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Proceedings of the 21st Arnold O. Beckman Conference |
1
Loyola University Medical Center, Department of Pathology, 2160 S. First Ave., Maywood, IL 60153.
2
Novartis Pharma GmbH, Deutschherrn Strasse 15, Nurnberg
9-429, Germany.
3
Southwestern Medical Center, Department of Medicine and
Pathology, 6780 Abrams Rd., Dallas, TX 75231.
a Author for correspondence. Fax 708-216-6660; e-mail jfareed{at}wpo.it.luc.edu.
Abstract
We review laboratory tests that evaluate thrombogenesis during acute coronary syndromes. These tests have been found to be valuable research tools in more clearly understanding the pathophysiology of acute coronary syndromes. In particular, we describe tissue factor, tissue factor pathway inhibitor, prothrombin fragment 1.2, thrombin-antithrombin complex, fibrinopeptide A, tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), t-PA-PAI complex, Bß 15–42-related peptides, fibrinogen degradation products, fibrin degradation products, D-dimer, platelet factor 4, ß-thromboglobulin, 5-hydroxytryptamine, thromboxane B2, prostacyclin, endothelin, angiotensin-converting enzyme, soluble thrombomodulin, C1-esterase inhibitor, anaphylotoxins C3a, C4a, and C5a, bradykinin, tumor necrosis factor, leukotriene C4, platelet activating factor, anti-phospholipid antibody, and von Willebrand factor. Some of these tests may prove to be useful in clinical diagnosis and management of acute coronary syndromes. Clinical outcome studies are needed to determine which tests may be cost effective and medically useful.
Coronary atherosclerosis results from multifactorial progressive vascular alterations that lead to the development of plaques within the coronary arteries. Acute coronary syndrome occurs when an unstable plaque ruptures and activates coagulation at the site, blocking blood flow and causing ischemic injury to the heart. Thrombogenesis is the final process whereby the exposed tissue factor (TF)1 triggers the activation of coagulation and the freshly formed clot fills the coronary artery lumen.
Despite several improvements in the diagnosis and management of acute myocardial infarction (AMI), this catastrophic event continues to be a major cause of death in the industrialized world. Annually in the United States nearly 1.5 million persons sustain AMI (1). Approximately two-thirds of people having an AMI are admitted to coronary intensive care units. Only 50% of all people suspected of AMI are actually confirmed (2). Several advances in the diagnosis and management of AMI have contributed to the decrease in the mortality rate (3). These include intracoronary and intravenous thrombolysis, increased use of aspirin, development of interventional approaches such as percutaneous coronary transluminal angioplasty (PTCA), improved pharmacologic agents utilizing ß-blockers, nitrates, angiotension-converting enzyme inhibitors, and newer antithrombotic drugs (4).
The success of thrombolytic therapy in the management of AMI depends on lysis of the formed clot. Thrombogenesis is also seen at the coronary site as a result of reperfusion injury, and the timely identification of this event is of major value in the optimal management of AMI and related syndromes. During pre-infarction phases, a hypercoagulable state caused by vascular distress, fibrinolytic deficit, procoagulant behavior of various mediators, cytokines, and adhesion molecules may be detectable. Patients with unstable angina are treated with anticoagulants and antiplatelet drugs to prevent thrombogenesis during plaque rupture. Anticoagulant therapy is required to manage AMI. Although heparin is commonly used with aspirin, newer drugs such as the low molecular weight heparins, r-hirudin, glycoprotein IIb/IIIa inhibitors, and ADP receptor blockers are also used. A profiling of these analytes along with the conventional tests of myocardial infarction (MI) injury may provide a useful approach for the diagnosis and management of AMI. We predict that new tests for thrombogenesis will be clinically validated for use in the diagnosis and treatment of acute coronary syndromes.
Pathophysiology of MI
Almost all MIs result from coronary atherosclerosis, which is
subsequently followed by coronary thrombosis. Progressive vascular
changes lead to significant occlusion (>80%) of the coronary artery
but do not lead to AMI because of the development of a profound
collateral network over time. Several factors contribute to the
evolution of atherosclerotic plaques that may rupture abruptly,
releasing several thrombogenic substances that mediate platelet
activation, thrombin generation, and fibrinolytic deficit (Fig. 1
). The freshly formed thrombus interrupts blood flow and causes
ischemic injury of the myocardium, eventually leading to myocardial
necrosis.
