Platelet activation appears to play a pivotal role in the development of the acute ob structive ischaemic syndromes of CHD. The evidence for this comes from a number
o f sources indicating that platelet activation is im portant in the pathophysiological process o f acute coronary throm bosis. It remains unclear, however, whether preex isting platelet activation predisposes to thrombus formation.
1.2.1 Acute Myocardial Infarction and Platelets
Platelet activation has been dem onstrated in patients with unstable angina and early during A M I.45,74 Changes in some m easures of platelet function indicating platelet activation are well documented. Firstly, an elevation o f beta-thromboglobulin (BTG) early during AMI has been reported.75'81 Increased BTG levels has been reported to be d ire c tly p ro p o rtio n a l to the sev erity o f C A D .77 O th er stu d ies have fo u n d in creased levels of BTG in patients w ith CAD w hich does not increase fu rth er with A M I,82 w hile others have shown increases in BTG only in a m inority o f patients w ith A M I.83 Secondly, m ost reports have also found an elevated p latelet facto r 4 (PF4) in the early phases o f A M I.84'88 H ow ever, others have failed to dem onstrate an in crease in PF4 ex cep t in association w ith invasive procedures or p latelet de granulation in vitro.89 A nother study reported an increase in PF4 in stable chronic CHD and no further increase associated with AM I.87 Thirdly, a metabolic product of thromboxane A2 (TXA2) excreted in the urine would appear to be a reliable measure o f p latelet activation since it is not associated with artefactual changes due to sam plin g p ro c e d u res.45 The m etabolic product, 2 ,3 ,d in o r-th ro m b o x an e B2 is clearly elevated in the urine o f patients with AMI and unstable angina.45'90 Increased TXA2 fo rm atio n m ust th e re fo re o ccu r at least in the early p h ase o f A M I and u n stab le angina. W hether there is a pre-m orbid increase contributing to the initiation o f the events is uncertain. Interestingly, platelet hyper-reactivity may be related to progno sis in AM I59 and CH D .91 Finally, activation o f prostacyclin (PGI2) synthesis occurs in these conditions,45,90,92 although there may not be an increase in PGI2 production in many patients during the acute thrombotic phase of AMI.93
M easures of platelet survival time do not appear to be strongly influenced by acute ischaemic syndromes of CHD. Platelet survival time is shortened in chronic CHD,94' 96 although during AM I there appears to be no additional m easurable reduction in platelet mean lifespan above that observed in chronic CAD.96
C linical studies w ith aspirin support the evidence for platelet involvem ent in these acu te o c c lu siv e c o ro n a ry a rte ry sy n d ro m es o f u n sta b le a n g in a and A M I.97' 103 Although the m echanism (s) for the beneficial influence of aspirin has not have been fully delineated, it is assumed to be the inhibitory effect on platelet cyclooxygenase, thereby inhibiting platelet aggregation. Aspirin has also been effective in secondary red u ctio n o f co ro n ary occlusive events after A M I,104,105 probably by p rev en tin g rethrombosis.
1.2.2 Unstable Angina and Platelets
The clinical syndrome o f unstable angina encompasses a diverse spectrum of patients and clinical presentations. Within those groups diagnosed as having unstable angina p e cto ris, there are certain subgroups w ith an in creased risk o f early m y o card ial infarction (MI) and even death.17,106' 109 A ngiographic,18'20,26,110' 115 autopsy,26,112 as well as angioscopic4,23 evidence indicates that throm bus form ation over a fissured
atherosclerotic plaque plays a key role in the development of unstable angina. Not surprisingly then, platelet activation has been demonstrated in unstable angina re fle c te d by elevated plasm a levels of p latele t d eriv ed p ro tein s, BTG and PP474,76,8i,83.ii6 purthermore, increased production of TXA2 as measured by urinary metabolites is evident.45,74 In unstable angina, there is a higher thromboxane B2 (TXB2) metabolite excretion in patients with persistent ischaemic symptoms than in those that respond to treatment. Similarly, higher levels are found in those with post infarctional angina.74 Enhanced excretion of TXB2 metabolite is frequently associat ed with angiographic evidence of thrombosis.74 In addition, prospective clinical trials have shown a reduction in CHD events and in mortality with antiplatelet drugs.97'98 Heparin also decreases the incidence of AMI associated with unstable angina.103,117
1.3 PLATELETS, PLATELET FUNCTION AND CORONARY HEART