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THEEFFECTIVENESS OF DRUGS THAT
Venous thrombi consist mainly of fibrin and trapped red blood cells but there is
evidenc e that some venou s thrombi originate in valve pockets as aggregates of
platelets which propagate with the formation of fibrin to form classical red thrombi
(Paterson , 1969; Sevitt , 1973). In addition, platelet thrombi may form at sites ofdirect
injury to veins, for exarnple, after trauma to the legs or to the femoral vein during hip
surgery (Clagett , Brier , RosofT, Schneider & Salzman, 1974; Clagett , Scheider, RosofT
& Salzman, 1975). It is possible , becau se of the role of platelets in the genesis of
venous thrombosis, that drugs that suppress platelet function may be of value in
prevent ing the formation of venous thrombi which arise principall y as platelet
aggregates. Four ant iplatelet drugs, aspirin, dipyridamole, hydro xychloroquine and
sulph inp yrazone have been tested in prospective clin ical tr ials for the prevention of
deep vein th rombosis, and in one study the efTect of aspirin on fatal pulmonary
embolism was evaluated. Dextran, a glucose polymer introduced as a volume
expander, also inhibits platelet function and has antithrombotic properties, but these
properties may not be due to its antiplatelet efTect alone.
In evaluating stud ies of venou s thrombosis prophylaxis, it is important to consider
the endpoints used to detect venous thrombosis and since clinical diagnosis is
notoriously inaccurate, result s of trials using clinical endpoints are not acceptable.
Three objective and accurate methods of diagnosing venous thrombosis are
acceptable for use in c1inical trials. These are i) the use of leg scann ing in patients
who have general surgical procedures or in medical pat ients ii) the combined use of
leg scanning and impedance plethysmography in patients who undergo hip surgery
iii) the use of venography in all patients (Hull & Hirsh, 1979).
In addition , onl y the result s of clinical trials that fulfill well-defined design criteria
(Genton, Gent, Hirsh & Harker, 1975) can be used to draw valid conclusions and will
be cons idered in this review.
The characteristics of the antiplatelet drugs evaluated in c1inical trials have been
investigated in vitro and in animaI model s of thrombosis. They have also been
studied in man by measuring their efTects on the bleeding time and on platelet
VENOUS THROMBOEMBOLISM AND ANTIPLATELET DRUGS 225
survival time and turnover. Each drug has different relative effects when measured by
these tests . Some are effective in vitro while others show greater effect in vivo and at
present, there is no test that can predict which antiplatelet drugs will be cIinically
effective in man. In addition, although the drugs that have been evaluated cIinically
inhibit one or more platelet reactions and are antithrombotic in animal models, each
has to be tested in prospective cIinical trials to determine its usefulness as a
Mode of action of antiplatelet drugs
The mechanism by which aspirin inhibits platelet function has recently been defmed.
Aspirin inhibits the synthesis of cyclic endoperoxides and thromboxane Al from
platelet membrane arachidonic acid (Smith & Willis, 1971; Roth & Majerus, 1975).
Thromboxane Al is a potent stimulus ofthe platelet release reaction and aggregation
and a powerful vasoconstrictor. Roth & Majerus (1975) demonstrated that the effect
Cahill (1971) dernonstrated that aspirin acetylates other platelet membrane proteins
and inhibits the platelet membrane enzyme, collagen-glucosal transferase. These
effects will also contribute to aspirin's inhibitory effect on platelet function . Although
aspirin is rapidly cIeared from the circulation, it has an irreversible effect on all ofthe
platelets that are circulating at the time ofits administration because platelets cannot
regenerate cyclo-oxygenase that has been acetylated by aspirin.
