The inhibition of plasmin, plasma kallikrein, plasma permeability factor, and the C'1r subcomponent of the first component of complement by serum C'1 esterase inhibitor.

The fraction of human serum designated as C'1 esterase inhibitor is known to inhibit the action of C'1 esterase, a plasma kallikrein, and PF/Dil, an enzyme in plasma enhancing cutaneous vascular permeability. In the present study, C'1 esterase inhibitor has been found to block the actions of plasmin and the C'1r subcomponent of the first component of complement, and to retard the generation of PF/Dil. No inhibition of blood clotting or of the generation of plasmin was demonstrable.

Studies on a complex mechanism for the activation of plasminogen by kaolin and by chloroform: the participation of Hageman factor and additional cofactors.

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.

Current status of antifibrinolytic drugs.

Antifibrinolytic drugs, in particular, epsilon-aminocaproic acid and tranexamic acid, have been used in the management of a wide range of both bleeding and non-haemorrhagic disorders. Recognition of their side-effects and complications, comparison of their efficacy with other forms of therapy and more critical evaluation of their value has reduced the range of their definitive indications to a limited number of relatively uncommon situations; these comprise primary hyperplasminaemia, menorrhagia in women in whom oestrogens are contraindicated or in those with von Willebrand's disease, severe traumatic hyphaema, dental extraction in haemophiliacs and hereditary angioedema in patients in whom treatment with anabolic steroids is contraindicated. In a few conditions the possible benefit of antifibrinolytic agents, alone or supplementary to other forms of therapy, is unresolved; these include upper gastrointestinal bleeding, recurrent epistaxis and abruptio placentae.

The effeCt of vitamin c supplements on serum cholesterol, coagulation, fibrinolysis and platelet adhesiveness.

The administration of ascorbic acid (1g/day) to healthy adults did not significantly influence the levels of serum cholesterol, plasminogen activator activity, plasminogen, fibrinogen, FR-antigen, partial thromboplastin time, platelet adhesiveness, a-1-antitrypsin or a-2-macroglobulin over the 3-month period of study.

The inhibition of tissue activator and urokinase by human plasma.

Plasma reduced the activity of urokinase and, to a lesser extent, tissue activator on unheated fibrin plates. After depletion of plasminogen by lysine-Sepharose the inhibitory effect of plasma was increased. Normal plasma separated on DEAE-Sepharose or, after passage through lysine-Sepharose, on Sephadex G-100 provided fractions in three regions capable of inhibiting tissue activator. The high molecular weight fractions inhibited both activators, but after plasma fractionation on Sephadex 4B the inhibitory activities against tissue activator and urokinase eluted separately. Urokinase inhibition eluted with alpha 2-macroglobulin: the inhibition of tissue activator was of higher molecular weight and of greater lability. Inhibition of tissue activator was found in two lower molecular weight regions: the fractions of one region inhibited tissue activator and coincided with the elution of fast-acting antiplasmin activity. The other region inhibited both tissue activator and urokinase. Alpha1-antitrypsin and antithrombin III eluted after both inhibitory regions.

Inhibitors of fibrinolysis in amniotic fluid.

Amniotic fluid inhibited the fibrinolytic, amidolytic and esterolytic activity of urokinase. Kinetic studies with AGLMe demonstrated non-competitive inhibition. A major part of the inhibitory activity could be separated from alpha 1-antitrypsin by ion-exchange chromatography on DEAE-Sephadex A-50. Plasminogen activator prepared from porcine heart was not inhibited by amniotic fluid. Amniotic fluid also inhibited the caseinolytic and amidolytic activities of plasmin.

The inhibition by plasma of urokinase and tissue activator-induced fibrinolysis in pregnancy and the puerperium.

The activity of urokinase and tissue activator on fibrin plates was inhibited by plasma from women in the third trimester of pregnancy to a greater extent than by non-pregnant plasma. Pregnancy also inhibited the amidolytic activity of urokinase. The high molecular weight fractions of pregnancy plasma gel filtered on Sephadex G-200 showed comparable inhibitory activity against urokinase as fractions for non-pregnant plasma; in contrast with non-pregnant plasma, the lower molecular weight fractions of pregnancy plasma were markedly inhibitory against urokinase. Plasma exposed to lysine-Sepharose to remove plasminogen and then fractionated on Sephadex G-100 provided a pattern of three areas of inhibition against tissue activator similar to that seen in non-pregnant plasma. The urokinase-inhibitory activity of lower molecular weight fractions of plasma separated on Sephadex G-200 fell within 1 hr of delivery and fell further over the following 18 to 30 hr.

Platelet adhesiveness and fibrinolysis after recent cerebro-vascular accidents and their relationship with subsequent deep venous thrombosis of the legs.

In fifteen patients with a cerebro-vascular accident resulting in an acute hemiplegia there was a subsequent rise in the platelet count and plasma fibrinogen level. There were no significant alterations in platelet adhesiveness, plasminogen activator, plasminogen, FR-antigen and haematocrit. Patients diagnosed as developing deep venous thrombosis with the 125I-fibrinogen technique had a significantly lower platelet adhesiveness and plasminogen level than those who were not.

Plasma fibrinogen and plasminogen levels in health and in ischaemic heart disease.

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% 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.

Fibrinolytic activity in malignant disease.

