Blood Substitutes 2nd ed - R. Winslow (AP, 2005) WW

563 Pages·2005·8.72 MB·English

P759760-Introduction.qxd 9/13/05 7:10 PM Page 2

Seetharama A.Acharya (39), Albert Einstein Univ.
School of Medicine, 1300 Morris Park Avenue,
Bronx, NY, USA

Paul Aebersold (3), Division of Blood Applications,
Center for Biologics Evaluation and Research,
FDA, Rockville, MD, USA

Abdu I.Alayash (18), Center for Biologics Evalua-
tion and Research – NIH Campus, FDA, Bethesda,
MD, USA

Vibhu Awasthi (43), University of Texas Health
Science Center at San Antonio, San Antonio, TX,
USA

Andrew D. Baines (20), Department of Laboratory
Medicine and Pathobiology, University of Toronto,
Ontario, Canada

Ann L. Baldwin (22), Department of Physiology –
College of Medicine, University of Arizona, Tucson,
AZ, USA

Andrea Bellelli (29), Dipartimento di Scienze Bio-
chimiche, Universita ‘La Sapienza’, Rome, Italy

Jan Blumenstein (41), Dextro-Sang Corporation,
Toronto, Canada

Liudmila A. Bogdanova (26), The Institute of
Theoretical and Experimental Biophysics of
RAS, Pushchino, Moscow Region, Russia

William S. Brinigar (32), Department of Chemistry,
Temple University, Philadelphia, PA, USA

Maurizio Brunori (29), Dipartimento di Scienze
Biochimiche, Universita ‘La Sapienza’, Rome, Italy

Enrico Bucci (42), Biochemistry and Molecular
Biology, University of Maryland Medical School,
Baltimore, MD, USA

Kenneth E. Burhop (23), Medication Delivery,
Baxter Healthcare Corporation, Deerfield, IL, USA

Pedro Cabrales (7, 8), Department of Bioengi-
neering, University of California, San Diego, La
Jolla, CA, USA

Thomas Ming Swi Chang (38, 45), Faculty of
Medicine, McGill University, Montreal, Quebec,
Canada

Keith W. Chapman (40), Sangart Inc., and Depart-
ment of Bioengineering, University of California,
San Diego, California, USA.

Pierre-Guy Chassot (14), Centre Hospitalier
Universitaire Vaudois, Lausanne, Switzerland

Felice D’Agnillo (19), Division of Hematology,
Center for Biologics, Evaluation and Research
Food and Drug Administration, NIH Campus,
Bethesda, MD, USA

Randal O. Dull (32), Department of Anesthesiology,
University of Utah, Salt Lake City, UT, USA

Barbara L. Ellington (21), Department of Neuro-
surgery, University of California San Francisco
and San Francisco Veterans Affairs Hospital, San
Francisco, CA, USA

Bengt Fagrell (17), Department of Medicine,
Karolinska Sjukhuset, Stockholm, Sweden

John A. Frangos (8), La Jolla Bioengineering Insti-
tute, La Jolla, CA, USA

Clara Fronticelli (32), Anesthesiology and CCM,
Johns Hopkins University, Baltimore, MD, USA

Maria S. Gawryl (36, 37), Research and Develop-
ment, Biopure Corporation, Cambridge, MA,
USA

Elizabeth A. Goins (43), Department of Radiol-
ogy, University of Texas Health Science Center at
San Antonio, San Antonio, TX, USA

J.
David Hellums (6), Department of Bio-
engineering, Rice University, Houston, TX, USA

Hirohisa Horinouchi (46), Department of General
Thoracic Surgery, School of Medicine, Keio Uni-
versity, Tokyo, Japan

List of Contributors

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Yubin Huang (46), Advanced Research Institute
for Science and Engineering, Waseda University,
Tokyo, Japan

Marcos Intaglietta (7, 8), Department of Bioengi-
neering, University of California, San Diego, La
Jolla, CA, USA

