The Platelets. Physiology And Pharmacology

486 Pages·1985·7.152 MB·English

by  Gesina Longenecker (Eds.)

Physiologic and Pharmacologic Bases of Drug Therapy
Series Editor
Stanley Greenberg
Berlex Laboratories, Inc.
Cedar Knolls, New Jersey
Gene C. Palmer (Editor) Neuropharmacology of Central Nervous
System and Behavioral Disorders, 1981
R. Douglas Wilkerson (Editor) Cardiac Pharmacology, 1982
Nicholas A. Mortillaro (Editor) The Physiology and Pharmacology of
the Microcirculation, Volume 1, 1983; Volume 2, 1984
Gesina L. Longenecker (Editor) The Platelets: Physiology and
Pharmacology, 1985
The Platelets
Physiology and Pharmacology
EDITED BY
Gesina L. Longenecker
Department of Pharmacology
College of Medicine
University of South Alabama
Mobile, Alabama
1985
Academic Press, Inc.
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United Kingdom Edition published by
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Library of Congress Cataloging in Publication Data
Main entry under title:
The Platelets : physiology and pharmacology.
Includes index.
1. Blood platelets. 2. Blood platelets-Effect of
drugs on. 3. Blood platelet disorders. I. Longenecker,
GesinaL. [DNLM: 1. Blood Platelets-drug effects.
2. Blood Platelets-physiology. WH 300 P7187]
QP97.P59 1985 612M17 84-21547
ISBN 0-12-455555-1 (alk. paper)
PRINTED IN THE UNITED STATES OF AMERICA
85 86 87 88 9 8 7 6 5 4 3 2 1
Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
G. A. Adams (1, 15), Blood Transfusion Service, Ottawa Centre, Canadian Red
Cross, Ottawa, Ontario K1S 3E2, Canada
Klaus Aktories (271), Pharmakologisches Institut der Universitat Heidelberg,
D-6900 Heidelberg, Federal Republic of Germany
John A. Colwell (341), Department of Medicine, Medical University of South
Carolina, Charleston, South Carolina 29425, and Veterans Administration
Medical Center, Charleston, South Carolina 29425
Thomas C. Detwiler (429), Department of Biochemistry, State University of
New York Downstate Medical Center, Brooklyn, New York 11203
Thomas A. Dix (187), Department of Chemistry, Wayne State University, De­
troit, Michigan 48202
Richard D. Feinman (429), Department of Biochemistry, State University of
New York Downstate Medical Center, Brooklyn, New York 11203
Maurice B. Feinstein (237), Department of Pharmacology, University of Con­
necticut Health Center, Farmington, Connecticut 06032
Michael B. Given (463), Department of Medicine, Veterans Administration
Medical Center, New Orleans, Louisiana 70146, and Department of Medi­
cine, Tulane University School of Medicine, New Orleans, Louisiana
70112
Elisabeth Granstrom (441), Department of Physiological Chemistry, Karolinska
Institutet, S-104 01 Stockholm, Sweden
Stephen P. Halenda (237), Department of Pharmacology, University of Con­
necticut Health Center, Farmington, Connecticut 06032
xi
xii Contributors
Perry V. Halushka (341), Departments of Medicine and Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425
Pavel Harriet (367), Clinical Research Institute of Montreal, Montreal, Quebec
H2W 1R7, Canada
John C. Holt (49), Thrombosis Research Center, Temple University Health
Sciences Center, Philadelphia, Pennsylvania 19140
Daniel H. Hwang (289), Louisiana Agricultural Experiment Station, Human
Nutrition and Foods, Louisiana State University, Baton Rouge, Louisiana
70803
Carol Ingerman-Wojenski (429), Cardeza Foundation, Thomas Jefferson Uni­
versity, Philadelphia, Pennsylvania 19107
Karl H. Jakobs (271), Pharmakologisches Institut der Universitat Heidelberg,