Aspirin also inhibits prostagiandin synthesis by blood vessel walls . This could have
important practical implications because prostacycIin, (PGI2) which is a potent
inhibitor ofplatelet aggregation and a vasodilator, is synthesized by endothelial cells
in response to a number of stimuli which incIude thrombin and bradykinin
(Moncada, Higgs & Vane, 1977). It is therefore possible that aspirin could inhibit an
important protective mechanism, although it has been recently demonstrated by
Baenziger, Dillender & Majerus (1977) that much higher doses ofaspirin are required
to inhibit prostagiandin synthesis by cultured vessel wall cells than by platelets.
These in vitro fmdings are supported by the results of in viva experiments in animals
by Kelton, Hirsh, Carter & Buchanan (1978) who demonstrated that a dose ofaspirin
that augmented thrombosis was much greater than the dose required to inhibit
Asp irin has been extensively tested for its antithrombotic effects in models of
experimental venous thrombosis in animals. Renaud & Godu (1970) produced
thrombosis in rats by infusing endotoxin and demonstrated that aspirinized animals
had a lower incidence of hepatic vein thrombosis than controls. Petersen & Zucker
(1970) reported that aspirin significantly reduced the incidence of thrombosis in
chemically-damaged rabbit femoral veins . In contrast, however, Arfors, Bergqvist &
size ofvenous thrombi produced by mechanical damage to jugular veins in rabbits. In
this study, thrombus size was quantitated by measuring IlsI-labelled fibrinogen
incorporation into the thrombi and aspirin reduced the size of the thrombi but the
effect was limited to male animals. These observations are of particular interest since
(Harris, Salzman, Athanasoulis, Waltman & De Sanctis, 1977) and with transient
cerebral ischemia (The Canadian Cooperative Study Group, 1978) was limited to
Aspirin in doses of300 mg prolongs the bleeding time for up to five days in normal
volunteers (Mielke , Ramos & Britten, 1973) but unlike other drugs which suppress
platelet function, aspirin does not prolong reduced platelet survival seen in a number
ofthromboembolic diseases (Harker & Slichter, 1972).
Dipyridamole is a pyridimo-pyrimidine compound that was introduced c1inically as
a vasodilator. Dipyridamole inhibits adenosine diphosphate-induced platelet
(Zucker & Peterson, 1970; Cucuianu, Nishizawa & Mustard, 1971).
Mills & Smith (1971) demonstrated that dipyridamole inh ibits phosphodiesterase
activity in platelets and so increases platelet cyclic AMP levels which in turn are
associated with inhibition ofplatelet function. It has been reported that dipyridamole
has a greater ex vivo than in vitro etTect in platelet function which has been related to
the ant icoagulants used in the in vitro measurement ofplatelet function (Buchanan &
Hirsh, 1978) and to the ditTerences in the albumin concentrations when platelets are
tested ex vivo compared with in vitro (Jergensen & StotTersen, 1978). Dipyridamole
has also been reported to have other etTects on platelet function . Ally, Manku,
Horrobin, Morgan, Karmazin & Karmali (1977) demonstrated that dipyridamole
inhibits thromboxane A2 synthesis, although Moncada & Korbut (1978) presented
evidence contrary to this, and Best, McGuier, Jones, Holland, Martin, Preston, Segal
& Russell (1979)demonstrated that dipyridamole inhibits prostagiandin synthesis.
Dipyridamole has mainly been tested in animal models of arterial thrombosis and
has proven only moderately etTective (Arfors et al., 1975).
Dipyridamole in doses of400 mg daily prolongs shortened platelet survival seen in
patients with a number of thrombotic diseases and when combined with aspirin
100 mg daily of dipyridamole prolongs platelet survival in these patients, wherea s
when given in doses of200 mg alone it has no etTect (Harker & Slichter, 1972; Harker,
Slichter, Scott & Ross, 1974).