Bahram I. Islamov (26), The Institute of Theoreti-
cal and Experimental Biophysics of RAS,
Pushchino, Moscow Region, Russia

Henrikh R.
Ivanitsky (26), The Institute of
Theoretical and Experimental Biophysics of
RAS, Pushchino, Moscow Region, Russia

Paul C. Johnson (9), Department of Bioengineer-
ing, University of California, San Diego, La Jolla,
CA, USA

Natalia B. Karmen (26), The Institute of Theoretical
and Experimental Biophysics of RAS, Pushchino,
Moscow Region, Russia

Peter E. Keipert (28), Sangart Inc., Sorrento Valley,
San Diego, CA, USA

Gregor Kemming (15, 16), Clinic of Anesthesiol-
ogy and Institute for Surgical Research, Ludwig-
Maximilian-University, Munich, Germany

Harvey G. Klein (2), Department of Transfusion
Medicine, Warren G. Magnuson Clinical Center,
National Institutes of Health, Bethesda, MD,
USA

Koichi Kobayashi (44, 46), Department of Surgery,
School of Medicine, Keio University, Tokyo, Japan

Raymond C. Koehler (21, 32, 42), Department of
Anesthesiology and Critical Care Medicine, Johns
Hopkins Medical Institutions, Baltimore, Maryland,
USA

Teruyuki Komatsu (46), Advanced Research Insti-
tute for Science and Engineering, Waseda Uni-
versity, Tokyo, Japan

Marie Pierre Krafft (24), Colloïdes et Interfaces,
Institut Charles Sadron, Strasbourg, France

George C. Kramer (12), Department of Anesthesiol-
ogy and Physiology, University of Texas Medical
Branch, Galveston, TX, USA

Herman Kwansa (42), Department of Biochemistry
and Molecular Biology, University of Maryland
Medical School, Baltimore, MD,USA

Laurence Landow (3), Division of Blood Applica-
tions, Center for Biologics Evaluation and
Research, FDA, Rockville, MD, USA

Kimberly
Lindsey
(3),
Division
of
Blood
Applications, Center for Biologics Evaluation and
Research, FDA, Rockville, MD, USA

Kenneth C.
Lowe
(25), Department of Life
Science, University of Nottingham – School of
Biological Sciences, Nottingham, England, UK

Eugene I. Maevsky (26), Thermodynamics and
Energetics of Biological Systems, Institute of
Theoretical and Experimental Biophysics of RAS,
Pushkino, Moscow Region, Russia

David H. Maillett (31), Department of Biochemistry
and Cell Biology, Rice University, Houston, TX,
USA

Belur N. Manjula (39), Departments of Physiology
and Biophysics, Albert Einstein College of
Medicine, Bronx, NY, USA

Igor A. Maslennikov (26), The Scientific-Productive
Company ‘Perftoran’, Pushchino, Moscow Region,
Russia

Barbara Matheson (42), Department of Biomedical
Science, University of Maryland Dental School,
Johns Hopkins Medical Institutions, Baltimore,
Maryland, USA

Konrad Messmer (15, 16), Institute for Surgical
Research,
University
of
Munich,
Munich,
Germany

Paula F. Moon-Massat (36, 37), Biopure Corpora-
tion, Cambridge, MA, USA

Ernest E. Moore (13), Denver Health, Denver, CO,
USA

Victor V. Moroz (26), The Research Institute of
General Reanimatology, Petrovsky Bulv., Moscow,
Russia

Paulo Nascimento (12), Resuscitation Research
Laboratory,
Department
of
Anesthesiology,
University of Texas Medical Branch, Galveston,
TX, USA

Deanna J. Nelson (34), BioLink Technologies, Inc.,
Cary, NC, USA

John S. Olson (31), Rice University, Houston, TX,
USA

Joel Olsson (11), Department of Anesthesiology,
University of Texas Medical Branch, Galveston,
TX, USA

