artifical blood
TRANSCRIPT
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Artifical Blood
Brig YK Goorha*, Maj Prabal Deb+, Lt Col T Chatterjee#, Col PS Dhot**, Brig RS Prasad, VSM++
Abstract
Elimination of, especially transfusion-transmitted diseases (HIV and hepatitis) and leucocyte-
mediated
allosensitisation, is an important goal of modern transfusion medicine. Theproblems and high cost
factorinvolved in collecting
and storing human blood and the pending world-wide shortages are the other driving forces
contributing towards the development
of blood substitutes. Two major areas of research in this endeavour are haemoglobin-based
oxygen carriers (HBOCs) and
perfluorochemicals.E
ven though they do not qualify as perfect red blood cell substitutes, theseoxygen carrying solutions have many potential clinical and non clinical usages.
These can reach tissues more easily than normal red cells and can deliver oxygen
directly. These are not without adverse effects, and extensive clinical trials are being conducted to
test their safety and efficacy.
New understandings on the mode of action of these products will help to define their utility and
application. Only after successful
clinical trials can they be used for patient management, after approval by the FDA.
MJAFI 2003; 59 : 45-50
Key Words : Blood substitute; Haemoglobin solutions; Perfluorocarbons
Introduction
there is a quest going on for a suitable blood
substitute, which can be stored on a shelf, and
infused safely at any time and in any place, regardless
of the blood type. Strictly speaking, infusion of any
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material other than autologous blood, is actually infusion
of blood substitute. Thus, the history of blood
transfusion can be regarded as the
HISTORY OF BLOOD SUBSTITUTE. Substances like milk, casein derivatives,
starch, saline and Ringers solution had been tried prior
to the first successful human to human transfusion
(Blundell, 1824). Since World War II, the search for a
suitable alternative to blood has been intensified, to
enable coping with war like situations and large-scale
civilian disasters. The functions of each blood
component and the substitution of each are quite familiar,
excepting that of oxygen carrying capacity. There has
been considerable progress in two major classes of
substitutes viz. haemoglobin solutions and
perfluorocarbon (PFC) emulsions [1].
The functions of each blood
component and the substitution of each are quite familiar,
excepting that of oxygen carrying capacity.The therapeutic goal of these compounds is to
avoid or reduce blood transfusion in different surgical
and medical situations of acute Hb deficiency. Their
main advantages include availability in large volumes,
storage for prolonged periods, rapid administration
(without typing and cross matching) and sterilisation by
pasteurisation.
Their main known disadvantages are,
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reduced circulation half-life, haemodynamic and
gastrointestinal perturbations, probably related to nitric
oxide (NO) scavenging, free radical induction, and
alterations of biochemical and haematological
parameters (increase in liver enzyme levels, platelet
aggregation) [1-3].
Purified haemoglobin solutions
The first step in the pursuit for red cell substitute was
Fig. 1 : Hemoglobin based red cell substitutes
*Commandant, Armed Forces Medical Store Depot, Delhi Cantt - 110 010, +Graded Specialist
(Pathology), IMTRAT, C/o 99 APO,
#Classified Specialist (Pathology), Base Hospital, Delhi Cantt, **Commanding Officer, Armed Forces
Transfusion Centre, Delhi Cantt,
++Deputy Director Medical Services, Head Quarter DGBR, Kashmir House, DHQPO, New Delhi - 110
011.
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Goorha, et al
to produce Hb in a mass scale and under sterile condition
efficiently, ensuring high purity but no denaturation. The
typical methods used were crystallisation ofstroma free
haemoglobin (SFH) obtained by hypotonic haemolysis;
high performance liquid chromatography (HPLC);
utilising the high stability of carboxylhaemoglobin
against heating and dialysis (Somatogen Co) produced
by Escherichia coli [4]; and transgenic human Hb
produced by transgenic swine (Swanson et al; DNX Co)
[5].
MODIFIED HAEMOGLOBIN
POLYMERISED HAEMOGLOBIN :
Initially, glutaraldehyde (a polymerising reagent for
proteins) was used to develop PLP-conjugated
polymerised Hb with an adequate oxygen affinity [6].
Since the number of molecules remained less, the
colloidal osmotic pressure could be kept low (20 Torr,
[Hb] = 15 gm/dl), thus enabling its transfusion as a
solution with high Hb concentration. It had a circulation
half-life of 24 hours and could be stored for more than 1
year. The drawbacks were related to the distribution of
the molecular weight, uncertainty of the position of
reacted sites, and high viscosity of the solution.
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Transient renal tubular vacuolation after multiple
injections have also been reported. These problems were
solved by using chromatographic separation techniques.
Initial trials were conducted on adult healthy males in
the United States, Guatemala and in Zaire [7]. In 1992,
the phase I clinical testing of a modified solution was
carried out by Northfield Laboratories after approval of
the FDA. The maximum dosage tried was 0.6 gm/Kg
(63 gm maximum). No abnormality such as
vasoconstriction was noticed. In the phase 1 trial using
polymerised bovine Hb, dosing of upto 0.2 gm/kg caused
a rise in blood pressure and a decline in heart rate,
resulting in suspension of the trial [1].
