Table Of ContentChristof Kessler
(Editor)
Platelets and
Atherosclerosis
With 34 Figures and 7 Tables
Springer-Verlag Berlin Heidelberg GmbH
Editor
Priv.-Doz. Dr. med. Ch. Kessler
Klinik für Neurologie der
Medizinischen Universität zu Lübeck
Ratzeburger Allee 160
W-2400 Lübeck 1
Library of Congress Cataloging-in-Publication Data.
Platelets and atherosclerosis/Christof Kessler (editor). Based on the Symposium on Platelet-Vessel Wall
Interaction held in June 1989 at the Medical University of Lübeck, sponsored by the University's Dept. of
Neurology.
Includes bibliographical references and index.
ISBN 978-3-540-53006-0 ISBN 978-3-642-58225-7 (eBook)
DOI 10.1007/978-3-642-58225-7
1. Thrombosis-Etiology-Congresses. 2. Blood platelet aggregation-Congresses. 3. Atherosclerosis-Pa-
thophysiology-Congresses. 4. Fibrinolytic agents-Mechanism of action-Congresses. I. Kessler, Ch.
(Christoff) II. Medizinische Universität zu Lübeck. Klinik für Neurologie. III. Symposium on Platelet-
Vessel Wall Interaction (1989: Lübeck, Germany)
[DNLM: 1. Arteriosclerosis-physiopathology-congresses. 2. Blood Platelets-physiology-congresses.
3. Blood Vessels-physiology-congresses. WG 550 P7164 1989] RC694.3.P578 1990 616.1'3071^dc20
DNLM/DLC for Library of Congress 90-10370
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Preface
In June 1989, the Department of Neurology of the Medical University of
Lubeck organized an international symposium on Platelet-Vessel Wall Inter
action. What was the purpose ofthis symposium? We felt that there was an
ever-increasinggapbetweenbasicthrombosisresearchanditsclinicalapplica
tions. Traditional strategies for treating patients with thromboembolic com
plications had to be questioned critically. Clinical trials have demonstrated
that aspirin in a high dosage of 1000mg per day or more is able to prevent
stroke in patients with transient ischemic attacks. The research on the
mechanism of action of aspirin at the molecular level has led, however, to
doubts about the antithromboticeffectofhigh-dosage aspirin, as it seems ac
tuallytofurtherthrombogenicity.
Anexplanationfor this"aspirindilemma" hasyet to beformulated. Apart
from aspirin, most drugs used clinically for preventing cardiovascular com
plications work as platelet aggregation inhibitors. This clinical strategy
proceeds on the assumption that platelets play the predominant role in the
development of atherosclerosis and its complications. As the latest results
presented in this volume show, macrophages and vessel wall factors are now
thoughttoplayanimportantroleinatherosclerosisanda newtherapeuticap
proachshouldaimatinfluencingthesepathways. Anotherimportantresultof
the Lubeck Symposium was that radiolabeling ofplatelets wasestablished as
an accepted laboratory method for evaluating the interaction ofthe platelets
with the vessel wall (see the contributions by M. Goldman, L. Harker, and
M.K. Dewanjee in this volume). There is thusanappropriate method for the
in vivo quantification ofplateletdeposits in vessel segments. The injection of
radiolabeled platelets allows the in vivo testing of different antithrombotic
drugs.
Insummary,theresultsoftheSymposiumonPlatelet-VesselWallInterac
tion show that the clinical treatment of atherosclerosis is turning from un
specified platelet inhibition to the use of well-chosen, specific drugs that
modulatethevesselwallresponsetothromboticstimuli.
Lubeck,September1990 ChristofKessler
ListofContributors
Bertomeu,M.-C.
McMasterUniversity,DepartmentofPathology,Hamilton,Ontario,Canada
Braun,M.
DepartmentofPharmacology,Heinrich-Heine-UniversiHit,Moorenstr. 5,
4000Dusseldorf,FRG
Buchanan,M.R.
