Review Article Drugs 12: 132-157 (1976) © ADIS Press 1976

Antithrombotic Drugs: Part 11 1 A.S. Gallus and J. Hirsh St. Joseph's Hospital and McMaster University, Hamilton, Ontario


The defibrinating agent ancrod has had limited clinical trial, but appears to give no advantagesover 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 randomised 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 arterialthromboembolism 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 suppressingdrugs 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 ofa number of multi-centre, prospective, randomised 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 plasminogenactivators now have a definite place in clinicalpractice. The plasminogen activators accelerate the lysis ofrecent 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. In patients with peripheral artery thromboembolism, the use of plasminogen activators is limited to those patients in whom surgery is contra-indicated. Benefit from thrombolytic therapy has not been demonstrated in myocardial infarction. 1 Final of a 2-part review. Part I appeared in the previous issue.

Antithrombotic Drugs


viper bites caused prolonged, severe hypofibrinogenemia, but relatively little bleeding (Reid et al., Infusion of ancrod results in hypofibrino- 1963). Subsequent animal experiments showed genemia. The aim of ancrod treatment is to lower that ancrod treatment could prevent experimental the plasma fibrinogen concentration to a level at venous and arterial thrombosis (Chan, 1969; which formation or extension of thrombi through Rahimtoola et al., 1970). It also results in net lysis fibrin deposition cannot occur . Thus, ancrod of experimental pulmonary emboli in dogs and should have similar anti thrombotic effects to the rabbits (Olsen and Pitney, 1969; Sharma et al., anticoagulant drugs. 1973), probably through the unopposed action of physiological fibrinolytic mechanisms when fibrin deposition is prevented. 3.1 Chemistry, Mode of Action, and PharmacoClinical studies have been limited , and have kinetics concentrated mainly on venous thrombosis. Three controlled studies have evaluated the effectiveness Ancrod is a purified coagulant fraction from of ancrod as a therapeutic agent for venous thromthe venom of the Malayan pit viper (Agkistrodon bosis (Kakkar et al., 1969a ; Davies et al., 1972; rhodostoma boie). It acts by removing fibrinopep- Tibbutt et al., 1974b), while a fourth assessed its tide A from fibrinogen (Ewart et al., 1970). The value as a prophylactic agent (Barrie et al., 1974). fibrin formed is more susceptible to fibrinolysis In the first study, by Kakkar et al. (1969a), than fibrin formed by the action of thrombin patients with recent venous thrombosis had veno(Pizzo et al., 1972), because ancrod (unlike graphy before and after treatment with ancrod, thrombin) does not activate factor XIII, and there- heparin, or streptokinase. Treatment with ancrod fore does not produce a cross-linked fibrin (Bell et or heparin prevented further extension of thromal., 1968a; Barlow et al., 1970). It has no action bosis , but did not produce significant thrombolysis on other coagulation factors (Bell et al., 1968a ; assessed at repeat venography. The use of strepBarlow et al., 1970). Ancrod infusion produces tokinase , on the other hand, produced thromhypofibrinogenemia by converting fibrinogen to bolysis in 6 of 9 patients. Davies et al. (1972), in a fibrin, which is rapidly lysed because it is not similar randomised study, confirmed that ancrod cross-linked and therefore does not lead to ischae- treatment and heparin treatment of patients with recent venous thrombosis produced similar clinical mic organ damage. After intravenous injection, ancrod initially dis- and venographic results while Tibbutt et al. appears from the circulation with a plasma half-life (197 4b) also showed lysis of venous thrombosis by of 3 to 5 hours, but after 90% of the dose has been streptokinase but not by ancrod. Thus, they obcleared, remaining drug is cleared more slowly, served substantial or complete lysis of venous with a plasma half-life of 9 to 12 days (Regoeczi thrombi in 15 of 17 streptokinase treated patients, and Bell, 1969). Because of this slow , late but only 2 of 15 ancrod treated patients (Tibbutt clearance a mild to moderate hypofibrinogenemia et al., 1974b). The use of ancrod to prevent venous thrombosis after hip fracture was evaluated may persist for some days after injection. in a controlled study by Barrie et al. (1974). In this small and inconclusive study, ancrod did not 3.2 Clinical Effectiveness reduce the incidence of postoperative thrombosis, but appeared to reduce the frequency of pulThe evaluation of ancrod as an antithrombotic monary embolism. These results are sufficiently agent was based on observations that Malayan pit promising to warrant further investigation.

3. Defibrinating Agents (Ancrod)


Antithrombotic Drugs

Results of ancrod treatment have also been reported in small numbers of patients with chronic obliterative arterial disease (Ehringer et al., 1973), retinal vein thrombosis (Bowell et al., 1970) or priapism (Bell and Pitney, 1969), but, as these were uncontrolled studies, it is impossible to conclude whether treatment benefited the patients. No benefit was shown in two double blind studies of ancrod treatment for sickle cell crisis (Mann et al., 1972; Haddock et al., 1973).

3.3 Route of Administration, Dosage Schedules and Laboratory Control Ancrod can be given intravenously or intramuscularly , but the intravenous route is preferred because intramuscular injection is more likely to lead to antibody-mediated resistance to the drug (Pitney et al., 1969). The degree of defibrination can be regulated by varying the dose given. Slow intravenous infusion of 1u/kg body weight over 12 hours, followed with further infusions of 0.5 to 1u/kg every 12 hours , results in sustained hypofibrinogenaemia of about 50mg{100rnl (Barrie et al., 1974). Increasing or decreasing the dose leads to a greater or less effect. The optimum level of hypofibrinogenaemia for prevention or treatment of various thrombotic disorders is not yet known.

3.4 Side-Effects Spontaneous bleeding has been rare during ancrod therapy, even when there is marked hypofibrinogenaemia (Bell et al., 1968b ; Sharp et al., 1968). However, severe bleeding from recent surgical wounds has been frequent during 'total' defibrination, which has also been associated with oozing from venipuncture sites and delayed wound healing (Sharp et al., 1968). More moderate hypo. fibrinogenaemia (about 50mg{100rnl) has been

reported to not lead to increased per- or postoperative bleeding (Barrie et al., 1974). One patient with a nephrotic syndrome has developed micro-angiopathic haemolytic anaemia during ancrod therapy (Sharp et a1., 1968), but no other evidence of organ damage from microvascular thrombosis has been reported in man. In animals, concurrent treatment with the fibrinolytic inhibitors, s-aminocaproic acid and aprotinin has increased the size of thrombi after ancrod infusion and prevented their lysis, and has resulted in organ damage and death of most animals (Silberman et al., 1971). For this reason , concurrent treatment with ancrod and fibrinolytic inhibitors is contra-indicated .

3.5 Antidote In case of excessive bleeding, antivenene should be used to neutralise ancrod , and fibrinogen should be given. Fibrinogen infusion without the use of antivenene is not likely to produce sustained elevation of the fibrinogen level because of continued action of the drug.

3.6 Conclusions on Role of Ancrod in Thromboembolic Disorders Ancrod is an interesting alternative to heparin treatment. It can produce a prolonged state of controlled hypofibrinogenaemia. However, it appears to give no clinical advantage over heparin, and further well controlled comparative studies are needed to defme its role, if any, in practical patient management.

4. Dextrans Dextrans are glucose polymers produced by the action of various strains of leuconostoc bacteria on sucrose. Initially introduced as plasma volume


Antithrombotic Drugs

expanders, they have subsequently also been used as antithrombotic agents (Atik, 1967 ; Gruber , 1969 ; Data and Nies, 1974) .

which is reported to have an increased susceptibility to fibrinolysis (Aberg et al., 1975; Wallenbeck and Tangen, 1975). In addition, dextran infusion has been reported to result in a moderate decrease of the levels of fibrinogen and other coagulation factors (Nilsson and Eiken, 1964; Langs4.1 Chemistry and Pharmacokinetics joen and Murray, 1971). Volume expansion is greater with dextran 70 Two dextran fractions are in common clinical use, one with a mean molecular weight of 70,000 than dextran 40 (Atik , 1967) , and an effect on (dextran 70), the other with a mean molecular platelet function has only been reported after dexweight of 40,000 (dextran 40) . Dextran is tran 70 infusion. Dextran 70 has been reported to removed from the blood by metabolism and by reduce ADP and collagen induced platelet aggregaexcretion in urine. It is probably degraded by tion, platelet factor 3 availability, and adhesion of dextran splitting enzymes which have been found platelets to glass beads (Ewald et al., 1965; Weiss, in the liver, spleen, and other organs of experi- 1967). In some studies, dextran 70 has been mental animals (Ingelman et al., 1969). Renal shown to prolong the bleeding time when reexcretion of dextran is limited to polymers of latively large amounts were given in a short time molecular weight less than 50,000; the rate of (Nilsson and Eiken, 1964 ; Cronberg et al., 1966). excretion being a function of the molecular weight The in vivo effects on platelet function are seen (Art urson et al., 1964 ; Arturson and Wallenius, some time after infusion of dextran 70, suggesting 1964) . that they may not be caused by simple coating of In man, about 55% of infused dextran 40 is platelets with unaltered dextran (Weiss, 1967; excreted in urine in the first 4 hours and 60 to Bygdeman, 1969). Dextran 40 does not prolong 80% by 24 hours. On the other hand, only 30% of the bleeding time (Cronberg et al., 1966). infused dextran 70 is excreted in urine in 4 hours and 40% after 24 hours (Art urson et al., 1964). 4.3 Preparations Available for Clinical Use The reason for partial urinary excretion of dextran 70 is that the preparation is heterogenous , so that Dextrans in clinical use are dissolved in either a proportion of molecules has a molecular weight 5% dextrose or 0.9% saline. Dextran 70 is supplied less than 50,000. in 6% or 10% concentration, while dextran 40 is available as a 10% solution . 4.2 Mode of Action The antithrombotic effect of dextran has been attributed to: (1) volume expansion and a consequent decrease of blood viscosity; (2) coating of surfacs by dextran, which results in a reduced interaction between endothelium and formed elements of blood (ponder and Ponder, 1961; Bloom et al., 1964); (3) reduced platelet function (Nilsson and Eiken, 1964 ; Cronberg et al., 1966; Weiss, 1967) , and (4) copolymerisation of dextran with fibrin monomer to produce an altered clot ,

4.4 Evidence of Effectiveness A number of animal models have been used to show that dextran can prevent experimental thrombosis. Dextran 70 has generally been more effective than dextran 40, and the required dose to prevent experimental thrombosis has been between 0.6 and 1.0g/kg body weight (Bygdeman, 1969). Clinical evidence of effectiveness has been conflicting. The usefulness of the drug for preventing


Antithrombotic Drugs

Table VIII. Results of thrombolytic therapy in randomised comparative studies of pat ients with embolism (H = heparin, UK = urok inase, SK = streptokinase) Study



% Resolution of embolism angiogram

lung scan

Death within 2 weeks

Urokinase pulmonary embolism trial (1973)

12 hours H 12 hours UK

78 82

14% 45%

10% 23%

9% 7%

Urokinase-streptokinase embolism trial (1974)

12 hours UK 24 hours UK 24 hours SK

59 54 54

42% 44% 43%

20% 29% 19%

7% 9% 9%

Tibbut et al. (1974a)

72 hours H 72 hours SK

12 11

15% 61%

venous thromboembolism has been most fully evaluated. Reports of its use for the treatment of established venous thrombosis (Sawyer, 1968; Bernard, 1969), the prevention and treatment of limb artery occlusions, stroke, or myocardial infarction (Powley, 1963; Bienenstock and Harding, 1964; Bergan et al., 1965; Langsjoen et al., 1968; Gilroy et al., 1969), the treatment of sickle-cell crisis (Barnes et al., 1965) and the treatment of ischaemia after frost bite (Mundth et al., 1964), failed to provide convincing evidence of its efficacy in these conditions.