List of Contributors
x

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Thomas C. Page (6), Sangart Inc. Sorrento Valley,
San Diego, CA, USA

S. Scott Panter (21), Greenwich, San Francisco,
CA, USA

L. Bruce Pearce (36, 37), Biopure Corporation,
Cambridge, MA, USA

William T. Phillips (43), University of Texas Health
Science Center at San Antonio, Department of
Radiology, San Antonio, TX, USA

Donald
S.
Prough
(11),
Department
of
Anesthesiology, The University of Texas Medical
Branch, Galveston, TX, USA

Robert Przybelski (35), Department of Medicine,
University
of
Wisconsin
Medical
School,
Madison, WI, USA

Sergey Yu. Pushkin (26), The Scientific-Productive
Company ‘Perftoran’, Pushchino, Moscow Region,
Russia

Carl W.
Rausch
(37),
Biopure Corporation,
Cambridge, MA, USA

Raymond F. Regan (21), Department of Emer-
gency Medicine, Thomas Jefferson University,
Philadelphia, PA, USA

Virginia T. Rentko (36, 37), Biopure Corporation,
Cambridge, MA, USA

Thomas J. Richard (27), ChemVantage Consult-
ants, LLC, St Louis, MO, USA

Jean G. Riess (24), MRI Institute, University of
California, San Diego, CA, USA

Hiromi Sakai (44), Advanced Research Institute
for Science and Engineering, Waseda University,
Tokyo, Japan

Robert F. Shaw (27), University of California at
San Francisco, HemaGen Corporation, CA, USA

Toby Silverman (3), Division of Blood Applica-
tions, Center for Biologics Evaluation and
Research, FDA, Rockville, MD, USA

Keitaro Sou (44), Advanced Research Institute
for Science and Engineering, Waseda University,
Tokyo, Japan

Donat R. Spahn (14), Service d’Anesthesiologie –
CHUV, Centre Hospitalier Universitaire Vaudois,
Lausanne, Switzerland

Christer Svensén (11), Department of Anesthesiol-
ogy, The University of Texas Medical Branch,
Galveston, TX, USA

Shinji Takeoka (44), Advanced Research Institute
for Science and Engineering, Waseda University,
Tokyo, Japan

Amy G.Tsai (7, 8), Department of Bioengineering,
University of California, San Diego, La Jolla, CA,
USA

Eishun Tsuchida (44, 46), Advanced Research
Institute for Science and Engineering, Waseda
University, Tokyo, Japan

Sumreen U. Vaid (12), Resuscitation Research
Laboratory,
Department
of Anesthesiology,
University of Texas Medical Branch, Galveston,
TX, USA

Kim D. Vandegriff (5, 40), Sangart Inc., Sorrento
Valley, San Diego, CA, USA

Robert M. Winslow (1, 4,10, 30, 33, 40), Sangart
Inc., and Department of Bioengineering, University
of California, Sorrento Valley, San Diego, CA,
USA

J. Tze-Fe Wong (41), Hong Kong University of
Science and Technology, Clear Water Bay, Kowloon,
Hong Kong

Hisashi Yamamoto (46), Pharmaceutical Research
Centre, NIPRO Corp., Kusatsu-shi, Shiga, Japan

Mark Young (40), Sangart Inc., and Department of
Bioengineering,
University
of
California,
Sorrento Valley, San Diego CA, USA