Resting fibrinolytic activity and fibrinolytic capacity were compared in 31 patients with malignant disease and in 24 control subjects without malignant disease. Patients with malignant disease had a lower mean fibrinolytic activity: this was particularly marked in those with disseminated disease. In contrast, patients with malignant disease had a fibrinolytic capacity which did not differ from that of the control subjects.

The fibrinolytic system in pre-eclampsia.

Plasma fibrinolytic activity and plasma inhibitory activity against urokinase and tissue activator were measured in primigravidae with moderate or severe pre-eclampsia and in gestation-matched primigravidae with uncomplicated pregnancy. The mean levels of fibrinolytic activity and inhibitory activity against urokinase and tissue activator did not differ significantly between the pre-eclampsia and uncomplicated pregnancy groups. The pattern of inhibitory fractions of plasminogen-depleted plasma from pre-eclamptic and uncomplicated primigravidae after gel filtration on sephadex G-100 was similar.

Fibrinolysis in leukaemia.

Components of the blood fibrinolytic system were measured in 43 patients with leukaemia. Increased fibrinolytic activity, indicated by a reduced plasma plasminogen level, was found in 14 patients. The combination of severe thrombocytopenia and increased fibrinolysis appeared to be a determinant in the production of a haemorrhagic tendency in leukaemia.

Changes in protease inhibitors after acute myocardial infarction.

Plasma levels of fibrinogen, alpha1-antitrypsin, alpha2-macroglobulin, antithrombin III, and C1 inactivator were measured serially for 10 days in 11 patients after acute myocardial infarction. Both fibrinogen and alpha1-antitrypsin rose markedly to reach peak levels 5-7 days after infarction while C1 inactivator levels rose slowly with the highest observed mean level on the 10th postinfarction day. Neither antithrombin III nor alpha2-macroglobulin changed significantly after myocardial infarction. No relationship between C1 inactivator levels and either fibrinogen or alpha1-antitrypsin was found in a study of 30 patients with a variety of disorders while fibrinogen and alpha1-antitrypsin levels were significantly correlated.

The fibrinolytic enzyme system in hepatic cirrhosis and malignant metastases.

Components of the blood fibrinolytic system were measured in 18 patients with hepatic cirrhosis, in two patients with acute hepatic necrosis, and in 10 patients with hepatic metastases. The frequency of an elevation of plasminogen activator and a reduction in plasminogen in hepatic cirrhosis has been confirmed. Patients with compensated cirrhosis had low levels of the serum inhibitor of plasminogen activation while those with severe hepatic insufficiency or coma due to cirrhosis or hepatic necrosis had elevated levels. The presence of hepatic metastases was associated with reduced plasminogen activator levels and an increase in the fibrinogen concentration.

Effect of local exercise and vessel occlusion on fibrinolytic activity.

Arterial occlusion of the upper limb did not affect the fibrinolytic activity in the venous blood of that limb; venous occlusion associated with venous distension resulted in a marked rise in activity. Local fibrinolytic activity was increased substantially by active exercise; passive exercise induced a smaller increase. Active exercise undertaken during arterial occlusion did not result in a rise in activator level. It is concluded from these results that blood flow into the venous system rather than accumulation of metabolites is responsible for the increased release of activator into the blood during local exercise and vessel occlusion.

Studies on the fibrinolytic enzyme system in obesity.

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.

The effect of age on the fibrinolytic enzyme system.

Components of the fibrinolytic enzyme system, FR-antigen and fibrinogen, were measured in 20 healthy volunteers aged 20-40 years and in 61 elderly subjects aged 66-96 years. Plasminogen activator levels did not significantly differ between the 20-40 and 66-75 age groups, but were higher in those over 75. Plasminogen showed no change with age except for a fall in those over 75. Fibrinogen, FR-antigen, alpha(1)-antitrypsin, and alpha(2)-macroglobulin all rose with age, but the mean fibrinogen concentration fell in the very elderly.

Platelet adhesiveness, coagulation, and fibrinolytic activity in obesity.

In a study of 41 fasting subjects it was confirmed that fibrinolytic activity was reduced in obese persons: an increase in fibrinogen was also associated with obesity. There was no correlation between obesity and the platelet count, platelet adhesiveness to glass, the level of serum fibrin degradation products, or the whole blood clotting time in plastic tubes.

The fibrinolytic enzyme system in hypertension.

Fibrinogen, fibrinogen-related antigen (FR-antigen), and components of the fibrinolytic enzyme system were measured in patients with essential hypertension, renal disease with and without hypertension, and normal subjects. Essential hypertension was associated with a decrease in plasminogen activator and an increase in FR-antigen. In renal disease these changes were accompanied by increases in plasminogen activation inhibitor, alpha(2)-macroglobulin, alpha(1)-antitrypsin, and fibrinogen.

The effect of age upon the coagulation system.

Factors V, VII, VIII, X, XI, and XII of the coagulation system, platelet count, and antithrombin III levels were assayed in 20 healthy volunteers aged 20-40 years and 61 elderly subjects aged 66-96 years whose skinfold thickness was also measured. Factors XI, XII, and antithrombin III levels tended to increase in women and decrease in men while factors X, VII, and V tended to increase in both males and females with advancing years. No age or sex differences were found in platelet counts or factor VIII levels. Factor VIII levels were inversely correlated with obesity in elderly males (r = -0.56, p < 0.005).