Prevention of venous thromboembolism: Although there have been many studies of the effects of dextran on the incidence of postoperative venous thromboembolism, their results are difficult to compare, because the preparation and dosage schedules used have varied, and because different methods have been used to diagnose the end-point of venous thrombosis or pulmonary embolism. Five double-blind studies have assessed the effect of dextran 40 or dextran 70 prophylaxis on the incidence of clinically diagnosed postoperative venous thrombosis and pulmonary embolism after major elective general abdominal

6% 0%

surgery. Generally, dextran was given in a dose of 500 to 1,000rnl preoperatively and immediately postoperatively, and in one study daily dextran infusions were then continued until the patient was mobile. One study , by Kline et a1. (1975), showed a statistically significant reduction of the total incidence of clinically diagnosed pulmonary embolism, and of pulmonary embolism thought to be the cause of death, in dextran 70 treated patients, but found no reduction of the incidence of clinically diagnosed venous thrombosis . Two other studies showed a strong trend, which was not statistically significant, towards a reduced incidence of venous thrombosis (diagnosed when venography confirmed the presence of clinically suspected thrombosis) (Huttunen et al., 1971; Jansen, 1972). In the study by Jansen (1972), this trend was present to an equal extent in both dextran 40 and dextran 70 treated patients, but the effect appeared to be limited to patients who had operations which lasted less than an hour . In both of these studies there was also a small trend towards a reduced incidence of pulmonary embolism in dextran treated patients. The other 2 studies showed little benefit (Brisman et al., 1971) or no benefit from prophylaxis (Hartshorn et al.. 1969).

Antithrombotic Drugs


Table IX. Lysis of venous thrombi with streptokinase. Results of randomised or non-randomised, venographically documented comparisons with results of heparin therapy (5 = streptokinase, H = heparin) Authors

Gormsen and Laursen (1967)


145 14 H

Randornised study

Durat ion of treatment (days)



Extent of lysis com- par plete tial








1 5


2 5



o o




6 2


Browse et al. (1968)


Kakkar et al. (1969a)


Robertson et al. (1970)

95 7H



Tsapogas et al. (1973)

195 14 H



Duckert et al. (1975)

935 42 H






3 6





9 13


31 38


* Total clearance or clearance at 'strategic point' for venous return, l .e, the confluence of the superficial and deep femoral veins and the long saphenous vein .. More than 75% or complete lysis .

There have been 6 prospective, randomised studies of the effect of dextran prophylaxis on the incidence of 125I.fibririogen leg-scan detected thrombosis after elective abdominothoracic surgery. Three studies showed a marked and statistically significant reduction of leg-scan detected thrombosis (Bonnar and Walsh,

1972; Bonnar et al., 1973; Carter and Eban, 1973), while three others did not (Becker and Scharnpi, 1973; Scottish Study, 1974; Kline et al., 1975). It is difficult to explain these differences. Thus, Bonnar and Walsh (1972) and Bonnar et a1. (1973) , found that 1 litre of dextran 70 given in 6 hours during and after surgery (the first 500ml given in 1 hour), was effective, while Kline et a1. (1975), using a similar infusion regimen, found no effect of dextran on the incidence of leg-scan detected venous thrombosis, though they did find a reduced incidence of pulmonary embolism in treated patients. By contrast, 4 randomised studies which evaluated dextran prophylaxis in patients having hip surgery, and which used routine postoperative venography to assess the effect of prophylaxis, all showed a statistically significant reduction of thrombosis in the treatment group (Ahlberg et al., 1968; Johnsson et al., 1968; Myhre and Holen, 1969; Evarts and Feil, 1971). In 3 studies, dextran was infused after hip fracture, starting either at admission (Myhre and Holen, 1969) or during surgery (Ahlberg et al., 1968; Johnsson et al., 1968) in a dose of 500rnl, and this dose was given at 2 to 3 day intervals at least until the fifth postoperative day. In the fourth study, Evarts and Feil (1971) found that I,OOOml dextran 70 per day starting during surgery and repeated daily for 10 to 12 days, reduced the incidence of venous thrombosis after elective hip replacement from 56% in the control group to 7%, and also resulted in a statistically significant reduction of the incidence of clinically diagnosed pulmonary embolism.

4.5 Principles of Laboratory Control There are no laboratory tests which measure the antithrombotic effect of dextrans. Recommended doses have therefore been determined empirically, through clinical trial.

Antithrombotic Drugs

4.6 Route of Administration and Dosage Schedules Dextrans are given intravenously and can only be recommended at present for the prevention of postoperative venous thrombosis. In general, the best results have been reported when a large volume (1,OOOrnl) is infused rapidly (over 4 to 6 hours) during and after surgery. In orthopaedic surgery, prophylaxis has been successful when infusions have been repeated daily or every second or third day throughout the period of bedrest . Prophylaxis starting after surgery has usually been ineffective (Rothermel et al., 1973; Stephenson et al., 1973; Wedge et al., 1974) . Most experience has been gained with dextran 70, but dextran 40 may be of similar value. 4.7 Side-Effects The major side-effect of dextran treatment is volume expansion, which limits its use in patients with reduced cardiac reserve. This effect is greater with dextran 70 (Atik , 1967). Allergic reactions, which rarely lead to acute hypotension, have been reported (Brisman et al., 1971; Salzman et al., 1971; Jansen, 1972; Data and Nies, 1974). They usually occur within minutes of the start of infusion and so may coincide with anaesthesia, causing diagnostic confusion. Dextran 40 infusion has been reported to cause oliguria (Bergentz et al., 1965) and occasionally acute renal failure (Morgan et al., 1966 ; Mailloux et al., 1967 ; Chinitz et al., 1971) in dehydrated or hypotensive patients, so that urinary output should be monitored during treatment. Bleeding has generally not been a problem in surgical patients, though excessive wound oozing in some patients has been reported (Kline et al., 1975). There has also been a case report of bleeding after repeated infusions of large amounts of dextran 40 in a patient with renal failure (Berliner and Lackner, 1972). Finally, blood cross-matching


with enzyme methods may be in error when dextran is present, so that blood for this purpose should be obtained before dextran infusion, or the blood-bank warned that dextran has been used (Murray and Dewar, 1971) .

5. Antiplatelet Drugs Many compounds have been observed to inhibit platelet function in vitro (Mustard and Packham, 1970b, 1975; Packham and Mustard, 1975; Kinlough-Rathbone , 1975), but only some show an antithrombotic effect when tested in experimental animals in vivo, and even fewer are suitable for use in man. Discussion will be limited to the 5 drugs which have been evaluated most extensively as prophylactic or therapeutic antithrombotic agents in man. These are aspirin, sulphinpyrazone, dipyridamole, hydroxychloroquine and clofibrate. All were initially introduced as therapeutic agents because of a pharmacological effect other than platelet function suppression, and it is not known if their antithrombotic effects are due to their described action on platelet function or to some other mechanism. These drugs have been evaluated in patients with cerebrovascular disorders, coronary artery disease or peripheral artery ischaemia, and in venous thromboembolism. Their value has also been assessed in patients with prosthetic heart valvesor arterio-venous shunts . 5.1 Aspirin 5.1.1 Mode ofAction Aspirin inhibits the platelet release reaction induced by adrenaline, collagen, antigen-antibody complexes or gamma globulin coated surfaces, but has only a weak inhibitory effect on thrombin induced platelet release and aggregation (Evans et al., 1968; Mustard and Packham, 1970b) . It is cleared rapidly from the circulation, but can

Antithrombotic Drugs

inhibit the platelet release reaction for 5 to 7 days (O'Brien, 1968; Weiss et al., 1968). The mechanism of this action is uncertain, but could be due to one or a combination of the following three effects : (1) acetylation of platelet membrane proteins (Rosenberg et al., 1971), (2) inhibition of the platelet membrane enzyme, collagen: glucosyltransferase (Jamieson et al., 1971), and (3) inhibition of the synthesis from arachidonic acid of a labile cyclic endoperoxide which induces platelet release and aggregation and is a precursor of prostaglandins E 2 and F 2 a (Flower, 1975; Weiss, 1975). A single dose of aspirin has been shown to prolong the bleeding time for up to 5 days in normal volunteers (Hirsh et al., 1973; Mielke et al., 1973) . 5.1.2 ClinicalEffects It is not known whether aspirin is effective in cerebrovascular disease. Data from two cases reports suggest that it may reduce the incidence of transient cerebral ischaemic episodes (Harrison et al.,1971; Mundall et al., 1972). This cannot be taken as strong evidence for effectiveness, but two large multicentre studies are currently underway to evaluate the use of aspirin in this disorder (Genton et al., 1975) . Two retrospective case control studies by the Boston Collaborative Drug Surveillance Group suggested that myocardial infarction occurs less frequently in subjects who regularly take aspirin than in non-aspirin takers (Boston Collaborative Drug Surveillance Program, 1974). On the other hand, in the one prospective randomised study by Elwood et al. (1974), 300mg aspirin/day did not significantly prolong survival after myocardial infarction. However, there were some interesting trends, the most notable of which was an apparently beneficial effect of aspirin in patients admitted to the study within 6 weeks of infarction . These results have led to a number of other large prospective studies in the UK and USA which are evaluating the use of aspirin after myocardial infarction (Genton et al., 1975).


The results of studies evaluating the use of aspirin for preventing venous thrombosis have been conflicting (Genton et al., 1975; Gallus and Hirsh, 1976a). Positive results have been reported when venous thromboembolism was diagnosed on clinical grounds alone (Salzman et al., 1971 ; Loew et al., 1974), but results have been negative (Medical Research Council, 1972; Wood et al., 1973; Soreff et al., 1975) or inconclusive (Harris et al., 1974; Clagett et al., 1974), when the diagnosis of venous thrombosis was made with 125 I-fibrinogen leg-scanning or venography. On present evidence, therefore , aspirin cannot be recommended as an effective prophylactic agent for venous thrombosis. Aspirin has been shown to reduce thrombus deposition on renal dialysis membranes (Lindsay et al., 1972; Stewart et al., 1975). It has not reduced the incidence of artery occlusion after brachial artery catheterisation (Hynes et al., 1973; Freed et al., 1974). Aspirin has also been shown to have no effect on the outcome of proliferative glomerulonephritis or nephrotic syndrome in children (Trygstad et al., 1973). The most impressive evidence for an antithrorn. botic effect of aspirin comes from a number of case reports which have demonstrated that aspirin prevents peripheral ischaemia in patients with thrombocytosis and spontaneous platelet aggregation (Vreeken and van Aken, 1971; Bierme et al., 1972; Preston et al., 1974). Most of these patients have a myeloproliferative disorder or malignant disease. These patients present with painful, ischaemic extremities and respond dramatically to aspirin. The clinical effect is associated with inhibition of spontaneous platelet aggregation, and both last for 2 to 3 days after a single 300mg dose of aspirin. Based on current evidence, aspirin can be recommended for the treatment of peripheral ischaemia associated with spontaneous platelet aggregation, but not for any of the other thromboembolic disorders in which it has been evaluated.

