`(1996)
`1537-1541
`
`42:9
`
`Thrombus precursor protein (TpP): marker of
`thrombosis early in the pathogenesis of myocardial
`infarction
`
`DAVID
`
`G.M.
`
`CARVILLE,l*
`NIKor
`ELAINE M. BRILL,1
`
`DIMITRIJEVIC,’
`NATASHA
`DREW,1
`
`MARK WALSH,2
`TAMARA
`and PAUL E. GARGAN1
`
`DIGIROLAMO,2
`
`mi-
`an enzyme-linked
`We have developed
`immunosorbent
`for quantifying
`munoassay
`pro-
`the
`immediate
`precursor
`teins
`to intravascular
`thrombi.
`This
`thrombus
`precursor
`(fpP)
`assay identifies
`active
`thrombosis
`in several
`protein
`clinical
`conditions,
`including
`early myocardial
`infarction
`for the GUSTO
`In
`(Ml).
`a study
`of patients
`recruited
`had concentrations
`of TpP
`intervention
`study, MI patients
`4-20-fold
`that of controls;
`patients
`diagnosed
`without
`MI
`had concentrations
`to
`the
`control
`subjects.
`In a
`similar
`the
`emergency
`separate
`study
`subjects
`presenting
`at
`of
`room with chest
`pain, MI patients who presented
`early after
`the onset
`of chest pain had TpP concentrations
`significantly
`(P <0.01)
`higher
`than controls.
`Patients
`presenting
`late or
`with other chest pain had concentrations
`diagnosed
`within
`of the TpP assay
`the
`reference
`range. The
`potential
`utility
`as an aid for
`diagnosis
`of
`thrombotic
`MI
`and other
`the
`thrombotic
`conditions
`is described.
`
`INDEXING
`enzyme
`
`thrombosis
`coronary
`mai1s:
`immunoassay.
`reference
`values
`
`#{149}fibrin
`
`polymers
`
`#{149}
`
`plays a key role in the pathogenesis
`Thrombosis
`states,
`including myocardial
`infarction
`(MI),
`angina
`(UA),
`deep
`vein
`thrombosis
`(DVT),
`embolism [1,2]. Thrombosis
`occurs
`in both
`
`of many disease
`stroke,
`unstable
`and pulmonary
`the venous
`and
`
`Biogenetic
`‘American
`Dame, Notre Dame,
`IN.
`2 The Department of Emergency Medicine
`
`Sciences & Lobund
`
`Laboratory,
`
`University
`
`of Notre
`
`and Care
`
`and the Office
`
`of
`
`Medical Education, St.Joseph’sMedical Center, South Bend, IN.
`*Address correspondence to this author, at: American Biogenetic Sciences
`
`IN 46635. Fax 219-271-3422; e-mail
`
`Dr., South Bend,
`Ironwood
`1539, N.
`PauI.E.Gargan.
`l@nd.edu.
`protein; MI, myocar-
`precursor
`thronibus
`TpP,
`Nonstandard
`abbreviations:
`dialinfarction;GUSTO, Global Utilization
`of Screpcokinase and Tissue plasmin-
`ogen activatorforOccluded coronary arteries; ER, emergency room; UA, unstable
`deep vein thrombosis;CK, creatinekinase;CKMB, creatine
`angina; DVT,
`kinase
`and EGG, eleccrocardiogram.
`MB isoenzyme;
`Received May 2, 1996; accepted June 27, 1996.
`
`1537
`
`predisposing
`by various
`and can be precipitated
`systems
`arterial
`disease
`(atherosclerosis),
`conditions,
`including
`vascular
`clinical
`vascular
`devices,
`anes-
`trauma, malignancy,
`prosthetic
`surgery,
`systemic
`lupus
`erythem-
`pregnancy,
`oral
`contraceptives,
`thesia,
`in
`and
`bacterial
`infection
`[2]. Congenital
`deficiency
`atosus,
`certain
`anticoagulant
`proteins
`(e.g.,
`protein
`C, protein
`5, and
`antithrombin
`III) can also predispose individuals
`to thrombosis
`[3-5]. Coronary
`thrombosis
`is the
`leading
`cause of
`artery
`cases of M.I each year
`mortality
`in the US, with
`1.5 million
`in >700 000 deaths [6]. In addition,
`cases
`>1 million
`resulting
`of UA present
`to the emergency
`room (ER) each year in the US,
`of which
`10-15% progress
`to MI
`[7].
