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PubMed1991

Identification of the rat Heymann nephritis autoantigen (GP330) as a receptor site for plasminogen.

Previous results have demonstrated the binding of a 76- and 80-kDa serum protein to the Heymann nephritis autoantigen, gp330. This 76-kDa serum protein was purified by column chromatography and preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A rabbit polyclonal antibody for the serum protein was produced and used to screen a rat liver cDNA expression library. Sequence analysis of an isolated clone identified the serum protein as plasminogen. Plasminogen was isolated from rat serum by standard techniques, and the binding of plasminogen to gp330 was confirmed by Western analysis. Enzyme-linked immunosorbent assay results demonstrated a time-dependent, saturable, and specifically inhibitable binding of plasminogen to gp330. There was no significant difference in the binding of the two carbohydrate forms of plasminogen to gp330. Plasminogen binding to gp330 could be completely inhibited by the addition of exogenous gp330. This binding could also be partially inhibited by benzamidine but only slightly by the lysine analogue, epsilon-aminocaproic acid. However, even a combination of these two inhibitors could not completely block the binding of plasminogen to gp330 indicating that gp330 may be binding to plasminogen through some other unknown interactions. These results demonstrate that gp330 is a receptor site for plasminogen.

Amino Acid Sequence↗
PubMed1987

Plasminogen activation by single-chain urokinase in functional isolation. A kinetic study.

The kinetics of the activation of Glu- and Lys-plasminogen by single-chain urokinase (sc urokinase) derived from the transformed human kidney cell line TCL-598 have been studied and compared with two-chain urokinase (tc urokinase). Plasminogen activation was determined by the increase in fluorescence polarization of fluorescein-labeled aprotinin, a high affinity inhibitor of plasmin. This methodology allows plasmin generation by sc urokinase to be measured in functional isolation, with no interfering generation of tc urokinase, sc urokinase was found to activate plasminogen to plasmin with apparent Michaelis-Menten-type kinetics. The Km for Glu-plasminogen activation was 47.7 microM, with a catalytic constant of 2.91 min-1. Lys-plasminogen activation by sc urokinase was characterized by a Km of 11.7 microM and a kcat of 5.60 min-1. The Km values for the activation of Glu- and Lys-plasminogen by tc urokinase were found to be similar to those for activation by sc urokinase (36.8 and 9.0 microM, respectively), but the catalytic constants were higher at 36.0 and 118 min-1, respectively. Therefore, on the basis of the catalytic efficiency kcat/Km, sc urokinase seems to have 16-27-fold lower activity than tc urokinase. This activity of sc urokinase is in contrast to its lack of activity against a low molecular weight peptide substrate (less than 0.2% of the activity of sc urokinase). The activation of sc urokinase to tc urokinase by plasmin was also characterized (Km = 3.0 microM, kcat = 105 min-1). Using these data, it was possible to calculate the theoretical rate of plasminogen activation by sc urokinase in the absence of aprotinin, when tc urokinase is generated by the action of plasmin. The calculated rate was in good agreement with that determined experimentally using the chromogenic substrate D-Val-Leu-Lys-p-nitroanilide. These data demonstrate that sc urokinase has properties which distinguish it from conventional serine protease zymogens. The lack of activity against low molecular weight peptide substrates demonstrates the inaccessibility of the substrate-binding pocket. However, there is a moderate activity against plasminogen, suggesting that plasminogen may be acting as both an effector and a substrate for sc urokinase.

Cell Line↗
PubMed1994

Osteonectin in matrix remodeling. A plasminogen-osteonectin-collagen complex.