Antithrombotic Drugs

5.1.3 Dosage, Contra-Indications and SideEffects Aspirin is a relatively safe drug, but has been reported to cause a slight increase of surgical bleeding (Loew et al., 1974) and of occult gastrointestinal bleeding (Leonards et al., 1973). It may also aggravate symptoms in patients with peptic ulcer. Because of its effect on the bleeding time, aspirin should be avoided in patients receiving anticoagulant drugs. The commonly used dose of aspirin as an antithrombotic drug is 300mg given 3 to 4 times per day. 5.2 Sulphinpyrazone

5.2.1 Mode ofAction Sulphinpyrazone is a uricosuric agent closely related to phenylbutazone , and was the first drug shown to inhibit platelet function (Smythe et al., 1965) . Sulphinpyrazone inhibits platelet release with collagen and adrenaline, but does not prolong the bleeding time in human volunteers (packham and Mustard, 1975). It does prolong reduced platelet survival seen in some patients with gout , prosthetic heart valves, coronary artery disease, rheumatic valvulitis and recurrent venous thrombosis (Smythe et al., 1965; Weily and Genton, 1970; Steele et al., 1973,1974,1975; Weily et al., 1974; Genton and Steele, 1975). The mechanism of the inhibitory effect on platelet function is not known. It can be removed by washing and resuspending platelets, suggesting that the effect of sulphinpyrazone, unlike that of aspirin, is reversible. The drug has a plasma halflife of about 2 hours, and , unlike aspirin, sulphinpyrazone is effective as an inhibitor of platelet function only for as long as it is present in the circulation . 5.2.2 Clinical Effects Sulphinpyrazone was shown by Evans (1972) to reduce the frequency of amaurosis fugax in a small double-blind cross-over placebo study (Evans and Gent , 1975), and by Blakely and Gent (1975)


to reduce the frequency of death from vascular causes in elderly institutionalised patients with a past history of stroke. However, both of these studies require confirmation and extension before firm recommendations on the value of sulphinpyrazone in these disorders can be made. Thus, the study on amaurosis fugax only examined shortterm end-points and did not evaluate the effectiveness of the drug on the more important end-points of stroke and death (Evans, 1972 ; Evans and Gent, 1975), while in the geriatric study of Blakely and Gent (1975) the cause of death was not confirmed by autopsy. The value of sulphinpyrazone in patients with transient cerebral ischaemia is now being further evaluated in a large multicentre Canadian Study (Genton et al., 1975). The effects of this drug in the prevention of death from vascular causes in patients with stroke is also being re-examined. The clinical effects of sulphinpyrazone have not been evaluated definitively in patients with venous thrombosis, but there is suggestive evidence that it may prevent further recurrence in selected patients presenting with recurrent venous thrombosis . Thus, Steele et al. (1973) reported that sulphinpyrazone normalises reduced platelet survival in patients with recurring venous thrombosis resistant to anticoagulants, and also observed that sulphinpyrazone treatment was associated with a decreased number of clinical recurrences. The results of a study by Evans and Gent (1975) also suggest that there is a clinical effect of sulphinpyrazone in recurrent venous thrombosis, but in these two studies the diagnosis of recurrence may have been inaccurate because it was based partly or wholly on clinical criteria, so that conclusions from the data must be made with caution. Perhaps the best evidence that sulphinpyrazone has an antithrombotic effect comes from 2 prospective, double-blind studies by Kaegi et al. (1974, 1975) which showed that sulphinpyrazone reduces the frequency of shunt thrombosis in patients with arterio-venous shunts used for chronic haemodialysis.

Antithrombotic Drugs

5.2.3 Dosage, Contra-Indications and SideEffects The antithrombotic dose of sulphinpyrazone appears to be 600 to 800mg/day given orally in 3 or 4 divided doses (Weily and Genton, 1970; Kaegi et al., 1974, 1975) . The drug is well tolerated, but may produce gastro-intestinal discomfort as well as increase of peptic ulcer symptoms. Abnormal bleeding from sulphinpyrazone alone has not been reported. 5.3 Dipyridamole

5.3.1 Mode ofAction Dipyridamole was initially used as a vasodilator. It is one of a number of pyrimido-pyrimidine compounds which inhibit platelet function . In high concentration in vitro these compounds inhibit primary and secondary ADP induced aggregation and the platelet release reaction induced by adrenaline , collagen or thrombin (Packham and Mustard, 1975). However, these effects cannot be demonstrated when dipyridamole is used in pharmacological doses in man and the drug does not prolong the bleeding time . The pyrimidopyrimidine compounds increase platelet cyclic AMP levels by inhibiting phosphodiesterase activity (Packham and Mustard, 1975). 5.3.2 Clinical Effects Acheson et al. (1969) evaluated dipyridamole treatment in patients presenting with transient cerebral ischaemic episodes or completed stroke and found that treatment did not reduce the frequency of subsequent transient ischaemic episodes or ischaemic stroke, and did not reduce mortality. Gent et al. (1968) also found no effect of dipyridamole treatment on mortality after myocardial infarction, but both studies were small and shortterm, so that a beneficial effect from treatment was not excluded. Treatment with dipyridamole and oral anticoagulants has been shown in a double-blind ran-


domised study to reduce the incidence of embolism from aortic or mitral prosthetic heart valves of the older type (Sullivan et al., 1971). Other , non-randomised studies have shown a similar effect (Meyer et al., 1971 ; Arrants et al., 1972) . One controlled , but apparently non-randomised study suggests that combined treatment with large doses of dipyridamole and aspirin may also reduce the incidence of systemic embolism after prosthetic valve replacement (Taguchi et al., 1975). The value of dipyridamole as a prophylactic agent for venous thrombosis was evaluated by Browse and Hall (1969) and Salzman et al. (1971), who reported that the drug had no effect on the incidence of clinically diagnosed postoperative venous thrombosis. However, the clinical diagnosis of venous thrombosis is inaccurate and the drug has not been evaluated using objective diagnostic tests such as 125 I-fibrinogen scanning, so that an antithrombotic effect of the drug in this setting has not been excluded. One prospective randomised trial suggests that the combination of dipyridamole and oral anticoagulants may reduce the severity of vascular and glomerular lesions in patients having renal allografts, but no effects on graft survival or renaI function were found, perhaps because of the relatively small number of patients available for this study (Mathew et aI., 1974). Treatment with a combination of dipyridamole, anticoagulants (heparin or warfarin) and immunosuppressive drugs has been reported to improve the prognosis of patients with rapidly progressive, glomerulonephritis (Brown et al., 1974; Cameron et aI., 1975). This was not a controlled study , as results in a consecutive series of treated patients were compared with results in previously observed untreated patients and in patients treated with immunosuppressive drugs alone. Any conclusions about the effectiveness of the antithrombotic therapy used must therefore remain tentative. On present evidence. therefore , dipyridamole is of value as an antithrombotic agent when com-

Ant ithrombotic Drugs

bined with oral anticoagulant treatment in patients with prosthetic heart valves, but there is insufficient evidence to recommend its use for other thrombotic disorders.

5.3.3 Dosage, Contra-Indications and SideEffects The dose of dipyridamole used in patients with prosthetic heart valves is 40Omg!day. In some reports this dose has caused vascular headache, nausea or vomiting in up to 25% of patients (Browse and Hall, 1969). It has been suggested that smaller doses of 100 to 200mg!day can be used if the drug is combined with aspirin, because this combination will normalise the reduced platelet survival seen in a number of thromboembolic disorders to the same extent as high dose dipyridamole alone (Harker and Slichter, 1972, 1974). However, the clinical antithrombotic effect of the combination of this lower dose of dipyridamole with aspirin has not been properly tested. 5.4 Hydroxychloroquine

5.4.1 Mode ofAction Hydroxychloroquine is an antimalarial drug which has also been used to treat rheumatoid arthritis and systemic lupus erythematosus because it has anti-inflammatory effects . It appears to weakly inhibit ADP induced platelet aggregation, but does not prolong the bleeding time in volunteers (Kinlough-Rathbone, 1975). 5.4.2 Clinical Effects Hydroxychloroquine has been reported by Carter et al. (1971) and Carter and Eban (1974) to prevent venous thrombosis diagnosed clinically, by venography, or with 125 I-fibrinogen leg scanning, and to prevent clinically diagnosed pulmonary embolism after elective general surgery. These were randomised prospective controlled studies, but they were not blind and the criteria for diagnosing thrombosis with 125 I-fibrinogen leg scan-


ning have been criticised (Genton et aI., 1975). These observations therefore need to be confirmed before .hydroxychloroquine can be recommended as a prophylactic agent for venous thromboembolism. The antithrombotic effects of the drug have not been evaluated in other clinical situations .

5.4.3 Dosage, Contra-indications and SideEffects In the studies by Carter et al. (1971) and Carter and Eban (1974), hydroxychloroquine was given in a dose of 800mg!day. Retinal toxicity has been reported after prolonged treatment for several months (Goodman and Gilman, 1975). 5.5 Clofibrate

5.5.1 Mode ofAction Clofibrate is a hypolipidaemic agent which also appears to reduce platelet adhesiveness to glass or latex particles in vitro (Kinlough-Rathbone , 1975). Further support for its action as a platelet function suppressing drug is provided by its effect in prolonging the reduced platelet survival seen in some patients with coronary artery disease (Steele et al., 1975). 5.5.2 Clinical Effects In a controlled study of patients presenting with transient cerebral ischaemic episodes or ischaemic stroke and hypercholesterolaemia, clofibrate did not prevent further transient ischaemic episodes and stroke or death, despite reduction of the cholesterol level by treatment (Acheson and Hutchinson, 1972). Because of its hypolipidaemic effect, clofibrate has been extensively evaluated in patients with myocardial infarction. Two studies of patients presenting with symptoms of angina, evidence of myocardial infarction or both, suggested that there was some benefit from treatment (Scottish Society of Physicians, 1971 ; Group of Physicians of the

Antithrombotic Drugs


Newcastle-upon-Tyne Region, 1971). In one , clofi- thromboembolic disease. At present , the following brate treatment was associated with reduced total recommendations can be made: mortality and a reduced incidence of sudden death 1) That aspirin is effective in relieving sympduring the study period (Scottish Society of Physitoms and signs of peripheral ischaemia in cians, 1971), but in the other this was not obpatients with thrombocytosis and spontanserved. However, in both studies there was a signieous platelet aggregation. This is a relatively ficant reduction of mortality and sudden death in uncommon condition which is usually seen the sub-group of patients presenting with angina in patients with myeloproliferative disorders pectoris. Both trials have been criticised on methoor malignancy. dological grounds (Feinstein , 1972; Friedewald 2) That sulphinpyrazone is effective in preventand Halperin, 1972; Rahlfs and Bedall, 1973; Genton et al., 1975), and a third study by the ing shunt-thrombosis in patients with arterioCoronary Drug Project Research Group (1975) has venous shunts who are undergoing chronic haemodialysis, and that it is probably also not confirmed any benefit from long-term clofibrate treatment in men with proven myocardial effective when combined with anticoaguinfarction. lants in patients who have developed recurWhile it was concluded from one other study rence of venous thrombosis despite the use that clofibrate can prevent ischaemic heart disease of anticoagulants alone. in men initially free of this disorder (Krasno and 3) That dipyridamole when combined with Kidera, 1972), this study too has been criticised warfarin is effective in preventing systemic on methodological grounds (Genton et al., embolism in patients with prosthetic heart 1975). valve replacements. At present, therefore, there is no convincing 4) That the current status of antiplatelet drugs evidence that clofibrate is an effective antithrornin the management of cerebrovascular botic drug. disease and coronary artery disease is uncertain , but it is hoped that the results of a 5.5.3 Dosage, Contra-Indications and Sidenumber of multicentre studies, which are Effects currently underway, will provide answers to The recommended dose of clofibrate as a hypothese very important questions. lipidaemic agent is 1.5 to 2g/day, given orally. Mild gastro-intestinal side-effects, including nausea 6. Thrombolytic Drugs and diarrhoea, occur in about 5% of patients and a number of other side-effects have also been The aim of thrombolytic therapy is to dissolve reported. There is an increased incidence of cholelithiasis during long-term treatment (Coronary thrombi or emboli by digesting their supporting fibrin framework. Three types of thrombolytic Drug Project Research Group , 1975). drugs are available: (1) plasminogen activators (e.g. streptokinase and urokinase); (2) proteolytic en5.6 Conclusions on Role of Antiplatelet Drugs zymes (e.g. plasmin and aspergillus proteases); and (3) the anabolic steroids, which increase the level in Thromboembolic Disorders of endogenous (physiological) plasminogen actiIn summary , a number of studies have now vator. The plasminogen activators will be discussed demonstrated . that drugs which suppress platelet in greatest detail, because their clinical value has function may be effective in the treatment of been best defmed.