`in thrombosis
`biochemical
`process
`the
`is
`A fundamental
`conversion
`of circulating
`soluble
`insoluble
`fibrinogen
`to the
`fibrin matrix
`that serves as a structural
`“glue”
`that consolidates
`and gives mechanical
`components
`of
`rigidity
`to the cellular
`the
`principal
`components
`of blood clots
`blood
`clot
`[8]. The
`cellular
`are activated platelets
`and erythrocytes.
`Venous
`clots tradition-
`ally form in areas of stasis and are composed mainly
`of eryth-
`and fibrin.
`circulation,
`In the arterial
`clots form under
`rocytes
`conditions
`of high
`flow and shear and are composed mainly
`of
`platelets
`together
`by fibrin
`strands [8].
`held
`In almost all cases, acute MI occurs by occlusive thrombosis
`of atherosclerotic
`arteries
`after
`rupture
`lesions
`in the
`coronary
`[9, 10]. This
`coronary
`thrombosis
`in stenosed vessels
`leads
`to
`total or partial
`occlusion
`in ischemia,
`of
`the
`vessel,
`resulting
`and eventually
`of the myocardial
`tissue [10]. The
`injury,
`necrosis
`duration
`the ischemia
`and the size of
`the area
`involved
`of
`determine
`the extent of necrosis
`the extent of
`and consequently
`[Ii].The early dissolution
`in ventricular
`loss
`function
`of
`the
`thrombotic
`occlusion
`by thrombolytic
`can dramatically
`therapy
`thereby preserving
`ventricular
`and sub-
`limit necrosis,
`function
`stantially
`reducing
`and mortality
`from acute MI
`morbidity
`[12, 13].
`of myocardial
`necrosis
`Irreversible
`occurs
`generally
`tissue
`the onset
`of chest pain and is associated
`between
`4 and 6 h after
`release of
`cardiac muscle
`cell
`proteins,
`including
`with
`the
`creatine kinase(CK) and its MB isoenzyme
`(CKMB),
`troponin,
`
`MYLAN - EXHIBIT 1017
`
`
`
`1538
`
`Carville
`
`et al.: Thrombus
`
`precursor
`
`protein
`
`and myoglobin
`these necrotic markers
`of
`[14, 15]. Detection
`for MI. Clearly,
`earlier
`tests
`forms
`the basis of current
`diagnostic
`markers of thrombotic occlusionand ischemiaof cardiacmuscle
`would greatlyfacilitatethe
`diagnosis
`of an evolving MI
`and
`permit more timely therapeutic
`intervention.Such therapy
`would
`reduce
`the extent of damage to the cardiac tissue.
`Considerable efforthas been investedby numerous
`groups
`in
`recent years in attempts to develop such diagnostictests[16].
`Even though the roleof thrombosis in MI has been under-
`has been little advance
`stood
`for
`some time,
`there
`in
`the
`development
`of direct
`diagnostic
`tests
`for
`active
`thrombosis.
`of noninvasive,
`Indeed,
`the development
`highly
`specific
`tests for
`the direct measurement
`of active
`thrombosis
`has proven
`partic-
`ularly
`difficult
`[17].
`of
`the activation
`of
`measure markers
`Several
`immunoassays
`system, which
`are not necessarily
`coinci-
`the blood
`coagulation
`of thrombosis.
`Such tests
`include
`assays
`for
`dent with the extent
`of prothrombin
`fragment
`F1.2
`and
`for
`en-
`the measurement
`complexes
`such
`as thrombin-antithrombin
`ITT
`zyme-inhibitor
`and
`plasmin-antiplasmin.
`However,
`because
`they measure
`the
`changes
`in activity
`of
`coagulation
`system,
`these
`tests
`have
`not been effective
`in aiding
`in the accurate
`diagnosis
`of MI [18].
