Sol Sherry

Thrombolytic Therapy in Thrombosis: A National Institutes of Health Consensus Development Conference

Excerpt For over three decades, the primary method of therapy used by almost all physicians for the management of acute deep-vein thrombosis and pulmonary embolism has been anticoagulation. This fo...

Coronary thrombolysis by intravenous streptokinase in acute myocardial infarction: Acute and follow-up studies

Coronary arteriography was performed before, immediately after, and 9 to 14 days after administering i.v. streptokinase (850,000 to 1,500,000 IU) to 43 patients within 6 hours of myocardial infarction. Ventricular function was determined by contrast ventriculography before and 9 to 14 days later and by radionuclide studies at clinical follow-up 8 months later. Early reperfusion occurred in 49% of patients, but in only 35% was it sustained. In patients with sustained reperfusion, early ventricular dysfunction was significantly reduced 9 to 14 days and 10 months later, and frequency of infarction, sudden death, and angina pectoris was not increased at follow-up. No serious bleeding occurred.

High-dose, brief intravenous streptokinase early in acute myocardial infarction☆

An acute thrombus at the proximal border of a high-grade atherosclerotic obstruction is the usual cause of myocardial infarction. Although intracoronary thrombolysis is potentially an exciting new therapy for reducing the extent of myocardial infarction by lysing coronary clot, a number of major difficulties limit its widespread application. It is a complex procedure requiring intracoronary visualization and infusion within a few hours of onset of symptoms. Since intravenous streptokinase could be widely applied if effective, we and others have wondered whether high-dose, brief-duration intravenous streptokinase infusion given early in myocardial infarction would lyse coronary clots without bleeding. To date we have treated 13 patients within 6 hours of onset of symptoms and with ECG and angiographic evidence of typical myocardial infarction caused by coronary clot. Clot lysis and angiographically proved coronary reperfusion were achieved in 6 patients within 1 hour of starting a systemic intravenous infusion of 850,000 IU of streptokinase. Schroeder et al., in Berlin, West Germany, achieved angiographically proved coronary reperfusion in 11 of 21 patients with acute myocardial infarction following a 30-minute intravenous streptokinase infusion of 500,000 IU. Neuhaus et al., in Göttinen, West Germany, achieved angiographically proved coronary reperfusion in 24 of 39 similar patients within 48 minutes by intravenous infusion of 1,700,000 IU of streptokinase. In these three studies, no serious bleeding occured; left ventricular function was improved in patients who achieved coronary reperfusion. We conclude that rapid intracoronary clot lysis and coronary reperfusion can be achieved early in myocardial infarction by brief-duration systemic intravenous infusion of high-dose streptokinase without a high incidence of serious bleeding.

Appraisal of various thrombolytic agents in the treatment of acute myocardial infarction

The immediate therapeutic objective after the onset of symptoms of an evolving myocardial infarction is to stop the process from progressing. Evidence has accumulated that this can be accomplished by the early dissolution of the clot within an acutely thrombosed artery, resulting in reperfusion of the ischemic area. There are five clot-dissolving agents currently being evaluated by intravenous administration for their ability to dissolve coronary thrombi and to produce clinical benefit; all are plasminogen activators and each has distinctive properties. Streptokinase, because it has been the agent most extensively studied and its clinical benefits have been established, now serves as a standard for comparison with the others (anisoylated plasminogen-streptokinase activator complex, urokinase, recombinant tissue plasminogen activator, and recombinant pro-urokinase). It is apparent that each of the agents has advantages and disadvantages and that none has established its superiority over the others as of yet.

Low potassium syndrome due to defective renal tubular mechanisms for handling potassium