List of Contributors
xi

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The precursor of this book was Hemoglobin-
based Red Cell Substitutes, published by the
Johns Hopkins Press in 1992 (Winslow, 1992).
The initial idea for the current book was to pro-
duce an updated edition, but somewhat less
austere and more accessible to a wider reader-
ship. As we worked on this idea it became less
and less appealing, partly because the field has
advanced so rapidly and so far since 1992.
Furthermore, I became less and less confident
that I would be able to do justice to the vast
amount of new research that has been done
since that time. Therefore it was decided that this
book would be multi-authored.
The book has several aims. First, it is intended
to be comprehensive. Invitations to contribute
were accepted by all but a few potential authors,
and, except for a few hard cases, the authors have
been extraordinarily prompt in accomplishing
their contributions. Second, the book aims not
to be a collection of disconnected essays, as so
often happens in symposium proceedings;
rather authors were asked to cover their field of

specialization with background for the non-
specialized reader before delving into the details
of their own research. Third, the book aims for a
degree of cohesiveness not usually found in
multi-authored books. We have tried hard to
ensure uniformity of usage and standardization of
abbreviations. During the writing and editing
stages, I frequently asked authors to resolve con-
flicts with other chapters and to document state-
ments that seemed to me to be matters of opinion.
Fourth, we have tried to make the book accessible
to the general reader. To do this, I have written a
short abstract of each chapter; these abstracts are
clearly identified as editor’s comments.
Robert M. Winslow, MD
San Diego

REFERENCES

Winslow, R. (1992). Hemoglobin-based Red Cell
Substitutes. Baltimore: Johns Hopkins University
Press.

Preface

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I am very grateful to all the authors who have
contributed to the book. All are experts in their
own field, with serious demands on their time.
Focusing on writing a chapter for a book like this
is often an unwanted and unrewarded distraction.
I hope the finished product is as useful to each of
them as it has been exciting to me to edit.
Margaret Macdonald and Victoria Lebedeva at
Elsevier have been totally supportive at each stage
of the project. I shall miss our monthly meetings

in London with tea and scones. At Sangart, Pam
Boltz has skillfully managed all of the daily chores
of interacting with authors about details, prodding
them to keep to deadlines and managing the pro-
fusion of computer files that accumulate as revi-
sions are collected.

Robert M. Winslow, MD
San Diego

Acknowledgements

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2,3-DPG
2,3-diphosphoglycerate, an
allosteric effector of hemoglobin
O2 binding
2-IT
2-iminothiolane (Traut’s reagent)
3,4 DHBA
3,4 dihydroxybenzoate
��-Hb
Hemoglobin crosslinked
between � chains at Lys92 with
bis-3,5(dibromo)salicylic acid
(DBBF)
AABB
American Association of Blood
Banks
A-ANH
Augmented acute normov-
olemic hemodilution
AAR
Abdominal aortic reconstruction
ABC
America’s Blood Centers
ABO
Red blood cell surface antigens
ADP
Adenosine diphosphate
AE
Adverse event
AHD
Acute preoperative hemodilution
AHSP
Alpha hemoglobin stabilizing
protein
ALT
Alanine aminotransferase
ANH
Acute normovolemic
hemodilution
aPTT
Activated partial thromboplastin
time
AR
Acetated Ringer’s solution USP
ARC
American Red Cross
ARDS
Acute respiratory distress
syndrome
AST
Aspartate aminotransferase
ATLS
Advanced trauma life support
ATP
Adenosine triphosphate, the
main substrate for energy
metabolism
AVM
Arteriovenous malformations

BAEC
Bovine aortic endothelial cells
BBB
Blood – brain barrier
BLA
Biological license application
BSE
Bovine spongiform encephalitis
BVDV
Bovine diarrhea virus
BvHb
Bovine hemoglobin

C(a – v)O2
Arterial – mixed venous O2
content difference
C3
A component of complement
C5a
A component of complement
CABG
Coronary artery bypass graft
cAMP
Cyclic adenosine mono-
phosphate
CBER
Center for Biologics Evaluation
and Research (a component of
the FDA)
CCLI
Chronic critical limb ischemia
CHO
Chinese hamster ovary cells
CI
Cardiac index (cardiac output
divided by bodyweight)
CJD
Creutzfeldt – Jakob disease
CK-MB
Creatinine kinase, myocardial
isoenzyme
CNmetHb
Cyanomet hemoglobin
CNS
Central nervous system
CO
Cardiac output
COP
Colloid osmotic pressure
(oncotic pressure)
CPB
Cardiopulmonary bypass

