The Risk of Myocardial Infarction Associated with Antihypertensive Drug Treatment in Persons with Uncomplicated Essential Hypertension

We conducted a case-control study based on computer-recorded information accrued in the United Kingdom General Practice Research Database to assess and compare the relation between different antihypertensive drug therapies and myocardial infarction in patients with no known clinical or laboratory risk factors for myocardial infarction other than hypertension. Cases were treated hypertensive patients with no other known risk factors who developed a first acute myocardial infarction between January 1, 1993, and October 31, 1994. They were ascertained from a review of the clinical record together with a questionnaire filled out by the attending general practitioner. Controls were matched to each case for age, sex, general practice, and index date. Antihypertensive therapy was derived from the computerized patient record. The study consisted of 210 cases and 793 controls. Compared with users of β-blockers alone, the adjusted relative risk (RR) estimates for all other treatment regimens were close to 1.0. A comparison of users of calcium channel blockers alone with users of β-blockers alone yielded a RR estimate of 0.9 (95% CI 0.5, 1.7). We conclude that the risk of acute myocardial infarction in otherwise healthy, treated hypertensive patients is not materially associated with the particular drug they receive.     

Side-to-side portacaval shunt versus nonsurgical treatment of Budd-Chiari syndrome

Although a side-to-side portacaval shunt will relieve some patients with Budd-Chiari syndrome, distinction between relief as a result of operation and spontaneous recovery may be inexact. A nonshunting operation relieved one of two patients as much as a side-to-side portacaval shunt did. In these two patients and one additional patient, streptokinase therapy may have been beneficial.     

Lipids, lipoproteins, fibrinogen and fibrinolytic activity in angiographically assessed coronary heart disease

Plasma lipids, lipoproteins, fibrinogen and fibrinolytic activity (FA) were measured in 202 consecutive patients undergoing coronary angiography. Twenty-one patients, 13 men and 8 women with a mean age of 52.8 years and 56.7 years respectively, were found to be angiographically free of coronary artery disease (CAD) and served as the principal control group. Since this group contained a disproportionate number of subjects with risk factors such as family history, hypertension and smoking, a second control group of clinically healthy subjects selected for age was also tested. Their laboratory results were not used in the statistical calculations. The group with angiographic CAD consisted of 130 men (mean age 57.6 years) and 51 women (mean age 61.5 years). Abnormal angiograms were graded according to the number of major vessels with more than 50% stenosis involved. The laboratory variables which were significantly (p less than .01-.001) associated with the presence of CAD were: High density lipoprotein (HDL) when determined by polyacrylamide gel electrophoresis (PAGE) and expressed as a percentage of total lipoproteins rather than concentration, presence of Intermediate Density Lipoprotein (IDL), percent of Very Low Density Lipoprotein (VLDL), fibrinogen concentration and FA. The HDL2 subfraction was significantly inversely correlated only in women. The total plasma cholesterol was normal and virtually identical in both groups. Within the CAD group, only two of the laboratory results were significantly correlated with the extent of disease. By univariate analysis, the FA showed the closest association with the score for severity of CAD (p less than .001) followed by the presence of IDL (p less than .01). In conclusion, lipoprotein analysis by a method which measures not only HDL, but also LDL, VLDL and IDL, together with the determination of fibrinogen and FA provides information useful in the identification of individuals at risk for CAD.     

Inactivation of single-chain urokinase (pro-urokinase) by thrombin and thrombin-like enzymes: relevance of the findings to the interpretation of fibrin-binding experiments