Osteonectin is an adhesive glycoprotein synthesized constitutively by osteoblasts, endothelial cells, and megakaryocytes. Bone-derived and platelet-derived osteonectins differ in their electrophoretic mobility and carbohydrate content, and each displays different affinities for collagen matrices. Both types of osteonectin bind to plasminogen (Kd(app), of 4.7 +/- 1.0 x 10(-8) M for bone osteonectin and 1.2 +/- 0.1 x 10(-7) M for platelet osteonectin). The osteonectin-plasminogen interaction is inhibited by alpha 2-antiplasmin and epsilon-aminocaproic acid, suggesting that the interaction is mediated through the kringle 1 region of plasminogen. Both osteonectins enhance the rate of plasmin generation by tissue-type plasminogen activator to approximately the same extent as fibrinogen. Equilibrium binding measurements conducted using total internal reflection fluorescence spectroscopy indicate that plasminogen binds to collagen in the presence of bone osteonectin (Kd = 1.30 +/- 0.1 x 10(-7) M). No binding of plasminogen to collagen matrix was detected in the presence of platelet osteonectin or in the absence of bone osteonectin. Bone osteonectin-dependent binding of plasminogen to collagen matrix is reversed by the addition of epsilon-aminocaproic acid. The ability of both types of osteonectin to bind to and influence plasminogen activation and of bone osteonectin to anchor plasminogen on collagen matrices suggests that osteonectin may play a role in directing extracellular matrix proteolysis.

Aminocaproic Acid↗
PubMed1993

Familial association of high levels of histidine-rich glycoprotein and plasminogen activator inhibitor-1 with venous thromboembolism.

High levels of histidine-rich glycoprotein (HRGP) and plasminogen activator inhibitor-1 (PAI-1) have been claimed to contribute to the hypofibrinolytic state observed in patients with venous thrombosis. These abnormalities were detected, respectively, in eight and 10 members of a family from which four of seven members with both abnormalities had venous thromboembolism. Binding of tissue plasminogen activator (t-PA) by PAI-1 may induce hypofibrinolysis. To determine whether plasminogen binding by HRGP may influence plasminogen activation, we studied the fibrinolytic activity of members of this family cohort with a system that detects modifications in plasmin generation by proteins interfering with the binding of plasminogen to fibrin. Plasminogen activation was performed by adding plasma to fibrin surfaces to which t-PA had been previously bound in the presence of 40 mg/ml bovine serum albumin and 20 mumol/L of the lysine analog trans-4-(aminomethyl)-cyclohexane carboxylic acid to prevent nonspecific binding and thereby the inhibitory effect of elevated PAI-1 levels. The generation of plasmin as a function of time was detected (1) by photometric analysis with a chromogenic substrate highly selective for plasmin and (2) by measuring the binding and activation of plasminogen at the fibrin surface with radiolabeled plasminogen. The amount of plasmin generated by plasma from patients having high levels of HRGP (160% to 280%) was similar to that of a control group having normal levels of HRGP (100% +/- 22%). Similar results were obtained with a plasma artificially depleted in HRGP and supplemented with various amounts of this protein. No correlation between HRGP level and t-PA-mediated plasminogen activation was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Elevation of plasminogen activators in cerebrospinal fluid of mice with eosinophilic meningitis caused by Angiostrongylus cantonensis.

A hallmark of parasitic meningitis is the infiltration of eosinophils into the subarachnoid space. Infection with Angiostrongylus cantonensis in mice induced proteinase activity in parallel with the pathological changes of eosinophilic meningitis. Zymogram analysis demonstrated that 70 and 55 kDa proteinases from cerebrospinal fluid (CSF) were active against the casein/plasminogen substrate. The proteinase activities were clearly inhibited by phenylmethanesulphonyl fluoride but not by ethylenediamine tetraacetic acid, 1,10-phenanthroline or leupeptin. Western blotting confirmed these enzymes to be tissue-type plasminogen activator and urokinase-type plasminogen activator, respectively. High activities of tissue-type plasminogen activator and urokinase-type plasminogen activator were detected in the CSF of mice with eosinophilic meningitis, and correlated positively with CSF eosinophil numbers and total protein, respectively. Immunohistochemistry demonstrated that tissue-type plasminogen activator and urokinase-type plasminogen activator localised in the endothelial cells of blood vessels, in blood clots and in infiltrated leukocytes. These results suggest that tissue-type plasminogen activator and urokinase-type plasminogen activator may be play a role in the pathogenesis of eosinophilic meningitis of angiostrongyliasis.