D5W
5% dextrose (glucose) in water,
an intravenous solution
Da
Dalton, a unit of molecular
weight
DAB
Diaminobenzoate
DBBF
bis-3,5(dibromo)salicylic acid, a
hemoglobin crosslinker
DBBF-Hb
Same as ��-Hemaglobin
DBBF-HvHb
Bovine hemoglobin crosslinked
with DBBF
DCLHb
Diaspirin crosslinked hemoglo-
bin Baxter’s preparation of ��-Hb
DCS
Decompression sickness
DECA
Sebacyl crosslinked hemoglobin
DHA
Dehydroascorbic acid
DHBA
2,3- and 2,5-dihydroxybenzoic
acids
DIC
Disseminated intravascular
coagulation

Abbreviations

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DMC
Degranulating mast cells
DMF
Drug master file
DMPG
Dimyristoyl-phosphatidyl
glycerol
DNA
Deoxyribonucleic acid
DO2
Oxygen delivery: cardiac
output � arterial O2 content
dP/dt
The maximum positive slope of
the arterial pressure curve
DPPC
Dipalmitoylphosphatidylcholine
DPPG
Dipalmitoyl-phospatidyl
glycerol
DSMB
Data Safety Monitoring Board
DSPC
Distearoylphosphatidylcholine
DxHb
Dextran-linked hemoglobin

EBL
Estimated blood loss
eBTr
Embryonic bovine trachea cells
EBV
Exchangeable blood volume
(also estimated blood volume)
EC50
The effective concentration of a
solution that kills 50 per cent of
neurons in culture
ECG
Electrocardiogram
ECMO
Extracorporeal membrane
oxygenation
EDRF
Endothelium derived relaxing
factor
EDTA
Ethylene diamine tetraacetic
acid
Ees
End systolic elasticity
EMEA
European Medicines Agency
eNOS
Endothelium-derived nitric
oxide synthase
EPO
Erythropoietin
EPR
Electron paramagnetic
resonance
EVA
Ethyl vinyl acetate
EYP
Egg-yolk phospholipid

FCD
Functional capillary density
FDA
US Food and Drug
Administration
FDMA
Food and Drug Modernization
Act
FiO2
Fraction of inspired oxygen
FOI
Swedish Defense
Establishment

GCP
Good clinical practices
GFR
Glomerular filtration rate
GLP
Good laboratory practices
GMP
Good manufacturing
practices

GPC
Gel permeation
chromatography
GSH
Glutathione

H1S
Hemopure 1 solution (Biopure)
H1S-2
Similar to H1S but with
reduced unpolymerized hemo-
globin
HAS
Human serum albumin
HAV
Hepatitis A virus
Hb
Hemoglobin
HbA
Hemoglobin A, the main
hemoglobin of the human red
blood cell
HbA0
HbA purified by
chromatography
HBOC
Hemoglobin-based oxygen
carrier
HBOC-201
A formulation of
glutaraldehyde-polymerized
bovine hemoglobin produced
by Biopure Corp.
HBOC-301
A formulation of glutaralde-
hyde-polymerized bovine
hemoglobin produced by
Biopure Corp. for veterinary
use (Oxyglobin™)
Hb-PEGP5K2
Hemoglobin modified by the
attachment of two strands of
PEG 5 kDa
Hb-PEGP5K6
Hemoglobin conjugated to six
strands of PEG 5000 kDa
Hb-PEGP10K2
Hemoglobin modified by the
attachment of 2 strands of PEG
10 kDa
HbS
Sickle cell hemoglobin
HBV
Hepatitis B virus
Hct
Hematocrit, the percentage
volume of blood that is red
blood cells
HCV
Hepatitis C virus
HES
Hydroxyethyl starch
HIF
Hypoxia inducible factor
HIV
Human immunodeficiency virus,
the causative agent of AIDS
HNLS
Hyperinflated non-collapsible
lung syndrome
HO-1
Heme oxygenase 1
HO-2
Heme oxygenase 2
HO-3
Heme oxygenase 3
HS
Hypertonic saline
HSD
Hypertonic saline dextran
HSHb
Hypertonic saline hemoglobin
HSP70
Heat shock protein 70