Antithrombotic Drugs

An understanding of the mode of action of these drugs depends on an understanding of the physiological fibrinolytic enzyme system. Endogenous plasminogen activator is found and perhaps synthesised in vascular endothelium (Todd , 1959; Warren, 1963 ; Kwaan, 1966). After release into the circulation, it activates plasminogen to the fibrinolytic enzyme, plasmin, which can digest fibrin (Alkjaersig et al., 1959; Robbins et al., 1967) . Normally, the action of plasmin in the circulation is inhibited by an excess of antiplasmins (mainly 0::2 -macroglobulin) [Norman, 1966; Ganrot, 1967] . When thrombosis occurs, there is release of activator from adjacent endothelium and this leads to thrombolysis. Two mechanisms have been postulated to explain why physiological fibrinolytic activity produces thrombolysis without any evidence of systemic proteolysis. These are: (1) that plasminogen activator diffuses into the thrombus and activates plasminogen co-precipitated with fibrin in the thrombus (Alkjaersig et al., 1959) , and (2) that plasminogen activator converts plasminogen to plasmin in the circulation , where it is complexed to antiplasmin , but that plasmin is then released from the complex at the surface of the thrombus and so produces fibrinolysis (Ambrus and Markus, 1960). Both of these postulated mechanisms have been invoked to explain therapeutic fibrinolysis with infused plasminogen activators . In addition, there is evidence that optimum therapeutic thrombolysis may depend in part on the continued diffusion of plasminogen from the circulation into the thrombus, where it is converted by plasminogen activator to plasmin (Chesterman et al., 1972; Strachan et al., 1974; Rice et al., 1975).

6.1 The Plasminogen Activators The two plasminogen activators which have been used for therapeutic thrombolysis (streptokinase and urokinase) differ in their detailed mode of action and dosage schedules, but clinical results of treatment with these drugs are similar.


6.1.1 Streptokinase a) Chemistry and pharmacokinetics: Streptokinase, a product of f3-haemolytic streptococci (Tillett and Garner, 1933), is a single chain protein with a molecular weight of 48 ,000 (DeRenzo et al., 1967). Like other streptococcal proteins, it is antigenic to man. Immune antibodies to streptokinase are present to a variable extent in all individuals, probably as a result of previous streptococcal infection, and react immediately with streptokinase to render it biochemically inert (Fletcher et al., 1958; Bachmann, 1968). The complex formed is then rapidly cleared from the circulation (Fletcher et al., 1958). After antibodies have been neutralised by streptokinase infusion, streptokinase circulates with a half-life of about 18 minutes (Fletcher et al., 1958). Streptokinase is not absorbed from the gastro-intestinal tract and must be infused directly into the blood stream. b) Mode of action: Streptokinase activates human plasminogen indirectly by first combining with plasminogen in equirnolecular proportions to form an activator complex , which then activates the remaining non-complexed plasminogen to plasmin by cleaving a single arginyl-valine bond (Ling et al., 1967; Summaria et al., 1969; Kline et al., 1971; Trobisch, 1973) . Because of this, the amount of plasmin generated depends on the relativeamounts of streptokinase and plasminogen present (Trobisch, 1973). When the ratio of streptokinase to plasminogen is low, only small amounts of activator are formed and most of the plasminogen remains available for conversion into plasmin. When the ratio of streptokinase to plasminogen is high, most available plasminogen is complexed as activator and little is available to form plasmin. This is the theoretical basis for using high doses of streptokinase therapeutically, the aim being to convert most of the circulating plasminogen to activator , and to produce relatively little plasmin activity in circulating blood .

Antithrombotic Drugs

c) Effect on haemostasis: Plasmin generated during the initial stages of streptokinase infusion produces a coagulation defect , which is due partly to reduced levels of fibrinogen and factors V and VIII (Fletcher et al., 1959; Schmutzler and Koller , 1969), and partly to the presence of large amounts of fibrinogen or fibrin degradation products, which act as circulating anticoagulants (Kowalski et al., 1964). With current infusion schedules, which aim at high activator and low plasmin levels, the initial phase of plasmin generation and the resulting plasma proteolytic state is transient (Schmutzler and Koller, 1969). However, the sustained high level of plasminogen activator during infusion results in digestion of the fibrin structure of haemostatic plugs as well as thrombi and so produces bleeding from recent wounds, even when the plasma coagulation defect is slight (Hirsh et al., 1968; Cade et al. , 1974b). d) Preparations for therapeutic use: Streptokinase is available from several manufacturers as a lyophilised powder in 250 ,000 unit vials. This is reconstituted at the desired concentration for intravenous or intra-arterial use.

6.1.2 Urokinase a) Chemistry and pharmacokinetics: Urokinase is a plasminogen activator with a molecular weight of 53 ,000 (Lesuk et al., 1965). It can be isolated from human urine or tissue cultures of human embryonic kidney cells (Ploug and Kjeldgaard, 1957; l..esuk et al., 1965; White et al., 1966; Bernik and Kwaan, 1967; Barlow and Lazer, 1972), and appears to be distinct from the circulating physiological plasminogen activator (Kucinski et al., 1968). It is not antigenic to man , so that its use is not complicated by the presence of neutralising antibodies (Genton and Claman , 1970). It is not absorbed from the gastro-intestinal tract and must be infused directly into the blood stream. After infusion, it is cleared from the circulation with a plasma half-life of 10 to 15 minutes (Fletcher et al., 1965).


b) Mode ofaction: Urokinase activates plasminogen directly to plasmin (Kjeldgaard and Ploug, 1957 ; Alkjaersig et al., 1958). c) Effect on haemostasis: Urokinase infusion also produces a plasma coagulation defect due to action of plasmin on fibrinogen and factors V and VllI. The. coagulation defect can be more predictably controlled by altering the infusion rate than is the case with streptokinase. d) Preparations for therapeutic use: At present, urokinase is expensive and only generally available in some European countries.

6.1.3 Clinical Results of Treatment with Plasminogen Activators Clinical studies have evaluated the effects of streptokinase and urokinase in pulmonary embolism, recent venous thrombosis, limb artery occlusion, myocardial infarction, and other thrombo-vascular disorders, including retinal vascular occlusion, priapism and the haemolytic uraemic syndrome. a) Acute major pulmonary embolism: The effects of streptokinase and urokinase have been compared with each other or with heparin in three collaborative multi centre randomised studies of patients presenting with angiographically proven acute pulmonary embolism. Two trials organised by the US National Heart and Lung Institute (NHU) compared the effects of urokinase (infused for 12 or 24 hours), streptokinase (infused for 24 hours) and heparin, on the rate of resolution of recent submassive or massive pulmonary emboli. The extent of lysis was assessed with pre- and post-treatment angiography , lung scanning and haemodynamic measurements (Urokinase Pulmonary Embolism Trial, 1973 ; Urokinase-Streptokinase Embolism Trial , 1974). All three thrombolytic regimens produced greater resolution at 24 hours than did heparin , and 24 hours of treatment with urokinase or strep-

Antithrombotic Drugs

tokinase gave no significant advantage over 12 hour treatment with urokinase (table VIII, page 136). It is of interest that after the first week, lung scan improvement in heparin treated patients was similar to that in urokinase treated patients . In a third, smaller study, Tibbutt et al. (1974a) also showed that 72 hours of streptokinase treatment results in significantly greater early lysis of acute major pulmonary emboli than does heparin therapy. In these studies, there was no difference of mortality between the heparin treated and any of the plasminogen activator treated groups (table VIII). However, the design of the studies made it unlikely that a reduction of mortality could have been shown, because the patients admitted to the studies had survived long enough to have angiography performed, and therefore were a group with a relatively good prognosis for survival. Therefore, until there is evidence to the contrary, it seems reasonable to use thrombolytic therapy in the following groups of patients:


treatment of venous thrombosis and minor embolism (Gallus and Hirsh, 1975a,b; Gallus et aI.,1976a).

b) Recent venous thrombosis: While anticoagulants are very effective for preventing pulmonary embolism in patients with venous thrombosis, they do not remove the thrombus, and so cannot prevent late venous insufficiency and chronic postphlebitic disability. Streptokinase has been shown to accelerate lysis of recent, venographically documented, venous thrombi in randomised and non-randornised controlled comparative studies (table IX, page 137). Successful thrombolysis has been shown to preserve venous valve function a year after treatment and is therefore likely to prevent postphlebitic disability (Kakkar et al., 1969b). However, the chance of success is probably reduced if the thrombus is over 4 days old (Schmutzler and Koller, 1969). In our experience, most patients who present with venous thrombosis are poor candidates for thrombolytic therapy, because the thrombus has 1) Those who are critically ill from severe been present for a long time, because it has ocmechanical pulmonary artery obstruction curred within 10 days of surgery when thrombolytic agents are contra-indicated, or because when they are first seen 2) The small group of patients who survive for thrombosis is associated with an incurable disease. 24 to 48 hours after an embolic episode, but For these reasons, most patients are treated with do not make the usual recovery during heparin, while thrombolytic therapy is reserved for heparin treatment, and the younger patient with a high risk of prolonged 3) Those patients with underlying cardiac or postphlebitic "disability and no contra-indications respiratory disease who have reduced cardio- to treatment. pulmonary reserve and in whom spontaneous resolution of embolism is often delayed c) Arterial occlusion: There have been no con(Chait et al., 1967). trolled comparisons of results of thrombolytic therapy with those of surgical, anticoagulant or It should, however, be remembered that most placebo treatment in acute or chronic arterial patients who die from massive pulmonary embo- occlusion. However, uncontrolled studies have lism do so within an hour of the embolic episode, shown that streptokinase treatment results in so that this disorder will remain a common cause partial or complete lysis of 50 to 75% of limb of death in hospital patients until available forms artery occlusions less than 3 days old (Hiemeyer, of effective prophylaxis are more widely used and 1967; Schmutzler and Koller, 1969; Amery et al., more attention is paid to the early diagnosis and 1970; Dotter et al., 1974). Nevertheless, since