Angiostrongylus cantonensis↗
PubMed2006

Contribution of somatic cell-associated activation of plasminogen to caseinolysis within the goat mammary gland.

Functional regression of the mammary gland is partly reflected by proteolysis of milk protein and tissue protein. The involvement of the plasminogen activation system in degradation of milk protein and mammary tissue damage has been demonstrated under inflammatory conditions. In this study, mammary secretion from 23 dairy goats primarily grouped as lactation (milking twice daily) or involution (milking once daily or less) was used to determine the ratio of gravity-precipitated casein to total milk protein (casein ratio) as an index of caseinolysis, and activities of components of plasminogen activation system as well as their expressions on somatic cells. Based on the casein ratio, lactation goats were subcategorized as very active (71.8 +/- 1.0%) or less active (29.9 +/- 1.0%) in mammary function; involution goats were subcategorized as gradual (21.7 +/- 1.0%) or acute (5.9 +/- 0.2%) involution. This result suggests that caseinolysis occurred during regular lactation as well as during involution. On the other hand, activities of components of the plasminogen activation system in mammary secretion were increased along with the decreasing casein ratio, in contrast to the similar activities of their counterparts in circulation throughout various mammary statuses. Correlation analysis between casein ratio and activities of plasminogen activation system of goat milk indicated a significant negative relationship for plasmin (r = -0.64), plasminogen (r = -0.69), and urokinase-type plasminogen activator (uPA; r = -0.78) during involution but not during lactation. As for the cellular components of plasminogen activation system, there was an increase in immunoreactivity on somatic cells toward both monoclonal antibodies of human uPA and human uPA receptor under involution conditions suggesting their upregulation relative to lactation condition. Collectively, these results suggest that plasminogen activation system within the mammary gland differentially contribute to milk caseinolysis along the various stages of goat lactation. Meanwhile, a somatic cell-mediated local elevation of plasmin activity may be committed to extensive caseinolysis during involution.

Animals↗
PubMed1988

Increased plasma levels of urokinase-type plasminogen activator with endometrial and cervical cancer.

Plasma concentrations of urokinase-type plasminogen activator (competitive radioimmunoassay), tissue-type plasminogen activator (sandwich enzyme-linked immunosorbent assay), and plasminogen activator inhibitor (functional assay) were measured in 17 women with endometrial cancer and 52 women with cervical carcinoma. Significantly increased plasma urokinase-type plasminogen activator antigen levels were found (11.3 +/- 4.7 ng/mL) in cervical cancer patients when compared with an age-matched control group (7.4 +/- 0.6 ng/mL). Women with endometrial cancer (9.9 +/- 2.0 ng/mL) showed a similar pattern of plasma urokinase-type plasminogen activator antigen levels. Patients with advanced cervical cancer (International Federation of Gynecology and Obstetrics stages III and IV) revealed higher plasma urokinase-type plasminogen activator antigen levels than those with stages I and II disease. Compared with an age-matched control group, neither carcinoma group showed elevated plasma concentrations of tissue-type plasminogen activator and plasminogen activator inhibitor.

Adenocarcinoma↗
PubMed1996

Effects of fibrin and alpha2-antiplasmin on plasminogen activation by staphylokinase.