Abbreviations
xviii

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HTLV
Human T lymphotropic cell
virus
HUVEC
Human umbilical vein
endothelial cells

IAD
Intraoperative autologous
blood donation
ICH
Intracerebral hemorrhage
ICP
Intracranial pressure
ICU
Intensive care unit
IHP
Inositol hexaphosphate
IL-5
Interleukin-5
IL-6
Interleukin 6, an inflammatory
cytokine
IND
Investigational New Drug
application to the FDA
IRB
Institutional Review Board
ISS
Injury severity score

JCAHO
Joint Commission for
Accreditation of Healthcare
Organizations

kDa
kiloDalton, 1000 Daltons

LAD
Left anterior descending
coronary artery
LAIR
Letterman Army Institute of
Research
LDCR
Late diastolic coronary
resistance
LDH
Lactate dehydrogenase
LEH
Liposome-encapsulated hemo-
globin
L-NAME
L-NG-nitro-arginine methyl ester
LPS
Lipopolysaccharide (endotoxin)
LR
Lactated Ringer’s solution USP

MalPEG-Hb
Hemoglobin modified by
attachment of maleimide-
activated PEG 5000
MAP
Mean arterial pressure
Mb
Myoglobin
MCA
Middle cerebral artery
MCP-1
Monocyte chemoattractant
protein-1
MMS
Monocyte-macrophage system
(reticuloendothelial system)
MOF
Multiorgan failure
MP4
MalPEG-Hb formulated at
4.2 g/dl in lactated Ringer’s
solution
MPAP
Mean pulmonary artery
pressure

MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
MVD
Maximum valid dilution

NADP
Nicotinamide adenine dinu-
cleotide phosphate
NADPH
Reduced form of NADP
NAG
N-acetyl-�-D-glucosaminidase
NAT
Nucleic acid amplification test
NDA
New Drug Application
NEM
N-ethyl maleimide
NFPLP
2-Nor-2-formylpyridoxal
5�-phosphate
NMR
Nuclear magnetic resonance
NO
Nitric oxide
NRC
Neo red cells

OEC
Oxygen equilibrium curve
OER
Oxygen extraction ratio
o-R-Poly-Hb
Hemoglobin polymerized with
o-Raffinose, a Hemosol product

P50
The PO2 at which hemoglobin
is half-saturated with oxygen
PaCO2
PCO2 of arterial blood
PAD
Perioperative autologous
donation of blood
PaO2
PO2 of arterial blood
PAOD
Peripheral arterial occlusive
disease
PCO2
Partial pressure of CO2
PDH
Hemoglobin permeability
coefficient
PEG
Polyethylene glycol
PEG-BvHb
Bovine hemoglobin modified
by surface conjugation to PEG
PEG-Hb
Bovine hemoglobin modified
by surface conjugation to
polyethylene glycol (PEG),
a product of Enzon, Inc.
PEG-PE
Phosphatidylethanolamines
PET
Positron emission tomography
PFC
Perfluorocarbon
PFD
Perfluorodecalin
PFMCP
Perfluoro-N-4-(methylcyclo-
hexyl)-piperidine
PFOB
Perfluorooctyl bromide
(Perflubron)
PFTMCH
Perfluorotetramethylcyclohexane
PFTPA
Perfluorotripropylamine
PGI2
Prostacyclin I2
PHP
Pyridoxalated hemoglobin
polyoxyethylene

Abbreviations
xix

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