Monitoring Edwin

Thrombolytic

G. Bovill, Richard

Becker, and Russell P. Tracy

HROMBOLYTIC THERAPY for acute myocardial infarction (MI) now represents the standard of care for many patients. A large number of clinical trials have demonstrated improvement in survival and cardiac function following treatment of acute MI with thrombolytic agents,‘.’ and the use of thrombolytic therapy is rapidly spreading to community hospitals. A number of clinical trials are focused on expanding the eligibility criteria for thrombolytic therapy to groups excluded from initial studies. The consequent widespread use of thrombolytic therapy will necessitate an understanding of the comphcations of this therapy and a strategy for their management. The major complications are failure of initial coronary reperfusion, coronary reocclusion, and hemorrhage. This article will review the fibrinolytic system and then examine the use of laboratory and noninvasive cardiac monitoring of clinical outcome following fibrinolytic therapy.

T

REVIEW OF THE FIBRINOLYTIC HEMOSTASIS

SYSTEM

IN

The physiologica response to vascular injury generates a hemostatic plug. Initially, platelets adhere to the damaged vessel wall by means of surface bound von Willebrand factor which binds to glycoprotein Ib on the platelet membrane. These adherent platelets then recruit other platelets through the release of a variety of mediators to form a platelet-rich “primary hemostatic plug” held together by fibrinogen bound to glycoprotein IIb/IIIa on the platelet surface. In the course of primary plug formation, platelets are activated and generate thrombin at their surface which cleaves fibrinogen to form a fibrin meshwork consolidating the initial response into the definitive plug. Thrombin also recruits more platelets into the growing hemostatic plug. Thus the generation and control of thrombin is central to the hemostatic process. Figure 1 shows the activation peptides released during thrombin generation from prothrombin and the binding of thrombin by antithrombin III, the major inhibitor of thrombin, and the other serine proteases of the coagulation cascade. Some activation peptides, and the anProgress

in CardiovascularDiseases,

Vol XXXIV,

Therapy

No 4 (January/February),

tithrombin III-thrombin complex, can be measured in blood and have undergone limited evaluation as potentially useful markers during thrombolytic therapy. During fibrin formation, plasminogen and tissue plasminogen activator (tPA) bind to fibrin at specific binding sites. TPA, a poor plasminogen activator in plasma, avidly cleaves the pro-enzyme plasminogen to plasmin when bound to the fibrin surface leading to localized fibrinolysis? The formation of fibrin thus triggers an autocontrol mechanism limiting the extension of physiological thrombi. Figure 2 outlines the procoagulant and fibrinolytic pathways. Two other physiological plasminogen activators have been identified. Urokinase was originally purified from urine but is also found in plasma at very low concentrations.” The socalled intrinsic system of plasminogen activation has been attributed to kallikrein generated by the contact factors of the procoagulant cascade-factor XII and high molecular weight kininogen. The physiological significance of these latter two pathways of plasminogen activation in blood is unclear at present. Each of the three physiological plasminogen activators have specific inhibitors in blood that limit plasmin generation in response to usual physioIogica1 stimuli; in addition, plasmin itself is rapidly inactivated by a specific inhibitor, c+-antiplasmin. The exogenous plasminogen activator, streptokinase, is produced by group C B-hemolytic streptococci. In contrast to the physiological plasminogen activators, streptokinase is not an enzyme. Streptokinase forms a 1:I compiex with plasminogen that exposes an active site in the complexed pro-enzyme which then activates

From the Department of Pathology, College of Medicine, Universily of” Vermont, Burlington, m; and the Division of Cardiology, Department of Medicine, University of Massachusetts, Worcester, MA. Address reprint requests to Edwin G. Bovill, MD, Department of Pathology, College of Medicine, University of Vermont, Burlington, VT 05405. Copyright 0 I992 by W B. Saunders Company 0033.062019213404-0003$5.003$5.0010 1992:

pp 279294

279

BOVILL,

280

F1.2

II -d-

Fibrin Protein

AT111

II aL

- II a’ AT111

formation (fibrinopeptide release) C activation (activation peptide release) Endogenous tPA release Platelet activation

Fig 1. The zymogen prothrombin (II) is activated to thrombin (Ila) by prothrombinase with the cleavage of an activation peptide, fragment 1.2 (F1.2). Free thrombin is then bound covalently to antithrombin Ill [ATIII), as well as other inhibitors, forming a thrombin-antithrombin Ill complex, which is cleared from the circulation. Thrombin has a wide variety of actions on the procoagulant, inhibitory, and fibrinolytic pathways.

other plasminogen molecules in plasma or at the fibrin surface. Urokinase and streptokinase have been used in therapeutic thrombolysis for many years. Streptokinase was first used to treat acute MI by Fletcher et al” in 1958. The results of this early experience were complicated by bleeding and the subsequently prevalent notion that thrombi played a minor role in the genesis of MI. Interest in thrombolytic therapy for acute MI waned over the next 2 decades. The demonstration in 1980 that thrombi were present in more than 80% of coronaries involved in acute MP2 and the nearly simultaneous identification and characterization of tPA9 generated renewed interest in thrombolytic therapy. Plasmlnogen

Plasmln Procoagulant Activators/lnhibltars 0

~2 AP aaMG

4

Thrombln

Fg

L>

Fn II)

FDP

Fig 2. A schematic diagram of the procoagulant inhibitory and fibrinolytic pathways leading to fibrin formation and dissolution. Abbreviations: UK, urokinase; T-PA, tissue type pbsminogen activator; SK, streptokinase; dP, 4-antiplasmin; qMG, qmacroglobulin; PAI, plasminogen activator inhibitor; PNI, protease nexin inhibitor; Fg, fibrinogen; Fn, fibrin; FDP, fibriniogen) degradation products.

BECKER, AND

TRACY

Urokinase and streptokinase have been referred to as nonfibrin-specific agents to distinguish them from tPA, which demonstrates a significant enhancement of plasminogen activation when bound to the fibrin surface. The fibrin specificity of tPA promised more specific therapy with little or no degradation of the hemostatic system. In contrast to tPA, urokinase and streptokinase are only effective after the naturally occurring inhibitor cl,-antiplasmin has been consumed and free plasmin becomes available for the lysis of thrombi. This latter sequence of events occurs because the plasma concentration of %-antiplasmin (1 pmol) is less than that of plasminogen (2 pmol). The aggregate effect of plasmin on the hemostatic system has been termed the lytic state. The lytic state is characterized by plasmininduced proteolytic degradation of both coagulation proteins and the cellular elements of the hemostatic system. The coagulation proteins degraded by plasmin include fibrinogen, fibrin, factor V, and factor VIII. The degradation of fibrinogen and fibrin lead to the release of fibrin(ogen) degradation products (FDP) that can inhibit fibrin polymerizationi3z’4 and platelet aggregation.‘5’16 Figure 3 shows a schema for the plasmin-induced degradation of fibrinogen and fibrin with the generation of a variety of FDPs and smaller peptide fragments. Both factor XIII cross-linked FDPs, the D-dimer fragments, and noncross-linked FDPs have undergone extensive evaluation in clinical trials of thrombolytic agents. The peptide fragments have been evaluated only in smah studies. The B beta l-42 fragment is of some interest as a measure of fragment X formation. Fragment X, the largest FDP, is formed rapidly and in large quantities during treatment with either tPA or streptokinase.” Because fragment X can still polymerize to form weak clots, it has been postulated to play a role in hemorrhagic complications.18 Plasmin readily degrades factors V and VII119,20 thus compromising the ability to form thrombin. However, recent work has demonstrated that initially there is an activation of factor V by plasmin before continued proteolysis leads to degradation.21 Furthermore, Eisenberg et a12223 have demonstrated plasmin-mediated procoagulant effects and platelet activation in vitro.

MONITORING

THROMBOLYTIC

281

THERAPY

FIBRINOGEN ._........................ .?%!!fl....-, 8-p1-42 L THROMBIN

-

L THROMBIN

FIBRINOPEPTIDE

FIBRIN

I

FIBRIN

I,

FACTOR

soluble, fibrinfogenl products

B

.._.._..____.__.___............ ? ! Y ! ! ? ! ! ! ! .. . ..-..