D-6900 Heidelberg, Federal Republic of Germany
Harold P. Jones (221), Department of Biochemistry, College of Medicine,
University of South Alabama, Mobile, Alabama 36688
Roger Kerry1 (113), Department of Biochemistry, King's College, Strand, Lon­
don WC2R 2LS, United Kingdom
Maria Kumlin (441), Department of Physiological Chemistry, Karolinska In-
stitutet, S-104 01 Stockholm, Sweden
Gesina L. Longenecker (159, 463), Department of Pharmacology, College of
Medicine, University of South Alabama, Mobile, Alabama 36688
Lawrence J. Marnett (187), Department of Chemistry, Wayne State University,
Detroit, Michigan 48202
Jacek Musial (407), Department of Medicine, Copernicus Academy of Medi­
cine, 31-066 Krakow, Poland
Adam Myers (201), Department of Physiology and Biophysics, Georgetown
University Medical Center, Washington, D.C. 20007
Simonetta Nicosia (201), Institute of Pharmacology and Pharmacognosy, Uni­
versity of Milan, Milan, Italy
Stefan Niewiarowski (49), Department of Physiology, Thrombosis Research
Center, Temple University Health Sciences Center, Philadelphia, Pennsyl­
vania 19140
Peter Ramwell (201), Department of Physiology and Biophysics, Georgetown
University Medical Center, Washington, D.C. 20007
Hans-Joachim Reimers (85), John Cochran Veterans Administration Medical
Center, Medical Service, St. Louis, Missouri 63125, and Division of Hem-
atology-Oncology, Department of Medicine, St. Louis University, St.
Louis, Missouri 63103
'Present address: Pharmaceuticals Division, Ciba-Geigy Ltd., Wimblehurst Road, Horsham,
West Sussex RH12 4AB, United Kingdom.
Contributors xiii
Michael C. Scrutton (113), Department of Biochemistry, King's College,
Strand, London WC2R 2LS, United Kingdom
Hideo Shio (201), Department of Neurology, Faculty of Medicine, Kyoto Uni­
versity, Kyoto 606, Japan
Paul H. Siedlik (187), Department of Chemistry, Wayne State University, De­
troit, Michigan 48202
Stephen M. StahP (307), Department of Psychiatry and Behavioral Sciences,
VA-Stanford Mental Health Clinical Research Center, Stanford University
Medical School, Stanford, California 94305, and Schizophrenia Biologic
Research Center, Veterans Administration Medical Center, Palo Alto, Cal­
ifornia 94304
Hidekatsu Sugimoto (367), Clinical Research Institute of Montreal, Montreal,
Quebec H2W 1R7, Canada
Ira /. Sussman (383), Department of Medicine, Montefiore Medical Center,
Albert Einstein College of Medicine, Bronx, New York 10467
Andrew Szczeklik (407), Department of Medicine, Copernicus Academy of Med­
icine, 31-066 Krakow, Poland
Johanne Tremblay (367), Clinical Research Institute of Montreal, Montreal,
Quebec H2W 1R7, Canada
Paul Weller (187), Department of Chemistry, Wayne State University, Detroit,
Michigan 48202
Par Westlund (441), Department of Physiological Chemistry, Karolinska In-
stitutet, S-104 01 Stockholm, Sweden
Peter D. Winocour3 (341), Department of Medicine, Medical University of
South Carolina, Charleston, South Carolina 29425, and Veterans Admin­
istration Medical Center, Charleston, South Carolina 29425
George Β. Zavoico (237), Department of Pharmacology, University of Connecti­
cut Health Center, Farmington, Connecticut 06032
2Present address: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Cen­
ter, Terlings Park, Eastwick Road,.Harlow, Essex CM20 2QR, United Kingdom.
3Present address: Department of Pathology, McMaster University, 1200 Main Street West, Ham­
ilton, Ontario L8N 3Z5, Canada.
