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TitleBlood Substitutes - Present and Future Perspectives - E. Tsuchida (Elsevier, 1998) WW
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Table of Contents
                            Front Cover
Blood Substitutes Present and Future Perspectives
Copyright Page
Table of Contents
Chapter 1. Perspectives of Blood Substitutes
Chapter 2. The Role of Blood Substitutes in Emerging Healthcare Systems
Chapter 3. Red Cell Substitutes: Evolution of Approaches for Demonstrating Efficacy
Chapter 4. The Clinical Utility of Human Polymerized Hemoglobins as a Blood Substitute Following Acute Trauma and Urgent Surgery
Chapter 5. Recent Progress in the Development of Recombinant Human Hemoglobin (rHbl.1) as an Oxygen Therapeutic
Chapter 6. Overview of the Effects of Diaspirin Crosslinked Hemoglobin (DCLHb) on Oxygenation, Perfusion of the Microcirculation, and Clinical Studies
Chapter 7. Update on Perfluorocarbon-Based Oxygen Delivery Systems
Chapter 8. Red Cell Substitutes: Past Problems, Current Dilemmas
Chapter 9. Round Table Discussion: "The Target and Assessment of Clinical Tests"
Chapter 10. Biophysical Criteria for Microcirculatory Efficacy of Blood Substitutes
Chapter 11. Experimental and Mathematical Simulation of Oxygen Transport by Hemoglobin-based Blood Substitute
Chapter 12. Tissue Oxygen Delivery and Tissue Distribution of Liposome Encapsulated Hemoglobin
Chapter 13. Polymeric Biodegradable Hemoglobin Nanocapsule as a New Red Blood Cell Substitute
Chapter 14. Evaluation of the Oxygen Transporting Capability of Hemoglobin Vesicles
Chapter 15. Microvascular Responses to Hemodilution with Hb-Vesicles: Importance of Resistance Arteries and Mechanisms of Vasoconstriction
Chapter 16. Hemoglobin-based Blood Substitutes and Mechanisms of Toxicity
Chapter 17. in vivo Oxygenation of Deoxy-Hemolink™ Following Exchange Transfusions of 50% or 90% the Blood Volume in Rats
Chapter 18. Safety and Efficacy of Hemoglobin Modified by Cross-linking or Polymerization
Chapter 19. The Heme Oxygenase System In Liver Microcirculation: A Key Mechanism for Hemoglobin Degradation
Chapter 20. Vascular Activities of Hemoglobin-Based Oxygen Carriers
Chapter 21. Zero-link Polymerization: a New Class of Polymeric Hemoglobins
Chapter 22. Recombinant Hemoglobins with Low Oxygen Affinity and High Cooperativity
Chapter 23. Properties of Poly(ethylene glycol)-conjugated Red Blood Cells
Chapter 24. Oxygen-Transport Albumin: A New Hemoprotein Incorporating Lipidheme as a Red Cell Substitute
Chapter 25. Fluorocarbon Emulsions as Blood Substitutes
Chapter 26. Heparin-like New Molecules with Blood
Chapter 27. Recent Developments and Future Perspectives for Preserved Platelets and Platelet Substitutes
Chapter 28. Development and Clinical Implications of Platelet Substitutes
Chapter 29. Impact on the Appearance of Blood Substitutes Replacing Blood in Transfusion Medicine
Document Text Contents
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Blood Substitutes
Present and Future Perspectives

Page 204

Blood Substitutes — Present and Future Perspectives 1̂5
E. Tsuchida (Editor)
© 1998 Elsevier Science S.A. All rights reserved.


Microvascular Responses to Hemodilution with Hb-Vesicles:
Importance of Resistance Arteries and Mechanisms of

H. Sakai, '̂̂ A.G. Tsai,* E. Tsuchida,^ and M. Intaglietta^

' University of California, San Diego, La Jolla, CA, USA; ^Waseda University, Tokyo, Japan


Phospholipid vesicles encapsulating concentrated hemoglobin (Hb vesicles, HbV)
have the potential of becoming industrially produced red cell substitutes. They most
closely reproduce the characteristics of natural blood including the red cell membrane
function of physically preventing direct contact of Hb with the cellular components of
circulation [1-3]. The desirability of this barrier function is evident in considering the
side effects found in the use of acellular Hb solutions such as chemically-modified Hb
and recombinant Hb which are now in chnical trials.

The principal systemic side effect consistently reported in the administration of a
red cell substitute based on Hb solutions is a pressor response [4,5]. This has been
widely regarded to be due to the nitric oxide (NO) scavenging effect of Hb, caused by
the intrinsic high affinity of NO to Hb, a process presumed to evoke vasoconstriction
[6]. Even though the pressor effect has been proposed to be beneficial as a remedy for
hypotension in endotoxin shock, vasoconstriction is deleterious to the downstream
microvascular function and tissue oxygenation. Conversely, it has been confirmed
that NO-related vasoconstriction by the liposome-encapsulated hemoglobin (Hb-
vesicles, HbV) does not occur in an ex vivo experiment using a rabbit aortic strips [7].
Direct microcirculatory observation, using a conscious hamster fitted with a dorsal
skin window, has shown that arterioles (diameter, less than ca. 50 ̂ m) do not
constrict [8]. Since local biochemical events interact with systemic regulation, the
understanding of phenomena such as Hb induced vasoconstriction requires the
combined microscopic and systemic analysis of vascular function [9].

