Studies of the Plasmin System

Norman, Philip S.

doi:10.1084/jem.106.3.423

Cited by 95 publications

(24 citation statements)

References 24 publications

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“…10 min later 1 U of thrombin was added and the samples were handled and observed as described above. Table III shows that addition of purified 19S cold agglutinin to the standard clot lysis system which was then coagulated at 4VC had no effect on the normal clot retraction or lysis.…”

Section: Resultsmentioning

confidence: 99%

Qualitative description of factors involved in the retraction and lysis of dilute whole blood clots and in the aggregation and retraction of platelets

Taylor¹,

Müller‐Eberhard²

1970

J. Clin. Invest.

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AB S T R A C T Dilute whole blood clots were prepared by addition of thrombin to blood diluted 1: 10 in phosphate buffer. The pH of this buffer was 7.4 and the ionic strength was 0.084. Though the ionic strength was low, there was no hemolysis of red corpuscles due to the contribution to the osmotic gradient by plasma salts and proteins. In the standard assay the clot was formed by addition of thrombin at 4VC then incubated at 370C. Retraction and lysis of these clots were inhibited by removal of platelets and by increasing concentrations of purified thrombin. Retraction and lysis were also inhibited by inactivation of any one of the following factors: YM globulin, complement components C4 and 3, and (in the case of lysis) plasminogen.Evidence that some of the above serum factors were adsorbed to the platelet membrane was obtained by aggregation of washed platelets by antisera to these factors (i.e. fibrinogen, 'yM, and C4 or C3). These platelets were not aggregated by antisera to other serum proteins (by albumin, transferrin, yG globulin).These and other studies suggested that platelets, thrombin, fibrinogen, yM globulin (cold agglutinin), complement components, and plasminogen influenced and facilitated retraction and lysis of clots. These studies also suggested that platelets and some of these factors were physically associated.Because of this physical association, and because of the fact that clot retraction is associated with aggregation and retraction of platelets, we extended the above observations to include a study of the effect of these same serum factors on serum-induced aggregation and retraction of washed platelets. (Other terms which have been in use in the past to describe serum-induced platelet aggregation and retraction have included those such as Received for publication 29 December 1969 and in revised form 22 June 1970. platelet "fusion" and "viscous metamorphosis," neither of which fully described the phenomena.)Platelet aggregation and retraction induced by serum was markedly accelerated by addition of increasing concentrations of thrombin and (or) cold agglutinin. Hirudin and antisera to yM globulin inhibited seruminduced aggregation and retraction of platelets. Reconstitution of inactivated serum with purified C4, 3, and 5 and thrombin restored its capacity to induce aggregation and retraction of platelets.Therefore, we postulated that platelet aggregation and retraction were necessary for clot retraction and that platelet aggregation and clot retraction facilitated clot lysis. More specifically we postulated that thrombin, in addition to catalyzing clot formation, also modified the platelet membrane such that yM globulin (cold agglutinin) and complement components can act on the platelet membrane leading to (a) aggregation and retraction of the platelets, (b) retraction of the clot, and (c) to the activation of plasminogen either on the surface of the platelet by C8i and (or) by release of platelet activators of plasminogen.

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Section: Resultsmentioning

confidence: 99%

Qualitative description of factors involved in the retraction and lysis of dilute whole blood clots and in the aggregation and retraction of platelets

Taylor¹,

Müller‐Eberhard²

1970

J. Clin. Invest.

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“…The present investigation restudies the mode of action of plasma inhibitors on plasmin, using the recently described caseinolytic assay (11). By several methods kinetic evidence was found for two inhibitory components for plasrain, one acting rapidly but reversibly, the other acting more slowly and at a rate that depends on temperature.…”

Section: (From the Biological Division Department Of Medicine Johnsmentioning

confidence: 97%

“…It seemed possible to assess such an effect by testing whether plasmin held partially inactivated by the presence of inhibitor would behave differently from plasmin used alone. Digestion of 2 per cent casein by plasmin is linear up to an optical density of 0.350 (11). If plasmin in the presence of inhibitor also digests casein in a linear fashion, it would be reasonable to conclude that no change in plasmin concentration occurs during the assay period.…”

Section: Immediate Inhibitormentioning

confidence: 99%

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Studies of the Plasmin System

