Antithrombotic drugs: part II.

The defibrinating agent ancrod has had limited clinical trial, but appears to give no advantages over heparin. Intravenous infusion of dextran, a glucose polymer, has been shown to have an antithrombotic effect in many experimental models of thrombosis. However, the evidence that dextran is a clinically valuable antithrombotic drug is conflicting. A number of controlled randomized studies have shown that dextran can prevent postoperative venous thromboembolism when a large volume of dextran 40 or 70 was infused rapidly during and after surgery. However, blood volume expansion during dextran treatment prohibits its use in patients with reduced cardiac reserve, and infrequent though sometimes severe, allergic reactions have been reported. Evidence that dextran is of value for the treatment of venous or arterial thromboembolism comes from uncontrolled studies and is not convincing. Many compounds have been shown to inhibit platelet function in vitro but only five of these drugs have been extensively evaluated as prophylactic or therapeutic antithrombotic agents in man. These are aspirin, sulphinpyrazone, dipyridamole, hydroxychloroquine and clofibrate. They have been evaluated mainly in patients with cerebral vascular disorders, coronary artery disease, peripheral artery ischaemia, venous thromboembolism, prosthetic heart valves, and in patients with arteriovenous shunts. The evaluation of the clinical effect of the platelet function suppressing drugs is in its early stages, but they appear to differ from each other in the spectrum of their clinical effectiveness, and they may be more effective in arterial than in venous thromboembolic disorders. Their role in the management of cerebral vascular disease and coronary artery disease is still uncertain, and should be clarified by the results of a number of multi-centre, prospective, randomized studies which are currently in progress. Three types of thrombolytic drugs have been evaluated clinically; the plasminogen activators streptokinase and urokinase, proteolytic enzymes such as plasmin, and agents which increase the level of endogenous plasminogen activator (e.g. anabolic steroids). Of these, the plasminogen activators now have a definite place in clinical practice. The plasminogen activators accelerate the lysis of recent venous thrombi and pulmonary emboli, and of arterial thrombi or emboli. Thrombolytic therapy with these agents should be considered particularly in patients with recent major pulmonary embolism, as lysis of recent emboli is rapid and substantial. It should also be considered in patients with recent extensive venous thrombosis, because total lysis of venous thrombi has been reported to result in long-term preservation of valve function, and is likely to prevent postphlebitic syndrome, though this has not been proven. However, plasminogen activator therapy carries a higher risk of bleeding than heparin treatment...

10. Antithrombotic therapy: role of platelet-inhibitor drugs. II. Pharmacologic effects of platelet-inhibitor drugs (second of three parts).

In this three-part series, the first part described the role of platelets in thrombogenesis, this second part considers the pharmacologic effects of platelet-inhibitor drugs, and the third part will discuss their clinical application. This second article comprises (1) the physiologic contribution of the vessel wall to the prevention of thrombosis, particularly the role of prostacyclin, (2) the mechanisms of action of platelet-inhibitor drugs in the prevention of thrombosis, (3) the ideal dose and ideal therapeutic combinations of conventional platelet-inhibitor drugs, (4) other agents and new agents that inhibit platelet function, and (5) drug side effects.

Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts.

Aspirin (325 and 900 mg/d) is effective for a period of 1 year in reducing the frequency of saphenous vein bypass graft occlusion when begun 1 day before operation or on the day of operation. Aspirin in combination with dipyridamole is not more effective than aspirin alone in the prevention of saphenous vein graft occlusion. Bleeding is higher among patients treated with aspirin (325 mg/d) than among controls if aspirin is started 1 day before operation. Bleeding in one trial was greater than controls if aspirin (300 mg/d) was started the day of operation, and in one trial there was no difference when aspirin (325 mg/d) was started the day of operation. Ticlopidine (500 mg/d), started 2 days after operation, was effective in maintaining graft patency. Oral anticoagulants were inconsistent in the maintenance of saphenous vein graft patency. The continued use of aspirin for 2 additional years after an initial year of aspirin therapy for the prevention of saphenous vein bypass graft occlusion showed no additional long-term benefit on graft patency at the end of the third year. Antithrombotic agents given to patients with internal mammary artery bypass grafts showed no benefit in comparison to placebo because patency on placebo was high.

Gastrointestinal blood loss in patients undergoing maintenance dialysis.

Gastrointestinal blood loss was measured for 14 days in 19 patients treated by hemodialysis and in 2 patients treated by chronic ambulatory peritoneal dialysis. 51Cr was used as a marker for erythrocytes. Fecal blood loss was 5.0 +/- 3.3 ml/day in hemodialysis patients who were not taking drugs affecting thrombocyte aggregation and 4.6 +/- 4.3 ml/day in those receiving sulfinpyrazone. There was no relationship between the severity of anemia, duration of dialysis, dose of heparin, grade of uremic intoxication, or dose of aluminum hydroxide and amount of fecal blood loss. It is concluded that gastrointestinal blood loss is not a major determinant of anemia in chronic renal failure. However, sulfinpyrazone is preferable to acetylsalicylic acid for prevention of shunt thrombosis in uremic patients because of their propensity for gastrointestinal bleeding.

Reduction of dialyzer fibrin deposition with sulphinpyrazone.