Dipyridamole has been evaluated for its antithrombotic etTect in man, singly and
in combination with aspirin using the doses that have been demonstrated to prolong
Hydroxychloroquine is an antimalarial drug that inhibits platelet function . Madow
(1960)demonstrated that red cell sludging was reduced by several antimalarial agents
particular1y hydroxychloroquine and subsequently, Carter, Eban & Perrett (1971)
or adrenaline-induced platelet aggregation after hydroxychloroquine ingestion. The
mechanism ofthe inhibitory etTect ofhydroxychloroquine and platelet function is not
known . Hydroxychloroquine has no etTect on the bleeding time and does not prolong
Hydroxychloroquine has been evaluated as an antithrombotic agent for venous
thrombosis prophylaxis in doses of600 to 1000 mg daily .
Sulphinpyrazone is a non-steroidal anti-inflamrnatory drug which was introduced as
a uricosuric agent. Sulphinpyrazone inhibits platelet aggregation by adrenaline and
VENO US THROMBOEMBOLlSM AND A NTIPLATELET DRUGS 227
collagen (Wylie, Chesterman, Morgan & Ca staldi, 1979) but there are conflicting
reports on its effect on ADP-induced platelet aggregation. Sulphinpyrazone also
inhibits platelet adhesion to coll agen in flowing blood but, at ph ysiological
Kinlough-Rathbone, Gent & Mu stard, 1979). The mode ofact ion ofsulphinpyrazone
is incompletely understood but there is evidence that sulphinpy ra zone is a
competitive inhibitor of cyclo-oxygenase (Ali & Ma cDonald, 1977). There is
evidence that a metabolite of sulphinpyrazone may be a more potent inh ibitor of
platelet aggregat ion than the parent compound. Buchanan, Ro senfeld & Hirsch
(1978) reported that platelet aggregation in vivo was inhibited for up to 18 h following
administration ofsulphinpyra zon e at whi ch time the drug had been cleared from the
plasma for 14 h. In addition, when normal platel ets were incubated with plasma from
rabbits pretreated with sulphinpyrazone 18 h previou sly, a signi ficant inhibition of
Arfors et al. (1975) demonstrated that sulphinpy razone did not prevent venous
th rombosis produced in rabbit femoral vein s by a combination ofendothelial damage
a nd stasis. Sulphinpyrazone prolongs reduced platelet survival in pati ents with gout
(Sm ythe, Ogruyzlo, Murphy & Mu stard, 1965) and a variet y of diseases associated
with thrombosis (We ily & Genton, 1970).
Sulphinpyrazone has been eva luated in two clinical tria ls for venous th rombosis
prophylax is in dose s of800 mg daily.
CIinical evaluation ofplatelet suppressant drugs in venous thromboembolism
Aspirin has been evaluated for the prevention of venous thromboembolism, either
alone or in combination with other antiplatelet drugs, in patients undergoing genera l
abdominothorac ic surger y or orthopaedic procedures. In general, aspirin has not
been effective in reducing the frequency of veno us thrombosis in general surgica l
patients and the results have been mixed in th e patients undergo ing orthopaedic
procedures. The results are summa rized in Table I.
Table 1 Random ized studies using aspirin in the prevention ofvenous thrombosis.
Author Dose tmg) Su rgery patients Control Treated
MedicalResearch Council (1972) 600 General 303 22 28
Clagett et al. (1 974) 1300 General 105 20 12
Shöndorf& Hey (19 77) 450 Orthopaedic 45 60 53
Har ris et al. (1 977) 1200 Orth opaedic 95 43 25
Hume et al. (19 77) 1200 Orth opaedic 71 35 30
McKenna et al.(1980) 900 Orthopaedic 43 75 78
Two studies on th e effect of aspirin, 600 mg and 2400 mg (ü'Brien , Tulevsk i &
Etherington, 1971) and 600 mg (Medical Research Council, 1972), for th e pr evention
of leg scan-detected venous thrombosis in patients undergoing thoracotomy a nd
general surgery showed no benefit from asp ir in. Similarl y, Clagett et al. (1974) found
no benefit with 1300 mg ofaspirin daily in gen eral surgica l patients using leg scanning
to detect venous thrombosis with venogra phic confirrnation. On the first an al ysis of
the dat a, th ere was 00 significa nt difference between the incidenc e of venous
thrombosis in the control group (20%) compared with the treated group (13%) but,
after 4 patients in the aspirin group in whom venous thrombosis developed were
excluded because they did not receive the drug, the difference became statistically
A combination ofaspirin and dipyridamole has been reported to produce a signifi -
cant reduction in the incidence of postoperative venous thrombosis detected by leg
scanning in general surgical patients by Renney, O'Sullivan & Burke (1976).