Staphylokinase obtains plasminogen activating activity by forming a complex with plasminogen. Although the enzymatic activity of staphylokinase is enhanced by fibrin, how fibrin enhances enzymatic activity has not been determined yet. The effects of fibrin, or fibrinogen fragments, on the activation of plasminogen by staphylokinase was investigated using CNBr-digested fibrinogen fragments (FCB-2 and FCB-5) and plasmin-degraded cross-linked fibrin fragments ((DD)E complex, DD fragments and E fragments). Kinetic analysis of the activity of staphylokinase revealed that its plasminogen activating activity, which was expressed as kcat/Km, was enhanced by FCB-2 (10-fold) and FCB-5 (5-fold). These fibrin fragments caused 38-, 30-, and 8.5-fold increases in activity for the DD fragment, (DD)E complex and E fragment, respectively. Although alpha2-antiplasmin inhibited the activation of plasminogen by staphylokinase, FCB-2 abolished its inhibitory effects, and the plasminogen activating activity of staphylokinase was restored. The inhibitory effects of alpha2-antiplasmin on the activation of mini-plasminogen by staphylokinase were less than for Glu- or Lys-plasminogen, and the inhibitory effect of alpha2-antiplasmin was not altered by fibrin or EACA. These findings indicate that the staphylokinase/plasmin(ogen) complex reacts with fibrin even in the presence of alpha2-antiplasmin, and efficient plasminogen activation takes place on the surface of fibrin.

Aminocaproic Acid↗
PubMed1996

Regulation of urokinase-type plasminogen activator expression by an ERK1-dependent signaling pathway in a squamous cell carcinoma cell line.

The urokinase-type plasminogen activator contributes to tissue remodeling by controlling the synthesis of the extracellular matrix-degrading plasmin. We undertook a study to determine the role of the extracellular signal-regulated kinases (ERKs) in the regulation of urokinase-type plasminogen activator expression in a squamous cell carcinoma cell line (UM-SCC-1) that contains a transcriptionally activated urokinase-type plasminogen activator gene. Transient transfection studies using a CAT reporter driven by the urokinase-type plasminogen activator promoter, which had progressive 5' deletions or which had been point-mutated, indicated the requirement of binding sites for AP-1 (-1967) and PEA3 (-1973) for its maximal activation. Expression of a mutant jun protein, which lacks the transactivation domain, caused a dose-dependent repression of a CAT reporter driven by either the urokinase-type plasminogen activator promoter or three tandem AP-1 repeats upstream of a thymidine kinase minimal promoter indicating the importance of AP-1-binding transcription factor(s) in the regulation of urokinase-type plasminogen activator synthesis. Mobility shift assays with UM-SCC-1 nuclear extract revealed binding of fos and junD proteins to an oligonucleotide spanning the AP-1 site at -1967. In-gel kinase assays indicated the constitutive activation of ERK1, which regulates fos synthesis via phosphorylation of p62TCF, but not ERK2, in UM-SCC-1 cells. Moreover, the expression of a dominant-negative ERK1, but not ERK2, repressed urokinase-type plasminogen activator promoter activity. Similarly, interfering with the function of the c-raf serine-threonine kinase, which lies upstream of ERK1, by the expression of a kinase-inactive c-raf repressed the activity of a CAT reporter driven by either the urokinase-type plasminogen activator promotor or tandem AP-1 repeats. These data suggest that urokinase-type plasminogen activator expression in UM-SCC-1 cells is regulated partly by an ERK1, but not ERK2, -dependent signaling pathway.

Blotting, Western↗
PubMed2001

Plasminogen binding is increased with adipocyte differentiation.

The purpose of this study was to examine the role of the plasminogen system in the development of adipose tissue. Plasminogen binding capacity was determined in differentiated and undifferentiated cells from adipose tissue of plasminogen deficient mice and 3T3 cells, a well-characterized tissue culture model. In 3T3 cells, plasminogen binding was fivefold higher in differentiated cells compared to the undifferentiated cells. Inhibition of binding by carboxyl-terminal lysine analogs was similar for the differentiated and undifferentiated cells with tranexamic acid > EACA > lysine. The binding of plasminogen was concentration-dependent and approaches saturation in the both cell types. The number of plasminogen binding sites was tenfold higher in the differentiated compared to the undifferentiated cells. In isolated mature fat cells and stromal cell cultures from mouse adipose tissue, plasminogen binding was also higher in the differentiated mature fat cells and differentiated stromal cells compared to undifferentiated stromal cells. Plasminogen binding was elevated in the differentiated cells from the Plg-/- mice compared to cells from the WT mice. These results suggest that the plasminogen system plays an important role in adipose tissue development.