Antithrombotic Drugs

rapid removal of obstruction is often necessary to preserve limb viability, and thrombolytic therapy acts slowly (Schmutzler and Koller, 1969), thrombolytic treatment is indicated only when surgery is contra-indicated.


bodies. This dose also rapidly converts available plasminogen to activator complex and plasmin. It is followed with a maintenance infusion , which ensures that any further plasminogen entering the circulation during treatment is largely converted to activator rather than plasmin. Because the antid) Myocardial infarction: A large number of streptokinase antibody level varies among indivirandomised trials have evaluated the effects of duals, it was usual to give a titrated loading dose thrombolytic treatment after myocardial infarc- which would overcome the patient's measured tion. Some well-designed studies have shown no streptokinase resistance (Schmutzler and Koller, effect of thrombolytic treatment, while others 1969). More recently, a standard loading dose have shown variable evidence of benefit. In designed to overcome the streptokinase resistance general, studies performed in coronary care units of the great majority of patients treated has been have shown no effect of streptokinase treatment, used. This second approach is more convenient, but the mortality in the control group was low, and has been shown to be safe and effective while studies conducted in general medical wards (Verstraete et al., 1966; Hirsh et aI., 1970b). have tended to show a high mortality in the Heparin should always be given after comcontrol group, which was significantly reduced by pleting a course of streptokinase therapy to prestreptokinase (Verstraete, 1971; Brogden et aI., vent rethrombosis. It may also be necessary to 1973; Simon et al., 1973; European Collaborative start heparin treatment during prolonged strepStudy , 1975). Thus, at this time , thrombolytic tokinase infusion when the anticoagulant effect therapy cannot be recommended for myocardial from the initial transient period of plasma proinfarction. teolysis subsides as fibrin-fibrinogen degradation products are cleared (Biggs, 1970; Hirsh et aI., e) Other indications: Plasminogen activator 1971). This is important, because thrombi formed therapy has also been used in a number of other during treatment are likely to be plasminogen conditions with a thrombotic, or possibly throm- depleted, and so resistant to further lysis. botic aetiology. These include chronic arterioLaboratory tests are often used during thromsclerotic peripheral artery disease (Poliwoda et al., bolytic therapy to insure that a thrombolytic 1969; Hume et al., 1970; Martin et al., 1971; effect has been achieved, and to monitor the Verstraete et al., 1971; Persson et al., 1973), extent and duration of the anticoagulant effect. retinal vascular occlusion, priapism (Schmutzler Generally, the plasminogen activator level is and Koller, 1969) and the haemolytic uraemic measured with the euglobulin lysis time and fibrin syndrome (Monnens et aI., 1972; Stuart et al., plate assay, while the anticoagulant effect is 1974), but data has come from uncontrolled measured with the thrombin clotting time. Other dosage schedules which rely on a synerstudies, often of small numbers of treated patients, and does not permit conclusions about the value gistic effect between heparin and low doses of of treatment. streptokinase have been evaluated in experimental pulmonary embolism in dogs (Cade et al., 1974a) 6.1.4 Dosage Schedules and Principles of and have limited clinical trial in patients with Laboratory Control venous thromboembolism (Gallus et aI., 1975). a) Streptokinase: To achieve a systemic effect , a loading dose of streptokinase must be given b) Urokinase: Urokinase is given in a standard which neutralises circulating streptokinase anti- dose by intravenous infusion. Thus, in the Urok-

Antithrombotic Drugs

inase Pulmonary Embolism Trial (1973) of the NHLI, urokinase was given in a loading dose of 2,000 CTA units per pound of body weight followed by the same dose given each hour. Anticoagulants are contra-indicated during treatment with this dose, but should be restarted at the end of therapy to prevent further thromboembolism.

6.1.5 Side-Effects, Contra-Indications and Antidotes These are similar for the two drugs and will be considered together. The major side-effect of thrombolytic therapy is bleeding. This generally occurs after invasive procedures (e.g. arterial or venous punctures and surgical wounds), when bleeding is more frequent and severe than during anticoagulant treatment. For this reason , treatment is contra-indicated within 10 days of surgery and within 24 hours of arterial puncture, unless a potential bleeding site can be easily controlled. Treatment is also contra-indicated in patients with active peptic ulcer and severe hypertension. Intramuscular injection should never be given during treatment. Fever and allergic reactions were common with early preparations of streptokinase , but are now less frequent. Thus , 24% of S4 patients treated with streptokinase in the Urokinase-Streptokinase Embolism Trial (1974) had a mild temperature elevation of more than O.gOC, but only one had a temperature above 40°C dur ing treatment. This compared with temperature elevation in 16% of the 113 urokinase treated patients. In the phase I trial, temperature elevation was identical in urokinase -treated and heparin-treated patients (Urokinase Pulmonary Embolism Trial, 1973). Allergic reactions other than fever were seen in 3 of S4 streptokinase-treated patients and 1 of 113 urokinase-treated patients (Urokinase-Streptokinase Embolism Trial, 1974) . Steroids are usually given during streptokinase treatment to prevent these side-effects , but their value is not proven. The management of bleeding during thrombolytic therapy depends on its nature and severity.


Thus , bleeding from venepuncture sites (the commonest source of bleeding) is usually insignificant, and can be readily controlled with a pressure bandage. If bleeding is potentially serious, and the thrombin clotting time is markedly prolonged, thrombolytic treatment may have to be abandoned and fibrinogen infused. If bleeding is serious, or if the patient needs emergency surgery (e.g. pulmonary embolectomy), then treatment should be stopped, the fibrinolytic effect of streptokinase or urokinase should be reversed with e-aminocaproic acid or aprotinin, and fibrinogen should be infused if the thrombin clotting time is prolonged.

6.1.6 Conclusions on Role of Thrombolytic Drugs in Thromboembolic Disorders Controlled clinical trials have demonstrated that treatment with plasminogen activators produces accelerated lysis of acute major pulmonary emboli and recent deep leg vein thrombi, so that these drugs have a definite place in the management of these disorders. However, because the risk of bleeding is greater than with anticoagulant treatment, plasminogen activator therapy should be used only after careful consideration of the expected benefits and hazards to the individual patient. Thrombolytic therapy should also be considered for acute arterial occlusion if surgery is contra-indicated. The value of plasminogen activator treatment in other thromboembolic disorders remains to be more fully defined . 6.2 Proteolytic Enzymes (Plasmin and Aspergillus Protease) Porcine plasmin was found by Storm et al. (1974) to lyse recent deep leg vein thrombi in a randomised, controlled study. Results appeared similar to those reported by others with streptokinase treatment. The aspergillus protease, brinase , has also been used to a limited extent in patients with throm-

Ant ithrombotic Drugs


effect on the incidence of postoperative venous thrombosis detected with 125 I-fibrinogen leg scanning. Active treatment produced a significant increase of fibrinolytic activity before surgery, but not after surgery. It is possible that longer pre6.3 Drugswhich Increase Endogenous Plasmino- treatment may have led to a pharmacological gen Activator Levels (Fibrinolytic Stimulants) effect after surgery also (Brown et al., 1971), and s.' have resulted in a reduced incidence of thromA number of anabolic steroids have been shown bosis. However, even if this were so, the need for a to produce a sustained increase of endogenous long pre-treatment period and the high incidence plasminogen activator levels, either alone or in of side-effects (10% in the study of Fossard et al., combination with biguanide hypoglycaemic drugs 1974) which include nausea and vomiting, make it (Fearnley et al., 1967; Davidson et al., 1972). The unlikely that these drugs would be widely used as detailed mode of action of these drugs is not prophylactic agents. known , but they may increase endothelial synNilsson and Isacson (1973) and Nilsson et al. thesis of activator (lsacson and Nilsson, 1970). (1975) have reported that treatment with phenThe commonly used drugs have been a combina- formin and ethylestrenol reduces the frequency of tion of ethylestrenol with phenformin , or stano- thrombotic episodes in patients with idiopathic zolol alone. Their fibrinolytic effect is mild, com- recurrent venous thromboembolism, but as this pared with that produced by streptokinase or was an uncontrolled study , the conclusion must be regarded as tentative. urokinase. There have been no clinical studies of the The possibility that these drugs could be useful antithrombotic agents was raised by the associa- effects of these drugs in arterial disorders. tion, in some studies, between impaired fibrino6.3.2 DosageSchedules lytic activity before or after surgery and an A sustained increase of fibrinolytic activity is increased risk of postoperative thrombosis (Mansfield, 1972; Gallus et al., 1973; Aberg et al., 1974; produced by the combination of ethylestrenol Gordon-Smith et al., 1974) , by observations that a 4mg bid with phenformin 50mg bid , or by stanolarge proportion of patients after myocardial zolol alone in a dose of lOmg/day. infarction or venous thrombosis have reduced fib6.3.3 Conclusions on Role of Fibrinolytic rinolytic activity (Chakrabart i et al., 1968; Isacson and Nilsson, 1972; Nilsson and Isacson, 1973), and Stimulants in Thromboembolic Disorders by the fact that this reduced fibrinolytic activity Drugs which increase endogenous plasminogen could be increased with drug treatment (Fearnley activator levels have potential value as antithromet al., 1967; Nilsson and Isacson, 1973). botic agents, but their use for this purpose will remain experimental until the results of further 6.3.1 ClinicalEffects clinical studies are available. Clinical studies with these drugs have been limited to the prevention and treatment of venous Acknowledgements thrombosis . Fossard et al. (1974) found in a double-blind, This work has been supported by the Province of randomised study that treatment with ethyles- Ontario, the Ontario Heart Foundation, and the St. trenol and phenformin for 3 weeks before and 1 Joseph's Hospital Foundation. Miss Louise Maher typed week after elective gynaecological surgery had no the manuscript.

boembolic disorders (Roschlau, 1971; Fitzgerald et al., 1972), but has not yet been properly evaluated.