There have been a number of trials on the use of aspirin in preventing venous
thrombosis inpatients undergoing surgery for hip fracture or following elective hip
replacement. Salzman, Harris & Oe Sanctis (1971) reported on a comparison of
aspirin, dipyridamole, warfarin and low-rnolecular weight dextran, using clinical
diagnosis as the endpoint, and reported that aspirin was as effective as warfarin, but
that dipyridamole was ineffective. In a second comparison using venography to
detect venous thrombosis (Harris et al., 1974) heparin was less effective than the other
three treatments but the incidence of thrombosis was high in all groups and in the
aspirin-treated group, there were more large and multiple thrombi. Harris et al.
(1977) reported the results of a prospective control double-blind study of aspirin,
1200 mg daily, in patients undergoing total hip replacement using venography as the
diagnostic endpoint. Venous thromboembolism developed in 11 of 44 patients
receiving aspirin compared with 23 of 51 patients receiving placebo. This difference
is significantly different. In this study, the beneficial effect of aspirin was limited to
men; 4 of23 men who received aspirin and 14 of23 who received placebo developed
venous thrombosis compared with 7 of 21 women who received aspirin and 9 or 26
women who received placebo. Review ofthe previous study by these authors showed
a similar differential benefit between men and women. Hume, Bierbaum, Kuriakose
& Surprenant (1977) reported the results of a non-randornized trial of aspirin
frequency was significantly lower in the aspirin-treated group compared with the
contro!. Sch öndorf & Hey (1978) reported that intravenous aspirin in doses of
900 mg had no effect on leg scan and venographically detected venous thrombosis in
patients undergoing elective hip surgery.
A study reported by McKenna, Galante, Bachman, Wallace, Kaushai & Meredith
(1980) in patients undergoing elective knee surgery is of particular interest as aspirin
was ineffective when used in a dose of 900 mg daily, but markedly reduced the
frequency of objectively detected venous thrombosis when used in a dose of 3500 mg
daily. The reason for this is not certain.
Zekert, Kohn, Vormittag, Poigenfurst & Thien (1974) reported the results of a
pulmonary embolism was one of the main endpoints, and all patients who died in
hospital had an autopsy. One hundred and twenty patients completed the study and
12 patients died, 3 in the aspirin-treated group and 9 in the placebo group. Although
there was no statistical difference in the total number ofdeaths, pulmonary embolism
was found in I patient treated with aspirin and in 8 patients treated with placebo. In
each case, pulmonary embolism was considered to be the cause of death. There was,
in addition, a reduced incidence of clinically diagnosed deep vein thrombosis and
pulmonary embolism in the aspirin-treated group. Thirty eight patients were
excluded from analysis of the study for a variety of reasons and 8 of them died; a
mortality four times greater than in the patients included in the study. Jennings,
Harris & Sarmiento (1976) reported on the use of 1200 mg of aspirin daily in patients
undergoing total hip replacement and found no pulmonary emboli in patients in
whom the expected incidence ofdeath from pulmonary embolism was 1-2%.