3T3 Cells↗
PubMed1993

Polarized secretion of tissue-plasminogen activator in cultured thyroid cells.

We studied the polarized secretion of tissue-type plasminogen activator in porcine thyroid cells cultured as a monolayer on porous bottom chambers. The presence of tissue-type plasminogen activator was detected by zymographic analysis on two independent media that were in contact either with the apical surface or with the basolateral membrane. The amount of tissue-type plasminogen activator was determined in both media by ELISA and enzyme assay. Measurable tissue-type plasminogen activator activity was found in the basal but not in the apical medium. However, on zymogram, a lytic zone corresponding to tissue-type plasminogen activator was visible in both media. In addition, a lytic band at 130 kDa suggested presence of a complex formed by tissue-type plasminogen activator and an inhibitor. Preferential basolateral tissue-type plasminogen activator antigen secretion (70%) has been observed, showing the possible relation between tissue-type plasminogen activator and extracellular matrix components. Neither tissue-type plasminogen activator level nor polarized secretion seemed to be regulated by thyrotropin (0.1 mU/ml).

Animals↗
PubMed1984

The binding of antifibrinolytic amino acids to kringle-4-containing fragments of plasminogen.

A monoclonal antibody to human plasminogen, 10-F-1, was found to interact with the lysine-binding site (LBS) on the kringle 4 (K 4) region of the molecule. This observation has been employed to measure the binding of various antifibrinolytic amino acid analogs of epsilon-aminocaproic acid (epsilon ACA) to its site on K 4 in appropriate elastolytic-derived fragments of human plasminogen and to other species of plasminogen to which antibody 10-F-1 cross-reacts. By analysis of the concentration dependence of epsilon ACA displacement of [125I]10-F-1 from human Glu1Pg, a KD for epsilon ACA of 7.1 +/- 1.0 mM was calculated. Similar experiments with K 4-containing fragments of Glu1Pg, viz., Lys77Pg, K 4, Lys77H and Val354Pg, yielded KD values of 6.6 +/- 1.0, 7.5 +/- 1.0, 6.6 +/- 1.0, and 12.0 +/- 2.0 mM, respectively. When baboon, goat, monkey, rabbit, and sheep plasminogens were substituted for human plasminogen, the KD values calculated ranged from 2.1 to 7.1 mM. The KD values for several analogs of epsilon ACA, i.e., 4-aminobutyric acid, 5-aminopentanoic acid, 8-aminooctanoic acid, L-lysine, and trans-aminomethyl cyclohexane-1-carboxylic acid, were measured to the K 4 region of Lys77Pg. The values obtained were 11.3 +/- 1.5, 9.0 +/- 1.0, 71.0 +/- 10, 38.0 +/- 5.0, and 1.1 +/- 0.4 mM, respectively. Additionally, the KD of trans-aminomethylcyclohexane-1-carboxylic acid towards the K 4 region of Glu1Pg, Lys77Pg, and isolated K 4 was found to be 2.4 +/- 0.5, 1.1 +/- 0.3, and 2.0 +/- 0.6 mM, respectively. These studies show directly that the LBS on the K 4 domain of plasminogen represents one of its 4-5 weak binding sites and that this site can be specifically probed with the use of monoclonal antibody 10-F-1. Furthermore, it appears as though this site is conserved in several important proteolytic fragments of plasminogen, providing additional evidence that these fragments exist as independent domains in the native molecule. Finally, this weak LBS on the K 4 domain of human plasminogen is also present in other species of plasminogen.

Amino Acids↗
PubMed1994

Thrombolytic efficacy of a modified tissue-type plasminogen activator, SUN9216, in the rat middle cerebral artery thrombosis model.