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Most of the patients who die of a MI exhibit atherosclerotic plaques, which are composed of fibrous tissue of varying densities and cellular infiltrates with superimposed thrombus. Platelet-rich thrombi are found on the surface of the most advanced atherosclerotic lesions, which are also characterized by calcified lesions, lipid deposits, necrotic debris, and trapped blood on a fibrous cap. The process of plaque rupture is an event having both immunologic and thrombotic activation. Plaque rupture is mediated by such enzymes as collagenase, gelatinase, and stromelysin, which degrade components of the interstitial matrix. These enzymes are usually released by the intracellular components of plaque. Several cytokines also contribute to the plaque rupture. Upon rupture, thrombogenic substances, in particular TF, activates the coagulation process.
The activation of coagulation is thought to involve a complex network
of proteases held in check by several inhibitors (Fig. 2
). In MI, the primary activation of the coagulation process is
through the activation of factor VII initiated by TF from the ruptured
plaque. TF is also capable of amplifying the activation of
monocyte-driven TF release to augment coagulation. Once the TF/factor
VII complex is formed, it is capable of activating factor X to Xa,
which in turn converts prothrombin to thrombin. At this stage,
prothrombin fragment 1.2 (F1.2) is released. The
formed thrombin cleaves fibrinopeptide A (FPA) from fibrinogen,
producing fibrin. Thrombin complexes with antithrombin III leading to
the formation of thrombin-antithrombin III (TAT) complexes. During
thrombogenesis in AMI, all three of these analytes may be increased.
The fibrin formed undergoes endogenous lysis, leading to formation of
fibrin degradation products. Thus, F1.2, TAT complexes,
FPA, and fibrin degradation products are suggestive evidence of the
thrombogenic process. On the other hand, several other analytes are
generated during the interaction between platelets and
endothelium/subendothelium. This process is depicted in Fig. 3
. Damaged or distressed (ischemic) endothelium leads to the
formation of prothrombogenic substances such as factor XII,
thromboxanes, endothelin, TF, and various growth factors. The activated
platelets in this milieu release plasminogen activator inhibitor (PAI),
von Willebrand factor (vWF), fibrinogen, fibronectin, and heparinase,
which contribute to the amplification of the thrombogenic response in
this syndrome. The freshly formed fibrin-rich clot is further
stabilized by factor XIIIa, which cross-links fibrin monomers. Older,
more cross-linked clots are more difficult to lyse.
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Treatment of Acute Coronary Syndromes
It is clear from the above discussion that the process of thrombogenesis is the final event for the occlusion of the coronary artery. This pathologic event was first described by Herrick in 1912 (5). Not until the introduction of thrombolytic agents was this observation reinforced. Thus the current approach to treat MI is founded largely on the fact that fresh clot is digestible by thrombolytic agents (6).
AMI is now managed in a stepwise manner where the use of anticoagulant, antiplatelet, and thrombolytic drugs play pivotal roles (7). Anticoagulation followed by thrombolysis is usually the first step in the management of AMI. Because of the age of the coronary thrombus, fibrinolytic deficit, and the presence of other factors resisting thrombolysis, other options–such as PTCA, rotablation, and stenting–must be used. These interventional procedures inherently represent an additional thrombotic risk, warranting continual antithrombotic therapy to prevent thrombogenesis, which may lead to re-occlusion. Thus, in addtion to the monitoring of MI tests such as the cardiac enzymes, troponins, and other analytes, the profiling of the activation analytes of coagulation and platelets along with the vascular distress analytes may provide valuable information for a managed approach. Simultaneous measurement of these analytes could provide a useful guide for management of the optimal therapeutic strategy. The activation of coagulation leads to expression of analytes of thrombin generation and its complex formation. The fibrinolytic deficit is detectable by measuring PAI-1, plasmin-antiplasmin complex, and tissue plasminogen activator (t-PA)/PAI complex. Platelet activation is measurable by quantifying thromboxanes, platelet factor 4, and thrombomodulin (TM). More recently, P-selectin has also been considered to be a analyte of platelet activation (8). The vascular injury distress analytes include increased PAI-1, soluble TM (S-TM), E-selectin, and adhesion molecules.
