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.

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.

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.