8-p

,5-~2

D-D

Dimer

Xlla+ I FIBRIN(CROSSLINKED)

Thus, the balance of procoagulant and fibrinolytic activity at the clot surface may be more complex than originally thought. The effect of plasmin on the cellular elements of blood has been most thoroughly studied in platelets, although similar processes likely effect leukocytes and endothelial cells. Plasmin disrupts the orderly process of platelet plug formation at a number of levels. Investigators have shown in in vitro systems that plateletbound or freely circulating plasmin can degrade platelet surface glycoproteins,24,25 degrade platelet-bound fibrinogen26 and plasma von Willebrand factor,27 and alter arachidonic acid metabolic pathways of platelet activation.28 FDPs can inhibit platelet aggregation and fibrin polymerization.13-‘” HEMORRHAGIC

Plus: other uncrosslinked degredation

l

FIBRINOPEPTIDE

Fig 3. Schematic diagram of fibrin formation and dissolution, highlighting plasmin-generated fibrinlogen) degradation products and smaller peptides. (Reprinted with permission.“)

A tlk?.!!!!

COMPLICATIONS

Extensive clinical trial experience with recombinant tPA has shown that although the systemic lytic state is less intense than observed with the nonfibrin-specific agents, a small but significant proportion of individuals develop a lytic effect similar to that observed with nonfibrin-specific agents. The intensity of the lytic effect is in part dose related. In the TIMI-II trial, nadir fibrinogen levels dropped below 100 mg/dL in 60% of patients at the 150-mg recombinant tPA dose compared with 11% at the lOO-mg dose.29 In spite of the variation in the lytic effect, only weak relationships have been observed between the intensity of the lytic effect and hemorrhagic complications among patients treated with fibrin-specific agents.*‘“’ Typically, the odds ratios associated with measures of the lytic state in recombinant tPA treated patients

!?.%!!!!.!.

.

. l

Plus: othw crosslinked degredation

soluble, fibrin products

(eg, nadir fibrinogen, peak FDP level) and peak tPA levels demonstrated a 1.5- to threefold increased risk of bleeding.29 With streptokinase therapy, where an intense systemic lytic state is induced in all patients, most studies have been unable to demonstrate any relationship between the lytic state and bleeding. However, the streptokinase arm of the TIMI-I trial demonstrated about a twofold increased risk of bleeding associated with nadir plasminogen levels and peak FDP levels.3o Odds ratios in the range of 1.5 to 3 yield useful information about risk in a large population but are not strong enough to have clinical predictive value for individual patients. The location and severity of bleeding complications have been nearly identical with fibrinspecific and nonfibrin-specific agents in direct comparison trials.30 Many investigators were surprised by the similarity of hemorrhagic complications with fibrin-specific and nonspecific agents. Their surprise was rooted in a misunderstanding of the cause of hemorrhage in patients treated with thrombolytic agents. The lytic state, with systemic degradation of the components of the hemostatic mechanism, was blamed for the onset of hemorrhagic complications. It has become apparent that plasmin generated by thrombolytic agents can not distinguish between physiological hemostatic plugs such as those forming around catheter insertions and pathological thrombi such as coronary thrombi. As a consequence of this lack of distinction between “good” and “bad” thrombi, plasmin-induced bleeding complications are initiated from similar sites and at similar frequencies regardless of the type of agent used. The rates of major hemorrhagic

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BOVILL,

Table 1. Major Thrombolytic

Hemorrhagic Therapy

Event Rates in Large Trials in Acute Myocardial Infarction

of

Major Event

strategy

Trial

ASSET’ European GISSI-1’

COO~“~

GISSI-2’24 ISSIS-25 TIMI PO TIMI I?

Abbreviations: type

plasminogen

Agent IN)

Rate (%)

Noninvasive

rtPA (2.495)

Noninvasive Noninvasive Noninvasive

SK (156) SK (5,680) SK (6,199)

1.4 1.3 0.3 1.0

Noninvasive Invasive

tPA (6,182) SK (8,377) SK (143)

0.5 0.6 15.6

Invasive Noninvasive

rtPA (147) rtPA (316) rtPA (1.079)

15.4 7.9 2.7

SK, streptokinase;

rtPA,

recombinant

tissue-

activator.

events in a number of large clinical trials are shown in Table 1. It is apparent that one of the major determinants of hemorrhagic events was the use of invasive procedures. Trials like TIMI-I, which involved early catheterization, had the highest rates of major hemorrhagic events, TIMI-II, with catheterization delayed to 18 to 48 hours, had lower rates, and the noninvasive studies had the lowest rates. The differences in hemorrhagic event rates among the noninvasive trials probably relates to the differing emphasis placed on recording hemorrhagic events in the various studies. Stroke is the most feared hemorrhagic complication of thrombolytic therapy. Stroke occurs in about 1% of patients with MI in the absence of thrombolytic therapy. Thrombolytic therapy does not appear to increase the overall incidence of stroke but does increase the relative proportion of hemorrhagic compared with thrombotic strokes.32 The largest experience of stroke in acute MI treated with thrombolytic therapy in which hemostatic parameters were measured was in the TIMI-II trial. In the TIMI-II trial no significant associations were observed between the occurrence of stroke and fibrinogen, FDP, plasminogen, or recombinant tPA levels.29*32 However, there was an increased incidence of stroke in patients treated with 150 mg of recombinant tPA compared with 100 mg.” When the dose was decreased from 150 to 100 mg of recombinant tPA, the decrease in major hemorrhagic events was almost entirely accounted for by the decrease in the stroke rate, which has led

BECKER,

AND

TRACY

to speculation that recombinant tPA may selectively affect the cerebrovasculature.‘,3z This latter speculation is tempered by the changes made in the TIM1 protocol coincident with the decrease in recombinant tPA dosage. The role of primary cerebrovascular disease in the occurrence of stroke in these patients is of some interest. Recent reports by Pendlebury et al33 have found an association between the presence and distribution of senile amyloid changes in the cerebrovasculature at autopsy in patients who succumbed to stroke following thrombolytic therapy. They hypothesize that these weakened vessels may be more susceptible to the local lytic effects of recombinant tPA. An important and often overlooked aspect of therapeutic thrombolysis is the nearly universal use of adjuvant anticoagulant therapy, usually heparin and aspirin. Cumulative event rate analysis of TIMI-II (Fig 4) documents the occurrence of hemorrhagic events over 3 to 4 days, long after completion of infusion of the thrombolytic agent but coincident with heparin and aspirin therapy. In TIMI-II, activated partial thromboplastin times (APTI’) greater than 90 seconds were associated with a 1.7-fold (P = .Ol) increased risk of major hemorrhagic events, suggesting that anticoagulation that prolongs the APTT beyond the usual therapeutic range is associated with bleeding.29 The effects of aspirin on platelet function are harder to assess. The effect of thrombolytic therapy on platelets has been recently reviewed by Loscalzo et al.34 Gimple et al35 demonstrated

/--ye

ccc-A-cc~ Invasive A Conservative

l

I.. 0

24

40

72

Hours

I., 90

I.. 120

L.. 144

I. 100

rJ 192

of Follow-up

Fig 4. Cumulative major and minor hemorrhagic events after thrombolytic therapy with 100 mg rtPA, heparin, and aspirin. (Reprinted with permission.**)

MONITORING

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283

THERAPY

a relationship between prolongation of the bleeding time and hemorrhagic events in patients treated with recombinant tPA. However, the magnitude of the relative risk of bleeding associated with the prolongation of the bleeding time was similar to that of the previously described hemostatic variables and therefore of limited use in individual patients. Thrombocytopenia (platelet counts < 150 x lO’)/L) was observed in TIMI-I and TIMI-II.29.3” Figure 5 illustrates a drop in platelet count over the first 5 days of hospitalization in TIMI-II, coincident with the intravenous infusion of heparin. These data suggest that heparin administration, a well-described cause of thrombocytopenis,” may have contributed to the decrease in platelet count. There was no relationship of the decrease in platelet count to the dose of recombinant tPA. In TIMI-II, 10% of patients had platelet counts below 150 x log/L and 1.6% had counts below 100 x lO”/L. Platelet counts below 100 x 109/L were associated with a 7.5-fold increased risk of bleeding, an observation of potential clinical use. Heparin-related thrombocytopenia has been associated with both bleeding and seemingly paradoxical thrombotic complications.3” Hemorrhagic events in the TIMI-II and TAM1 trials”‘3’ were also studied for associations with demographic and clinical variables. Univariate analysis showed that older age, female gender, lower weight, physical signs of cardiac decompensation, and a history of hypertension were all associated with a two- to threefold increased

l n

04 0

I 1

, 2

I 3

Days Fig 5. thrombolytic (Reprinted

Platelet counts therapy with with permission.m)

I 4

after

, 5

r-t-PA. rt-PA.