Antithrombotic Drugs

References Aberg, M.; Isacson, S. and Nilsson, I.M.: The fibrinolytic system and postoperative thrombosis following operation of rectal carcinoma. A preliminary report. Acta Chirurgica Scandinavica 140: 352-354, (1974). Aberg, M.; Bergentz, S-E. and Hedner, U.: The effect of dextran on the lysability of ex-vivo thrombi. Annals of Surgery 181 : 342-345, (1975). Acheson, J.; Danta, G. and Hutchinson, E.C.: Controlled trial of dipyridamole in cerebral vascular disease. British Medical Journal 1: 614-615, (1969) . Acheson, J. and Hutchinson, E.C.: Controlled trial of clofibrate in cerebral vascular disease. Atherosclerosis 15: 177-183 (1972). Ahlberg, A.; Nylander, G.; Robertson, B.; Cronberg, S. and Nilsson, I.M.: Dextran in prophylaxis of thrombosis in fractures of the hip. Acta Chirurgica Scandinavica (Suppl. 387): 83-85 (1968) . Alkjaersig, N.; Fletcher, A.P. and Sherry , S.: The activation of human plasminogen: A kineti c study of activation with trypsin,urokinase, and streptokinase. Journal of Biological Chemistry 233: 86-90, (1958). Alkjaersig, N.; Fletcher, A.P. and Sherry , S.: The mechanism of clot dissolution by plasmin. Journal of Clinical Investigation 38: 1086-1095 (1959) . Ambrus, C. and Markus, G.: Plasmin-antiplasmin complex as a reservoir of fibrinolytic enzyme s. American Journal of Physiology 199: 491-494, (1960). Amery, A.; Deloof, W.; Verrnylen, J. and Verstraete, M.: Outcome of recent thromboembolic occlusions of limb arteries treated with streptokinase. British Medical Journal 4: 639-644 (1970). Arrants, J.E. and Hairston, P.: Use of persantin in preventing thromboembolism following valve replacement. American Surgeon 38: 432-435 (1972). Arturson, G. and Wallenius, G.: The renal clearance of dextran of different molecular sizes in normal humans. Scandinavian Journal of Clinical and Laboratory . Investigation 16: 81-86 (1964). Arturson, G.; Granath, K.; Thoren, L. and Wallenius, G.: The renal excretion of low molecular weight dextran. Acta Chirurgica Scandinavica 127: 543-551 (1964). Atik , M.: Dextran 40 and Dextran 70. A Review. Archives of Surgery 94: 664-672 (1967). Bachmann, F.: Development of antibodies against perorally and rectally administered streptokinase in man. Journal of Laboratory and Clinical Medicine 72: 228-238 (1968). Barlow, G.H.; Holleman, W.R. and Lorand , L.: The action of Arvin on fibrin stabilizing factor (factor XIII). Research Communications in Chemical Pathology and Pharmacology 1: 39-42 (1970)


Barlow, G.H. and Lazer, L.: Characterization of the plasminogen activator isolated from human embryo kidney cells: comparison with urokinase. Thrombosis Research I : 201-207 (1972). Barnes, P.M.; Hendrickse, R.G. and Watson-Williams,E.J .: Low-molecular-weight dextran in treatment of bonepain crises in sickle-cell disease. A double-blind trial. Lancet 2: 1271-1273 (1965). Barrie, W.W.; Wood, E.H.; Crumlish, P.; Forbes, C.D. and Prentice, C.R.M.: Low-dosage ancrod for prevention of thrombotic complications after surgery for fractured neck of femur. British Medical Journal 4: 130-133 (1974). Becker, J. and Schampi, B.: The incidence of postoperative venous thrombosis of the legs. A comparative study on the prophylactic effect of Dextran 70 and electrical calf-muscle stimulation. Acta Chirurgica Scandinavica 139 : 357-367 (1973). Bell, W.R.; Bolton G. and Pitney, W.R.: The effect of Arvin on blood coagulation factors. British Journal of Haematology 15: 589 -602 (1968). Bell, W.R. ; Pitney, W.R. and Goodwin , J.F.: Therapeutic defibrination in the treatment of thrombotic disease. Lancet 1: 490-493 (1968b). Bell, W.R. and Pitney, W.R.: Management of priapism by therapeutic defibrination. New England Journal of Medicine 280: 649 -650 (1969). Bergan, J.J.; Trippel , O.H.; Kaupp, H.A.; Kukral, J.C. and Nowlin, W.F.: Low molecular weight dextran in treatment of severe ischemia. Archives of Surgery 91 : 338-341 (1965). Bergentz, S-E.; Falkheden, T. and Olson, S.: Diuresis and urinary viscosity in dehydrated patients. Influence of Dextran-40,000 with and without mannitol. Annals of Surgery 161: 582-586 (1965). Berliner, A.D. and Lackner, H.: Hemorrhagic diathesis after prolonged infusion of low molecular weight dextran. American Journal of the Medical Sciences 263: 397-403 (1972). Bernard, H.R.; Powers, S.R.; Leather, R.P. and Clark, W.R.: A prospective double blind study of clinical dextran in thrombophlebitis. Surgery 65: 191-196 (1969). Bernik, M.B. and Kwaan, H.C.: Origin of fibrinolytic activity in cultures of the human kidney . Journal of Laboratory and Clinical Medicine 70: 650-661 (1967). Bienenstock , J. and Harding, E.L.T.: Low-molecularweight dextran ('Rheomacrodex') in ischaemic ulceration of the skin. Lancet 1: 524-525, (1964). Bierrne R.; Boneu , R.; Guiraud, B. and Pris, J.: Aspirin and recurrent painful toes and fingers in thrombocythaemia. Lancet 1: 432 (1972).

Antithrombotic Drugs

Biggs, J.C.: Thrombolytic therapy in arterial and venous thrombosis. Australasian Annals of Medicine 19: (Suppl. 1) 19-24 (1970). Blakely, J.A. and Gent, M.: Platelets, drugs and longevity in a geriatric population, p284; in Hirsh, Cade, Gallus and Schonbaum (Eds) Platelet, Drugs and Thrombosis (Karger, Basel 1975). Bloom, W.L.; Harmer, D.S.; Bryant, M.F. and Brewer, S.S.: Coating of vascular surfaces and cells. A new concept in prevention of intravascular thrombosis. Proceedings of the Society for Experimental Biology and Medicine 115: 384-386 (1964). Bonnar , J. and Walsh, J.: Prevention of thrombosis after pelvic surgery by British Dextran 70. Lancet 1: 614-616 (1972). Bonnar, J.; Walsh, J.J. and Haddon , M.: Thromboembolism following radical surgery for carcinoma - prevention by Dextran 70 infusion during and immediately after operation. Proceedings IVth Congress International Society on Thrombosis and Haemostasis, p278 (Vienna, Austria 1973) . Boston Collaborative Drug Surveillance Group. Regular aspirin intake and acute myocardial infarction. British Medical Journal 1: 440-443 (1974). .Bowell, R.E. ; Marmion, V.J. and McCarthy, C.F .: Treatment of central retinal vein thrombosis with Ancrod. Lancet 1: 173-174 (1970). Brisrnan, R.; Parks, L.C. and Haller, J.A.: Dextran prophylaxis in surgery. Annals of Surgery 174: 137-141 (1971). Brogden, R.N.; Speight , T.M. and Avery, G.S.: Streptokinase: A review of its clinical pharmacology, mechanism of action and therapeutic uses. Drugs 5: 357-445 (1973). Brown, C.B.; Wilson, D.; Turner, D.; Cameron, J.S.; Ogg, C.S.; Chantler, C. and Gill, D.: Combined immunosuppression and anticoagulation in rapidly progressive glomerulonephritis. Lancet 2: 1166-1172 (1974). Brown, I.K.; Downie, R.J.; Haggart, B.: Littler, J.; Murray G.H.; Robb, P.M. and Sauter, G.J.: Pharmacological stimulation of fibrinolytic activity in the surgical patient. Lancet 1: 774-776 (1971). Browse, N.L.; Lea Thomas, M. and Pirn, H.P.: Streptokinase and deep vein thrombosis. British Medical Journal 3: 717-720 (1968) . Browse, N.L. and Hall, J.H.: Effect of dipyridamole on the incidence of clinically detectable deep-vein thrombosis. Lancet 2: 718-720 (1969). Bygdernan, S.: Prevention and therapy of thromboembolic complications with dextran. Progress in Surgery 7: 114-139 (1969). Cade, J.F. ; Hirsh, J. ; Rogoeczi, E.; Gent , M.; Buchanan , M.R. and Hynes, D.M.: Resolution of experimental


pulmonary emboli with heparin and streptokinase in different dosage regimens. Journal of Clinical Investigation 54: 782-791 (1974a). Cade, J.F .; Basu, D.; Muckle, T.J. and Hirsh, J.: Effects of thrombolytic therapy on hemorrhage from postoperative wounds. TItrombosis et Diathesis Haemorrhagica 32: 592 -599 (1974b) . Cameron, J.S.; Gill, D.; Turner, D.R.; Chantler, C.; Ogg, C.S.; Vosnides, G. and Williams, D.G.: Combined immunosuppression and anticoagulation in rapidly progressive glomerulonephritis. Lancet 2: 923-925 (1975). Carter, A.E.; Eban, R. and Perrett, R.D.: Prevention of post-operative deep venous thrombosis and pulmonary embolism . British Medical Journal 1: 312-314 (1971) . Carter, A.E. and Eban , R.: The prevention of postoperative deep venous thrombosis with Dextran 70. British Journal of Surgery 60 : 681-683 (1973). Carter, A.E. and Eban , R.: Prevention of post-operative deep venous thrombosis in legs by orally administered hydro xychloroquine sulphate. British Medical Journal 3: 94 -95 (1974) . Chait, A.; Summers, D.; Krasnow, D. and Wechsler, B.M.: Observations on the fate of large pulmonary emboli . American Journal of Roentgenology 100: 364-373 (1967). Chakrabarti, R.: Hocking, S.D.; Fearnley, G.R.; Mann, R.D.; Attwell, T.N. and Jackson, D.: Fibrinolytic activity and coronary heart disease. Lancet 1: 987-990 (1968). Chan, K.E.: The comparison of the antithrombotic action of the thrombin-like fraction of Malayan pit viper venom and heparin. Cardiovascular Research 3: 171-178 (1969). Chesterman , C.N.; Allington, M.J. and Sharp , A.A.: Relationship of plasminogen activator , to fibrin. Nature (New Biology) 238: 15-17 (1972) Chinitz, LL.; Kim, K.E.; Onesti, G. and Swartz, C.: Pathophysiology and prevention of dextran4D-induced anuria. Journal of Laboratory and Clinical Medicine 77: 76-87 (1971). Clagett, C.P.; Brier, D.F. ; Rosoff, C.B.; Schneider, P.B. and Salzman, E.W.: Effect of aspirin on postoperative platelet kinetics and venous thrombosis. Surgical Forum 25: 473-476 (1974). Coronary Drug Project Research Group. : Clofibrate and niacin in coronary heart disease. Journal of the American Medical Association 231: 360-381 (1975). Cronberg , S.; Robertson, B.; Nilsson, I.M. and Nilehn, J.E .: Suppressive effect of dextran on platelet adhesiveness. Thrombosis et diathesis haemorrhagica 16: 384-394 (1966).