We have developed a model whereby the middle cerebral artery in an experimental animal can be occluded by a photochemical reaction between rose bengal and green light. This causes endothelial injury followed by platelet adhesion, aggregation and formation of a platelet-rich thrombus at the site of the photochemical reaction. SUN9216, a modified tissue-type plasminogen activator, is a new thrombolytic agent which consists of the fibrin kringle 1 domain of plasminogen and the two kringles, the serine protease domains of the native tissue-type plasminogen activator. The mannose glycosylation site on the kringle 1 of tissue-type plasminogen activator is modified to yield a compound with a longer half-life in the blood than native tissue-type plasminogen activator. We evaluated the thrombolytic effects of recombinant tissue-type plasminogen activator and SUN9216 in the thrombotically occluded rat middle cerebral artery. SUN9216 was administered by continuous infusion or as a single bolus injection 30 min after the middle cerebral artery had been occluded by a thrombus. Both SUN9216 and recombinant tissue-type plasminogen activator caused reopening of the middle cerebral artery by thrombolysis. The efficacy of SUN9216 was higher than that of recombinant tissue-type plasminogen activator. Further, the area of ischaemic cerebral damage caused by the middle cerebral artery occlusion was significantly (P < 0.05) reduced by SUN9216, but in this respect, recombinant tissue-type plasminogen activator was ineffective.

Analysis of Variance↗
PubMed1986

Local synthesis of plasminogen by the seminiferous tubules of the testis.

Plasminogen activation occurs through conversion of plasminogen to plasmin by plasminogen activators. In adult mammals, liver has been the only known site for plasminogen synthesis. Seminiferous tubules secrete plasminogen activator, but are behind a barrier that excludes the entrance of many macromolecules to this tissue. Therefore, it became of interest to study the existence of plasminogen in this system. After metabolic labeling, a 90 kDa lysine-binding polypeptide was found. This protein could be immunoblotted by anti-plasminogen antibody, and was shown to possess urokinase-dependent proteolytic activity. The findings suggest that plasminogen is synthesized by seminiferous tubules. We propose that local plasminogen synthesis may occur in tissues which are separated by specific anatomical barriers.

Affinity Labels↗
PubMed1985

Plasma histidine-rich glycoprotein and plasminogen in patients with liver disease.

Histidine-rich glycoprotein (HRG) has been reported to be a fibrinolysis regulating protein due to its capacity to bind to the high affinity lysine binding sites of plasminogen. Using immunological methods we have measured the concentrations in plasma of HRG and total plasminogen and calculated the amounts of plasminogen not bound to HRG (free plasminogen) in 28 patients with moderate to severe liver disease. All three parametres showed wide individual variations, but with decreasing functional capacity of the liver the individual levels of plasminogen were reduced earlier than those of HRG leading to decreased amounts of free plasminogen. Simultaneous determinations of HRG and total plasminogen combined with a calculation of free plasminogen might yield valuable information when evaluating patients for the availability of plasminogen.

Adult↗
PubMed1991

Determinants of recurrent ischaemia and revascularisation procedures after thrombolysis with recombinant tissue plasminogen activator in primary coronary occlusion.

This paper reports the immediate effects of thrombolysis and their subsequent influence on revascularisation procedures and clinical outcome over the subsequent twelve months. Coronary arteriography was performed at 21 days on 131 of 145 patients who received recombinant tissue plasminogen activator (n = 68) or placebo (n = 63) within 2.5 hours of symptom onset after primary coronary occlusion. Patency rates (TIMI grades 2 and 3) of the infarct-related artery were 81% with plasminogen activator and 63% with placebo (P = 0.02). Early (within 21 days) angiography for recurrent ischaemia was necessary in 31 (21%) patients (20 plasminogen activator, 11 placebo NS) and definite reinfarction occurred in 8 (5%) patients (4 plasminogen activator, 4 placebo). During one year follow-up without planned secondary intervention, coronary artery bypass grafting was more frequent in patients who had received thrombolytic therapy (23% plasminogen activator, 4% placebo P = 0.001); coronary angioplasty procedures were similar in both groups (12% plasminogen activator, 11% placebo NS). Mortality at 21 days was 5% (4 plasminogen activator, 4 placebo) and at one year was 7% (5 plasminogen activator, 5 placebo). Logistic regression analysis identified models comprising characteristics predictive of subsequent bypass grafting (plasminogen activator, multivessel disease, occluded infarct-related artery) and coronary angioplasty (non-q wave infarction, severe (91-99%) residual stenosis, left anterior descending infarct-related artery). Initial non-q wave infarction was the only predictor of early recurrent ischemia (odds ratio 4, P = 0.02) irrespective of residual stenosis severity.