Abstract Prolonged observations were made on the characteristics and the mechanism of production of the low potassium syndrome in a forty-two year old Chinese male with nephritis of unknown etiology. The syndrome consisted of intermittent bouts of muscular weakness, atony of the bladder, constipation and electrocardiographic changes of a broad flattened T wave, prolonged Q-T interval, prolonged P-R interval and dropped beats, all associated with low serum potassium levels. The plasma potassium level varied between 1.5 and 2.3 mEq./L. when the patient was on a regular diet (104 mEq. potassium daily), fell as low as 1 mEq./L. on a low potassium intake (30 mEq. potassium daily) and rarely exceeded 4 mEq./L. even when the potassium intake was six times greater than normal (625 mEq. potassium daily). The potassium balance was negative on an average potassium intake and became positive only when the daily potassium intake was increased to 425 mEq. or more. In general the serum sodium levels were low and sodium balance tended to be negative except when sodium intake was high. A reciprocal relationship between the potassium and sodium balances was apparent when the potassium intake was varied. Variations in sodium intake and balance, however, were not attended by reciprocal changes in the potassium balance. The plasma chloride level was usually low and chloride balance appeared to be related to the sum of the sodium and potassium balance in that chloride was retained when base was retained and vice versa. Potassium depletion appeared to affect adversely muscle strength and the vegetative nervous system. The severity of signs and symptoms referable to these systems varied in the presence of a constant plasma potassium level; nor was development of symptoms inevitable at any particular plasma potassium level. The height of the T wave of the electrocardiogram could be correlated with the plasma potassium level in acute experiments after potassium administration. Although electrocardiographic abnormalities occurred only during periods of potassium depletion, the day-to-day correlation between the height of the T wave and plasma potassium levels was poor. Glomerular filtration rate, renal plasma flow and maximum capacities of the renal tubules to excrete p-aminohippurate and to reabsorb glucose were approximately one-third of normal. The rate of glomerular filtration, but not the other functions, varied directly although not precisely with the level of daily potassium intake. During periods of low potassium intake and in spite of very low plasma potassium levels the kidneys continued to excrete urine containing appreciable amounts of potassium. Loss of potassium in the urine was not due to inability of the kidneys to defend by the usual mechanisms against either alkalosis or acidosis. Under conditions of low potassium intake as much as 50 per cent of the potassium filtered at the glomeruli appeared in the urine (normal = less than 20 per cent). Tubular excretion of potassium was easily demonstrable whenever the patient was on a high potassium intake. Potassium given during a period of potassium depletion and at a time when an abnormal amount was being lost in the urine demonstrated that the tubules were capable of reabsorbing additional potassium. A similar experiment performed during a period of high potassium intake resulted in a greater increase in the amount of potassium in the urine than in the glomerular filtrate. It is probable that both decreased absorption and increased excretion of potassium were a part of the renal tubular defect responsible for the excessive loss of potassium in the urine.

Coronary Thrombolysis for Evolving Myocardial Infarction

SummaryAn acute thrombus at the site of an atherosclerotic obstruction is the usual cause of myocardial infarction. Thrombolytic therapy is an exciting new therapy for reducing the extent of myocardial infarction by lysing intracoronary clots. Such therapy has now been widely applied by: prolonged intravenous infusion of streptokinase during the first 24 hours of infarction; intracoronary infusion of streptokinase, urokinase, or tissue plasminogen activator; early, high dose, brief duration intravenous infusion of streptokinase; or intravenous infusion of tissue plasminogen activator.Intracoronary streptokinase or urokinase achieves reperfusion of the coronary artery in 75% of patients and is associated with serious bleeding in 4.8% of patients. Intravenous infusion of streptokinase achieves reperfusion of the coronary artery in 50 to 80% of patients. The incidence of serious bleeding with intravenous streptokinase averaged 0.8% in 5 studies of 237 patients and was 12.8% in I additional study of 80 patients. Salvage of the jeopardised myocardium and improvement in left ventricular function occurred when coronary reperfusion was achieved. Mortality in streptokinase-treated patients was significantly reduced at 30 days and at 6 months after infarction in the single randomised mortality study done to date; however, more data are needed on this important question. Reocclusion after thrombolysis averages 17% in patients treated with streptokinase by either intracoronary or intravenous infusion.The newly reperfused coronary artery has been stabilised in some patients by coronary bypass surgery or percutaneous transluminal angioplasty, but further studies are needed to define criteria for appropriate patient selection for these procedures.

High-dose, brief-duration intravenous infusion of streptokinase in acute myocardial infarction: description of effects in the circulation

The effects in the circulating blood of a 1-hour intravenous infusion of 1.5 X 10(6) units of streptokinase (SK) were measured during the subsequent 24-hour period in 7 patients with acute myocardial infarction. At the end of the infusion, the activator activity, expressed in SK units, averaged 65 U/ml, all of the plasminogen had disappeared, only a small amount of free plasmin was still present and functionally active alpha 2 antiplasmin had been reduced to 21% of the preinfusion level. All of the native fibrinogen had been degraded and the thrombin-coagulable protein was composed entirely of fragment X species, but the circulating plasma also contained significant amounts of the more extensively degraded fragments Y, D and E. The biologic half-life of the SK-induced activator activity was 23 minutes and that of the fibrinogen degradation products was 6.3 hours. The lytic effects persisted for 4 hours before any signs of recovery from the hemostatic defect were evident; considerable recovery was present at 25 hours.

The origin of thrombolytic therapy

The origin of thrombolytic therapy is briefly reviewed. It began 40 years ago with the demonstration that the injection into patients of a partially purified activator of the native plasminogen-plasmin enzyme system was capable of dissolving clotted blood and fibrinous loculations in the chest. However, the application of this form of therapy for the dissolution of intravascular thrombi had to await a series of further developments, including extensive purification of the thrombolytic agents, evidence that plasminogen activators would be more appropriate than plasmin for thrombolysis and proof, first in animals and then in humans, that thrombi could be dissolved by the systemic administration of plasminogen activators. The first study of thrombolytic therapy in acute myocardial infarction was reported in 1958. However, despite many studies conducted during the next 20 years, with encouraging reductions in mortality, thrombolytic therapy for acute myocardial infarction became established only when angiography provided visual evidence of the presence of a thrombus obstructing an infarct-related artery and of the achievement of prompt lysis with the administration of thrombolytic agents.

