PLATELETS AND VASCULAR OCCLUSION

Pathophysiology of coronary occlusion in acuteinfarction

ATTILIO MASERI, M.D., SERGIO CHIERCHIA, M.D., AND GRAHAM DAVIES, M.D.

ABSTRACT Coronary angiography has proved beyond doubt that complete coronary occlusion isthe rule in the very early hours of infarction. The 60% to 80% rate of coronary recanalization afterthrombolytic therapy has proved that thrombosis is a major component of the occlusion at the timewhen the procedure is performed a few hours after the onset of symptoms. However, the trigger forcoronary thrombosis and the causes of failure of thrombolytic therapy are still a matter of speculation.The relatively rare occurrence of acute coronary occlusion in the life of an individual with even severe

coronary disease can be explained on the basis of the necessity of either (1) extremely powerful isolatedstimuli, which only occurs rarely, or (2) the casual simultaneous presence in one coronary arterialsegment of multiple unfavorable events, such as plaque fissuring, enhanced reactivity of coronary

smooth muscle to constrictor stimuli and displacement of the thrombotic-thrombolytic equilibriumtoward thrombosis. Coronary artery constriction possibly caused by vasonconstrictor substances re-

leased by thrombus, represents the potential element of a vicious cycle causing persistent coronary

occlusion and reocclusion when reflow occurs with thrombolysis.Circulation 73, No. 2, 233-239, 1986.

THE NOTION of coronary artery occlusion is tradi-tionally associated with that of myocardial infarction.However, total coronary occlusions in the absence ofinfarction are frequently observed both during angio-graphic and postmortem examination in patients with-out symptoms or signs of ischemic events. Coronaryocclusions are most likely to cause myocardial necro-sis when occurring suddenly in vessels that are notalready critically obstructed and have no adequate orno functional distal collaterals. Conversely, when oc-clusions are not associated with detectable ischemicevents they probably developed gradually in vesselswith distal functioning collaterals.i The alternativeview, that coronary occlusion may be a consequencerather than a cause of infarction,2 although attractivelyexplaining some puzzling observations,3 lacks objec-tive evidence. Thus it seems reasonable to assume thatthe development of infarction is usually determined bythe balance between four factors: (1) the rate of pro-gression of the occlusion, (2) its duration or intermit-tance, (3) the extent of collateral blood flow, and (4)the coronary and myocardial response to ischemia.We will consider only the mechanisms of acute

From the Royal Postgraduate Medical School, Hammersmith Hospi-tal, London.

Supported by British heart Foundation and Medical Research Councilprogramme grant PG979/1033.

Address for correspondence: Attilio Maseri, M.D., Royal Postgradu-ate Medical School, Hammersmith Hospital, Ducane Road, LondonW12 OHS, England.

Vol. 73, No. 2, February 1986

coronary occlusion, attempting to separate facts fromextrapolations so that future lines of research can bedefined from a more rational basis.

Evidence for coronary occlusion in the early phases ofinfarction. The angiographic studies by De Wood et al.4have definitively clarified the issue by showing beyonddoubt that, in the first 4 hr of the onset of symptoms,the coronary artery supplying the infarcted area is in-deed occluded in over 87% of patients and is patent,although severely narrowed, in the remaining 13%.These findings have been largely confirmed by subse-quent reports on intracoronary thrombolysis. It is con-ceivable that in the few cases in which the artery wasfound to be patent, it may have been occluded pre-viously, since occlusions do tend to recanalize sponta-neously and patent vessels are found in 32% of patientswithin 12 hr4 and in about 50% at 2 to 3 weeks.5

Therefore, because enough evidence has now beengathered to establish that the coronary artery supplyingthe infarcted region in indeed totally occluded, at leastin the early phases of infarction, it is appropriate todiscuss the nature of the occlusion and its initiatingmechanisms.

Nature of the acute coronary occlusion. From a theoreti-cal point of view, acute coronary occlusion may becaused by intravascular plugging by blood constitu-ents, by some form of vasospasm (see below), byembolization, by intraplaque hemorrhage, or possiblymore often by a variable combination of these factors.

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The relative role of these mechanisms is probably notthe same in all patients and may vary in time as theacute event evolves.