McMasterUniversity,DepartmentofPathology,Hamilton,Ontario,Canada
Clowes,A.W.
DepartmentofSurgery,UniversityofWashington,Seattle,USA
Dewanjee,M.K.
RadiopharmaceuticalLaboratory,JacksonMemorialMedicalCenter,
ProfessorofRadiology,SurgeryandBiomedicalEngineering,Universityof
Miami,SchoolofMedicine,Miami,USA
Eisert,W.G.
DepartmentofPharmacology,Dr.K.ThomaeGmbH, BirkendorferStr. 65,
7950Biberach,FRG
Fingerle,J.
MNF,PhysiologieI,ObdemHimmelreich7,7400Tubingen1,FRG
Fitscha,P.
AtherosclerosisResearchGroup(ASF)Vienna,SchwarzspanierstraBe17,
1090Vienna,Austria
Goldman,M.
DepartmentofSurgery,EastBirminghamHospital,TheUniversityof
Birmingham,BordesleyGreenEast,BirminghamB9SST,GreatBritain
Gourevitch,D.
DepartmentofSurgery,EastBirminghamHospital,TheUniversityof
Birmingham,BordesleyGreenEast,BirminghamB9SST,GreatBritain
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ListofContributors IX
Kubler,W.
MedizinischeUniversitiitsklinik,AbteilungIII,Kardiologie,
BergheimerStr. 58,6900Heidelberg,FRG
Majesky,M.W.
DepartmentofPathology,UniversityofWashington,Seattle,USA
Moore,S.
DepartmentofPathology,McGillUniversity,Montreal,PQ1821,Canada
Muller,T.H.
DepartmentofPharmacology,Dr.K.ThomaeGmbH, BirkendorferStr. 65,
7950Biberach,FRG
Reidy, M.A.
DepartmentofPathology,UniversityofWashington, Seattle,USA
Schror,K.
InstitutfUrPharmakologie,Heinrich-Heine-Universitiit,4000Dusseldorf,
FRG
Sinzinger,H.
AtherosclerosisResearchGroup(ASF)ViennaSchwarzspanierstral3e17,
1090Vienna,Austria
Strobach,H.
InstitutfUrPharmakologie,Heinrich-Heine-Universitiit,4000Dusseldorf,
FRG
Virgolini,I.
AtherosclerosisResearchGroup(ASF)ViennaSchwarzspanierstral3e17,
1090Vienna,Austria
Contents
TheRoleofPlateletsintheEarlyStagesofAtherosclerosis
(S. Moore) . 1
ProliferationofVascularSmoothMuscleCellsintheAbsence
ofPlatelets.InVivoStudyinDeendothelializedCarotidArteries
ofThrombocytopenicRats
(1. Fingerle, R. Johnson, M.W. Majesky, A.W. Clowes, M.A. Reidy) . 11
TheRoleofMacrophagesinAtherogenesis
Platelet/MonocyteInteractions
(E. vonHodenberg,S. Heinen,M. Hauptmann,J. Kreuzer,
H. Henningsen, W. Kubler) . 19
AnimalModelsEvaluatingPlatelet-ModifyingDrugs
(L.A. Harker) . . . . . . . . . . . . . . . . 25
PreventiveMeasurestoReduceInjuredVesselWallThrombogenicity
(M.R. Buchanan, M.-C. Bertomeu). . . . . . . . . . . . . 31
InteractionsBetweenPlateletsinWholeBloodandaThrombogenic
SubendothelialMatrix:AcetylsalicylicAcidandDipyridamoleInhibit
ThrombusFormationExVivoinHumanVolunteers
(T.H. Muller, W.G. Eisert). . . . . . . . . . . . . . . . .. 39
HumanEndothelialCellsModulateThrombusFormation
inanInVitroModelofPlatelet-VesselWallInteractions
(T.H. Muller, W.G. Eisert). . . . . . . . . . . . . 45
CerebralVasocontractionInducedbyThrombin-StimulatedWashed
HumanPlatelets-ANewInVitro ModeltoStudyCerebralVasospasm
(M. Braun, H. Strobach, K. Schror). . . . . . . . . . . . . .. 53
RadioisotopicMonitoringoftheMainMechanismsInvolved
inHumanAtherogenesis
(H. Sinzinger,I. Virgolini, P. Fitscha). . . . . . . . . . . 59
ModificationofPlateletProstheticInteractionbyEndothelialCells
(M. Goldman, D. Gourevitch). . . . . . . . . . . . . . . . 65
XII Contents
QuantitationofPlateletThrombusinCardiacValveProstheses
withtheRadiolabeledPlatelets