`has been to develop
`a specific and reproducible
`Our approach
`that can measure
`of proteins
`the concentrations
`previously
`test
`shown to be present
`in the blood of patients with thrombosis
`[1].
`poly-
`These
`proteins
`are high-molecular-weight
`soluble
`fibrin
`to the insoluble
`fibrin
`found in
`mers,
`the immediate
`precursors
`a thrombus.
`The
`immunochemical
`test
`for
`these
`thrombus
`precursor
`proteins
`(TpP;
`American
`Biogenetic
`Sciences)
`uses a
`specific for polymeric
`fibrin
`[19].
`monoclonal
`antibody
`highly
`In this study we investigated
`of this
`the diagnostic
`accuracy
`samples from MI
`new direct
`test
`for active
`thrombosis
`in blood
`and non-MI
`patients who presented
`to the ER with
`symptom-
`atic chest
`pain.
`
`Materials and Methods
`
`SUBJECTS
`in chest pain patients
`studies were performed
`Two
`independent
`presenting to the ER. The first study included
`47 patients who
`had
`been
`recruited
`specifically
`for
`the Global
`Utilization
`of
`and Tissue
`activator
`for Occluded
`Streptokinase
`plasminogen
`coronary arteries
`(GUSTO)
`intervention
`study. These
`patients
`all GUSTO entrance criteria,i.e., had symptomatic
`met
`chest
`pain, showed classic
`(ECG)
`electrocardiogram
`changes,
`and
`the onset of pain [20].
`presented to the ER within
`4 h after
`Patientswere diagnosed with MI, UA, or other
`chest
`pain.
`study, we included a largerpatient
`In the
`second
`cohort,
`recruiting300 ER patients.These patientswere categorizedas
`MI earlypresenters(i.e., met GUSTO criteriaand had refer-
`ence
`of cardiac
`proteins); MI
`late present-
`range
`concentrations
`to the ER >6 h after
`ers (who presented
`the onset of pain or had
`of CK); other chest pain; and other
`above normal
`concentrations
`conditions
`in which
`intravascular
`fibrin formation
`was indicated.
`was made by extensive review of
`the individual
`The
`diagnosis
`medical
`records. Both studies were approved by the institutional
`board at St. Joseph’s Medical Center. All patients’
`blood
`review
`to the ER.
`samples were drawn at presentation
`
`PROCEDURES
`Sample processing. Blood samples were
`drawn by hospital person-
`nel
`Tubes (Becton Dickinson,
`into Vacutainer
`Rutherford,
`NJ)
`containing
`buffered
`sodium citrate
`(129 mmol/L
`final
`concen-
`tration). Within
`30 mm of collection,
`the blood was centrifuged
`for
`15 mm,
`the plasma
`was aspirated,
`at
`1SOO-l800g
`and
`aliquoted,
`and stored
`frozen
`-20
`#{176}Cuntil
`analysis.
`
`at
`
`used the microtiter
`ELISA
`plate
`of TpP. We
`Measurement
`anti-TpP
`the
`described
`previously
`In
`brief,
`procedure
`[21].
`antibody was coated
`onto
`the wells of a 96-well microtiter
`plate
`(Nunc Maxisorb;
`Fisher
`Scientific,
`Glendale,
`IL). Calibrators,
`for 15 mm at 37 #{176}C),
`and controls were
`plasma
`samples
`(thawed
`incubated
`in the wells. Samples with visible
`clots
`and extensive
`hemolysis
`or
`lipemia
`were
`rejected
`from the
`analysis.
`Bound
`TpP was detected
`after
`incubation
`with a nonspecific
`detection
`antibody
`conjugated
`to horseradish
`peroxidase
`and
`then with
`3,3’ ,5,5 ‘-tetramethylbenzidine
`substrate.
`Absorbance
`of samples
`was
`read at 450 nm (Molecular
`Devices, Menlo
`Park, CA),
`and
`the concentration
`of TpP
`in patients’
`samples was determined
`by comparison
`with a calibration
`curve
`constructed
`with a set of
`TpP calibrators.
`interval
`a reference
`We
`estimated
`(men
`and women,
`healthy
`volunteers
`suspected
`intravascular
`thrombosis.