Oechavanne, Ville, Viala, Kher, Faivre, Pousset & Dejour (1975) and Silvergleid,
VENOUS THROMBOEMBOLlSM A ND ANTIPLATELET DRUGS 229
Bernstein, Burton, Tanner, Silverman & Schrier (1977) found that the combination of
aspirin and dipyridamole did not reduce the incidence of venous thrombosis after
elective hip replacement. Morris & Mitchell (1977) reported that daily doses of
900 mg aspirin combined with 300 mg dipyridamole, or of flurbiprofen 150 mg
or dipyridamole of 300 mg did not reduce the frequency of isotopically diagnosed
venous thrombosis in patients with hip fractures, when compared with control
patients receiving no treatment, but in this study, since leg scanning was used to
detect venous thrombosis, no account was made for the possible occurrence of
isolated thrombi at the fracture sites.
An early study wh ich evaluated the effect of dipyridamole on postoperative venous
comparing dipyridamole alone or in combination with aspirin (see above). The study
preventing venous thrombosis using leg scanning in hip fracture patients, none of
these regimens significantly reduced the incidence of venous thrombosis.
Dechavanne et al. (1975) reported that low-dose heparin was more effective than
dipyridamole plus aspirin in leg scan-detected venous thrombosis following hip
replacement. In contrast, both Renney et al. (1976) and Plante, Boneu, Vaysse,
Barret, Gouzi & Bierme (1979) reported that aspirin plus dipyridamole was effective
in decreasing leg scan-detected venous thrombosis following elective general surgery.
There have been a number of c1inical trials on the use of hydroxychloroquine for the
prevention of venous thrombosis in general surgical and orthopaedic patients. The
results are summarized in Tab!e 2. In each of the three trials involving general
surgical patients (Carter et al., 1971; Carter & Eban, 1974; Wu, Tsapogas & Jordan,
1977) where the risk of thrombosis would be considered moderate, a significant
reduction in deep vein thrombosis was detected in the hydroxychloroquine-treated
patients. Conflicting results have been reported in the studies of patients undergoing
orthopaedic procedures. Chrisman, Snook, Wilson & Short (1976) in a comparison of
hydroxychloroquine and placebo for the prevention of venous thrornbosis, in
patients with fractures or orthopaedic procedures to the knee or pelvis, reported that
venous thrombosis, diagnosed by impedance plethysmography and confirrned by
venography, was significantly reduced in the hydroxychloroquine group compared
Table 2 Randomized studies using hydroxychloroquine in the prevention of venous
with the placebo. On the other hand, studies by Hansen, Jessing, Lindewald,
Ostergaard, Olesen & Malver (1976), Hume et al. (1977), and Cooke, Dawson,
Ibbotson, Bowcock , Ainsworth & Pileher (1977) failed to demonstrate any benefit in
patients having surgery for fractured hip or after elective hip replacement using leg
scanning and venography to diagnose venous thrombosis.
There have been two prospective trials on the use of sulphinpyrazone for the
prevention ofpostoperative deep vein thrombosis. Gruber, Fuser, Frick, Loosli, Matt
& Segesser (1977) reported the results ofa prospective study comparing the effects of
sulphinpyrazone, heparin and dextran on the incidence of venous thrombosis after
elective general surgery using leg scanning to detect venous thrombosis. Both dextran
and heparin were more effective than sulphinpyrazone in reducing the frequency of
postoperative venous thrombosis. Rogers, Walsh, Marder, Basak, Lachman, Ritchie,
Oppenheimer & Sherry (1978) carried out a randomized double-blind study
comparing sulphinpyrazone, low-dose heparin or placebo in patients undergoing hip
surgery and reported no significant reduction in the frequency of venous thrombosis
detected by leg scanning and venography in either treatment group compared with
Of the platelet function suppressant drugs tested for the prevention of deep vein
thrombosis, aspirin is the only one that has been used in practice. However, the
results of the studies using aspirin have been inconsistent, although positive results
three studies of patients undergoing general abdominothoracic surgery but to be
ineffective in patients undergoing orthopaedic procedures. Dipyridamole and
sulphinpyrazone have been shown to be ineffective for the prevention of deep vein
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