Sulfinpyrazone: A Review of its Pharmacological Properties and Therapeutic Use

SummarySynopsis: Sulfinpyrazone1 has long been recognised as a potent uricosuric agent, but has more recently been studied extensively as a platelet inhibitor and antithrombotic agent. It is active in man following oral administration and has been reported to be effective in reducing the incidence of transient ischaemic attacks, thromboembolism associated with vascular and cardiac prostheses, recurrent venous thrombosis, arteriovenous shunt thrombosis and sudden cardiac death following myocardial infarction. Sulfinpyrazone has not been demonstrated to be effective in preventing or reducing the risk of stroke or death in patients with cerebrovascular disease with a recent history of cerebral or retinal ischaemic attacks.The normal total dose of sulfinpyrazone as an antithrombotic agent is 800mg daily. The drug has been used continuously for up to 4 years with no serious adverse reactions or laboratory abnormalities. There has been no apparent diminution of effect with time. Sulfinpyrazone is not a substitute for conventional anticoagulant agents (e.g. the coumarin derivatives) in the treatment of venous thrombosis, but is an important drug for the treatment of conditions associated with arterial thrombosis and possibly for the prophylaxis of recurrent venous thrombosis. Pharmacodynamic Studies: In animals and man, sulfinpyrazone extends platelet survival and correspondingly reduces platelet turnover. The drug also reduces mural thrombus formation and platelet aggregation which have been induced by various stimuli in numerous animal models. Platelet aggregates which form as a result of complement-dependent immunological responses are also inhibited by sulfinpyrazone with the result that graft function (e.g. kidney transplantation in the dog) is prolonged. With relatively low oral doses, sulfinpyrazone stimulates fibrinolytic activity as evidenced by the normalisation of prolonged euglobulin clot lysis time in rats with kaolin paw edema. In baboons pretreated with infusions of homocysteine to induce endothelial damage, sulfinpyrazone significantly normalised platelet turnover and aortic endothelial desquamation. Significant antiarrhythmic effects have been observed with sulfinpyrazone in several animal models including cats, dogs and rats. Pharmacokinetic Studies: Sulfinpyrazone is rapidly absorbed from the gastrointestinal tract and is more than 95% protein-bound. In 1 study in normal volunteers, the half-life was calculated to be from 2.2 to 2.7 hours. However, a prolonged platelet inhibitory effect with sulfinpyrazone has been reported following a single oral dose in human volunteers (up to 72 hours depending on the method used). Approximately 50% of the drug is excreted unchanged in the urine after a single dose. Therapeutic Trials: In an extensive double-blind investigation in 1558 recent myocardial infarction patients, sulfinpyrazone significantly reduced cardiac deaths over a 2-year observation period as compared to placebo. This protective effect was particularly marked in the prevention of sudden cardiac death during the second through seventh month immediately following a myocardial infarction. A similar decrease in deaths of vascular origin was recorded in a 4-year study of geriatric patients with atherosclerosis.In patients with transient cerebral ischaemia, sulfinpyrazone has been reported to increase platelet survival time and significantly reduce the frequency of ischaemic episodes. In another study, the drug significantly reduced episodes of amaurosis fugax. Nevertheless, in a large multicentre study, sulfinpyrazone did not reduce the risk of continuing transient ischaemic attacks, stroke or death in patients with transient cerebral or retinal ischaemia.Arteriovenous shunt thrombosis and thrombus formation in arteriovenous fistulas and bovine grafts are highly susceptible to the antithrombotic effect of sulfinpyrazone. Chronic haemodialysis patients and patients with end-stage renal disease tolerated the drug well for up to 12 months of observation.Sulfinpyrazone has been very effective in the prophylaxis of recurrent venous thrombosis. In 1 double-blind study the drug significantly reduced the incidence of venous thrombi over 24 months of observation as compared to placebo. Side Effects: Sulfinpyrazone is well tolerated with chronic use, even in geriatric patients and patients with severe renal disease. The most common side effects are mild upper gastrointestinal disturbances. Blood dyscrasias and allergic reactions have been observed only occasionally, without establishment of a cause-effect relationship. Dosage: The usual recommended adult dose is 800mg per day given in 4 doses. The total daily dose should not exceed 1000mg per day. Sulfinpyrazone should be taken with meals or milk.

Prospects in antithrombotic therapy

Abstract Currently there is an increasing awareness of the magnitude and scope of the problem of thrombosis; renewed interest in this lesion also has been spurred by better appreciation of the limitations inherent in the use of the available anticoagulant agents as well as developments in new forms of antithrombotic therapy. Surprisingly, concern over coronary artery thrombosis as a proximate event precipitating acute myocardial infarction has not received the attention it deserves even though the most recent studies indicate that a thrombotic episode occurred in approximately 90 percent of patients who died after a classic acute myocardial infarction. This article briefly reviews (1) current concepts of the pathogenesis of acute coronary thrombosis; (2) the basis for, and developments in, the use of anti-platelet aggregating agents for prophylactic purposes; and (3) prospects for the application of thrombolytic agents to the treatment of acute myocardial infarction.