`
`TpP in 45
`by assaying
`ages 22-70
`years) without
`
`in all chest
`of cardiac proteins. CK was determined
`Determination
`and CKMB
`pain patients
`those
`isoenzymes
`were
`tested
`in
`confirmed MI. Both CK and CKMB were mea-
`patients
`with
`sured with test kits
`from Abbott
`IL). The refer-
`(Abbott
`Park,
`ence interval
`for CK is <150
`for CKMB,
`it is <6% of total
`U/L;
`CK.
`
`For
`Statistical methods.
`samples from patients
`the Statview
`software
`Concepts,
`Berkeley,
`subjected
`to ANOVA.
`
`statistical
`recruited
`application
`CA). The
`
`the
`for
`results
`the
`of
`analysis
`study, we used
`for
`the second
`for
`the Macintosh
`(Abacus
`four
`patients’
`categories
`were
`
`Results
`curve for
`calibration
`the TpP
`A typical
`1) was
`assay (Fig.
`consis-
`of TpP
`calibrator
`that
`by using
`a preparation
`generated
`tently
`demonstrates
`linearity
`to 40 mg/L.
`The
`calibrator
`TpP
`has demonstrated
`for >12 months with no significant
`stability
`loss in immunoreactivity
`stored
`at
`-20
`
`#{176}C,4 #{176}C,room
`when
`or 37 #{176}C.
`temperature,
`The concentration
`of TpP in the healthy
`controls
`and normal
`control
`plasma
`from 1 to 6 mg/L,
`ranged
`was used to validate the assay. The
`processing
`of samples was
`by testing
`TpP
`validated
`concentrations
`in
`fresh
`samples
`#{176}C.TpP demonstrated
`and again after storage at
`(n >50)
`-20
`stability when
`stored under
`the conditions
`described.
`In inde-
`the TpP concentrations
`pendent
`studies,
`in an age-
`and
`sex-
`matched population
`(including
`smokers and nonsmokers)
`<50
`years old was <4.0 mg/L
`not shown).
`(data
`groups:
`Initially,
`we studied patients
`categorized
`three
`into
`(n =
`chest pain
`18), and other
`15), UA (n =
`(n =
`14).
`
`MI
`
`
`
`ClinicalChemistiy
`
`42, No.
`
`9, 1996
`
`1539
`
`pulmo-
`(n = 24), e.g., DVT,
`thrombosis
`ated with intravascular
`failure.
`embolism,
`data
`heart
`Individual
`congestive
`nary
`and
`patients
`diagnosed
`with other
`points
`for
`the MI patients,
`those
`in Fig.
`(n = 45) are summarized
`chest pain, and healthy controls
`By the time
`study,
`reference
`calibrators were
`2 (right).
`of
`this
`of TpP concentrations.
`available for quantification
`with
`control
`subjects, MI
`presenting
`Compared
`patients
`6 h of
`the onset
`of pain had
`(P <0.01)
`within
`significantly
`increased TpP; MI patients
`diag-
`presenting
`late
`and patients
`nosed with
`pain did not.
`other
`chest
`Patients
`diagnosed
`with
`other
`conditions
`of active
`fibrin
`formation
`also demonstrated
`higher TpP concentrations
`significantly
`than the healthy
`con-
`trols (data not
`shown).
`In several cases, patients diagnosed with UA or noncardiac
`chest pain were
`later diagnosed
`with MI. Among
`these was a
`woman who presented at the ER with
`chest pain. A
`53-year-old
`nonspecific ECG led to her being
`diagnosed
`with UA and she
`(30.0 mgfL),
`patient’s TpP concentration
`was discharged.
`This
`(4.0
`however,
`was much
`higher
`than
`that
`for a control
`sample
`a highly increased extent of
`mg/L)
`and clearly indicated
`throm-
`the ER the
`bosis.
`Returning
`to
`next
`day,
`the
`patient
`was
`at the ER
`with MI.
`In another
`diagnosed
`patient who presented
`the ECG showed nonspecific ST depression of
`with chest pain,
`T wave
`<1 mm on initial
`presentation;
`20 h later,
`however,
`inversion
`was detected
`in the ECG profile,
`and both CK and
`CKMB
`were increased
`-10% of
`total CK,
`to 437 U/L
`and
`respectively.