, 6

, 7

1OOmg 15Omg , 6

, 9

, 10

Treatment

over the first 10 days following 100 mg rtPA, heparin, and aspirin.

1

risk of bleeding.29 Multivariate analysis was performed to identify possible subgroups at high risk of hemorrhagic complications, for example, small, older females with low fibrinogens. We were unable to identify subgroups whose increased risk of complications was great enough to be of clinical usefulness. Finally, considerable effort is being devoted to the development of better antithrombin agents3’ and better antiplatelet medications, such as monoclonal antibodies directed against platelet membrane receptors and drugs that interfere with platelet activation at different loci than aspirin.-‘8 These agents are in initial clinical trials and will require careful study to understand their impact on hemorrhagic complications. ISCHEMIC

COMPLICATIONS

Although the area of cardiac therapeutics has generated substantial interest and debate, the fundamental hypotheses and basic framework on which thrombolytic therapy is based have remained essentially unchallenged. They include (1) coronary arterial thrombosis is the proximate cause of acute MI, (2) early recanalization provides the greatest overall patient benefit, and (3) maintaining coronary patency is necessary to sustain the benefits of early reperfusion. Clinical studies designed to determine which patients derive benefit from adjunctive intervention, such as coronary angioplasty, are in progress. Central to the implementation of a recommended approach, will be the ability to assess rapidly and effectively whether or not coronary patency has been restored and maintained. At the present time, coronary angiography provides a gold standard for assessing reperfusion after thrombolytic therapy. However, facilities to perform coronary angiography are not widely available. In addition, routine angiography imparts a substantial additive cost and is associated with a small but identifiable risk. These limiting factors underscore the importance of developing reliable noninvasive markers of reperfusion and reocclusion to determine whether the objectives of treatment have been achieved (Table 2).

284

BOVILL,

Table

2. Noninvasive

Markers Reperfusion

Patient symptoms Sudden relief of chest Electrocardiogram Decreased ST segment Bradyarrhythmia (with Biochemical markers Early (~4 hours) Early (90 minutes) baseline)

of Coronary

elevation right coronary

total CK peak MB-CK increase

artery

Early (120 minute) myoglobin increase baseline) Early (60 to 120 minutes) FPA decrease

Abbreviations:

defect size on serial Tc-99m infarct-zone MRI images CK,

creatine

kinase; complexes;

above increase

(>4.5-fold

Early (60 to 120 minutes) TAT decrease Myocardial perfusion imaging Decreased defect size on serial thalliim-201

TAT, thrombin-antithrombin magnetic resonance imaging.

reperfusion)

(> 2.5-fold

above

TRACY

Reper@sion Arrhythmias images sestamibi

FPA,

AND

sion. Decreases of 20% to 50% occur over the initial 20 to 30 minutes and readings return to baseline by 60 to 100 minutes.4z4s In contrast, ST segment elevation among patients with unsuccessful reperfusion resolves slowly, reaching an electrocardiographic steady state between 3 and 4 hours after treatment initiation.45 Although complete resolution or a significant partial decrease in ST segment elevation is a sensitive marker for coronary reperfusion, a small number of patients have these findings.46 Therefore, as with resolution of chest pain, the overall predictive value of ST segment changes is limited.

pain

Early (120 minutes) MBJMB, ratio isoform (> 3.8-fold above baseline) Early (120 minute) MM, isoform increase

Decreased Enhanced

Arterial

BECKER,

images

fibrinopeptide

A;

Tc, technetium;

MRI,

Patient Symptoms

Rapid relief of chest pain is the earliest marker suggesting that reperfusion has occurred. It typically begins within minutes of the angiographic demonstration of reperfusion and occurs simultaneously with other nonangiographic manifestations.39-41 The resolution of symptoms may be prompt; however, a degree of residual, low-intensity chest discomfort may persist. In addition, some patients actually may experience a transient worsening of symptoms following the restoration of blood flow to ischemic or necrotic areas of myocardium. Although relief of chest pain has been considered the sine qua non of coronary reperfusion, a relatively small percentage of patients with angiographically confirmed patency can be defined through symptom relief alone. Therefore, its predictive value is limited. ST Segment Changes

Continuous ST segment Holter recordings with quantitative analysis and trending evaluation of patients receiving thrombolytic therapy have identified a lessening of ST segment elevation within minutes of angiographic reperfu-

Laboratory and clinical experience has shown that reperfusion of ischemic myocardium is associated with a propensity toward ventricular arrhythmias, at times life-threatening in nature.47-50Accelerated idioventricular rhythms and late diastolic ventricular systoles are common reperfusion arrhythmias, occurring in 60% to 80% of patients.‘l However, they lack specificity and, therefore, should not be used independently when assessing coronary patency.52 In contrast, bradyarrhythmia, particularly when accompanied by systemic hypotension, may be a useful marker for reperfusion of the right coronary artery.52 Biochemical Markers of Reperfusion and Reocclusion Creatine kinase. Creatine kinase (CK) is a dimer composed of two protein chains, M and B. Three distinct CK isoenzymes have been recognized: MB, ‘BB, and MM. In normal human subjects, MB-CK is found primarily in the heart, comprising up to 15% of total CK activity in that tissue. BB-CK is found in many tissues; however, its relative and absolute concentrations are greatest in the brain. MM-CK is the predominant form of CK in both skeletal and heart muscle. Early washout and peaking of plasma total CK have been observed in patients with angiographically confirmed coronary reperfusion. In the TIMI-I tria1,53 patients with reperfusion experienced a peak CK within 4 hours of treatment initiation. In contrast, patients with persis-

MONITORING

THROMBOLYTIC

THERAPY

tent coronary occlusion had a delayed CK peak, approaching 20 hours. An increase in plasma MB-CK activity also has been correlated with the onset of coronary reperfusion. Garabedian et al: in a study of 32 patients receiving a 90-minute infusion of recombinant tissue-type plasminogen activator, found that a rapid increase in MB-CK was a sensitive and specific marker of reperfusion. Patients with angiographically confirmed reperfusion had a six- to eight-fold increase in MB-CK over pretreatment levels by completion of the thrombolytic infusion. In contrast, patients with persistent occlusion were not found to have an early MB-CK increase. Overall, when a greater than 2.5-fold increase in MB-CK activity at 90 minutes was taken as evidence for reperfusion, approximately 90% of individuals were correctly identified. MB isoforms. The unmodified form of MBCK, MB,, is present within myocytes. Release of MB, and other macromolecules from infarcted tissue requires breakdown or severe dysfunction of the myocardial sarcolemma. Following reperfusion, MB, release is abruptly increased as reflected by a marked increase in plasma activity. Conversion of MB, to the modified isoform MB, occurs through the action of a plasma enzyme, carboxypeptidase-N, which cleaves a c-terminal lysine residue from the M subunit. Following release of MB-CK from necrotic myocardium, plasma MB, activity increases; simultaneously, conversion to MB, begins. Thus, the MBJMB, ratio is determined by the rate of CK release and the rate of conversion of MB, to MB,. Among patients with acute MI, MB, activity and the MBJMB, ratio begin to increase approximately 2 hours after symptom onset, reaching a plateau within 4 to 6 hours. In addition, abnormal MB isoform activity can be detected hours before conventional MB determinations.55 Coronary reperfusion is associated with a sudden increase in MB, activity. In contrast, failed reperfusion allows a more gradual egress of CK from infarcted tissue, causing a greater proportion of newly released MB, to be converted to MB,. An MBJMB, ratio greater than 3.8 accurately identifies approximately 70% of