Angioplasty, Balloon, Coronary↗
PubMed2005

Plasminogen interaction with platelets: the importance of carboxyterminal lysines.

INTRODUCTION: Thrombin stimulation enhances plasminogen binding to platelets and promotes platelet-dependent plasmin generation. The objective of this study was to determine whether carboxyterminal lysines (C-lysines) are important for these processes, as they are in other cell types. MATERIALS AND METHODS: 125I-plasminogen and varying concentrations of unlabeled plasminogen were added to washed platelets that were either resting or stimulated with thrombin, thrombin receptor activating peptide, or ADP. In some experiments the platelets were digested with carboxypeptidase B to remove C-lysines. Platelet-dependent plasmin generation was also studied by adding plasminogen and tissue plasminogen activator to platelet suspensions and monitoring the conversion of a plasmin specific chromogenic substrate. The cells were either resting or stimulated with thrombin, thrombin receptor activating peptide, or ADP. The effect of the thrombin inhibitor lepirudin and the plasmin inhibitor aprotinin on plasminogen binding and the appearance of C-lysines was also investigated. RESULTS: Thrombin, but not thrombin receptor activating peptide or ADP, stimulated high-affinity binding of plasminogen and greatly promoted platelet-dependent plasmin generation. Digestion with carboxypeptidase B eliminated thrombin-induced high-affinity binding and reduced thrombin-induced plasmin generation by increasing the Michaelis constant. Lepirudin, but not aprotinin, inhibited thrombin-stimulated plasminogen binding to platelets. CONCLUSION: C-terminal lysines are necessary for high-affinity binding of plasminogen to platelets and for platelet-supported plasmin generation. The origin of the C-lysines is not clear, but they may result from a direct effect of thrombin, rather than an intermediate enzyme such as plasmin.

Blood Platelets↗
PubMed2000

Effect of plasminogen activator inhibitor-1 4G/5G polymorphism in Turkish deep vein thrombotic patients with and without FV1691 G-A.

A decreased fibrinolytic activity due to increased levels of plasminogen activator inhibitor-1 has been shown in deep vein thrombosis patients. Elevated plasma plasminogen activator inhibitor-1 levels are associated with the 4G allele of a 4G/5G polymorphism located in the promoter region of the plasminogen activator inhibitor-1 gene. Because there is no existing data in the Turkish population, we aimed to study these mutations in patients with deep vein thrombosis (n = 136) and normal controls (n = 113), consecutively selected among unrelated healthy subjects without personal and familial history of atherothrombosis from Ankara, Turkey. DNA was extracted by conventional methods, and polymerase chain reaction of the plasminogen activator inhibitor-1 4G/5G polymorphism was performed according to a previously described method. Genotype distributions of FV 1691G-A and plasminogen activator inhibitor-1 4G/5G are as follows: plasminogen activator inhibitor-1 4G (patients) 0.562, plasminogen activator inhibitor-1 4G (controls) 0.50 (p = 0.6); FV1691A (patients) 0.147, FV1691A (controls) 0.035 (p = 0.005). Our data indicated that plasminogen activator inhibitor-1 4G/5G does not have an effect on the thrombotic risk. Carrying the 4G allele either in heterozygous or homozygous state increases the risk in the presence of FV1691A (odds ratio: 9.8 and 6.9, confidence interval 95% 2.9-32.7 and 1.3-35.8). FV1691A is an independent risk factor for thrombosis (odds ratio: 5.5, confidence interval: 95% 2.5-12.1). We concluded that coexistence of FV1691A and plasminogen activator inhibitor-1 4G allele leads to an increased risk for thrombosis leading a further evidence to another prothrombotic factor that may be necessary for the development of a manifest thrombotic event.

Adult↗