Page 1932 - Hematology_ Basic Principles and Practice ( PDFDrive )

1712 Part XI Transfusion Medicine

by 50%). More modest hemodilution (e.g., removal of 2 units of coagulation factors and WBCs. There are two main categories of
blood at the beginning of surgery) is also beneficial, according to oxygen carriers that show promise as RBC substitutes: perfluorocar-
some investigators but the amount of red cells saved is small. Fur- bons (PFCs) and Hb-based oxygen carriers (HBOC).
thermore, one group has provided evidence that hemodilution may
jeopardize patients at risk of ischemic myocardial injury. More
research is needed to establish the safety, efficacy, and ideal protocols Perfluorocarbons
for this form of blood conservation. The availability of blood substi-
tutes may facilitate augmented hemodilution for some patients who PFCs are chemically and biologically inert artificial fluorinated
are expected to have large volumes of blood loss or who refuse blood organic fluids that are immiscible in water and have a high solubility
transfusions. for oxygen. The amount of dissolved oxygen in PFC is linearly related
to the ambient oxygen tension, unlike Hb; gas molecules are not
chemically bound to PFCs but are absorbed and released by simple
BLOOD SUBSTITUTES diffusion. Products require oxygen inhalation by the patient, as the
oxygen delivery capacity is less than 30% of normal blood. PFC has
The search for blood substitutes began when our early scientific been shown to reduce the need for RBC transfusion, but has been
ancestors tested alternatives to human blood, including animal blood, associated with an increase in stroke rates. Although some PFCs are
milk, and wine. Modern research into the use of animal blood still being investigated, there are no major trials ongoing and no
includes the work by Amberson et al, who reported the successful use licensed products in the United States.
of a bovine hemosylate for exchange transfusions in cats and dogs.
Further work revealed that human and bovine hemosylates caused
renal dysfunction in human recipients. The suspected cause of this Hemoglobin-Based Oxygen Carriers
nephrotoxicity was the stromal lipid component of the RBC mem-
brane. The logical next step in the search for the ideal substitute was As RBCs age and degrade, the stroma and unmodified Hb released
the development of stroma-free Hb (Hb tetramer). Unfortunately, in can lead to various adverse effects in the transfused recipients. There-
1978 Savitsky et al demonstrated renal dysfunction, hypertension, fore, the HBOC that were most recently in clinical development were
and abdominal pain using stroma-free Hb in healthy volunteers. It stroma-free and engineered to produce desirable oxygen dissociation
was hypothesized that these adverse events were due to the instability characteristics as well as an adequate in vivo half-life with minimal
of the Hb tetramer. Since then, efforts have been made to produce toxicities. Stroma-free Hb has a very high oxygen affinity compared
stabilized products with desirable oxygen off-loading characteristics with native Hb in a RBC because of a lack of 2,3-DPG. Furthermore,
and extended intravascular retention times. the Hb tetramer is such a small molecule that the kidney rapidly
Today, the United States blood supply is increasingly safe and has removes it.
sufficient capacity to meet most patient needs. There is room for Four different methods have been suggested to avoid toxicities:
considerable improvement, however, in supply levels and risk reduc- stabilization, polymerization, conjugation, and Hb vesicles. HBOC
tion. The shrinking donor pool (owing to lack of willingness and/or can be prepared from different Hb sources (e.g., bovine RBCs or
ability) and the increasing transfusion requirements of an aging recombinant Hb harvested from bacteria/yeasts). However, the safety
population may lead to shortage of blood products. The threat of concerns of using Hb from nonhuman sources, such as the potential
new and emerging infections results in the vulnerability of human- for transmitting diseases, immunogenicity, and toxicities have not
derived oxygen carriers. The continuous battle against emerging been fully addressed. While one of the commercially available
infectious diseases underscore the risk of a tainted blood supply and HBOCs (e.g., Bovine-derived Oxyglobin, HBOC-301) is approved
depletion of transfusion resources. Theoretically, the ideal red cell for veterinary use, there is no HBOC product approved for clinical
substitute would solve both of these issues (Table 111.6). There have use although several products are in clinical development phases. All
been many attempts to develop red cell substitutes in the past, but faced significant challenges in proving their safety and efficacy in early
no product has been able to fulfil all of the above criteria or meet the and late phase clinical trials. A large metaanalysis by Natanson et al
Food and Drug Administration’s requirements of purity, potency, and identified 16 randomized controlled trials in which adult patients
safety. There is no licensed red cell substitute available. received HBOCs therapeutically. The analysis reviewed the associa-
tion between HBOCs and the risk of MI and mortality in clinical
trials. The study included five different HBOCs in the analysis and
RED BLOOD CELL SUBSTITUTES reported a 30% increase in risk of death and threefold increase in risk
of MI when all HBOC trials were pooled. The metaanalysis has been
It is important to differentiate between “blood substitutes” and red criticized for including trials of varying methodologies performed on
cell substitutes. Red cell substitutes are oxygen carriers and do heterogeneous patient populations in different settings with different
not replace all components and functions of blood, for example, controls. The authors of the metaanalysis criticized the United States
government oversight, as well as the transparency and timeliness in
reporting the results of the HBOC clinical trials. The editorial that
accompanied the publication in the Journal of the American Medical
TABLE The Ideal Red Cell Substitute Association made a recommendation that further phase III trials of
111.6 HBOCs should not be conducted until the mechanisms and potential
Delivers oxygen (and maybe enhances delivery) toxicities are better understood. The effects may be due to the interac-
Does not transmit disease tion of Hb and nitric oxide, a concern not fully appreciated in the
Does not have immunosuppressive effects early days of blood substitute research, but potentially addressed by
Available in abundant supply the expansion of knowledge about NO and mitigating its effects.
Universally compatible (no need to type and crossmatch) Although some HBOCs are still being investigated, there are no
Prolonged shelf-life and stable at a range of temperatures major trials ongoing and no licensed products in the United States.
Similar in vivo half-life to the RBC
Available at a reasonable cost
Easy to administer Potential Clinical Applications
Able to access all areas of the human body (including ischemic tissue)
Effective on room air or ambient conditions RBC substitutes have many potential applications. One of the most
compelling needs would be the use for rapid resuscitation during
RBC, Red blood cell.
military and civilian traumas. In developing a specific plan to avoid