Reperfusion during thrombolysis or angioplasty increases oxygenation
and revitalization of the injured myocardium and decreases various
analytes of thrombogenesis (Table 1
). This therapy is not without hazard–it is capable of
inflicting additional injury beyond that attributable to
occlusion-caused ischemia (9)(10). Such an
injury produces ventricular arrhythmias and myocardial stunning. If the
therapy is continued, the late reperfusion damage may cause necrosis
and microvascular injury, impairing the collateral perfusion. This may
lead to reperfusion injury and produce ischemic damage, which may be
sometimes lethal. Numerous reports have shown that myocardial ischemia
and reperfusion injury are acute inflammatory processes in which white
blood cells have a primary role (11). Cell adhesion
molecules of the selectin, integrin, and immunoglobulin families are
intimately involved in leukocyte adhesion, which subsequently leads to
myocardial reperfusion injury. During thrombolysis and PTCA, the
ischemia and reperfusion injury play a key role in converting
endothelium into a thrombogenic lesion. This is primarily because of an
increase in the expression of P-selectin and intracellular adhesion
molecules. This leads to neutrophil adherence and the release of
procoagulant material (12)(13)(14). The activated endothelium
releases thrombotic mediators such as interleukin-8, platelet activator
factor (PAF), TF, tumor necrosis factor (TNF), and other additional
adhesion molecules. Knowledge of these activation processes have led to
the development of several newer approaches to treat this syndrome. It
is clear that the complex pathophysiologic event seen in acute coronary
syndromes eventually develops into a thrombotic process. Therefore,
control of this event is of key value in reducing mortality
(15).
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Specific Tests of Thrombogenic Activity
Until recently, the nature of the thrombotic process remained
difficult to establish before and after MI. It is now clear that
thrombosis is the result of a progressive alteration of the blood and
vascular system. Epidemiologic studies have clearly shown a
relationship between the existence of risk factors leading to blood
activation, which progressively saturates the thromboresistant capacity
of the body. Use of laboratory assays of hemostatic activation may
represent an approach to identify high-risk patients in whom several of
these indicators can be used to guide therapy (16). During
the past few years, several methods to evaluate various tests for
thrombogenesis have been described (17)(18)(19)(20)(21)(22)(23)(24)(25). Table 2
lists various analytes that are found in increased circulating
amounts during the activation or inhibition of the coagulation process.
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TF is a 30-kDa integral membrane glycoprotein that serves as a cofactor and is required for the activation of factor VII. TF is primarily present in the cellular membranes, and when tissue is damaged, its concentrations are increased. Thus at the site of thrombogenesis, the concentration of this mediator of thrombogenesis may be increased. More recently, a specific inhibitor of TF, namely tissue factor pathway inhibitor (TFPI), has been found to play a key role in the control of TF-mediated activation of the clotting process (17). This Kunitz type of inhibitor is capable of inhibiting serine proteases, which are similar to trypsin and possess an active serine site. TFPI is released during heparin therapy and has a key role in the control of thrombogenesis during acute coronary syndromes. Because of the pathophysiologic activation processes in cardiovascular disorders, TFPI is likely to provide important diagnostic information in both thrombotic and cardiovascular disorders (18). TFPI is a useful indicator of endothelial function as well as of the efficacy of heparin and other glycosaminoglycan therapies. Impaired release of this agent during heparinization may be related to heparin resistance in patients. Only limited information is available concerning the physiologic role of TF, and it is proposed that this factor may be involved in various other processes. F1.2 is found during the activation of the coagulation process in which factor Xa converts prothrombin into thrombin (19). This analyte is, therefore, a reliable indicator of thrombin generation. Thus, patients with persistent thrombotic events may exhibit high concentrations of this analyte. Furthermore, during antithrombotic therapy, this analyte is decreased, suggesting that the anticoagulant drugs are capable of suppressing its formation. Once thrombin is formed, it circulates bound to endogenous serine protease inhibitors such as antithrombin III. The TAT complex readily formed during the thrombotic process circulates in the blood of patients who suffer from thrombotic disorders.
On the other hand, FPA is formed by the action of thrombin on fibrinogen. Thus, this analyte is specific for thrombin activity and the formation of fibrin. FPA is increased in patients having a hypercoagulable state. The therapeutic effectiveness of antithrombotic drugs can be assessed by a decrease in FPA (16).
t-PA is released from the endothelium and facilitates the digestion of
on-site fibrin clots. The impairment of t-PA release during
fibrinolytic deficit in certain disorders, such as diabetes, leads to
thrombotic complications in these patients. Vascular dysfunction and
several drugs also contribute to the deficit of this modulator of
fibrinolysis. PAI is also released from the endothelial cells and is
capable of neutralizing the actions of t-PA. PAI concentrations are
increased in many patients suffering from fibrinolytic disorders.