285

patients within 75 minutes of treatment initiation. Maximal segregation of patients with and without reperfusion can be achieved within 2 to 3 hours (sensitivity and specificity approximately 90%).56 MM isofoms. In 1977 Weavers et a15’.‘* reported that prolonged electrophoresis resulted in the separation of MM-CK into three distinct species or isoforms: MM,, MM,, and MM,. Animal and human studies have shown that a majority of MM-CK activity in the heart is MM,. The subsequent conversion of MM, is mediated by carboxypeptidase-N which removes a single carboxy-terminal lysine residue from either one or two MM chains, producing the MM, and MM, isoforms, respectively.59 In the setting of acute MI, MM, increases promptly, exceeding control values as early as 1 hour after symptom onset.‘j’ Following coronary reperfusion, a surge of MM, into the circulation occurs, accelerating its rate of increase and the MMJMM, ratio. Animal and human studies have shown that peak MM, activity, its rate of increase, and the MMJMM, ratio can reliably assess patency status after thrombolytic therapy, frequently within 2 to 3 hours of treatment initiation.6’ In patients with flow-limiting residual coronary stenoses, the initial rate of MM, increase may be a more reliable marker than peak activity, which may be delayed by as much as 50%.62 Myoglobin. Myoglobin is an intracardiac protein that is rapidly released from injured myocardium after coronary reperfusion, with peak plasma levels occurring within 2 hours of treatment initiation. However, in patients without reperfusion, peak levels are delayed for up to 6 hours.63 A rapid increase of more than 4.6-fold above pretreatment myoglobin levels correctly identifies 85% to 90% of patients achieving coronary patency.62 Fibrinopeptide A. Although factors precipitating coronary thrombosis have not been elicited fully, activation of thrombin, the pivotal enzyme in all coagulation processes, is common to thrombotic disorders in general. Fibrinopeptide A (FPA), a 16-amino acid peptide liberated from fibrinogen following thrombin-mediated proteolysis, is a marker of intravascular thrombosis in general and throm-

BOVILL,

bin activity in particular. In small pilot studies, patients with acute MI, particularly those with Q-wave infarctions observed within 10 hours of symptom onset, have elevated FPA levels.M Following thrombolytic therapy, a prompt decrease is observed among patients achieving successful coronary reperfusion. However, FPA levels remain elevated in patients failing to reperfuse and in those with initial reperfusion followed by early reocclusion.65 Thrombin-antithrombin complexes. Clotting activation leads to the generation of thrombin. The rapid complexing of free thrombin by antithrombin III (thrombin-antithrombin complex [TAT]) can, therefore, be measured and used as a marker for ongoing intravascular thrombosis. Preliminary studies have shown that TAT are elevated in patients with acute MI. As with FPA levels, a prompt decrease in TAT concentration is observed, typically within 60 to 120 minutes, following successful coronary reperfusion. Similarly, patients either failing to reperfuse or experiencing early reocclusion have persistently elevated levels, despite system anticoagulation with heparin.66 Although both FPA and TAT fail to differentiate patients with persistent occlusion from those with reperfusion at risk for early reocclusion, these two groups may not differ significantly from a clinical perspective. In both, additional intervention may be required to assure complete treatment success. D-dimers. D-dimer is a product of plasminmediated degradation of cross-linked fibrin (Fig 3). Its quantitation has been considered a potential biochemical marker for thrombus dissolution. However, although temporally related with coronary thrombolysis, post-treatment elevations in D-dimer concentration have not correlated closely with reperfusion success.67 Circulating (soluble) cross-linked fibrin polymers increase substantially in some patients with acute MI. Fibrin-rich atherosclerotic plaques may be a potential source of D-dimer production during and after thrombolytic therapy, decreasing its sensitivity and overall predictive value further.66-68 Earlier investigation of D-dimer concentration during thrombolytic therapy was confounded by cross-reactivity with

BECKER,

AND

TRACY

non-cross-linked fibrin(ogen) degradation productP; however, an improved enzyme-linked immunosorbent assay (ELISA) technique may provide a more sensitive marker of fibrinolysis and reperfusion in the future.6y Fibrinogenljibrin(ogen) degradation products. Thrombolytic therapy has variable effects on circulating fibrinogen and the production of fibrin(ogen) degradation products (FDP). Depending on the fibrin specificity, total dose, and overall dosing strategy of a given thrombolytic agent, a minimal or marked systemic lytic state may ensue. As with other fibrinolytic parameters, changes in fibrinogen and FDPs have not been shown to correlate with reperfusion statUS,70,71although weak correlations have been observed between higher levels of FDP and protection from reocclusion.31 Heparin monitoring. Following deep arterial injury, heparin has been shown to decrease platelet deposition and thrombus formation.72 Indeed, three recently completed clinical trials73-75have confirmed the benefits of intravenous heparin after thrombolytic therapy with tPA, reducing reocclusion primarily within the initial 24 to 48 hours. A therapeutic APTT (1.5 to 2.0 times the control) during this time period correlated directly with sustained arterial patency, whereas levels of subtherapeutic heparinization were more likely to occur in patients experiencing early reocclusion.74*75 These findings are consistent with those of previous trials including patients with thromboembolic disease, showing that the overall efficacy of heparin is optimized when a systemic state of anticoagulation is achieved and maintained.76-7y Platelet function. Individuals with ischemic heart disease have been shown to have increased sensitivity to platelet aggregating agonists.80 In the Caerphilly Collaborative Heart Study,*’ patients with the greatest degree of ADP-induced platelet aggregation were twice as likely to have experienced a previous MI when compared with patients in whom minimal aggregability was identified. More recently, a relationship between in vitro platelet aggregability and increased risk for recurrent infarction and cardiac death has been shown in patients surviving an acute MI.” Despite the central role that platelets play in

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ischemic heart disease and the beneficial effects of aspirin in preventing recurrent cardiac events among patients with MI receiving thrombolytic therapyB3 or not,84 potential correlations between a prolonged bleeding time or other measures of platelet dysfunction (ie, documented response to antiplatelet therapy) and an improved clinical outcome have not been investigated. Myocardial Perjiuion Imaging

During MI, the extent of myocardial necrosis is determined by the overall area at risk, collateral blood flow, and duration of coronary arterial occlusion. Noninvasive imaging techniques capable of (1) assessing the area of myocardium at risk, (2) determining the degree of flow restoration, and (3) estimating the extent of myocardial salvage would, therefore, have clinical value. Thallium-201 scintigraphy. Myocardial thallium-201 scintigraphy has been used to assess the efficacy of coronary reperfusion following thrombolytic therapy. New thallium uptake after intracoronary tracer administration suggests reperfusion and the restoration of myocardial nutrient blood flo~.~~-~~ When thallium-201 is injected intravenously during coronary occlusion, the degree of redistribution after thrombolytic administration is proportional to the degree of flow restoration and myocardial viability.89-9’ Thallium scintigraphy also can be delayed for 24 hours after treatment when an improvement in defect size from pretreatment images predicts coronary arterial patency.9z Delayed imaging also may prevent overestimation of myocardial salvage as a result of early hyperemic blood flow. Technetium-99m isonitriles. Efforts have been directed toward the development of technetium99m (Tc 99m)-labeled isonitrile compounds for assessing regional perfusion and viability. One of the most promising, Tc 99m sestamibi, has undergone extensive laboratory testing. Like thallium-201, uptake of Tc 99m sestamibi in myocardial tissue is proportional to blood flow. However, unlike thallium-201, it has minimal redistribution, allowing intravenous injection and delayed imaging. A second dose then can be injected at a later time to delineate both the

degree of flow improvement and extent of myocardial salvage.93 In addition to this favorable characteristic, Tc 99m sestamibi has photon emissions that are ideal for gamma camera imaging. Therefore, the images obtained are of extremely high quality. The ability of Tc 99m sestamibi to identify patients with successful reperfusion has been demonstrated. Wackers et al,” in a study of 23 patients receiving thrombolytic therapy within 4 hours of symptom onset, showed that a decrease in myocardial defect size of greater than 30% on serial images was a sensitive marker of coronary patency. Unfortunately, however, the delayed images were obtained 18 to 48 hours after thrombolytic therapy, preventing the early detection of persistent occlusion or early reocclusion. Magnetic resonance imaging. Magnetic resonance imaging (MRI) has the potential to characterize normal and necrotic myocardium. Myocardial perfusion with the paramagnetic contrast agent gadolinium-diethylene-triamine pentaacetic acid (DTPA) increases the observed contrast between infarcted and normal myocardium on Tl-weighted spin-echo images.95x96 Ex vivo MRI of reperfused hearts using gadolinium DTPA has verified contrast enhancement within reperfused myocardial zones.97 Increased signal intensity within infarcted myocardium has been observed in humans with patent infarct-related vessels. The image intensity is particularly increased immediately after gadolinium DTPA injection; therefore, patency can be assessed by quantitating image enhancement as a function of time.98 CONCLUSIONS