Antithrombotic Drugs

Data, J.L. and Nies,A.S.: Dextran 40. Annals of Internal Medicine 81: 500-504 (1974). Davidson, J.F.; Lochhead, M.; McDonald, G.A. and McNicol, G.P.: Fibrinolytic enhancement by stanozolol: A double-blind trial , British Journal of Haematology 22: 543-559 (1972). Davies, J.A .; Merrick, M.V.; Sharp , A.A. and Holt, J.M.: Controlled trial of ancrod and heparin in treatment of deep-vein thrombosis of lower limb. Lancet 1: 113-115 (1972). DeRenzo, E.C.; Siiteri, P.K. Hutchings, B.L. and Bell, P.H.: Preparation and certain properties of highly purified streptokinase. Journal of Biological Chemistry 242: 533 -542 (1967). Dotter, C.T.; Rosch, J. and Seaman, A.1.: Selective clot lysis with low-dose streptokinase. Radiology 111: 31-37 (1974). Duckert, F.; MUller, G.; Nyman, D.; Benz, A.; Prisender , S.; Madar, G.; DaSilva, M.A.; Widmer, L.K. and Schmitt, H.E.: Treatment of deep vein thrombosis with streptokinase. British Medical Journal 1: 479-481 (1975). Ehringer, H.; Dudzak , R. and Lechner , K.: Therapeutische Defibrinierung mit Ancrod . Deutsche Medicinische Wochenschrift 48: 2298-2304 (1973) . Elwood, P.C.; Cochrane , A.L.; Burr, M.L.; Sweetnam , P.M.; Williams, G.; Welsby, E.; Hughes, S.J. and Renton, R.: A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. British Medical Journal 1: 436-440 (1974) . European Collaborative Study: Controlled trial of urokinase in myocardial infar ction. Lancet 2: 624 -626 (1975). Evans, G.; Packham. M.A.; Nishizawa, E.E.; Mustard, J.F. and Murphy, E.A.: The effect of acetylsalicylic acid on platelet function. Journal of Experimental Medicine 128: 877 -894 (1968). Evans, G.: Effect of drugs that suppress platelet surface interaction on incidence of amaurosis fugax and tran sient cerebral ischemia. Surgical Forum 23: 239-241 (1972). Evans, G. and Gent , M.: Effect of platelet suppressive drugs on arterial and venous thromboembolism. p258; in Hirsh, Cade, Gallus and Schonbaum (Eds) Platelets , Drugs and Thrombosis (Karger, Basel 1975). Evarts, C.M. and Feil, E.J .: Prevention of thromboembolic disease after elective surgery of the hip. Joumal of Bone and Joint Surgery 53A: 1271 -1280 (1971). Ewald, R.A.; Eichelberger, J.W.; Young, A.A.; Weiss, H.J. and Crosby, W.H.: The effect of dextran on platelet factor 3 activity: In vitro and in vivo studies. Transfusion 5: 109-119 (1965).


Ewart , M.R.; Hatton, M.W.C.; Basford, J.M. and Dodgson, K.S.: The proteolytic action of arvin on human fibrinogen. Biochemical Journal 118 : 603 -609 (1970). Fearnley, G.R.: Chakrabarti, R.; Hocking, E.D. and Evans, J.F .: Fibrinolytic effects of diguanides plus ethyloestrenol in occlusive vascular disease. Lancet 2: 1008-1011 (1967). Feinstein, A.R.: Clinical biostatistics: XVIII : The clofibrate trials: Another dispute about contratrophic therapy. Clinical Pharmacology and Therapeutics 13: 953 -968 (1972). Fitzgerald , D.E.; Frisch, E.P. and Thomes, R.D.: Thrombolytic therapy with brinase of chronic peripheral arterial disease. Preliminary report. Journal of the Irish Colleges of Physicians and Surgeons 1: 123-129 (1972). Fletcher, A.P.; Alkjaersig, N. and Sherry, S.: The clearance of heterologous protein from the circulation of normal and immunized man. Journal of Clinical Investigation 37: 1306-1315 (1958). Flet cher, A.P.; Alkjaersig, N. and Sherry, S.: The maintenance of a sustained thrombolytic state in man. I. Induction and Effects Journal of Clinical Investigation 38: 1096-1110 (1959). Fletcher, A.P.; Alkjaersig, N.; Sherry , S.; Genton, E.; Hirsh, J. and Bachmann, F.: The development of urokinase as a thrombolytic agent. Maintenance of a sustained thrombolytic stat e in man by its intravenous infusion. Journal of Laboratory and Clinical Medicine 65: 713-731 (1965). Flower , R.J .: Aspirin , prostaglandins, endoperoxides and platelets. Natur e 253: 88-89 (1975). Fossard, D.P. Friend , J.R .; Field, E.S.; Corrigan, T.P.: Kakkar , V.V. and Flute P.T.: Fibrinolytic activity and postoperative deep-vein thrombosis. Lancet 1: 9-11 (1974). Freed , M.O.; Rosenthal, A. and Tyler, D.: Attempts to reduce arterial thrombosis after cardiac catheterization in children : use of percutaneous technique and aspirin. American Heart Journal 87 : 283-286 (1974). Gallus, A.S.; Hirsh, J. and Gent, M.: Relevance of preoperative and postoperative blood tests to postoperative leg-vein thrombosis. Lancet 2: 805 -809 (1973). Gallus, A.S.; Hirsh, 1.; Tuttle, R.J. ; Trebilc ock, R.; O'Brien, S.E.; Carroll, J.J.; Minden, J.H. and Hudecki, S.M.: Small subcutaneous doses of heparin in prevention of venous thrombosis. New England Journal of Medicine 288 : 545 -551 (1973). Gallus, A.S.; Hirsh, J. ; Cade, J.F.; Turpie, A.G.G.; Walker, I.R. and Gent , M.: Thrombolysis with a combination of small doses of streptokinase and full doses of heparin. Seminars in Thrombosis and Hemostasis 2: 14-32 (1975).

Antithrombotic Drugs

Gallus, A.S.; Hirsh, J. ; Hull, R. and van Aken, W.G.: Diagnosis of Venous Thromboembolism. Seminars in Thrombosis and Hemostasis 2: 203-231 (1976a). Ganrot, P.O.: Inhibition of plasmin activity by 0:2macroglobulin. Clinica Chimica Acta 16: 328-330 (1967). Gent, A.E.; Brook, C.G.D.; Foley, T.H. and Miller, T.N.: Dipyridamole. A controlled trial of its effect in acute myocardial infarction. British Medical Journal 4: 366-368 (1968). Genton, E. and Claman, H.N.: Urokinase: Antigenic studies in patients following thrombolytic therapy. Journal of Laboratory and Clinical Medicine 75: 619-621 (1970) . Genton, E. and Steele. P.: Platelets, Drugs and Heart Disease; in Hirsh, Cade, Gallus and Schonbaum (Eds) Platelets , Drugs and Thrombosis p.263 (Karger, Basel 1975) . Genton, E.; Gent , M.; Hirsh, J. and Harker, L.: Plateletinhibiting drugs in the prevention of clinical thrombotic disease. New England Journal of Medicine 293 : 1174-1178 (1975). Gilroy, J.; Barnhart, M.I. and Meyer, J.S.: Treatment of acute stroke with dextran 40. Journal of the American Medical Association 210: 293-298 (1969) . Goodman , L.S. and Gilman, A.: (Eds) The Pharmacological Basis of Therapeutics p.l052 (Macmillan, New York 1975). Gordon-Smith, I.C.; Hickman, J.A. and LeQuesne, L.P.: Postoperative fibrinolytic activity and deep vein thrombosis. Brit. J. Surg. 61: 213 -218 (1974). Gormsen, J. and Laursen, B.: Treatment of acute phlebothrombosis with streptase . Acta Medica Seandinavica 181: 373-383 (1967). Group of Physicians of the Newcastle-upon-Tyne Region: Trial of clofibrate in the treatment of ischaemic heart disease. British Medical Journal 4: 767-775 (1971). Gruber, U.F.: Blood replacement, p.55 (Springer-Verlag Berlin 1969). Haddock, D.R.W.; Botoney-Ahulu, F.I.D .; Janosi, M.; Aukra-Badu, G. and Reid, H.A.: Thrombosis in sicklecell pain crises? Controlled trial of ancrod (arvin) in young adults . Journal of Tropical Medicine and Hygiene 76: 274-278 (1973) . Harker, L.A. and Slichter , S.J. : Platelet and fibrinogen consumption in man. New England Journal of Medicine 287: 999-1005 (1972) . Harker, L.A. and Slichter, S.J.: Arterial and venous thromboembolism: Kinetic characterization and evaluation of therapy. Thrombosis et Diathesis Haemorrhagica 31: 188-203 (1974) . Harris, W.H.; Salzman, E.W.; Athanasoulis, C.; Waltman, A.C.; Baum, S. and DeSanctis, R.W.: Comparison of


warfarin, low-molecular-weight dextran, aspmn, and subcutaneous heparin prevention of venous thromboembolism following total hip replacement. Journal of Bone and Joint Surgery 56A: 1552-1562 (1974). Harrison, M.J.G.; Marshall, J.; Meadows, J.C. and Russell, R.W.R.: Effect of aspirin in amaurosis fugax. Lancet 2: 743-744 (1971). Hartshorn , J.W.S.; Teale, S.N. and Faiz, M.: Dextran 75 and postoperative phlebitis. Archives of Surgery 98: 694-697 (1969). Hiemeyer, V.: Thrombolytic therapy in acute vascular occlusion. German Medical Monthly 12: 461 (1967) . Hirsh, J.; O'Sullivan, E.F. and Martin, M.: Evaluation of a standard dosage schedule with streptokinase. Blood 35: 341-349 (1970b). Hirsh, 1.; McDonald, I.G.; Hale, G.A.; O'Sullivan, E.F . and Jelinek, V.M.: Comparison of the effects of streptokinase and heparin on the early rate of resolution of major pulmonary embolism. Canadian Medical Association Journal 104: 488 -491 (1971) . Hirsh, J. ; Street, D.; Cade, J.F. and Amy, J.: Relation between bleeding time and platelet connective tissue reaction after aspirin. Blood 41: 369-377 (1973). Hume, M.; Gurewich, V.; Thomas, D.P. and Dealy, J.B.: Streptokinase for chronic arterial occlusive disease. Archives of Surgery 101: 653-657 (1970) . Huttunen, H.J.; Mattila, M.A.K.; Hakalehto, J.; Kettunen, K.; Rehnberg, V. and Babinski, M.: Single infusion of Dextran 70 in the prophylaxis of postoperative deep venous thrombosis. Annales Chirurgiae et Gynaecologiae Fenniae 60: 119-122 (1971). Hynes, K.M.; Gau, G.T.; Rutherford, B.D.; Kazmier, F.J. and Frye, R.L. : Effect of aspirin on brachial artery occlusion following brachial arteriotomy for coronary arteriography. Circulation 47: 554-557 (1973). Ingelman, B.; Gronwall, A.; Gelin, L-E. and Eliasson, R.: Properties and applications of dextrans. Acta Academiae Regiae Scientiarum Upsaliensis 12: 7-90 (1969). Isacson, S. and Nilsson, I.M.: Effect of treatment with combined phenformin and ethyloestrenol on the coagulation and fibrinolytic systems. Scandinavian Journal of Haernatology 7: 404-408 (1970). Isacson, S. and Nilsson, I.M.: Effective fibrinolysis in blood and vein walls in recurrent 'idiopathic' venous thrombosis. Acta Chirurgica Scandinavica 138: 313-319 (1972). Jamieson , G.A.; Urban, C.L. and Barber, A.J.: Enzymatic basis for platelet: collagen adhesion as the primary step in haemostasis . Nature (New Biology) 234 : 5-7 (1971). Jansen, H.: Postoperative thromboembolism and its prevention with 500ml Dextran giving during operation.