Plasmin-
2-antiplasmin complex is involved during
fibrinolytic activation and fibrinolytic therapy. Patients with
disseminated intravascular coagulation and primary fibrinolysis also
exhibit increased concentrations of the
plasmin-2-antiplasmin complex. The Bß 15–42-related
peptides are small peptide cleavage products released by the action of
plasmin on fibrinogen and represent a sensitive indicator of
fibrinolytic activity. The concentrations of these analytes are
increased even before any measurable decrease in the fibrinogen
concentration. These analytes, therefore, represent a sensitive index
of fibrinolytic activation. When fibrinogen and fibrin are exposed to
the action of circulating plasmin, this digestion leads to the
formation of respective digestion products. The digestion of fibrinogen
yields fragments X, Y, D, and E, which are collectively known as
fibrinogen degradation products. On the other hand, the digestion of
fibrin yields distinct cleavage products such as the XY, DD, and DY.
These products are specific indicators of the formation of fibrin and
its digestion by plasmin. D-dimer is a sensitive indicator of the
formation of fibrin and its digestion and is commonly used to measure
the extent of secondary fibrinolytic disorders. The fibrin degradation
products are collectively known as FbDPs. Thus, a profiling of these
degradation products can be useful in the differential diagnosis of
primary and secondary fibrinolysis.
Platelet factor 4, ß-thromboglobulin, and serotonin are specific products of platelets that are released on the activation of platelets (20). On the other hand, thromboxane B2 is generated during the activation of platelets by the enzymatic action of cyclooxygenase on arachidonic acid. These products of platelet activation are extremely sensitive tests for arterial thrombotic disorders such as thrombotic stroke, peripheral vascular disorders, and platelet-related thrombotic disorders. These analytes are also detectable at high concentrations in patients where platelets are activated by other disorders (21). Antiplatelet drugs such as aspirin suppress the release of these analytes, indicating that the activation of platelets is also impaired.
A metabolite of prostacyclin, namely 6-keto-prostaglandin
F1, is a specific analyte of endothelial function
and is only synthesized by healthy vascular endothelium. Vascular
masking occurs when the endothelial cell lining is covered by plaque or
stripped by vascular damage. Plaque-covered endothelium fails to
produce 6-keto-prostaglandin F1. Thus, during exercise,
the decreased concentrations of this analyte may indicate vascular
dysfunction. Similarly, t-PA is also a analyte of vascular function,
and its release is also impaired in patients with vascular defects.
Endothelin is a peptide analyte of endothelial distress. Ischemia and
other pathologic conditions cause increased synthesis of this analyte
of endothelial distress. Therefore, in patients with vascular
dysfunction, this analyte is increased. Angiotensin-converting enzyme
may also be a analyte of vascular damage and is released in patients
who suffer from vascular damage and related disorders.
S-TM is a vessel-specific protein that plays an important role in the neutralization of thrombin and conversion of protein C to protein Ca (22). Most of the endogenous TM is bound to blood vessels. However, vascular damage leads to release of this protein. Thus, S-TM is increased in plasma. In certain patients with atherosclerotic disease and vasculitis, S-TM is found to be increased.
C1-esterase inhibitor, C1, C3, and C5 are all components of the complement system. C1-esterase inhibitor is an important inhibitor that is consumed during the activation of the complement system. The C1-esterase thus generated forms complexes and leads to the formation of C1-esterase inhibitor complex. This complex is increased in various thrombotic disorders where the simultaneous activation of the complement cascade takes place. The anaphylotoxins represent the peptide fragments of the C1, C3, and C5 components of the complement system. These cleavage products are formed during immunoactivation and are also present at increased concentrations in various thrombotic complications.
Contact activation of blood generates kallikrein, an enzyme that can convert kininogens into kinins. Kinins are potent mediators of pain and vasodilation. Kinins can also activate white cells and facilitate their procoagulant actions. Thus, kinins are considered important analytes of hemostatic activation.
TNF is a product of macrophages and is known to produce multiple effects on cells, including platelets. TNF is one of the main mediators of pathologic responses during septic shock. TNF also plays a key role in the cellular signaling process and regulates the synthesis of certain mediators of inflammation, necrosis, and activation. Increased circulating concentrations of TNF are found in patients with thrombotic disorders associated with cancer. Leukotriene C4 is a metabolite of arachidonic acid that is found in the white cells. In thrombotic complications associated with inflammation, this analyte of cellular activation is also increased. PAF is synthesized by mast cells and is increased in the circulating blood of patients with mast cell activation. During transplant rejection, the concentrations of TNF, PAF, and leukotriene C4 are increased substantially. Furthermore, in various thrombotic disorders where mast cells are involved, the PAF concentration is increased.