Preface
"The Platelets: Physiology and Pharmacology" differs from other works con­
cerning platelets in perspective and content. It is limited to fewer, related topics,
each covered in depth by an individual or group active in the particular area. In
addition, the volume is divided into three broad areas: critical reviews of basic
platelet systems, methodologic critiques, and critical reviews of platelet involve­
ment in major disease states. In each area, the physiology (pathophysiology) and
biochemistry of the system under examination are presented with possibilities
for, and consequences of, pharmacologic manipulation.
Coverage of more basic material extends from Chapter 1 through Chapter 13.
Chapters 1 and 2 deal with the basic processes of platelet aggregation and
adhesion. Chapter 3 presents critical and up-to-date information on types and
functions of platelet α-granule proteins. Chapter 4 deals with aspects of adenine
nucleotide levels, regulation, and storage. Receptors for catecholamines and
consequences of their agonism are covered in Chapter 5. Metabolism of arach-
idonic acid, its manipulation, consequences, and metabolite receptors are cov­
ered thoroughly in Chapters 6, 7, and 8. Second-messenger entities, specifically
calmodulin, calcium, and cyclic AMP, are covered from several standpoints in
Chapters 9, 10, and 11. A topic often difficult to locate in critical review form,
i.e., species variability in platelet behavior, is covered in detail in Chapter 12,
with emphasis on comparisons of man and commonly used laboratory animals.
The last chapter of the basic area, Chapter 13, deals with an increasingly impor­
tant but still neonatal area, namely, the use and appropriateness of the use of
platelets as models of neurons, with some emphasis on serotonergic neurons.
Beginning with Chapter 14 are critical reviews of platelet involvement in
XV
xvi Preface
diabetes (Chapter 14), hypertension and peripheral vascular disease (Chapter
15), atherogenesis/atherosclerosis (Chapter 16), and ischemic heart disease
(Chapter 17). It is clear that these disease states have some common features, but
it should also be noted that in each of these chapters critiques utilize topics
covered in the basic chapters, thus allowing maximal interplay between these
sections. For the disease oriented, a particular mechanism can be examined in
detail, while for the mechanistically oriented, disease-induced change can be
examined.
Separate critiques of specific techniques can be found in Chapters 18 (lumi-
aggregometry), 19 (eicosanoid measurements), and 20 (serotonin uptake and
release). However, critiques of other basic methodologic aspects, including
clinical study design, are also included in each of the other chapters, albeit they
are not as extensive in the latter. The purpose of the methods critiques is to
provide the reader with background for the evaluation of data presented in the
volume as well as of data derived from future research. There is no "cookbook"
utility, although certainly many specific methods are referenced.
The volume was planned for those interested in platelets, but it will be of
particular interest to pharmacologists and biochemists by virtue of its extensive
coverage of receptors, second messengers, and drug manipulation of multiple
processes. Clinicians interested in platelet involvement in disease will find this
work particularly useful because of the extensive coverage of related basic mate­
rial. It will also be very useful to those embarking on platelet research because of
the in-depth reviews, attention given to critiques of methods and approaches, and
rationale for interest because of applicability to disease. This work will also serve
as a timely and thorough reference for those already engaged in platelet research.
Special thanks are offered to Stan Greenberg for his confidence and gener­
osity, to the staff of Academic Press for their continued help, to Lani Longe-
necker for typing and other assistance, to Bart Longenecker for helping with
computerization of index preparation and general moral support, to Gene and
Aimee Lee Longenecker for trying to understand my time commitments, and
most importantly, to the international cast of contributors for their remarkable
confidence, cooperation, and contributions.