`The TpP in this
`second
`patient was >40 mg/L (off
`scale), and the patient
`progressed
`to transmural MI.
`the 6-h window
`In 8 of
`the 33 MI patients
`presenting
`within
`of chest pain, TpP and CK were measured
`after the onset
`in
`serial
`samples
`collected
`at 12 and 24 h after
`admission.
`Fig.
`3
`shows
`the temporal
`profile
`of these
`analytes.
`In all MI patients,
`TpP was
`increased
`at presentation
`and
`returned
`to normal
`at 12 h (Fig. 3, top). The
`converse was observed
`for CK:
`values
`to the ER after
`the onset of
`i.e., MI patients
`presenting
`early
`chest pain with normal
`concentrations
`of CK had increased
`CK
`at
`the second
`time point.
`
`#{149}1,
`y =
`
`- 4.1429e-3
`
`+ 2.0463e-2x
`
`R2 = 0.998
`
`EC0U
`
`) a
`
`)
`C.)
`
`C 0C
`
`l)
`
`Fig. 1. Dose-response
`assay.
`
`Calibrator Concentration
`
`(mg/L)
`
`calibration curve for the TpP immunochemical
`
`of TpP in these three groups
`of the concentrations
`Comparison
`13) is summarized
`in healthy
`controls
`in Fig. 2
`(n =
`with those
`study, TpP was expressed in
`early
`chest-pain
`this
`(left).
`In
`ELISA units
`a well-defined
`of the calibra-
`because
`formulation
`tor had not yet been developed.
`In patients
`diagnosed
`with MI,
`the TpP concentrations
`were 4-
`to 20-fold
`those of healthy
`controls.
`In
`contrast,
`15 of
`the
`18 UA patients
`had TpP
`concentrations
`approximating
`that of
`the controls,
`as did the
`patients
`diagnosed with
`other
`chest pain (e.g., angina pectoris,
`Of
`pulmonary
`edema,
`anxiety,
`indigestion).
`and
`the
`3 UA
`who had increased TpP,
`all progressed
`patients
`to MI within
`by the diagnosis on discharge.
`48 h, as indicated
`into four
`In the second study,
`the patients were categorized
`separate groups: MI
`patients who presented
`to the ER <6 h
`the onset of chest pain (n = 21); MI patients presenting
`after
`to
`the ER >6 h after
`the onset of chest pain, most of whom had CK
`with other
`>150 U/L
`(n =
`33); patients
`diagnosed
`chest
`pain
`(n =
`130); and patients diagnosed with other conditions
`associ-
`
`Other
`Controls Chest Pain
`(n=45)
`(n=130)
`
`MI Late
`Ml Early
`Presenters Presenters
`(n=21)
`(n=33)
`
`50 -
`
`40 -
`
`30
`
`20
`
`10
`
`0
`
`4II
`
`Ml Patients
`n=15
`
`Other Chest
`Pain
`n=14
`
`Unstable
`Angina
`n=18
`
`Healthy
`Controls
`n=13
`
`Progressedto Ml
`
`.j
`
`E
`
`0.
`0.
`I.-
`
`44
`
`.
`
`..
`
`*
`
`600 -
`
`550-
`
`500 -
`
`450 -
`
`400-
`
`350 -
`
`300-
`
`250 -
`
`200-
`
`150 -
`
`100 -
`
`so-
`
`25
`
`-
`
`initial study) patients recruited for the GUSTO intervention study and (right
`Fig. 2. TpP data for (left
`with chest pain symptomatic of Ml.
`One point (*,
`right panel) was offscale
`(82 mg/LI.
`
`second study) patients presenting to the ER
`
`
`
`1540
`
`Carville
`
`et al.: Thrombus
`
`precursor
`
`protein
`
`of highly specific probes (MAbs)
`[1]. The
`generation
`conditions
`to be technically
`difficult
`[19]
`has proven
`for
`fibrin
`intact
`to its
`and conformationally
`similar
`because fibrin
`is structurally
`and to the plasmin-derived
`deg-
`precursor
`protein
`(fibrinogen)
`radation
`products
`of
`fibrin, which include D-dimer.