Newer and reliable immunoassay methods for quantification of antiphospholipids have recently become available. The presence of anti-phospholipid antibodies is linked with arterial and venous thrombotic disorders (23). These antibodies are generated by changes in the vascular lipid membrane. Individual methods for the quantification of these antibodies and a collective concentration of these anti-phospholipid antibodies, therefore, provide a reliable means of detecting this syndrome. vWF is also increased in various prethrombotic states involving both the arterial and venous systems. This protein is involved in the functionality of platelets. Plasma concentrations of vWF can be readily measured using an antigenic or a functional method.
In addition to the generation of various thrombogenic analytes in blood, several other plasma analytes have been identified as potential risk factors for the coronary artery disease (24)(25)(26)(27)(28)(29). These include hyperhomocysteinemia, factor V Leiden, antibodies to Helicobacter pylori, polymorphism of factor V, VII, and fibrinogen, and increased concentrations of factors VII and fibrinogen. The simultaneous presence of two or more of these risk factors greatly enhances the risk for MI. Thus, a screening that includes some of these tests might be useful in identifying high-risk groups.
Methods Used for Thrombogenic Tests
The chemical nature and the reference values of these thrombogenic
laboratory tests are listed in Table 3
. As can be seen, these analytes are a heterogeneous group of
chemicals representing peptides, proteins, lipids, glycoproteins,
lipoproteins, and molecular complexes. The circulating amount of these
analytes at resting stages also represents a wide range. However, most
of these analytes are present in extremely low amounts (ng-µg/L).
Some of these analytes are not present at resting stages and can only
be found during active pathologic states. The circulating half-life of
these analytes are rather short unless the pathophysiologic event is
persistent.
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It is, therefore, important to obtain proper blood or tissue fluid samples for measurement of these analytes. Proper blood drawing plays a crucial role in the quantification of the physically relevant concentrations of these analytes. Specific guidelines have been established for the proper collection of biologic fluids and storage of these samples for analysis (30)(31).
Table 4
contains a compilation of the origin of various analytes of
hemostatic activation and techniques available for their measurement.
These analytes are generated from cellular sites or in blood after
pathophysiologic activation. The generation of these analytes may be
localized, as in the case of tumors and MI, or widely produced in such
conditions as the hypercoagulable state and disseminated intravascular
coagulation. Because most of these analytes are generated at µg/L or
ng/L concentrations, enzyme immunoassays have been extremely useful for
their measurement. The detection limit of immunoassays is within the
range of the amounts generated during physiologic and/or pathologic
activation processes. Furthermore, these immunoassays are highly
specific for a given analyte, and other endogenous substances do not
interfere in their quantification. As listed on this table, both RIA
and ELISA can be used for the quantification of these analytes. Several
commercially available kits have been introduced and are currently
being used in several laboratories (32).
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Table 5
is a projected list of various laboratory tests that are
altered during the pregnancy-associated hypercoagulable state,
atherosclerosis, and vascular spasm. The pregnancy-associated
hypercoagulable state may lead to venous thrombosis. Thus,
thrombin-specific analytes such as F1.2, FPA, and
fibrin-specific degradation products are increased. During
atherosclerosis, on the other hand, platelet activation, vascular
dysfunction, and analytes of platelets and blood vessels are
generated (33). Thus, platelet factor 4,
ß-thromboglobulin, serotonin, and thromboxane B2 may be
increased. ET, S-TM, and vWF are also increased, suggesting that
vascular dysfunction is associated with the atherosclerotic process.
The relative increases in these analytes are dependent on several
factors; however, these factors may provide crucial information of the
pathophysiologic process. If proper treatment is followed, the
concentrations of these analytes may be proportionately decreased.
Thus, these analytes may be useful in monitoring therapeutic effects of
antithrombotic drugs.