Gesina L. Longenecker
1
Platelet Aggregation
G. A. Adams
Blood Transfusion Service
Ottawa Centre
Canadian Red Cross
Ottawa, Ontario, Canada
I. Introduction 1
II. Early Events in Platelet Aggregation 2
III. Methods of Measurement 3
A. Turbidimetric and Lumi-Aggregometers 3
B. Whole Blood Aggregometers 3
C. Particle Counting 5
IV. Pathways of Platelet Activation 5
A. ADP Pathway 5
B. Arachidonic Acid Pathway 6
C. Ether Phospholipid Pathway 7
V. Synergisms 9
References 11
I. Introduction
Platelets respond to a number of stimuli by changing shape from discoid cells to
spherical spiny cells and aggregating into large clumps. This process is rapid and
is associated with the exposure of previously cryptic receptors for fibrinogen
(Mustard et al., 1979; Leung and Nachman, 1982; Phillips and Baughan, 1983)
and the expression of procoagulant activity, which has both a phospholipid
(Bevers et al., 1982) and a protein receptor component (Tracy and Mann, 1983).
Experimentally, a platelet suspension is stirred, a stimulus is added, and the
coalescence of the individual platelets into aggregates is measured. The extent of
aggregation depends on anticoagulant, pH, size and shape of the cuvette, size
and shape of the stir bar, rate of stirring, temperature, and the concentration of
the stimulating reagent. All these parameters must be standardized to obtain
reproducible results.
There are many possible biochemical and physiological pathways of autoac-
tivation of platelets. The three most studied pathways are the release of ADP, the
liberation and metabolism of arachidonate, and the synthesis of platelet-ag-
l
THE PLATELETS: PHYSIOLOGY Copyright © 1985 by Academic Press, Inc.
AND PHARMACOLOGY All rights of reproduction in any form reserved.
ISBN 0-12-455555-1
2 G. A. Adams
gregating factor (PAF, l-0-alkyl-2-acetyl glycerophosphocholine). Each one of
these pathways generates compounds which act as intercellular mediators to
propagate the rapid activation of all the platelets. These pathways are discussed
in detail later. It is currently thought that the mechanism of stimulation by
endogenous pathways is through a common intracellular trigger, possibly cal­
cium (Rittenhouse, 1982; Gerrard et al., 1981).
II. Early Events in Platelet Aggregation
The earliest morphological events in the response of platelets to stimulation have
recently been investigated using a stopped-flow laser turbidimeter (Deranleau et
al., 1982). Within 50 msec of stimulation, platelets begin to change from discoid
shapes to spherical forms which then convert to spiny spheres. This process has a
constant rate of conversion between forms and is probably a continuous process
which, for purposes of analysis, has been divided into three stages. Mathematical
modeling of the process predicts that 6 sec after stimulation, all three forms will
be present in equal numbers. However, since the extinction coefficients for the
three arbitrarily defined forms are different, the minimum transmittance, as
measured by turbidimetry, is delayed until about 13 sec, at which time the ratio
of disks: spheres: spiny spheres is 1:2:4. These experiments were conducted
under unstirred conditions, as aggregation would completely obscure the laser
measurements. However, pseudopod and sphere formation can be monitored in
stirred aggregating platelet suspensions using electronic signal processing of the
scattered light 40° from the angle of incidence (Affolter and Pletscher, 1982).
Procedures to look at the morphology of aggregates during early aggregate
formation have ranged from manual subsampling and fixation with microscopy,
to quench-flow exposures with particle counting (Gear, 1982; Milton and Froj-
movic, 1983; Packham et al., 1977). In general, the formation of dimers, tri-
mers, and tetramers begins within 1 sec of stimulation and continues at a constant
rate for the first 2 or 3 sec, These lower-order aggregates grow continually; half
the platelets are part of associations larger than tetramers by 4 to 5 sec and all
available platelets are incorporated into larger aggregates by 14 sec. About 10%
of the platelets in citrated platelet-rich plasma (PRP) do not become incorporated
into aggregates. It is quite possible that there is a continual growth and decay of
aggregates and it is the net changes that are being measured. The aggregation of
platelets is correlated with the time sequence of conversion from spheres to spiny
spheres suggesting pseudopod formation may be required for normal cohesion.
Platelet aggregation without shape change is a hallmark of responses to epi­
nephrine stimulation, indicating that expression of fibrinogen receptors is possi­
ble, exclusive of shape change (Peerschke, 1982). An added concept is that