Established myocardial infarction. Undoubtedly throm-bosis must play a major role at 2 to 6 hr from the onsetof symptoms, when thrombolysis is usually per-formed, considering the very high incidence of recana-lization resulting from the procedure. Conversely,within this same period, spasm (at least of the typeresponsible for variant angina, which is usally prompt-ly relieved by nitrates) seems to play a minor rolebecause, with a single exception,6 all reports show alow incidence of recanalization after intracoronary ni-troglycerin.7 "No definite explanation is yet availablefor the 20% to 30% of cases in which both nitrates andthrombolysis are ineffective in reopening the artery. Intwo such cases no thrombus was found at postmortemexamination at the site of severe stenosis.9 Thrombusnot reached by or resistant to thrombolytic agents, orspasm refractory to nitrates, are possible alternatives.

Developing myocardial infarction. In an earlier phase themechanisms of occlusion seem to be complex as sug-gested by a recent study performed in our institution. 1'2In nine instances in which we could begin intracoro-nary streptokinase 45 to 120 min from the onset ofsymptoms, we observed reocclusion (five patients) orocclusion of an initially patent artery (1 patient) whileinfusing the drug at 5000 IU/min; the occlusion wastransient in four patients but irreversible in two; in twoinstances the vessel became patent promptly, but onlytransiently, after intracoronary administration of ni-trates. Thrombosis still developing in spite of highconcentrations of streptokinase, or spasm only tran-siently relieved or refractory to nitrates (see below),could account for our findings. An alternative explana-tion could be provided by subintimal hemorrhage intoa plaque. However, postmortem studies suggest thatthis event is a rare cause of occlusion'31- and it isusually confused with plaque fissuring, which, havinga large opening toward the lumen, cannot cause ob-structions by itself unless associated with thrombosis.

Coronary arterial lesions and composition ofthrombi. Post-mortem studies, although probably biased toward mostsevere lesions, provide us with some information on atleast one type of patient with acute infarction: thosethat die. Thrombus is found in 21% to 54% of patientsin one series of studies and in above 66% to 100% inanother series. 16 Patient selection, definitions, andmethod of examination account for these wide discrep-ancies. Thrombi are found less frequently in subendo-cardial and small recent infarcts than in large olderinfarcts complicated by pump failure. Early spontane-

ous recanalization as suggested by the studies of DeWood et al.4 and of Bertrand et all may explain theabsence of occlusive thrombus at postmortem study.

Systematic studies would be useful to assess thecharacteristics of the vessel wall at the site of thrombo-sis in relation to residual vascular lumen, length andseverity of the preexisting atheromatous lesion, thepresence of intimal damage, plaque fissure, intra-plaque hemorrhage, the preservation of medial smoothmuscle, and features of the adventitia with particularattention to vasa vasorum, nerve endings, and inflam-matory cells.A careful postmortem study of the composition of

thrombi, when possible, would provide clues to theirorigin. If platelets and fibrin are the main componentsof at least one section of the occlusion, the "whitethrombus" must have developed gradually in flowingblood. Conversely, if red cells are present in all seg-

ments of the thrombus in the same percentage as incirculating blood, without any trace of white throm-bus, the "red thrombus" or clot must be secondary tototal occlusion by other mechanisms. In turn, whenplatelet-rich white mural thrombi do not occlude thelumen completely, either postmortem release of spasmor partial lysis must be invoked to explain the absenceof total occlusion. Although partial postmortem lysiscannot be excluded, this process is considered ratherunlikely. 14 17

A potential vicious cycle. Local coronary vasoconstric-tion caused by substances released by thrombi such as

thromboxane A2, 8 serotonin 19 and thrombin20 is a pos-

sible mechanism of persistent or recurring occlusion.Theoretically, if the local constrictor response of thearterial wall is sufficiently great, these compoundscould be the elements of a potential vicious cycle de-termining total occlusion by spasm in the presence ofintraintimal and mural thrombosis and favoring reoc-

clusion whenever release of spasm brings blood flowand hence more platelets.2' Conversely, during throm-bolytic therapy, release of spasm would allow deliveryof thrombolytic agents over the whole length of thethrombus.

Initial causes of occlusion. Although the predominantrole of thrombosis in acute coronary occlusion is un-

questionable, the mechanisms responsible for its initi-ation and progression are still speculative.