AND PRACTICAL

GUIDELINES

Pre-analytic Variables

The proteolytic activity of plasmin must be blocked before any laboratory study is performed on blood samples obtained from patients undergoing thrombolytic therapy. Failure to block plasmin in the blood samples leads to progressive in vitro lysis and renders the samples useless for clinical interpretation. A number of anticoagulants and antiproteases alone and in combination have been used, including aprotinin, D-phenylalanine-proline-argininechlormethylketone (PPACK), monoclonal antibodies directed against recombinant tPA, and

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acidified citrate. Tubes containing acidified citrate (Biopool, Hamilton, Ontario, Canada) are the only commercially available preparations. Hemorrhagic Complications The correlations between markers of hemostasis and hemorrhagic complications have been too weak to have useful clinical predictive value. Consequently, there is no evidence to support routine monitoring of patients during thrombolytic therapy. However, baseline screening of patients is important. The most important evaluation is the clinical history, and the literature abounds with exhaustive lists of contraindications.g9-10zThe baseline laboratory investigation should include a prothrombin time, partial thromboplastin time, and complete blood count with platelet count. These assays screen for most hemostatic abnormalities and the baseline APTT can be useful in monitoring heparin therapy. Patients with short baseline APTIs can be less sensitive to heparin, possibly because of elevated levels of factor VIII, an acute-phase reactant. In this situation infusions of excessive amounts of heparin may be necessary to achieve the usual 1.5 to 2 times control APTI level. One approach to this problem is to adjust the heparin dose to 1.5 to 2 times the baseline APIT; another approach is to use an alternative assay system, such as the thrombin time or direct measurement of heparin levels. One must remember that the APTT is invalid in patients with low fibrinogen levels (eg, < 75100 mg/dL) and alternative assays may be necessary for these patients over the first 12 to 24 hours following thrombolytic therapy. Any patient treated with heparin should also have a daily platelet count to screen for thrornbocytopenia. Some investigators advocate obtaining a baseline fibrinogen level for patients treated with streptokinase in order to follow the drop in fibrinogen as an indicator of achievement of the lytic state. The frequency and titer of antistreptococcal antibodies against streptokinase has not been carefully evaluated in North American populations, so the incidence of resistance to streptokinase is unknown but presumed to be rare, based on the European experience.lo3 In the event of major hemorrhage, laboratory

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assessment of the hemostatic system and a predetermined clinical approach is essential to successful therapy. The first step is to stop the infusion of the thrombolytic agent and adjuvant anticoagulants. However, transfusion of blood products with its attendant risks may be unavoidable. The choice and dose of blood products used can be guided by appropriate hemostatic monitoring. The most useful single assay is the fibrinogen level, which can usually be obtained rapidly and helps to determine the need for cryoprecipitate and/or plasma replacement. A low fibrinogen level ( < lOOmg/dL) helps to decide the need for cryoprecipitate and/or plasma replacement. Cryoprecipitate can be given empirically if a fibrinogen assay is not readily available. Follow-up fibrinogen levels should be performed after the completion of cryoprecipitate infusion to assess the intensity of the lytic state. In patients with persistent fibrinogenolysis, the use of antifibrinolytic drugs may be warranted (eg, epsilon amino caproic acid, aprotinin, transexamic acid). The status of factor V and VIII is harder to assess because of the effect of heparin and hypofibrinogenemia on the APIT. However, if the fibrinogen level is adequate (75 to 100 mg/dL for most systems) the heparin can be cleared with commercially available heparin adsorbents and the factor levels determined to guide the use of plasma replacement. If the platelet count is less than 100 X 109/L, platelet transfusion is required. If the platelet count is greater that 100 x log/L, then an assessment of platelet function is useful. The only practical bedside assessment is the bleeding time. Although the presence of aspirin may complicate the interpretation, a markedly prolonged bleeding time suggests platelet transfusion may be useful. Another useful therapeutic approach in the face of a platelet functional disorder is the use of D-des amino arginine vasopressin (DDAVP).lW Patients who suffer catastrophic hemorrhagic events, such as intracranial hemorrhage, should have blood component therapy started empirically and antifibrinolytic therapy should be strongly considered. The use of antifibrinolytic agents carries a significant risk of recurrent coronary occlusion, but this risk is probably

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outweighed by the gravity of intracranial hemorrhage. The laboratory can then be used to guide the continued treatment of these patients. The plasmin-induced lytic state will improve spontaneously over 6 to 12 hours necessitating a continued monitoring of the patient’s hemostatic status in order to appropriately adjust therapy. Ischemic Complications

Early coronary arterial recanalization, established within a time window that promotes salvage of ischemic yet viable myocardium, is considered the primary contributor to preservation of ventricular function and a reduction in patient mortality. Therefore, the most rational treatment for acute MI is thrombolytic therapy, used either alone or in combination with other interventional modalities, as a means to achieve vessel patency as rapidly and as frequently as possible. The presence of a patent infarct-related artery may be the best predictor of patient survival.lU5.107 Experimental studies suggest that reperfusion, even when established beyond the predicted time window of myocardial salvage, reduces ventricular dilation and aneurysm formation.‘“’ In humans, this may translate to (1) reduced infarct expansion, preventing ventricular dilation, congestive heart failure, and cardiac death, and (2) improved electrical stability. ‘093’1”Measurement of hemostatic parameters for the prediction and management of ischemic complications are in an early stage of development and should be restricted to groups involved in clinical research. Failed thrombolysis. The clinical approach to patients in whom reperfusion is not established following thrombolytic therapy is in evolution. Although three previous clinical trials have”l-l~3 suggested that routine balloon angioplasty is not of clinical benefit and may, in fact, be associated with an increased incidence of complications, the recently completed Thrombolysis and Angioplasty in Myocardial Infarction (TAMI-5) tria1114identified a potential role for immediate cardiac catheterization with angioplasty in patients with failed thrombolysis, reducing the incidence of in-hospital adverse events (death, stroke, reinfarction, reocclusion,

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heart failure, or recurrent ischemia) when compared with a more conservative approach of deferred predischarge catheterization. Therefore, information supporting the use of early mechanical intervention, even among patients who appear clinically stable, and the overall importance of documenting early vessel patency is available for the first time. However, the question remains whether routine coronary angiography will be required for assessment or if a noninvasive strategy with sufficient sensitivity, specificity, and predictive value to identify candidates for more aggressive intervention can be developed. Cardiogenic shock, Cardiogenic shock is a lethal complication of MI, with an in-hospital mortality rate approaching 80% to 90%. To date, trials of thrombolytic therapy, although showing a decreased incidence of congestive heart failure and cardiogenic shock in treated patients, have not been able to identify an improvement in survival for those individuals presenting with cardiogenic shock. Because the development of shock frequently signals extensive myocardial ischemia or necrosis, with either persistent occlusion of the infarct-related coronary artery, multivessel coronary disease, or a mechanical abnormality (papillary muscle rupture, ventricular septal defect), emergent cardiac catheterization is recommended. Several nonrandomized studies”5-“’ have suggested that successful coronary angioplasty can reduce mortality in patients with MI complicated by cardiogenic shock. In addition, patients in cardiogenic shock treated aggressively with coronary angioplasty, despite a relatively high in-hospital mortality, have been found to have low l-year mortality and reinfarction rates.‘“’ Coronary reocclusion. Despite an initial success rate of 75% to SO%, coronary arterial reocclusion occurs in 10% to 14% of patients, typically within the first 48 to 72 hours following thrombolytic administration. Although silent reocclusion does occur, recurrent symptoms of myocardial ischemia or MI are observed frequently, in a majority of cases without warning.“’ The clinical alternatives available for treating patients with evidence of early recurrent myocar-

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dial ischemia (unresponsive to nitrates, p-adrenergic blockade, and calcium channel antagonists) include (1) repeat thrombolytic therapy administration, (2) coronary angioplasty, and (3) emergent coronary artery bypass grafting. Repeat infusions of tPA have been used in clinical practice, reducing ischemia in a majority

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of cases and sustaining the observed improvement nearly 50% of the time.“’ However, where cardiac catheterization is available, assessment of the coronary anatomy should be considered, followed by coronary angioplasty when technitally feasible or bypass surgery for patients with advanced multivessel disease.lz3

