cases of cerebral infarction and 37 cases of SLE for their activities and antigen levels of plasminogen. M±SD of the activity of donor blood was 83.5±17.3% and that of antigen level was 111±19μg/ml, i. e. 86.7±14.8%. The mean activity-antigen ratio (AC/AG) was 0.96±0.15. It was found that 82 cases had plasminogen activity lower than 60%, and finally 50 cases (3.8%) were diagnosed as abnormal plasminogen as they had AC/AG less than 0.66. Zymogram and immunostaining after IEF of these specimens revealed that the phenotype of one case was homozygote (type 1′-1′) and those of 49 were heterozygotes (type 1-1′). The incidences of the abnormality were not statistically different between three separate prefectures. The incidence of this abnormality was 4.7% (8/171) in cases of cerebral infarction and that in SLE was 10.8% (4/37). It was concluded that abnormal plasminogen is regarded not as the primary causative factor but the predisposing one of thromboembolism. High risk of thrombosis develops when abnormal plasminogen is complicated with any form of vascular damages, such as trauma, operation and inflammation.

Dysplasminogenemias.

This review on dysplasminogenemias describes a growing relationship between genetic polymorphisms of plasminogen and dysplasminogenemias. Plasminogen variants found in eight families in America, Japan and Europe are discussed. Methods used to identify abnormal plasminogens are described in detail. These methods include (a) plasminogen functional to antigen ratios, (b) plasmin generation rates with several plasminogen activators, e.g. urokinase, streptokinase, and the plasmin light (B) chain.streptokinase complex, and (c) plasma and purified plasminogen isoelectric forms. The functional defect including plasminogen kinetics of activation parameters are reviewed, including the formation of plasmin. The molecular defect found in one family, Tochigi I, is described, a single amino acid substitution was found. Finally, the lack of relationships between the abnormal plasminogen variants is reviewed. The variants fall into two classes: one class with a complete absence of a functioning active center, and the second class with different plasminogen kinetics of activation parameters.