A B S T R A C T As demonstrated by others, fibrinolytic activity was generated in diluted, acidified normal plasma exposed to kaolin, a process requiring Hageman factor (Factor XII). Generation was impaired by adsorbing plasma with glass or similar agents under conditions which did not deplete its content of Hageman factor or plasminogen. The defect could be repaired by addition of a noneuglobulin fraction of plasma or an agent or agents eluted from diatomaceous earth which had been exposed to normal plasma. The restorative agent, tentatively called Hageman factor-cofactor, was partially purified by chromatography and had an apparent molecular weight of approximately 165,000. It could be distinguished from plasma thromboplastin antecedent (Factor XI) and plasma kallikrein, other substrates of Hageman factor, and from the streptokinase-activated pro-activator of plasminogen. Evidence is presented that an additional component may be needed for the generation of fibrinolytic activity in mixtures containing Hageman factor, HF-cofactor, and plasminogen.The long-recognized generation of plasmin activity in chloroform-treated euglobulin fractions of plasma was found to be dependent upon the presence of Hageman factor. Whether chloroform activation of plasminogen requires Hageman factor-cofactor was not determined, but glass-adsorbed plasma, containing Hageman factor and plasminogen, did not generate appreciable fibrinolytic or caseinolytic activity. These studies emphasize the complex nature of the mechanisms which lead to the generation of plasmin in human plasma. INTRODUCTIONPlasminogen, a normal constituent of human plasma, is the precursor of plasmin, a protease of broad specificity. The conditions which lead to its activation are still uncertain. Hypotheses suggesting the existence of a physiologic blood activator of plasminogen (1, 2), whose level is enhanced by various stresses (3)(4)(5)(6)(7)(8)(9), are supported by a considerable volume of experimental evidence (10)(11)(12). The origin of this plasminogen activator is uncertain, although vascular endothelial cells have been implicated (13)..The fibrinolytic properties of normal human plasma, presumably due to the generation of plasmin, are greatly enhanced by incubation with kaolin after acidification and lowering of the ionic strength (14, 15). and Iatridis and Ferguson (15) observed that this elaboration of fibrinolytic activity was strikingly reduced in plasma deficient in Hageman factor (Factor XII) and suggested that this clotting factor had a role in the ultimate formation of plasmin. Their hypothesis has been reinforced by the finding that the expected increase in blood fibrinolytic activity in response to physical exertion (16) with that proactivator of plasminogen through which streptokinase brings about the formation of plasmin (23,24). In the present study, evidence is assembled that an activator of plasminogen can be derived from human plasma which is separable from the proactivator upon which streptokinase acts. This agent is dependent upon th...

SYNOPSIS Plasma fibrinogen and plasminogen levels were measured in 122 male and 56 female healthy adult subjects and in 64 men with ischaemic heart disease. Plasma fibrinogen levels were found to rise markedly and progressively with age in both male and female healthy subjects; plasminogen showed only a slight rise with age. No sex differences were found for either fibrinogen or plasminogen. The correlation between plasminogen and fibrinogen levels was low, reaching the 5 Y.level of significance only in men. Patients with ischaemic heart disease were found to have significantly increased fibrinogen and plasminogen levels in the 31-45 years age group only.Plasminogen is the inactive precursor of the proteolytic enzyme plasmin which, under physiological circumstances, specifically digests fibrin and thus causes lysis of thrombi or fibrinous exudates. Conversion of plasminogen to plasmin takes place by activators which are widespread in body tissues and present in small amounts in circulating blood. Plasminogen has a close affinity for fibrinogen and fibrin and this affinity forms part of the evidence for the theory of thrombolysis put forward by Sherry, Fletcher, and Alkjaersig (1959) which suggests that the function of plasminogen is to endow fibrin with the capacity for subsequent lysis. They showed that clots of low plasminogen content lyse poorly when exposed to activator.Because of the possibility that a defect in the fibrinolytic enzyme system has a role in the causation of thrombotic disease we have studied the plasminogen content of plasma in a group of healthy controls and in patients with ischaemic heart disease. In view of the affinity of plasminogen for fibrin and previous reports that fibrinogen levels are elevated in patients with ischaemic heart disease (McDonald and Edgill, 1957; Merskey, Gordon, Lackner, Schrire, Kaplan, Sougin-Mibashan, Nossel, and Moodie, 1960;Pilgeram, 1961; Egeberg, 1962;Katz, McDonald, Davies, and Edgill, 1963) we have also studied the plasma fibrinogen in the same groups and its relationship to plasminogen levels. PLASMA FIBRINOGEN This was determined by a modification of the method of Ratnoff and Menzie (1951). Oxalated plasma, 0-25 ml., was mixed with 4-5 ml. 0-85 % saline and 0-2 ml. thrombin (100 units/ml.).After standing for 30 minutes the clots were filtered on squares of fibre glass and washed with saline. The clots were compressed in the fibre glass to remove the fluid trapped in the fibrin interstices. After further washing the fibrin the fibre glass was dried between cloths. The folded fibre glass squares with the enclosed fibrin was boiled with 2 ml. 0-2 N sodium hydroxide for 10 minutes. When cool, 6 ml. 12-5 % w/v sodium carbonate and 1 ml.Folin-Ciocalteu's reagent (diluted 1:2) were added. After 15 minutes the intensity of the colour was read at 670 miu. The fibrin content of the clot was read from a standard curve prepared from purified fibrinogen (Kabi Pharmaceuticals Ltd.). All determinations were performed in duplicate.Blood samples were obtained with the m...

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SYNOPSIS Plasma fibrinolytic activity, inhibitors of fibrinolysis, and fibrinogen were estimated in 34 subjects of varying ratio of observed to standard weight. The inverse relationship between fibrinolytic activity and the ratio of observed to standard weight was confirmed. No significant correlation was found between anti-plasmin or anti-urokinase and the ratio of observed to standard weight. It was therefore concluded that the decreased plasma fibrinolytic activity in obese subjects is due to decreased production of plasminogen activator rather than to excessive inhibition.