REFERENCES 1. Gruppo Italian0 per lo Studio Della Streptochinasi nell’brfarto Miocardico (GISSI): Effectiveness of intravenous thrombolytic treatment in acute MI. Lancet 1:397-402, 1986 2. The I.S.A.M. Study Group: A prospective trial of intravenous streptokinase in acute myocardial infarction (I.S.A.M.). Mortality, morbidity, and infarct size at 21 days. N Engl J Med 314:1465-1471,1986 3. Kennedy JW, Martin GV, Davis KB, et al: The Western Washington intravenous streptokinase in acute myocardial infarction randomized trial. Circulation 77:345352.1988 4. White HD, Norris RM, Brown MA, et al: Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med 317:850-8551987 5. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group: Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 2:349-360,1988 6. Van de Werf F, Arnold AE: Intravenous tissue plasminogen activator and size of infarct, left ventricular function, and survival in acute myocardial infarction. Br Med J 297:1374-1379,1988 7. Wilcox RG, von der Lippe G, Olsson CG, et al: Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 2:525-530,1988 8. AIMS Trial Study Group: Effect of intravenous APSAC on mortality after acute myocardial infarction: Preliminary report of a placebo-controlled clinical trial. Lancet 1:545549,1988 9. Collen D: Tissue-type plasminogen activator and single chain urokinase-type plasminogen activator (scu-PA): Potential for fibrin-specific thrombolytic therapy. Prog Hemost Thromb 8:1-18; 1986 10. Pannel R, Gurewich V: Pro-urokinase: A study of its stability in plasma and of a mechanism for its selective fibrinolytic effect. Blood 67:1215-1220,1986 11. Fletcher AP, Sherry S, et al: The maintenance of a sustained thrombolytic state in man. II. Clinical observations on patients with MI and other thromboembolic disorders. J Clin Invest 38:1111-1119,1959 12. DeWood MA, et al: Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 303:897-900,198O 13. Hermans J, McDonagh J: Fibrin: Structure and interactions. Semin Thromb Hemost 8:11-24,1982

14. Williams JE, Hantgan RR, Hermans J, et al: Characterization of the inhibition of fibrin assembly by fibrinogen fragment D. Biochem J 197:661-668,198l 15. Prentice CRM, Hassanein AA, Turpie AGG, et al: Changes in platelet behaviour during Arvin therapy. Lancet 1644~647,1969 16. Kowalski E: Fibrinogen derivatives and biologic activities. Semin Hematol5:45-59,1968 17. Mentzer RL, Budzynski AZ, Sherry S: High-dose, brief-duration intravenous infusion of steptokinase in acute myocardial infarction: Description of effects in the circulation. Am J Cardio157:1220-1226,1986 18. Francis CW, Marder VJ: Increased resistance to plasmic degradation of fibrin with highly crosslinked a-polymer chains formed at high factor XIII concentrations. Blood 71:1361-1365,1988 19. Collen D, Bounameaux H, De Cock F, et al: Analysis of coagulation and fibrinolysis during intravenous infusion of recombinant human tissue-type plasminogen activator in patients with acute myocardial infarction. Circulation 73:511517,1986 20. Kasper W, Erbel R, Meinertz T, et al: Intracoronary thrombolysis with an acylated streptokinase-plasminogen activator (BRL 26291) in patients with an acute myocardial infarction. J Am Co11Cardiol4:357-363,1984 21. Lee CD, Mann KG: Activation/inactivation of human factor V by plasmin. Blood 73:185-190,1989 22. Eisenberg P, Miletich J, Sobel B: Factors responsible for the differential procoagulant effects of diverse plasminogen activators in plasma. Fibrinolysis 1991 (in press) 23. Winters KJ, Sandoro S, Miletich J, et al: Relative importance of thrombin compared with plasmin-mediated platelet activation in response to plasminogen activation with streptokinase. Circulation 1991 (in press) 24. Wate R, Savidge GF: Rapid thrombolysis and preservation of valvular function in high deep venous thrombosis. Acta Med Stand 205:293-298,1979 25. Stricker RB, Wond D, Shin DT, et al: Activation of plasminogen by tPA in normal and thromboasthenic platelets: Effect of surface proteins and platelet aggregation. Blood 68:275-280,1986 26. Loscalzo J, Vaughan DE: Tissue plasminogen activator promotes platelet disaggregation in plasma. J Clin Invest 79:1749-1755,1987 27. Kowalski E: Fibrinogen derivatives and biologic activities. Semin Hematol5:45-59,1968 28. Schafer AI, Adelman B: Plasmin inhibition of platelet function and of arachidonic acid metabolism. J Clin Invest 75:456-461,1985

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29. Bovill EG, Terrin ML, Stump DC, et al: Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI), Phase II Trial. Ann Intern Med 115:256265,199l 30. Rao AK Budzynski AZ, TIM1 Investigators: Plasma plasminogen activator activity in patients treated with intravenous recombinant tissue plasminogen activator and streptokinase. Clin Res 34:337a, 1986 (abstr) 31. Stump DC, Califf RM, Top01 EJ, et al: Pharmacodynamics of thrombolysis with recombinant tissue type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction. Circulation 80:1220-1230,1989 32. Gore JM, Sloan M, Price TR, et al: Intracerebral hemorrhage, cerebral infarction, and subdural hematoma following acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction (TIMI) Study. Thrombolysis in Myocardial Infarction, Phase II Pilot and Clinical Trial. Circulation 83:448-459,199l 33. Pendlebury WW, Iole ED, Tracy RP, et al: Intracerebra1 hemorrhage related to cerebral amyloid angiopathy and tPA treatment. Ann Neurol29:210-213,199l 34. Loscalzo J: Platelets and thrombolysis. J Vast Med Biol 1:213-218, 1989 35. Gimple LW, Gold HK, et al: Correlation between template bleeding times and spontaneous bleeding during treatment of acute myocardial infarction with recombinant tPA. Circulation 80:581-588, 1989 36. Warkentin TE, Kelton JG: Heparin-induced thrombocytopenia. Prog Hemost Thromb lO:l-34, 1991 37. Runge MS: Prevention of thrombosis and rethrombosis-New approaches. Circulation 82:655-657,199O 38. Coller BS: Platelets and thrombolytic therapy. N Engl J Med 322:33-42,199O 39. Rentrop KP, Blanke H, Karsch KR, et al: Acute myocardial infarction: Intracoronary application of nitroglycerin and streptokinase. Clin Cardiol2:354-363, 1979 40. Mathey DG, Kuck KH, Tilsener V, et al: Nonsurgical coronary artery recanalization in acute transmural myocardial infarction. Circulation 63:489-497, 1981 41. Davies GJ, Chierchia S, Maseri A: Prevention of myocardial infarction by very early treatment with intracoronary streptokinase. N Engl J Med 311:1488-1492,1984 42. Hardarson T, Henning H, O’Rourke RA, et al: Variability, reproducibility, and applications of precordial ST-segment mapping following acute myocardial infarction. Circulation 57:1096-1103, 1978 43. Madias JE, Hood WB: Precordial ST-segment mapping: 3. Stability of maps in the early phase of acute myocardial infarction. Am Heart J 93:603-609,1977 44. Von Essen R, Schmidt W, Uebis R, et al: Myocardial infarction and thrombolysis. Electrocardiographic short term and long term results using procordial mapping. Br Heart J 54:6-lo,1985 45. Krucoff MW, Green CE, Satler LF, et al: Noninvasive detection of coronary artery patency using continuous ST-segment monitoring. Am J Cardiol57:916-922, 1986 46. Califf RM, O’Neil W, Stack RS, et al: Failure of