Whereas crude bovine thrombin activated single-chain urokinase-type plasminogen activator (scu-PA), otherwise called pro-urokinase (pro- UK), purified human thrombin converted pro-UK (scu-PA) to a two-chain form that had no amidolytic activity. The two chains (Mr approximately 33,000 and 22,000) were disulfide linked and resistant to subsequent activation by plasmin. By contrast, thrombin did not inactivate tissue plasminogen activator or two-chain urokinase. The enzyme from snake venom Agkistrodon contortrix, relatively specific for fibrinopeptide B, had an effect similar to thrombin, whereas the enzyme from Agkistrodon rhodostoma (ancrod), specific for fibrinopeptide A, did not. When pro- UK (scu-PA) was present during thrombin clotting of fibrinogen, degradation of 125I-pro-UK (scu-PA) in the clot supernatant was seen, whereas virtually full recovery (95%) of radioactivity was found. A loss of latent amidolytic activity in the clot supernatant was also found, the extent of which could be correlated with the degree of degradation of the radiolabeled probe. It was concluded that thrombin inactivation of pro-UK (scu-PA) accounts for the loss of amidolytic activity in the clot supernatant, which has been attributed to fibrin binding. Further confirmation was obtained from experiments in which ancrod was used as the clotting agent. Full recovery of both radioactivity and latent amidolytic activity of pro-UK (scu-PA) in the supernatant was obtained under these conditions. These findings indicate that thrombin may introduce an artifact in the results of certain experiments designed to study the fibrin affinity or fibrinolytic effect of pro-UK (scu-PA).     

The Role of Fibrin Monomer and an in vivo Thrombin-Induced Anticoagulant in Experimental Venous Thrombosis

The functional role of soluble fibrin monomer (FM) complexes in vivo is not known and the clinical significance of its laboratory measurement unclear. The effect of FM on the development of experimental venous thrombosis was evaluated. Laboratory determination of FM by ethanol gelation and protamine sulfate paracoagulation in the presence of serum-induced thrombosis was performed. FM in vivo was formed by the administration of thrombin and by the infusion of soluble fibrin. FM was found not to significantly potentiate thrombus formation in this experimental model. Furthermore, extensive thrombosis occurred without demonstrable circulating FM. The results suggest that the presence of FM in the blood is not a reliable measure of incipient venous thrombosis. The laboratory demonstration of FM in association with deep vein thrombosis probably reflects the result and not the cause of the thrombus. During this study, a potent anticoagulant and antithrombotic activity induced by thrombin in vivo was demonstrated. Some of the experimental results were related to this activity. Preliminary studies of this activity are presented and its pathophysiologic significance considered.     

Fibrin activatable urokinase (FA-UK): a latent form of UK found in urine related to a complex with an inhibitor/fibrin-interacting cofactor

In order to investigate the binding of pro-urokinase (pro-UK) in urine to fibrin/Celite, the property which led to its discovery, the effect of fibrin on the plasminogen activator activity of urine was studied. The plasminogen activator activity in urine was found to be consistently about 2-fold higher when measured by fibrin plate assay than by amidolytic substrate (S-2444), when normalized against the UK reference standard. When the amidolytic activity measurement was preceded by incubation of urine with soluble fibrin, a 2-fold increase in amidolytic activity was also found. Fibrin similarly increased plasmin generation in urine enriched with Glu- or Lys-plasminogen as determined by synthetic substrate S-2251. The observed promoting effect was common to several forms of soluble fibrin and was dose dependent, whereas fibrinogen had little effect. The promoting effect of fibrin was not expressed in the presence of pro-UK or two-chain UK (TC-UK) in buffer and therefore was attributed to another constituent of urine. Since the activity was inhibited by antibodies to UK but not to t-PA, it was called fibrin activatable UK (FA-UK). Gel filtration (Sephacryl-200) of urine revealed FA-UK activity in fractions eluting at a molecular weight of approximately 100K. A 100 K band of activity was also consistently seen when concentrated urine was subjected to zymography. Treatment of concentrated urine with hydroxylamine (1 M) eradicated both these activities and was associated with an increase in baseline amidolytic activity in the urine sample indicative of the release of UK from an inhibitor complex. Moreover, passage of urine over insolubilized monoclonal antibody against UK-inhibitor (PAI-3) complexes resulted in loss of FA-UK activity and of the 100 K band on the zymogram suggesting that the complex responsible for FA-UK was related to a PAI-3 complex. Since the FA-UK activity appeared to bind to fibrin/Celite, attempts were made to investigate complexation with pro-UK. Unfortunately, due to the instability of pro-UK in urine, no reliable data were obtained. It was concluded that PAI-3 may serve as a fibrin-interacting co-factor of UK, and therefore may play a role in fibrinolysis.