Plaque fissuring. Fissuring of plaques seems a mostlikely triggering event for coronary thrombosis. Stud-ies based on microanatomic reconstruction of vascularsegments with fresh thrombi in acute infarction2 23

consistently showed the presence of a fissured plaquewith intraintimal thrombus extending into the lumen

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(which excludes postmortem artifacts). Plaque fissurewith variable degree of intraintimal hemorrhage ex-tending toward the media was also frequently observedby Falk24 in patients with unstable angina who came topostmortem examination. This author suggested, aswe have done in the past,2' that plaque rupture withvariable degree of intimal hemorrhage and luminalthrombosis could represent the missing link betweenmorphology (atherosclerosis) and function (spasm).24However, it is possible that the arterial segment corre-sponding to the fissured plaque develops occlusivespasm in response to constrictor substances released bythe intraintimal and mural thrombi, only if coronarysmooth muscle hypereacts to constrictor stimuli.

In 100 cases of sudden coronary death, Davies andThomas'5 found plaque fissures with intraintimalthrombus in 74%; in 44% a large thrombus extendedinto the residual lumen and reduced it by more than50%; in an additional 30% mural thrombi were at-tached to the intima. However, they also found plaquefissuring with intraintimal thrombus in 10% of controlhearts, suggesting that this alteration is quite frequentin the general population. Occurrence of plaque rup-ture in atherosclerotic coronary arteries is not surpris-ing, considering that these vessels are continuouslysubjected to rhythmic motion and undergo frequentchanges in distending pressure and smooth muscletone.

Critical stenosis. Turbulence at the site of a criticalstenosis creating high shear stress was proposed tocause platelet damage and aggregation either directly25or because of ADP release by damaged red cells.26 Inanimals, transient platelet plugs form only at the site ofan acute stenosis narrowing the lumen more than 95%and reducing slightly even resting blood flow.27 Lumenreductions of lesser severity (up to 70%) still allow a300% to 400% increase of flow during reactive hyper-emia.28 Therefore it appears that only a very severestenosis coupled with high flow rates can produce suf-ficiently high shear stress to damage platelets and redcells. In patients who died after acute infarction, thepreexisting obstruction at the site of thrombosis isfound to reduce the lumen by 70% or more in 80% to90% of the cases; collaterals are often present in pa-tients with the most severe stenoses3 reducing forwardflow. However, less severe or even minimal lesions

3, 13, 14,17are found in 10% to 20% of cases.

Thrombusformation. Endothelial damage undergoes a

repair process that is self-limiting, although less severe

forms of wall damage result in a much more limitedreaction than larger ones, involving deeper layers ofthe vessel wall.29 A dynamic equilibrium between

thrombosis and thrombolysis has been postulated30 andthis view seems to be gaining acceptance.3' High flowrates tend to limit thrombus size in three ways: (1) thesubstances that cause platelet aggregation and can ini-tiate coagulation locally are rapidly diluted in the bloodstream (thus limiting thrombus growth); (2) plasmin,which has a very short half life, can be reformed bynewly delivered plasminogen and its activators (thusfavoring thrombolysis); (3) the superficial layers ofthrombus will tend to be dislodged because of the sheareffects of flow (and indeed platelet emboli can befound distally to a fresh thrombus24).

Thus, although it is understandable that largethrombi may form at the site of major obstructiveplaques with large tears, the mechanisms of thrombot-ic occlusion in segments of arteries with only minor orwith no detectable fissures and without critically ob-structive plaques are less clear. In this case, local fac-tors such as spasm and/or marked displacement of thethrombotic-thrombolytic equilibrium toward thrombo-sis may play an important role. The persistent tendencyof thrombosis to recur in discrete episodes at the samesite observed in patients with unstable angina24 is alsodifficult to explain, since usually endothelial repairafter thrombosis is rapid, at least in normal arteries.29

Coronary spasm. The reduction of caliber of epicardialcoronary arteries in response to constrictor stimuli israther small both in dogs32 and man,33 34 and it canimpair flow only in pliable segments of arteries with acritical subintimal plaque.35 Conversely, spasm as seenin "variant" angina causes total occlusion, even in ves-sels without critical lesions, in response to stimuli thatcause only moderate or no detectable constriction inpatients who are not in an acute phase of this syn-drome.36 Excessive smooth muscle response can beseen in the same patient after adrenergic, serotoniner-gic, and histaminergic stimuli.37 At present, no stimulicapable of producing occlusive spasm in the absence ofa local hyperreactivity and/or of a critical subintimalplaque are known.