291

simple clinical measurements to predict perfusion status after intravenous thrombolysis. Ann Intern Med 108:658662,1988 47. Jennings RB, Sommers HM, Smyth GA, et al: Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Arch Path01 Lab Med 70:68-78,196O 48. Meesman W, Gulker H, Kramer B, et al: Time course of changes in the ventricular fibrillation threshold in myocardial infarction: Characteristics of acute and slow occlusion with respect to the collateral circulation of the heart. Cardiovasc Res 10:466-473,1976 49. Balke CW, Kaplinsky E, Michelson EL, et al: Reperfusion ventricular arrhythmias: Correlation with antecedent coronary occlusion tachyarrhythmias and duration of myocardial ischemia. Am Heart J 101:449-456, 1981 50. Priori SG, Mantica M, Napolitano C, et al: Early after depolarizations induced in vivo by reperfusion of ischemic myocardium. A possible mechanism for reperfusion arrhythmias. Circulation 81:1911-1920,199O 51. Kaplinsky E, Ogawa S, Michelson E, et al: Instantaneous and delayed ventricular arrhythmias after reperfusion of acutely ischemic myocardium: Evidence for multiple mechanisms. Circulation 63:333-341,198l 52. Gore JM, Ball SP, Corrao JM, et al: Arrhythmias in the assessment of coronary artery reperfusion following thrombolytic therapy. Chest 94:727-730,1988 53. Gore JM, Robert R, Ball SP, et al: Peak creatine kinase as a measure of effectiveness of thrombolytic therapy in acute myocardial infarction. Am J Cardiol 59:1234-1238, 1987 54. Garabedian HD, Gold HK, Yasuda T, et al: Detection of coronary artery reperfusion with creatine kinase-MB determinations during thrombolytic therapy: Correlation with acute angiography. J Am Co11 Cardiol11:729-734,1988 55. Puleo PR, Guadagno PA, Roberts R, et al: Early diagnosis of acute myocardial infarction based on assay for subforms of creatine kinase-MB. Circulation 82:759-764, 1990 56. Puleo PR, Perryman MB: Noninvasive detection of reperfusion in acute myocardial infarction based on plasma activity of creatine kinase MB subforms. J Am Co11 Cardiol 17:1047-1052,199l 57. Wevers RA, Olthuis HP, VanNiel JC, et al: A study on the dimeric structure of creatine kinase. Clin Chim Acta 79:377-385, 1977 58. Wevers RA, Wolters RJ, Soons JBJ: Isoelectric focusing and hybridization experiments on creatine kinase. Clin Chim Acta 78:271-276,1977 59. Abendschein DR, Morelli RL, Carlson CJ, et al: Creatine kinase MM isoenqme subforms in myocardium, cardiac lymph, and blood after coronary artery occlusion in dogs. Cardiovasc Res 18:690-696,1984 60. Devries SR, Sobel BE, Abendschein DR: Early detection of myocardial reperfusion by assay of plasma MM-creatine kinase isoforms in dogs. Circulation 74:567572,1986 61. Jaffe AS, Serota H, Grace A, et al: Diagnostic changes in plasma creatine kinase isoforms early after the onset of acute myocardial infarction. Circulation 74:105109,1986

292

BOVILL,

62. Nohara R, Myears DW, Sobel BE, et al: Optimal criteria for rapid detection of myocardial reperfusion by creature kinase MM isoforms in the presence of residual high grade coronary stenosis. J Am Coll Cardiol 14:10671073,1989 63. Ellis AK, Little T, Masud 2, et al: Early noninvasive detection of successful reperfusion in patients with acute myocardial infarction. Circulation 78:1352-1357,1988 64. Eisenberg PR, Sherman LA, Schectman K, et al: Fibronopeptide A: A marker of acute coronary thrombosis. Circulation 71:912-918,1985 65. Eisenberg PR, Sherman L, Rich M, et al: Importance of continued activation of thrombin reflected fibrinopeptide A to the efficacy of thrombolysis. J Am Co11 Cardiol 7:1255-1262,1987 66. Gulba DC, Barthels M, Westhoff-Bleck M, et al: Increased thrombin levels during thrombolytic therapy in acute myocardial infarction. Relevance for the success of therapy. Circulation 83:937-944, 1991 67. Brenner B, Francis CW, Fitzpatrick PG, et al: Relation of plasma D-dimer concentrations to coronary artery reperfusion before and after thrombolytic treatment in patients with acute myocardial infarction. Am J Cardiol 63:1179-1184,1989 68. Lawler CM, Bovill EG, Stump DC, et al: Fibrin fragment D-dimer and fibrinogen BB peptides in plasma as markers of clot lysis during thrombolytic therapy in acute myocardial infarction. Blood 76:1341-1348,199O 69. Eisenberg PR, Jaffe AS, Collen D, et al: Activation of plasminogen does not increase D-dimer in plasma in the absence of clot lysis. Circulation 80:11-115, 1989 (suppl 2) (abstr) 70. Rao AK, Pratt C, Berke A, et al: Thrombolysis in Myocardial Infaraction Trial Phase I: Hemmorhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Co11 Cardiol ll:l-11, 1988 71. Arnold AER, Brower RW, Collen D, et al: Increased serum levels of fibrinogen degradation products due to treatment with recombinant tissue-type plasminogen activator for acute myocardial infarction are related to bleeding complications, but not to patency. J Am Co11 Cardiol 14:581-588, 1989 72. Heras M, Chesebro JH, Penny WJ, et al: Importance of adequate heparin dosage in arterial angioplasty in a porcine model. Circulation 78:645-660,1988 73. Bleich SD, Nichols TC, Schumacher RR, et al: Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction. Am J Cardiol66:1412-1417,199O 74. Hsia J, Hamilton WP, KIeiman N, et al: A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 323:1433-1437,199O 75. European Cooperative Study Group-Phase Med J 1991 (in press) 76. Basu D, Gallus A, Hirsh J, et al: A prospective

6: Br study

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of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 287:324327,1972 77. Turpie AGG, Robinson JG, Doyle DJ, et al: Comparison of high-dose with low-dose subcutaneous heparin to prevent left ventricular mural thrombosis in patients with acute transmural anterior myocardial infarction. N Engl J Med 320:352-357,1989 78. Kaplan K, Davison R, Parker M, et al: Role of heparin after intravenous thrombolytic therapy for acute myocardial infarction. Am J Cardiol59:241-244,1987 79. Camilleri JF, Bonnet JL, Bouvier JL, et al: Thrombolyse intraveineuse dans l’infarctus du myocarde: Influence de la qualite de l’anticoagulation sur le taux de recidives precoces d’angor ou d’infarctus. Arch Ma1 Coeur 81:10371041,1988 80. Meade TW, Vickers MV, Thompson SG, et al: Epidemiological characteristics of platelet aggregability. Br Med J 290:428-431,1985 81. Elwood PC, Renaud S, Sharp DS, et al: Ischemic heart disease and platelet aggregation. The Caerphilly Collaborative Heart Disease Study. Circulation 83:38-44, 1991 82. Trip MD, Cats VM, van Capelle FJL, et al: Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med 322:1549-1554,199O 83. Trip MD, Cats VM, van Capelle FJL, et al: Platelet hyperactivity and prognosis in survivors of myocardial infarction. N Engl J Med 322:1549-1554,199O 84. Antiplatelet Trialists Collaboration: Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 296:320-331,1988 85. Maddahi J, Ganz W, Ninomiya K, et al: Myocardial salvage in intracoronary thrombolysis in evolving acute myocardial infarctions. Evaluation using intracoronary injection of thallium-201. Am Heart J 102:664-675,198l 86. Markis JE, Malagold M, Parker JA, et al: Myocardial salvage after intracoronary thrombolysis with streptokinase in acute myocardial infarction assessment by intracoronary thallium-201. N Engl J Med 305:777-782,198l 87. Schafer J, Montz R, Mathey DG: Scintigraphic evidence of the “no reflow” phenomenon in human beings after coronary thrombolysis. J Am Coil Cardiol 5:593-598, 1985 88. Schafer J, Mathey DG, Montz R, et al: Use of dual intracoronary scintigraphy with thallium-201 and technetium-99m pyrophosphate to predict improvement in left ventricular wall motion immediately after intracoronary thrombolysis in acute myocardial infarction. J Am Co11 Cardiol2:737-744,1983 89. Reduto LA, Freund GC, Gaeta JM, et al: Coronary artery reperfusion in acute myocardial infarction: Beneficial effects of intracoronary streptokinase on left ventricular salvage and performance. Am Heart J 102:1168,1981 90. Simoons ML, Wijns W, Balakumaran K, et al: The effect of intracoronary thrombolysis with streptokinase on myocardial thallium distribution and left ventricular function assessed by blood-pool scintigraphy. Eur Heart J 3:433-440,1982