Antithrombotic Drugs

Acta Chirurgica Scandinavica Suppl. 427 : 1-73 (1972). Johnsson, S.R.; Bygdeman, S. and Eliasson, R.: Effect of dextran on postoperative thrombosis. Acta Chirurgica Scandinavica Suppl. 387 : 80-82 (1968). Kaegi, A.; Pineo, G.F .; Shimizu , A.; Trivedi, H.; Hirsh, J. and Gent, M.: Arteriovenous-shunt thrombosis. Prevention by sulfinpyrazone, New England Journal of Medicine 290: 304-306 (1974). Kaegi, A.; Pineo, G.F .; Shimizu, A.; Trivedi, H.; Hirsh, J. and Gent, M.: The role of sulfinpyrazone in the prevention of arterio-venous shunt thrombosis. Circulation 52: 497-499 (1975). Kakkar , V.V.; Flanc, C.; Howe, C.T.; O'Shea, M. and Flute , P.T.: Treatment of deep vein thrombosis. A trial of heparin, streptokinase and arvin. British Medical Journal I: 806-810 (1969a). Kakkar, V.V.; Howe, C.T.; Laws, J.W. and Flanc , C.: Late results of treatment of deep vein thrombosis. British Medical Journal 1: 810-811 (1969b). Kinlough-Rathbone, R.L.: The effects of some other drugs on platelet function; Hirsh, Cade, Gallus and Schonbaum (Eds) Platelets, Drugs and Thrombosis, p.124 (Karger, Basel 1975). Kjeldgaard, N.O. and Ploug, J.: Urokinase. An activator of plasminogen from human urine. II Mechanism of plasminogen activation. Biochimica et Biophysica Acta 24: 283-289 (1957). Kline, A.; Hughes, L.E.; Campbell, H.; Williams, A.; Zlosnick, J. and Leach , K.G.: Dextran 70 in prophylaxis of thrombo-embolic disease after surgery: A clinically oriented randomized doubleblind trial . British Medical Journal 2: 109-112 (1975). Kline, D.L. and Tsao, C.H.: Activation of human plasminogen by streptokinase in absence of plasmin-SK activator. American Journal of Physiology 220: 440-443, (1971) . Kowalski, E.; Budzynski, A.Z.; Kopec, M.; Latallo, Z.S.; Lipinski, B. and Wegrzynowicz, Z.: Studies on the molecular pathology and pathogenesis of bleeding in severe fibrinolytic states in dogs. Thrombosis et Diathesis Haemorrhagica 12: 69-86 (1964). Krasno, L.R. and Kidera, G.J.: Clofibrate in coronary heart disease: effect on morbidity and mortality. Journal of the American Medical Association 219: 845-851 (1972). Kucinski, C.S.; Fletcher, A.P. and Sherry, S.: Effect of urokinase anti-serum on plasminogen activators: Demonstration of immunologic dissimilarity between plasma plasminogen activator and urokinase . Journal of Clinical Investigation 47 : 1238-1253 (1968).


Kwaan, H.C.: Tissue fibrinolytic activity studied by a histochemical method (review) Federation Proceedings 25: 52-56 (1966). Langsjoen, P.H.; Sanchez, S.A.; Lynch, D.J. and Inmon, T.W.: The treatment of myocardial infarction with low-molecular weight dextran. American Heart Journal 76: 28-34 (1968). Langsjoen, P.H. and Murray, R.A.: Treatment of postsurgical thromboembolic complications. Journal of the American Medical Association 218: 855-860 (1971). Leonards, J.R.; Levy, G. and Niemezura, R.: Gastrointestinal blood loss during prolonged aspirin administration. New England Journal of Medicine 289 : 1020-1022 (1973). Lesuk, A.; Terminello, L. and Travez, J.H.: Crystalline human urokinase. Some properties. Science 147: 880-882 (1965). Ling, C.M.; Summaria, L. and Robbins, K.C.: Isolation and characterization of bovine plasminogen activator from a human plasminogen streptokinase mixture. Journal of Biological Chemistry 242 : 1419-1425 (1967). Lindsay, R.M.; Prentice , C.R.M.; Ferguson , D.; Burton, J.A. and McNicol, G.P.: Reduction of thrombus formation dialyser membranes by aspirin and RA 233, Lancet 2: 1287-1290 (1972). Loew, D.; Wellmer, H.K.; Baer, V.; Merquet, H.; Rumpf, F.; Petersen , H.; Bromig, G.; Persch, W.F.; Marx, F.J. and von Bary, S.M.: Postoperative Thromboembolie prophylaxe mit Acetylsalicylsaure. Deutsche Medizinische Wochenschrift 99: 565-572 (1974). Mailloux, L.; Swartz, C.D.; Capizzi, R.; Kim, K.; Onesti, G.; Ramirez , O. and Brest, A.N.: Acute renal failure after administration of low-molecular weight dextran. New England Journal of Medicine 277: 1113-1118 (1967). Mann, J.R .; Deeble, T.J .; Breeze, G.R. and Stuart, J.: Ancrod in sicklecell crisis. Lancet 1: 934-937 (1972). Mansfield, A.O.: Alteration in fibrinolysis associated with surgery and venous thrombosis. British Journal of Surgery 59: 754-757 (1972). Martin, M.; Levy, H.; Schoop, W. and Zeitler , E.: Thrombolysis in patients with chronic arterial occlusions; in Mammen, Anderson and Barnhart (Eds) Thrombolytic Therapy, p.235 (Schattauer, Stuttgart 1971) . Mathew, T.H.; Kincaid-Smith, P.; Clyne, D.H.; Saker, B.M.; Nanra, R.S.; Morris, P.J. and Marshall, V.C.: A controlled trial of oral anticoagulants and dipyridamole in cadaveric renal allografts. Lancet 1: 1307-1310 (1974). Medical Research Council (Report of the Steering Committee): Effect of aspirin on postoperative venous thrombosis. Lancet 2: 441-444 (1972).

Antithrombotic Drugs

Meyer, J.S.; Charney, J.Z. ; Rivera, V.M. and Mathew, N.J. : Cerebral embolization ; prospective clinical analysis of 42 cases. Stroke 2: 541 -552 (1971). Mielke, C.H.; Ramos, J.C. and Britten, A.F.H .: Aspirin as an antiplatelet agent : Template bleeding time as a monitor of therapy. American Journal of Clinical Pathology 59: 236-242 (1973). Monnens, L.; Kleynen, F.; Van Munster, P.; Schretlen, E. and Bonnerman, A.: Coagulation studies and streptokinase therapy in the haemolyticuraemic syndrome. Helvetica Paediatrica Acta 27: 45-54 (1972). Morgan, T.O.; Little, J.M. and Evans, W.A.: Renal failure associated with low molecular weight dextran infusion. British Medical Journal 2: 737-739 (1966). Mundall, J.; Quintero, P.; von Kaulla, K.N.; Harmon; R. and Austin, J.: Transient monocular blindness and increased platelet aggregability treated with aspirin : A case report. Neurology 22: 280-255 (1972). Mundth, E.D.; Long, D.M. and Brown, R.B.: Treatment of experimental frost bite with low molecular weight dextran. Journal of Trauma 4: 246-257 (1964). Murray, S. and Dewar, P.J.: Low-molecular weight dextran and matching by enzyme technics. Transfusion 11: 378-381 (1971). Mustard, J.F. and Packham, M.A.: Factors influencing platelet function: adhesion, release and aggregation. Pharmacological Reviews 22: 97-187 (1970b). Myhre, H.O. and Holen , A.: Tromboseprofylakse. Dextran eller warfarin-natrium? Nordisk Medicin 82: 1534-1538 (1969). Nilsson, l.M. and Eiken, 0. : Further studies on the effect of dextran of various molecular weights on the coagulation mechan ism. Thrombosis et Diathesis Haernorrhagica 11: 38-50 (1964). Nilsson, l.M. and Isacson, S.: New aspects of the pathogenesis of thromboembolism. Progress in Surgery 11: 46-68 (1973). Nilsson, l.M.; Hedner , U. and Isacson, S.: Phenformin and ethyloestrenol in recurrent venous thrombosis. Acta Medica Scandinavica 198 : 107-114 (1975). Norman, P.S.: Antiplasmins. Federation Proceedings 25: 63-67 (1966). O'Brien, J.R.: Effects of salicylates on human platelets. Lancet 1: 779-783 (1968). Olsen, E.G.J. and Pitney, W.R.: The effect of arvin on experimental pulmonary embolism in the rabbit. British Journal of Haematology 17: 425-429 (1969). Packham, M.A. and Mustard, J.F.: Non-steroidal antiinflammatory drugs, pyrimido-pyrimidine compounds and tricyclic compounds. Effects on platelet functions ; in Hirsh, Cade, Gallus and Schonbaum (Eds) Platelets, Drugs and Thrombosis, p.ll1 (Karger, Basel 1975).


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of clotting problems in long-term hemodialysis; in Mammen, Anderson , and Barnhart (Eds) Thrombolytic Therapy, p.3l5 (Schattauer, Stuttgart 1971) . Rosenberg, F.J .; Gimber-Phillips, P.E.; Groblewski , G.E.; Davison, C.; Phillips, D.K.; Goraluick, SJ. and Cahill, E.D.: Acetylsalicyclic acid : Inhibition of platelet aggregation in the rabbit. Journal of Pharmacology and Experimental Therapeutics 179: 410-418 (1971). Rothermel, J.E .; Wessinger, LB . and Stinchfield, F.E.: Dextran 40 and thromboembolism in total hip replacement surgery. Archives of Surgery 106: 135-137 (1973). Salzman, E.W.; Harris, W.H. and De Sanctis , R.W.: Reduction in venous thromboembolism ·by agents affecting platelet function . New England Journal of Medicine 284 : 1287-1292 (1971) . Sawyer, R.B.: Clinical experience with dextran treatment. Acta Chirurgica Scandinavica, Suppl. 387: 58-60 (1968). Schmutzler, R. and Koller, F.: Thrombolytic therapy; in Poller, (Ed) Recent Advances in Blood Coagulation p.299 (Churchill , London 1969). Scottish Societ y of Physicians (Research Committee): Ischaemic heart disease: A secondary prevention trial using clofibrate. British Medical Journal 4: 775-784 (1971). Scottish Study: A multi-unit controlled trial: Heparin versus dextran in the prevention of deep-vein thrombosis. Lancet 2: 118-120(1974). Sharma, G.V.R.K. ; Godin , P.F.; Belko, J.S.; Bell, W.R. and Sasahara, A.A.: Arvin therapy in experimental pulmonary emboli sm. American Heart Journal 85: 72-77 (1973) . Sharp, A.A.; Warren, B.A.; Paxton , A.M. and Allington, M.J.: Anticoagulant therapy with a purified fraction of malayan pit viper venom. Lancet 1: 493-499 (1968). Silberman, S.; Potter, E.V. and Kwaan, H.C.: Effects of arvin in mice. Immunofluorescent and histochemical studies. Experimental Molecular Pathology 14: 67-74 (1971). Simon , T.L. ; Ware, J.H. and Stengle, J.M.: Clinical trials of thrombolytic agents in myoca rdial infarction. Annals of Internal Medicine 79: 712-719 (1973). Smythe, H.A.; Ogryzlo, M.A.; Murphy, E.A. and Mustard, J.F. : The effect of sulfinpyrazone (anturan) on platelet economy and blood coagulation in man. Canadian Medical Association Journal 92: 818-821 (1965) . Soreff , J.; Johns son, H.; Diener, L. and Goran sson, L.: Acetyl salicylic acid in a trial to diminish thromboembolic complications after elective hip surgery. Acta Orthopaedica Scandinavica 46: 246-255 (1975) .


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Authors' address: Dr A.S. Gallus and Dr J. Hirsh, St. Joseph's Hospital and McMaster University, Hamilton, Ontario LBN 1 Y4 (Canada) .

Antithrombotic drugs: part II.

Review Article Drugs 12: 132-157 (1976) © ADIS Press 1976 Antithrombotic Drugs: Part 11 1 A.S. Gallus and J. Hirsh St. Joseph's Hospital and McMaster...
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