In patients with variant angina, infarction is relative-ly rare considering the frequency of episodes of spasm.Out of over 7000 episodes of transient ischemia causedby spasm observed in a large group of patients withvariant angina, we found only 28 episodes that pro-gressed to infarction.38 However, although the mecha-nism leading to persistent coronary occlusion is mostlikely to be different from the form of spasm responsi-ble for variant angina, spasm must in some way berelated to infarction, since this occurred consistently inthe area supplied by vessels shown to undergo spasmduring transient ischemic episodes.2" 3 In three pa-

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tients we were unable to reestablish patency by largedoses of intracoronary nitrates, although the same ves-sel was patent 24 hr later. Angiography showed a pat-tern consistent with recanalized thrombus in two

cases, and the post mortem examination revealed amural platelet thrombus in another.39 Thrombosis wasalso observed in angiographically normal vessels afterspasm.42

In an unselected group of patients with recent myo-cardial infarction, Bertrand et al.43 observed that coro-nary arteries are supersensitive to spasmogenic stim-uli; ergonovine produced spasm in 20% of theirpatients with a recent infarction, a smaller percentagethan in patients with angina at rest (38%) but muchgreater than in patients with old infarction (6%) and inthose with stable angina (4%).

Thus it seems possible that persistent coronary oc-clusion may result both from spasm causing a plaque torupture and from plaque fissure in an arterial segmentsupersensitive to constrictor stimuli released by thedeveloping thrombus. Also, the possible occurrence ofspasm resistant or refractory to nitrates as observed insome cases after ergonovine provocation44 or after by-pass surgery45 cannot be dismissed. Persistent spasmwas observed at postmortem examination in patientswith variant angina who died during an attack.46 46aCatheter-induced spasm of the brachial artery and veinis a typical example of severe vasospasm that cannotbe relieved by sublingual, intravenous, and even local-ly injected nitrates or calcium antagonists. Extremesmooth muscle sensitivity to constrictor stimuli, per-sistence of the stimulus, or formation of latch bridgesthat require minimal energy expenditure to maintaincontraction47 are possible explanations for persistentspasm resistant to vasodilators.A unifying hypothesis. Acute coronary occlusion is an

occasional event in the life of an individual even whenextremely severe coronary atherosclerosis is present.Infarction is also relatively rare in patients with unsta-ble angina: 13% within 6 months in the Edinburghstudy48 49 and 8% within 1 month in the Rotterdamstudy.50 The relatively rare occurrence of acute coro-nary occlusion could be explained by the occurrence of(1) extremely powerful but rare stimuli or (2) the ne-cessity for the simultaneous occurrence of multipleindependent pathologic events in the same coronaryarterial segment.One such possible set of unfavorable events could be

a plaque rupturing in an arterial segment supersensitiveto vasoconstrictor stimuli with a local thromboticthrombolytic equilibrium displaced toward thrombo-sis. (figure 1).

Initial Mechanisms of Acute,Persistent Coronary Occlusion

FIGURE 1. The probability of developing an acute persisting coronaryocclusion in a patient with coronary disease over days, months, andyears is small and it may result from the casual combination of eventspresent at the same time. Three critical elements, potentially linked bypositive feedback mechanism, may be necessary to initiate coronaryocclusion. Plaque fissuring (a) and spasm (b) are related to the localcoronary artery pathology; the formation and progression of thrombusare related to local vascular anatomic and hemodynamic factors as wellas to the balance between thrombotic and thrombolytic factors (c). Thusthe probability of developing acute persisting coronary occlusion, P,can be seen as 1/(a x b x c), where a = development of plaque fissure,b = presence of local coronary artery supersensitivity to constrictivestimuli, and c = displacement of the thrombotic-thrombolytic equilibri-um toward thrombosis. However, an extreme alteration of either a or balone or a combined alteration of a and b, b and c, or a and c may besufficient to cause occlusion.

Thus the probability of developing an acute persis-tent coronary occlusion (P) can be seen as:

pa x b x c

where a = development of plaque fissure, b = pres-

ence of local coronary artery supersensitivity to con-

strictive stimuli, and c = displacement of the throm-botic-thrombolytic equilibrium toward thrombosis.

However, an extreme alteration of any of these fac-tors alone or a combination of a and b, b and c, or a andc may be sufficient to cause occlusion.