(M.K. Dewanjee). . . . . . . . . . . . . . . . 71
99mTc-HMPAOThrombocytes:InVitroComparison
with In-OxineThrombocytesandPreliminaryClinicalExperience
111
(M.R. Hardeman) . . . . . . . . . . . . . . . . . . . 87
ThrombogenesisandAntithromboticAgentsinanInVivoModel
forMinimalEndothelialDamage
(K.S. Hermann) . . . . . . . . . . . . . . . . . . . . 95
Indium-IIIPlateletScintigraphyinStrokePatients
(H. Henningsen) 101
Subject Index. . 109
The Role ofPlateletsin theEarly Stages
ofAtherosclerosis
S. Moore
While it is widely accepted that platelets playa significant partin the athero
scleroticprocess, many view theseeventsasoccurringin relation to growth of
the plaque, by incorporation of thrombus [1], or the sequelae of thrombus
formation on a disrupted plaque, leading to platelet aggregate embolism or
occlusive thrombosis [2]. The formation ofplatelet masses on the surface of
disrupted plaques and their dissemination distally causes amaurosis fugax or
transient ischemic attacks [3] and is associated with unstable angina and sud
dencardiacdeath [4]. Occlusivethrombusleadstoinfarctionofpartofthe ter
ritorysupplied by the occludedarteryas in myocardialinfarction organgrene
ofthefoot.
The role ofplatelets in the initiation ofthe processissomewhatmorecon
troversial. About 15 years ago it wasconsidered to be a pivotalevent and the
sequence of events stemming from platelet adherence to a damaged arterial
wall was widely accepted as the "response to injury hypothesis" [5]. More
recently, the platelethas been relegated to a secondary role, and thecurrently
popularconceptisthatthe initiallesionisthefattydot orstreak,composedof
lipid-ladenmacrophagesin a thickenedintima. Such lesionsareconsidered to
rupture their surfaceendothelialcovering, attractplatelets, and then undergo
an expansion due to migration and proliferation ofsmooth muscle cells from
the medial coat[6]. Thefatty dot orstreakisconsidered to ariseinconditions
ofdietarily induced or endogenous hyperlipidemia [7] and commences with
the attraction of monocytes to areas where lipid accumulates [8]. The
monocytes then attach to the endothelium, migrate into the intima, and take
up lipid. There is a significant problem with this formulation in that
monocytes lack receptors for unmodified low-density lipoprotein (LDL) [7].
The paradox may be resolved by postulating an alteration in lipoprotein,
which makes it acceptable to the "scavenger receptor." The modification
whichismostwidelybelievedtooccur,isoxidationofLDL[9]. Themodelob
tainsinanimalsfed onlipidto raise bloodcholesterol to levelsapproximating
those seenin the Watanaberabbit[10], the hyperlipidemicSt. Thomas Hospi
tal strain ofrabbits [11], or in humans who are homozygous for the various
defects in the LDL receptor [12]. There is no convincing evidence that oxida
tive modification of LDL occurs in vivo. The proposition that fatty streaks
rupture to permit platelet adhesion and subsequent migration and prolifera
tion of smooth muscle cells is based on one report of diet-induced hyper
cholesterolemia in monkeys [13]. The clinical association of dys
lipoproteinemia with atherosclerotic disease seems to relate more to an im-
PlateletsandAtherosclerosis
Ed.:Kessler
©Springer·VerlagBerlinHeidelbergt990