To determine whether sulphinpyrazone reduces thrombus formation within artificial kidneys, dialyzer 125I-fibrinogen and platelet and fibrinogen levels during dialysis were compared during a non-treatment control period and while patients were receiving sulphinpyrazone. Mean fibrin deposition within the dialyzers, measured as gram X 10(-3) of clottable fibrinogen, was significantly less during sulphinpyrazone treatment (2.5) than during the control period (5.3). Arterial blood platelet counts and plasma fibrinogen levels during dialysis were higher on treatment despite similar predialysis values during control and treatment periods. The results indicate that sulphinpyrazone reduces fibrin formation within artificial kidneys and, since the reduction in deposition of fibrin alone is insufficient to explain the higher plasma fibrinogen levels during treatment with sulphinpyrazone, suggests that this therapy reduces fibrinogen consumption within the patient during hemodialysis.

Secondary prevention of coronary events after myocardial infarction. Beta-blockers and/or anti-platelets: to whom, when and for how long. A review.

The institution of a "Cardioprophylactic" drug regimen after myocardial infarction should take into consideration the concept of high or low risk patients for secondary coronary events and the concept of a decremential mortality rate as time elapses after myocardial infarction. Thus, the efficacy of a particular drug in preventing secondary coronary events may vary with the time elapsed from infarction and thus with the underlying patho-physiologic mechanism. Furthermore, the administration of a possible effective or proven effective "Cardioprophylactic" drug or drug regimen at a specific time from infarction must take into account the balance between expected benefit and untoward side effects.

Antiplatelet drugs or dicoumarol: what is the most effective prophylaxis in occlusive arterial disease?

Arterial thromboses lead to disturbances of vital function: myocardial infarction, ischemic cerebral infarction, disorders of peripheral blood flow, nephrosclerosis. Prophylaxis of thrombosis is still an unsolved problem, since diseases caused by thrombosis remain the first cause of death, at least in Western countries. After describing the pathomorphological and pathobiochemical findings, a survey of the literature on prophylaxis of occlusive arterial diseases is presented and the difference between anticoagulants and aggregation inhibitors is pointed out.

[Anti-platelet aggregating drugs in the prevention of thromboembolic diseases]. / I farmaci antiaggreganti piastrinici nella prevenzione delle malattie tromboemboliche

The treatment and prevention of arterial thrombosis have been improved in recent years by the use of drugs acting on certain platelet characteristics, such as clumping capacity, adhesivity, release of factors 3 & 4, and survival. Many substances have been proposed for clinical employment. Mechanisms of action are discussed on the basis of personal experience, particularly with dipyrimadol and beta-blocking drugs. It would seem that the best results are obtainable with drugs whose effect on platelet clumping comes from stablisation of the membrane, such as the non-steroid anti-inflammatory preparations, in association with drugs than enhance intraplatelet cyclic AMP.

Etiology and prevention of thromboembolic disease. Taming a complex circulatory malfunction.

Deep venous thrombosis is a complex process involving many factors in the circulatory system, an important one apparently being the intrinsic fibrinolytic system. Specific activators of the process include venous trauma and hypercoagulability states. In spite of efforts at prophylaxis, venous thrombosis will occur, a dangerous condition in itself and also a precursor of pulmonary embolism. Several schemes for prophylaxis, including drug regimens and mechanical means, have been tried, and future research will surely identify others. A patient's best protection against thrombosis at present, however, is a vigilant physician with a high index of suspicion who will expedite diagnosis and treatment if necessary.

Antiplatelet drugs in thromboembolism.

Evidence is mounting that three drugs that inhibit platelet function--aspirin, dipyridamole, and sulfinpyrazine--have an antithrombotic effect in humans. Particularly in men, aspirin is beneficial in controlling transient ischemic attacks and stroke, and there is evidence that it may be effective in preventing thrombotic and embolic complication of hip surgery. It abolishes symptoms in peripheral ischemia associated with thrombocytosis and spontaneous platelet aggregation and may prove effective in coronary artery disease. When combined with oral anticoagulants, aspirin is more effective than oral anticoagulants alone in preventing systemic embolism in patients with prosthetic heart valves. Dipyridamole in combination with oral anticoagulants reduces the incidence of systemic embolism after prosthetic heart valve replacement. Sulfinpyrazone reduces the incidence of sudden death in the first year after myocardial infarction, decreases the incidence of arteriovenous shunt thrombosis in patients undergoing chronic hemodialysis, and when combined with anticoagulants, may be effective in reducing the frequency of episodes in recurrent venous thrombosis.

Influence of antiplatelet drugs on occlusion of arteriovenous fistula in uraemic patients.

A long-standing arteriovenous (A-V) fistula may develop thrombotic complications. In 20 patients on intermittent peritoneal dialysis (IPD) arteriovenous fistula was made surgically. We evaluated the efficacy of three antiplatelet drugs: Ibustrin (Group A), sulphinpyrazone (Group B) and alpha-tocopherol (Group C) in preventing thrombotic occlusion of A-V fistulas. Results of the trial indicate that the three drugs significantly reduce spontaneous platelet aggregation and ADP induced aggregation. The heparin neutralizing activity was significantly increased during treatment. Significant prolongation of bleeding time was observed only in Groups B and C. In patients receiving antiplatelet drugs no occlusion of A-V fistulas was observed. In the control group such complications occurred in 3 of the 20 patients. Our results indicate that antiplatelet drugs by inhibiting the platelet function may prevent thrombotic occlusions of A-V fistulas in IPD patients.