`To over-
`come this problem, we used antigen-free
`technology
`to generate
`(MHI),
`a fibrin-specific
`which
`recognizes
`a conforma-
`MAb
`tional epitope found only on the intact polymeric
`fibrin
`struc-
`antibody
`is used as the specific
`capture MAb
`ture [19].This
`in
`the TpP test.
`pain
`of chest
`from onset
`the time
`samples,
`study
`In the first
`to ER presentation
`were
`h. Specificity
`and sensitivity
`was <6
`thrombosis
`leading
`to MI.
`coronary
`100% for
`data
`These
`test has clinical
`potential
`in combination
`indicate
`that
`the TpP
`other
`tests
`for both rule-in
`and rule-out
`early in the clinical
`with
`event, when intervention
`with clot-dissolving
`therapies
`and (or)
`is beneficial
`for
`[13].
`angioplasty
`salvage
`of cardiac muscle
`Results from the second study support
`the finding
`from the
`GUSTO study.
`(n = 300),
`In this
`(second)
`expanded
`study
`the
`of TpP in MI patients presenting
`concentrations
`early after
`the
`onset of chest pain were
`increased by as much as 18 times above
`TpP
`that observed in a healthy
`control
`population.
`However,
`concentrations
`increased in patients
`presenting
`were not
`>6 h
`after the onset of chest pain, andwho had high concentrations
`of
`markers of cardiac damage (total CK).
`Indeed,
`in many of
`the
`MI patients who were early presenters
`and had above-normal
`concentrations
`of TpP,
`subsequent
`samples at 12 and 24 h
`the TpP concentrations
`off as the concen-
`showed
`that
`dropped
`trations
`of other
`cardiac markers
`(e.g.,
`total CK)
`began
`to
`increase (Fig.
`3). These
`findings
`are in agreement with
`the
`that TpP has
`pathological
`in MI, and suggest
`processes
`involved
`the potential
`to detect
`the initial
`thrombotic
`occlusive process in
`MI, which occurs before
`and overlaps with the ischemic
`stages of
`the disease (Fig. 4). A large patient
`study is currently
`underway
`to define
`the temporal
`relationship
`between
`TpP
`and the
`necrosis: CK, CK1VIB, cardiac
`following
`markers
`of cardiac
`I, and myoglobin.
`troponin
`the
`In most UA patients,
`were within
`concentrations
`TpP
`(as
`some who had active thrombosis
`reference
`interval,
`but
`by the TpP test) progressed
`to MI. Although
`larger
`indicated
`that
`the
`studies
`are required,
`these
`initial
`observations
`indicate
`TpP test may have an important
`role in risk stratification
`clinical
`
`MARKER
`
`TpP
`
`STAGE OF INJURY
`
`Thrombosis
`& Occlusion
`
`Small Cardiac
`Proteins
`
`lschemia
`
`Larger Cardiac
`Proteins (e.g.CK,
`CKMB)
`
`Necrosis
`
`0
`
`12
`6
`Time from Onset of Chest Pain (hours)
`
`Fig. 4. Potential utility of TpP and other biochemical markers for
`diagnosing thrombosis in early MI.
`
`-#{149}--PtA
`PtB
`-e--
`
`-U--
`
`-a-
`
`---
`
`-.O--.
`
`-#{149}-
`
`-#{149}-
`
`ptD
`PtE
`PtF
`
`PtG
`PtH
`
`ER
`
`12
`
`24
`
`49
`
`Time (hours)
`
`50
`
`40
`
`30
`
`20
`
`10
`
`E 0
`
`.
`
`0
`
`Time (hours)
`
`Fig. 3. Concentrations of TpP and CK in eight Ml patients presenting to
`
`the ER early (<6 h) after the onset of chest pain.