The presence of red cell substitutes that utilize Hb as an oxygen carrier induces
vasoconstriction by variety mechanisms in addition to the NO-Hb reaction, all of
which affect the "resistance vessels" that regulate peripheral blood flow [10]. At first
this chapter summarizes the non-invasive technique to observe the microvascular
perfusion and the responses to the hemodilution with HbV. Then, we discuss

Page 205


proposed mechanisms which may cause vasoconstriction and reduced downstream
blood flow, and discusses applications to the design of red cell substitutes to improve
microcirculation and tissue oxygenation.

Microhemodynamic measurements and hemoglobin vesicles

Method to observe microhemodynamics and tissue oxygenation

Types of the animal preparations for microvascular observation which are often used
are, sartorius, cheek pouch, cremaster, conjunctiva, cremaster, mesentery, pia mater,
skeletal muscle, etc., or in special case bat wings. An ideal preparation should have the
following properties: no anesthesia, no trauma, immobility, transparency, accessi-
bility and undisturbed environment of the tissue (no irrigation, plastic films, air, etc.)
[11,12]. Hamster dorsal skin fold window chamber preparation is currently used in
our experiment of hemodilution with red cell substitutes because of no need of
anesthesia during observation, less trauma, enough transparency, and long term
potency for observation [8,9]. A cover glass (diameter, 12 mm) was surgically installed
on the exposed skin allowing intravital observation of the microvasculature and
tissues as shown in Fig. 1. Polyethylene catheters were implanted in the jugular vein

Fig. 1. Dorsal skinfold chamber in a Syrian golden hamster used to visualize microvessels in
the subcutaneous tissue.

Page 408


Table 4

Estimated risk of major transfusion reaction


Hepatitis B
Hepatitis C

Reported transfusion reactions from hospitals to

No. (follow-up




Cases of high-probability
caused by transfusion



blood centers



From: Transfusion Information Pamphlet (9705-37), by JRC Central Blood Center.

The summary of major transfusion-associated adverse reactions and their fre›
quencies is hsted in Table 4. Since a great deal of effort has been made to reinforce the
virus screening tests, the incidence of adverse reactions has decreased in Japan. With
regard to hepatitis B, after the introduction of the combination analysis system
using anti-HBc antibody and HBs antigen, the transfusion-associated hepatitis B has
remarkably reduced in number and now the risk is about 1 case out of 1.5 million
transfusion cases in Japan. A similar situation is also made possible for hepatitis C
and the risk is about 1 case out of 4.7 milUon transfusion cases. There has been no
report relating to transfusion-associated HTLV-1 transmission. In order to reduce the
transfusion-associated risks to "zero", the development of blood substitutes should
be necessary.

Future aspect of transfusion medicine

It is necessary to estabhsh the safer transfusion or "zero" risk blood transfusion.
The reduction of homologous blood transfusion is one of the main strategies and the
prevailing of the autologous blood transfusion should also be the point. Again
the efforts to reinforce the laboratory screening tests should be conducted further.
The strategy to remove viruses or virus inactivation of the blood products should be
further applied. In order to reduce the adverse reactions relating to contaminating
leukocytes, the system to remove leukocytes or inactivate leukocytes must be
prevailed in the clinical field. The development of blood substitutes will cover the
functions of plasma, red cells and platelets. In addition, recent advancements in
molecular biology will enable us to apply several hematopoietic cytokines to regulate
the hematopoiesis. If we can expand hematopoietic stem cells, progenitor cells and
mature functioning cells in a mega-culture system, it will become applicable to
transfuse or transplant cultured cells into recipients (Fig. 6).

Page 409


Homologous Transfusion

Donor recruitment
Laboratory screening tests
Virus removal and inactivation

• Leukocyte removal and inactivation

Artificial oxygen carrier
(Artificial red cells)

Artificial platelet

Recombinant products

No Transfusion-Associated
Side Effects

More Effective Transfusion

Autologous transfusion Cytokines therapy

Mega-cultured blood

Fig. 6. Blood transfusion in the future.

Among them, the development of red cell substitutes have become near to practical
usage. It is my opinion that the red cell substitutes will be used for the blood loss
below 1200 ml and a further blood loss will be rescued by autologous blood or
combined use of erythropoietin. The application protocol of artificial red cells should
be discussed officially in early convenience [3].


The final goal of the blood program is to create a transfusion system which completes
self-sufficiency by non-remunerated voluntary donors and supplys safer blood and
blood products with "zero" transfusion-associated adverse reactions. To reach this
goal, blood substitutes and substitute therapies can contribute a great deal in the near


[1] S. Sekiguchi, Donor apheresis: recent advances and future development, Vox Sang., 70
(Suppl 3) (1996) 126-134.

[2] S. Sekiguchi, M. Fujihara, Recent transfusion reaction and prevention. Journal of Clin.
Anesth. (in Japanese), 21 (1997) 7-17.

[3] S. Sekiguchi, The impact of red cell substitutes on the blood service in Japan. Artif. Cells
Blood Substit. Immobil. BiotechnoL, 25 (1997) 53-60.

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