Norman

1958

The Journal of Experimental Medicine

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106

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Plasma exhibits an ability to neutralize or destroy the characteristic proteolytic action of active plasmin. The importance of irthibitors has been realized in evaluating the function of the plasmin system; but the nature of blood inhibitors is poorly understood and has been the subject of differing observations.A rather slow, temperature-dependent inhibition was described by Guest, Daly, Ware, and Seegers (1), as well as by Ungar and Damgaard (2). On the other hand, Shulman (3), Jacobsson (4), and Thomas and Dingle (5) have reported rapid and apparently stoichiometric reactions that did not particularly depend on temperature. Grob (6) found a rapid but reversible inhibition of plasmin by serum and, more recently, Shulman (7) isolated a low molecular weight inhibitor from plasma and urine which also reacted rapidly and reversibly, but which accounted for only a small portion of inhibitor activity of whole plasma. Meyers and Burdon found that the variations in proteolytic activity of dilutions of whole serum activated by streptokinase suggested a dissociable inhibitor (8). These apparently conflicting observations may be reconciled by the suggestion of Ratnoff that there are several plasmin inhibitors in blood with differing actions (9). Subsequently, Ratnoff, Lepow, and Pillemer have given evidence for at least three inhibitors in plasma. In their experiments, one plasma component was destroyed by heating at 56 ° for 30 minutes. The remaining heatstable inhibitor they further subdivided on the basis that part of the inhibitory power was inactivated by ammonia and primary amines, leaving a component stable to both heat and these chemicals (10).The present investigation restudies the mode of action of plasma inhibitors on plasmin, using the recently described caseinolytic assay (11). By several methods kinetic evidence was found for two inhibitory components for plasrain, one acting rapidly but reversibly, the other acting more slowly and at a

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“…Casein (Hammersten quality, Nutritional Biochemicals Corp., Cleveland) was prepared in a 5 percent solution by the method of Norman (13) and then dialyzed against the buffer used in the test system for 18 hours at 4°C. Epsilon aminoeaproic acid in a final concentration of 0.1 ~s was included in casein preparations incubated with eugiobulins containing this material, except as noted.…”

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confidence: 99%

The Enhancement of Chloroform-Induced Plasma Proteolytic Activity by Epsilon Aminocaproic Acid

Donaldson

Ratnoff

1962

The Journal of Experimental Medicine

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Proteolytic activity develops in human plasma treated with streptokinase (1), urokinase (2, 3), tissue particles or extracts (4, 5) or chloroform (6). The protease which evolves in each case has been referred to by the generic name, plasmin, and seems to be derived from the same proenzyme, plasminogen (7-10). The activation of plasminogen by streptokinase, urokinase and tissue extracts may be significantly inhibited by epsilon aminocaproic acid (11,12). The effect of this substance upon the activation of plasminogen by chloroform has not been reported.The present study is concerned with the effect of epsilon aminocaproic acid upon the development of proteolytic activity in chloroform-treated euglobulin fractions of human plasma. Epsilon aminocaproic acid not only failed to impede but actually enhanced the development of proteolytic activity, as measured upon a substrate of casein. Although fibrinolytic activity was also enhanced, this could be demonstrated only if the chloroform-treated euglobulin was first freed of epsilon aminocaproic acid by dialysis. The techniques described, then, permit the preparation of plasmin of high proteolytic activity, yet readily separated from the activating agents. The implications of these observations will be discussed; our studies have not provided an adequate explanation for this unexpected effect of epsilon aminocaproic acid. Nomenclature, Materials and MethodsPl~min (or fibrinolysin) designates the one or several enzymes of plasma which can digest fibrinogen, fibrin, casein and certain other proteins at or near neutrality. It exists in plasma in the form of an inactive precursor, plasminogen (or profibrinolysin). Plasminogen can be activated by streptokinase (a principle found in filtrates of cultures of certain beta hemolytic streptococci) (1), uroldnase (a substance found in normal urine) (2, 3), tissue particles (4,5)

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Studies of the Plasmin System

Cited by 95 publications

References 24 publications

Qualitative description of factors involved in the retraction and lysis of dilute whole blood clots and in the aggregation and retraction of platelets

Qualitative description of factors involved in the retraction and lysis of dilute whole blood clots and in the aggregation and retraction of platelets

Studies of the Plasmin System

The Enhancement of Chloroform-Induced Plasma Proteolytic Activity by Epsilon Aminocaproic Acid

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