MONITORING

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91. DeCoster PM, Melin JA, Detry JMR, et al: Coronary artery reperfusion in acute myocardial infarction: Assessment by pre- and post-intervention thallium-201 myocardial perfusion imaging, Am J Cardiol55:889-895, 1985 92. Schwarz F, Schuler G, Katus H, et al: Intracoronary thrombolysis in acute myocardial infarction: Correlations among serum enzyme, scintigraphic and hemodynamic findings. Am J Cardiol50:32-38, 1982 93. Sinusas AJ, Trautman KA, Bergin JD, et al: Quantification of area at risk during coronary occlusion and degree of myocardial salvage after reperfusion with technetium99m methoxyisobutyl isonitrile. Circulation 83:1424-1437, 1990 94. Wackers FJ, Giboons RJ, Verani MS, et al: Serial quantitative planar technetium-99m isonitrile imaging in acute myocardial infarction: Efficacy for noninvasive assessment of thrombolytic therapy. J Am Coil Cardiol 14:861873, 1989 95. Wesbey GE, Higgins CB, McNamara MT, et al: Effect of gandolinium-DTPA on the magnetic relaxation times of normal and infarcted myocardium. Radiology 153:165-169, 1984 96. Rehr RB, Peschock RM, Mallow CR, et al: Improved in vivo magnetic resonance imaging of acute myocardial infarction after intravenous paramagnetic contrast agent administration. Am J Cardiol57:864-868,1986 97. Peshock KM, Malloy CR, Buja LM, et al: Magnetic resonance imaging of acute myocardial infarction: Gadolimium diethylenetriamine pentaacetic acid as a marker of reperfusion. Circulation 74:1434-1440,1986 98. Van Rossum AC, Visser FC, Van Eenige MJ, et al: Value of gadolinium-diethylenetriamine pentaacetic acid dynamics in magnetic resonance imagaing of acute myocardial infarction with occluded and reperfused coronary arteries after thrombolysis. Am J Cardiol65:845-851,199O 99. Sherry S: Bleeding complications in thrombolytic therapy. Hosp Pratt 25:1-21.1990 (suppl5) 100. Sane DC, et al: Bleeding during thrombolytic therapy for acute myocardial infarction: Mechanisms and management. Ann Intern Med lll:lOlO-1020,1989 101. Marder VJ, Sherry S: Thrombolytic therapy: Current status (2 parts). N Engl J Med 318(21):1585-1.595; 318(23):15l’2-1520,198s 102. Genton RE, Sobel B: Early intervention for interruption of acute myocardial infarction. Mod Cone Cardiovasc Dis 56:35-41,1987 103. Verstraeta M, Tytgat G, Amery A, et al: Thrombolytic therapy with streptokinase using a standard dosage. Thromb Diathes Haem 21:493-498,1966 104. Mannucci PM: Desmopressin (DDAVP) for treatment of disorders of hemostasis. Prog Hemost Thromb 8:19-46, 1986 105. Simoons M, Van den Brand M, DeZwaan, et al: Improved survival after early thrombolysis in acute myocardial infarction: A randomized trial of the Interuniversity Cardiology Institute in the Netherlands. Lancet 2:578-582, 1985 106. Kennedy JW, Ritchie JL, Davis KB, et al: Western Washington randomized trial of intracoronary streptoki-

293

nase in acute myocardial infarction. N Engl J Med 301-481: 1477,1983 107. Dalen JE, Gore JM, Braunwald E, et al: Six and twelve month follow-up of the Phase 1 Thrombolysis in Myocardial Infarction Trial. Am J Cardiol62:179-185, 1988 108. Hochman JS, Choo H: Limitation of myocardial infarction expansion by reperfusion independent of myocardial salvage. Circulation 75:299-306, 1987 109. Kerschot IE, Brugada P, Ramentol P, et al: Effect of early reperfusion in acute myocardial infarction on arrhythmias induced by programmed stimulation: A prospective, randomized trial. J Am Co11 Cardiol7:1234-1242, 1986 110. Vermeer F, Simoons ML, Lubsen J: Reduced frequency of ventricular fibrillation after early thrombolysis in myocardial infarction. Lancet 1:1147-1148, 1986 111. Top01 EJ, Califf RM, George BS, et al: A randomized trial of immediate versus delayed elective angioplasty after acute myocardial infarction. N Engl J Med 317:581588,1987 112. The TIM1 Research Group: Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction: TIM1 IIA results. JAMA 260:2849-2858,198s 113. Simoons ML, Arnold AE, Betriu A, et al: Thrombolysis with tissue plasminogen activator in acute myocardial infarction: No additional benefit from immediate PTCA. Lancet 1:197-203,1988 114. Califf RM, Top01 EJ, Stack RS, et al: Evaluation of combination thrombolytic therapy and timing of cardiac catheterization in acute myocardial infarction. Results of Thrombolysis and Angioplasty in Myocardial Infarction Phase 5 Randomized Trial. Circulation 83:1543-1556, 1991 115. Lee L, Walton JA, Bates E, et al: Cardiogenic shock complicating acute myocardial infarction: Changing therapies and prognosis. Circulation 74:II-276, 1986 (suppl2) 116. Shani J, Rivera M, Greengart A, et al: Percutaneous transluminal coronary angioplasty in cardiogenic shock. J Am Co11 Cardiol7:149A, 1986 (abstr) 117. Heuser RR, Maddoux GL, Goss JE, et al: Coronary angioplasty for acute mitral regurgitation due to myocardial infarction: A nonsurgical treatment preserving mitral valve integrity. Ann Intern Med 107:852-85.5,1987 118. Brown TM Jr, Iannone LA, Gordon DF, et al: Percutaneous myocardial perfusion (PMR) reduces mortality in acute myocardial infarction (MI) complicated by cardiogenic schock. Circulation 72:111-309,198s (suppl3) 119. Lee L, Bates ER, Pitt B, et al: Percutaneous transluminal coronary angioplasty improves survival in acute myocardial infarction complicated by cardiogenic shock. Circulation 78:1345-1351,1988 120. Stack RS, Cal% RM, Hinohara T, et al: Survival and cardiac event rates in the first year after emergency coronary angioplasty for acute myocardial infarction. J Am Co11 Cardiol 11:1141-1149,1988 121. Ellis SG, Debowey D, Bates ER, et al: Treatment of recurrent ischemia after thrombolysis and successful reperfusion for acute myocardial infarction: Effect on inhospital mortality and left ventricular function. J Am Co11 Cardiol 17752-757, 1991

294

BOVILL,

122. Barbash GI, Hod H, Roth A, et al: Repeat infusion of recombinant tissue-type plasminogen activator in patients with acute myocardial infarction and early recurrent myocardial ischemia. J Am Co11Cardiol 16:779-783, 1990 123. Ellis SG, Top01 EJ, George BS, et al: Recurrent ischemia without warning. Analysis of risk factors for in-hospital ischemic events following successful thromboly-

BECKER,

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sis with intravenous tissue plasminogen activator. Circulation 80:1159-1165,1989 124. Gruppo Italian0 per lo Studio Della Streptochinasi nell’lnfarto Miocardico (GISSI): Lancet 2:62-71,199O 125. European Cooperative Study Group. Streptokinase in acute myocardial infarction. N Engl J Med 301:797-802, 1979

ANNOUNCEMENTS

American Journal of Cardiac Imaging The Mel Marcus Young Investigator’s Award in Cardiac Imaging Commencing in 1992 the American Journal of Cardiac Imaging will award, on an annual basis, the Mel Marcus Young Investigator’s Award for Cardiac Imaging for the best original manuscript in cardiac imaging research. Each manuscript must be based on original research in cardiac imaging. The candidate should be a physician or life scientist less than 35 years of age. The abstract or the original paper could have been presented at a national meeting, but the original paper must not have been submitted to another journal for publication. The original paper and four copies must be sent to James V. Talano, MD, Editor-in-Chief, American Journal of Cardiac Imaging, 250 E. Superior, Chicago, IL 60611. Deadline for submission is June 1, 1992. Winners will be announced in the December 1992 issue. First prize is $500, second prize is $250. For further information, please consult the “Information for Contributors” section within the Journal or call the editorial office at (312) 9084687. 0

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American Journal of Cardiac Imaging Expedited Review of Original Articles In order to offer rapid dissemination

of important scientific information, the American Journal of Review of original imaging research. If an author selects the Expedited Review process, the manuscript submitted must conform to the following guidelines. 0 The manuscript must be 10 pages or less of standard size type, ie, 10 characters per inch. l No more than 5 figures and 2 tables; black and white figures only. 0 Twenty references or less. 0 Key words and an abstract must be included. Each manuscript submitted under Expedited Review should be sent to the Editor-in-Chiefs office at the American Journal of Cardiac Imaging, at 250 E. Superior, Chicago, IL 60611. Within 24 hours of receipt it will be recorded and the article will then be sent to one of the Journal’s Associate Editors. The Associate Editor will expedite the editorial review process, and requests for revisions, if any, will be sent directly from the Associate Editor’s office. A letter of acceptance or rejection will be sent directly from the Associate Editor’s office. Once accepted, the article will be sent directly to W.B. Saunders. The article will be placed in the very next issue, under “Original Contributions, Expedited Review.”

Cardiac Imaging will now offer Expedited