In diseased coronary arteries that remain occludedfor a period of time, the development and extension ofred thrombus may occur irrespective of the originalcause of occlusion (figure 2). The possibility of latethrombus formation 51. 52 or of its extension53 has beendemonstrated by the incorporation into thrombi of ra-

diofibrinogen injected after the onset of symptoms and

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Determinants of Coronary Thrombosis

S PA S M | WHITE THROMBUS

Transient or persistent coronary occlusion

(overall balance of thrombosis - thrombolysis - platelets - spasm)

ED THROMBUS or CLOT

(consequence of occlusion -_ cause of its' persistence and extension)

FIGURE 2. Initial acute coronary occlusion can be caused by whitethrombus forming gradually in flowing blood, by spasm, or by theircombination. Flowing blood tends to inhibit thrombus growth because itdilutes locally formed coagulant factors, it brings new plasminogen, andit tends to fragment unstabilized thrombus. In occluded vessels redthrombus may forn and extend depending on the balance betweenthrombotic and thrombolytic tendency, degree of vessel wall damage,and local hemodynamics. When a red thrombus has formed, the occlu-sion persists also when spasm has disappeared; conversely, restorationof flow by spontaneous thrombolysis or relief of spasm brings newplatelets that can adhere to the damaged wall and release vasoconstrictorsubstances, which may favor recurrence of spasm and reobstruction.Intermittent coronary occlusion seems a frequent feature in the veryearly phases of myocardial infarction in patients.

previously suggested by some postmortem studies forpatients with large infarcts and pump failure.545When an occlusive red thrombus is present, the vesselwill remain occluded even when spasm is relieved.

Implications for the prevention of myocardial infarction.In terms of treatment of acute coronary occlusion inacute infarction, intracoronary and intravenous throm-bolysis appears quite often effective in recanalizing theocclusion. The available evidence indicates that veryearly interventions (less than 2 hr) can prevent infarc-tion in about 50% of cases'2; lysis at 2 to 4 hr is likely toreduce size rather than preventing infarction. The mul-tiple factors involved in the genesis of infarction (fig-ure 3) and the possible stuttering progression of theocclusion suggests that the time from onset of symp-toms to irreversible necrosis maybe quite variable'2;thus decisions on maximum acceptable delay of throm-bolytic attempts should not be based only on the timeafter the onset of pain but also on the stage of theelectrocardiographic changes. Furthermore, consider-ing the possible late occurrence of thrombus extension,even late interventions might contribute to reduction ofthe infarct size and to the propagation of occlusive clotalong the vessel. The results with tissue-type plasmin-ogen activator are promising,56 57 but even with thisagent supposed to have a thrombospecific action therate of recanalization seems to be only 60% to 70% and

patients who do not respond also fail to respond tostreptokinase; reocclusion also seems to be a commonproblem, and bleeding is also observed.On the basis of these arguments, it may be desirable

to associate thrombolytic agents with drugs capable ofeffectively reducing coronary smooth muscle tone, butthis may not be possible until the mechanisms of coro-nary constriction in acute persistent coronary occlu-sion are better understood.

In terms of prevention, aspirin appears to reducesignificantly the occurrence of infarction and of sud-den death in patients who went through a phase ofunstable angina."1589 However, the mechanisms of thisbeneficial effect are not clear. Intravenous heparin alsowas found to reduce the occurrence of infarction in theintermediate coronary syndrome60; the result with anti-vitamin K anticoagulants are less clear.6' Thus theresults obtained so far with thrombolytic and anti-thrombotic agents for the treatment and prevention ofmyocardial infarction can be considered promising butonly partially successful.The reported beneficial effects of [3-blockers in

postinfarction patients seem more related to preventionof arrhythmic deaths than to reduction of infarction.62No large studies of the effects of calcium antagonistsand/or nitrates on mortality in early infarction and inunstable angina are available, but theoretically itwould seem reasonable to assume an additive effect ofa combined prophylaxis with antivasospastic and an-tithrombotic agents.The task of preventing acute persisting coronary

occlusions, occurring unpredictably and very rarely ina patient's life as a result of events localized in one

Mechanisnis of Infarction

FIGURE 3. Coronary occlusion is one of the determinants of infarc-tion and of its size but not necessarily the only one. The site of occlusion(at the site of an old severe stenosis or in a near-normal vessel) and theintermittence of the occlusion are also critical. Additional potentialdeterminants of infarction and of its size are represented by the behaviorof resistive and collateral vessels and by the response of the myocardiumto ischemia.

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coronary arterial segment and caused by a variablecombination of mechanisms, is arduous. The chancesof success depend not only on the identification of theprevailing initiating and feedback mechanisms, butalso on the possibility of intervening effectively in thevaried local pathologic processes of the coronary ar-tery wall.

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A Maseri, S Chierchia and G DaviesPathophysiology of coronary occlusion in acute infarction.

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