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Factors Influencing the Future Utility of These Tests
The relative role of laboratory tests for the identification of active thrombogenesis in acute coronary syndromes is of major importance for the diagnosis and treatment of this disorder. The presence of these analytes in blood is indicative of an ongoing thrombogenic process, which may be related to the failure of therapy or reperfusion injury-related pathogenesis. Because re-occlusion and embolization are commonly associated with therapeutic approaches for MI, simultaneous measurement of analytes of thrombogenesis can be used in the optimization of the management of MI (F1.2, FPA, and TAT complexes). Newer analytes such as P-selectin and S-TM may provide useful information on platelet/endothelial interaction.
During the past decade some dramatic developments in the management of
MI have taken place. The impact of new antithrombotic drugs in the
management of acute coronary syndromes is rather remarkable
(34). The introduction of these drugs has revolutionized the
management of acute coronary syndromes and secondary prevention of
coronary syndromes. Fig. 4
shows a comparison of various anticoagulant and
antithrombotic drugs. In addition to the conventional anticoagulants
such as heparin, aspirin, and oral anticoagulant drugs, many newer
drugs have been recently introduced (7). Heparin is now
depolymerized to develop low molecular weight heparin. Synthetic
heparin derivatives have also been produced. Through recombinant
technology such potent anticoagulants as hirudin have been developed.
Several antithrombin peptides have also been developed. TFPI is also
produced by recombinant technology. Many newer antiplatelet drugs such
as ticlopidine, clopidogrel, and ReoPro® have been developed. Unlike
heparin, these drugs have monotherapeutic effects. The safety and
efficacy of these agents is not fully understood, and these agents
require monitoring.
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The diagnostic usefulness of these tests needs to be validated in well-designed clinical trials. Although multiple profiling of these analytes may be expensive, initial screening might provide reliable data on the diagnostic validity of a select number of analytes that can be correlated with a given disorder. However, despite the introduction of >24 diagnostic kits for the detection of various hemostatic alterations, no clinical trial to measure their diagnostic and monitoring value has been undertaken. However, some limited data are available on the diagnostic efficacy of some of the analytes.
Despite the cost limitations, the application of some of these analytes, such as F1.2, FPA, platelet factor 4, and D-dimer have provided useful information for the differential diagnosis of the hypercoagulable state and thrombotic response during MI. The thrombotic complications observed during reperfusion injury can also be readily assessed using some of these analytes. Unlike the conventional coagulation tests, which are only useful in the detection of hypercoagulable states caused by a disease or drug, these analytes are extremely useful in the diagnosis of hypercoagulable states and subclinical activation or inhibition of the hemostatic system during interventional cardiologic procedures such as stenting and PTCA.
Anticoagulant therapy has undergone some major developments in recent years. Conventional drugs that produce anticoagulant effects, such as heparin and oral anticoagulants, are no longer considered the only candidates for the anticoagulant/antithrombotic management of patients. Recombinant hirudin, glycoprotein IIb/IIIa-targeting antibodies, synthetic peptides such as hirulog, and efegatran® are being tested for their efficacy. These drugs produce their effects at different sites. To monitor their overall effects on the hemostatic system, molecular analytes offer a very practical and reliable approach. Thus, for the monitoring of antithrombin drugs, analytes of thrombin generation are useful, whereas the efficacy of antiplatelet drugs can be assessed by monitoring the platelet release products. Furthermore, polytherapy utilizing several anticoagulant and antithrombotic drugs in combination has been considered. In these situations, the use of molecular analytes may also prove to be invaluable.
It is expected that the introduction of simple technologies such as the test strip or particle agglutination methods may be available for the measurement of many of these analytes in the near future. This will be extremely useful for the ready availability and reduced cost of individual analyte testing. Furthermore, this type of technology can be used at the bedside, off-site, and in doctors' offices. It is clear that molecular analyte profiling provides us useful information on the nature of pathophysiology of a given thrombotic disorder. However, for practical use, a cost-effective and simpler assay-based approach will greatly enhance their use, and these tests will be readily accepted at both the laboratory and clinical levels.
Footnotes
1 Nonstandard abbreviations: TF, tissue factor; AMI, acute myocardial infarction; PTCA, percutaneous coronary transluminal angioplasty; MI, myocardial infarction; F1.2, prothrombin fragment 1.2; FPA, fibrinopeptide A; TAT, thrombin-antithrombin; PAI, plasminogen activator inhibitor; vWF, von Willebrand factor; t-PA; tissue plasminogen activator; TM, thrombomodulin; S-TM, soluble thrombomodulin; PAF, platelet activator factor; TNF, tumor necrosis factor; and TFPI, tissue factor pathway inhibitor. 
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