`
`Discussion
`remains the leading
`cause of death in the developed
`Thrombosis
`the reasons for
`[2]. Among
`this is that clinical
`condi-
`countries
`tions induced by thrombosis
`not diagnosed until
`are frequently
`after acute clinical
`become manifest
`and tissue dam-
`symptoms
`age has occurred
`[22]. One such clinical
`condition
`induced
`in
`most
`cases by coronary
`is MI. Definitive
`thrombosis
`early
`diagnosis of MI
`is difficult
`because the ECG has a diagnostic
`sensitivity
`of only
`[23] and the biochemical markers
`50-70%
`(CKMB,
`troponin,
`etc.) are increased
`only after
`the death of
`cardiac tissue.
`in delays
`in MI patients can result
`problems
`These diagnostic
`and misdiagnosis.
`As has been
`in appropriate
`intervention
`in the interventional
`trials,
`thrombo-
`conclusively
`demonstrated
`lytic
`intervention
`of chest pain can
`within 5 h after
`the onset
`substantially
`reduce mortality
`and salvage cardiac muscle [13].
`there is a clear clinical need for a diagnostic modality
`Therefore,
`that can detect active thrombosis
`to aid in the administration
`of
`appropriate
`therapies [13, 23].
`In the current
`study, we describe
`how a new diagnostic
`assay,
`the TpP test, can measure active
`in MI patients
`thrombosis
`early after
`pain
`the onset of chest
`even though the patients still have no detectable increase in the
`biochemical markers of cardiac necrosis.
`detected by the TpP test have
`polymeric
`fibrin
`The
`species
`in patients with MI and other
`been demonstrated
`thrombotic
`
`
`
`ClinicalChemistiy 42, No.
`
`9, 1996
`
`1541
`
`in
`
`in
`
`cases of UA are recorded
`1 million
`for MI. About
`of UA patients
`at ERs
`in the US each year, of whom an estimated
`10-15% will
`[7, 24]. UA patients
`progress
`to MI
`with
`ongoing
`coronary
`thrombosis
`may
`benefit
`from thrombolytic
`intervention
`with
`[25, 26]. By detect-
`tissue plasminogen
`activator
`or streptokinase
`the TpP test has
`the
`ing active
`thrombosis,
`potential
`to be a
`beneficial
`aid in patient
`selection
`for thrombolytic
`therapy
`in the
`of a hospital ER.
`acute-care
`environment
`conditions
`clinical
`MI and UA are just
`two of the potential
`could
`have
`diagnostic
`which
`this
`for
`active
`thrombosis
`test
`The TpP
`itself
`to application
`utility.
`test may
`also
`lend
`complication
`postoperative
`thrombosis,
`a major
`in
`patients
`and
`orthopedic
`procedures
`undergoing
`thoracic,
`abdominal,
`DVT is responsible
`[27, 28]. Postoperative
`for
`increased
`mor-
`tality
`in surgical
`patients,
`its
`clinical
`sequela
`of pulmonary
`embolism
`being
`the
`largest
`single
`cause
`of postoperative
`mor-
`tality [2 7-29]. Although
`great
`strides
`have been made
`in devel-
`oping
`interventional
`and prophylactic
`therapies
`for postopera-
`tive thrombosis,
`one of the most
`important
`needs
`for
`improving
`the
`efficacy
`of
`these
`approaches
`is a specific
`assay
`capable
`detecting
`active
`thrombosis
`to identify
`those
`patients
`requiring
`Intrasurgical monitoring
`additional
`anticoagulation
`of ac-
`[27].
`tive
`thrombosis
`is also an important
`clinical
`need
`during
`such
`procedures
`as angioplasty,
`where
`thrombus
`formation
`at
`the site
`of vascular
`damage
`can result
`in abrupt
`closure
`of the coronary
`MI, emergency
`vessel and lead to periprocedural
`coronary
`artery
`or death [30].
`bypass
`surgery,
`
`of
`
`the TpP test
`for
`specific
`to be highly
`appears
`In conclusion,
`thrombosis;
`as such,
`it has many
`potential
`clinical
`intravascular
`Ongoing
`large-scale
`studies
`include
`chest
`pain
`applications.
`cardiac
`catheterization,
`thrombosis
`as a conse-
`management,
`quence
`of trauma,
`and postsurgical
`monitoring
`of DVT.
`
`the protein C
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