Currently, soluble, cell-free, o-raffinose cross-linked
and oligomerised human Hb (O-r-poly-Hb)(Hemolink,
Hemosol, Canada)(molecular weight ranging from 32>
500 kDa) is in a phase III clinical trial for peri-operative
use in cardiac and orthopaedic surgery (at doses from
25g (250 ml)/100 g (1000 ml) [2,8]. Its affinity for
oxygen appears lower than normal blood and an n (Hill
coefficient) value of about 1 indicates a very low degree
of co-operativity. Probably related to the low O2 affinity
value and to the high molecular weight, O-r-poly-Hb
has been shown to induce lesser haemodynamic
perturbations than other first generation modified Hbs.
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Polymer Conjugated Haemoglobin :
This was produced by increasing the molecular weight
of Hb, by bonding it with a water-soluble polymer defined
and distribution of the number of conjugated POE chains.
Since this is a polymer-conjugated type, viscosity is high
and the colloidal osmotic pressure is also as high as 24
Torr, even at a Hb concentration of 8 gm/dl. The system
that bonds bovine Hb may result in problems of
antigenicity on repeated usage [9]. Other conjugated
Hbs like, dextran-benzene-tetracarboxylate-conjugated
Hb (Hb-Dex-BTC), is undergoing animal trials [10].
Intramolecular Cross-Linked Haemoglobin :
Diaspirin (3,5-dibromosalicyl fumarate; DBBF) was
used to cross-link, a-units and, b-units of Hb, and form
diaspirin cross-linked Hb (DCL Hb). It was thought
that cross-linking would prevent its dissociation and
increase half-life during circulation (mean half-life is
10 hours). The viscosity of the solution is very low (2
cP), and the colloid osmotic pressure 28 Torr. At present,
a production facility for mass yield is in operation. Phase
I trial studies conducted by Baxter in 1992 have revealed
considerable success, excepting a dose-related elevation
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of blood pressure and decline in heart rate, corresponding
to maximum dosage of 0.1 gm/Kg [1]. OHara et al
observed an increase in whole blood methaemoglobin
fraction (0.84 +/- 0.77% at baseline to 4.08 +/-1.36%)
during 48 hours of the DCL Hb infusion (dosage :936
+/-276 mg/Kg), but it did not reach a range associated
with complications [10-12].
Recombinant Haemoglobin :
Recombinant Hb (r Hb 1.1) is a method in which a
few parts of an amino acid sequence of human Hb are
replaced to prevent the dissociation into dimers and to
maintain adequate oxygen affinity. The phase I clinical
trial in 1992 recorded side effects like fever, chill and
headache. By improving on the purification process,
the endotoxin component was eliminated, thus reducing
the adverse effects. Further trials in 1993, with a
maximum dosage of 25.5 gm, recorded rise in blood
pressure and mild gastrointestinal symptoms [1,4]. The
phase II trials involved testing of a newer variant ie.
rHb 414, where two rHb 1.1 were conjugated to obtain
a double oxygen carrying capacity and a five times
prolonged half-life per unit volume [1].
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Haemoglobin Vesicles :
The advantages of Hb vesicles are : 1) no denaturation
or modification of the Hb; 2) made of purified Hb and
lipids. To simulate Hb encapsulation within RBCs,
microcapsules made of nylon, collodion, gelatin, gum
arabic and silicon were tried, but they were rapidly
removed by the reticuloendothelial system. In 1977,
Djordjevich and Miller [13] successfully used the theory
of phospholipid vesicles for use in encapsulation and
prepared Hb vesicles out of phospholipids, fatty acids,
MJAFI, Vol. 59, No. 1, 2003
Artificial Blood
cholesterol etc. [1]. Present research is focussed on
liposome-encapsulated Hb (LEH) sterilisation, control
of size, effective encapsulation and stabilisation of the
vessels [12]. Recently a biodegradable polymer
membrane-like polylactide has been used to develop Hb
nanocapsules [8].
Toxicity
Cell-free Hbs, chemically altered or genetically
expressed in microbial host systems (i.e. unmodified
SFH), possibly cause excessive filtration of Hb dimers
and tubular obstruction leading to a decreased glomerular
filtration rate and renal damage. The major concern
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pertains to the interference of Hb and its oxidation
products with the vascular redox balance, potentially
impeding its clinical usefulness. Endotoxin contaminants,
residual cellular stroma, and lipid fragments are known
mediators of toxicity leading to vasoconstriction,
complement activation and generation of free radicals
[1,10,14,15].
Perfluorocarbons :
PFC are chemically inert compounds consisting of
fluorine-substituted hydrocarbons. Unlike Hb-based
substitutes, PFCs have the following advantages : 1)
they do not react with oxygen or other gases; 2) increase
the oxygen solubility in the plasma compartment; 3) the
dissolved oxygen is not subject to the effects of
temperature, pH, 2,3-DPG etc. (thus the oxygen
dissociation curve is linear); and 4) facilitate effortless
transfer of oxygen from the red cells to the tissue. Since
they are insoluble in water, need for an emulsification
prior to intravenous use was felt. Some workers
advocated use of albumin and lecithin, whereas Geyer
et al used Pluronic F-68, which is a mixture of short
chain polymers [15].
First generation perfluorocarbons :
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The first commercially available PFC was Fluosol DA
20% (Green Cross, Osaka, Japan). This used
Pluronic F-68, as an emulsifying agent, and was able to
maintain a balance between the oxygen carrying capacity
and tissue retention. It comprised two PFCs,
perfluorodecalin (PFD) and perfluorotrypropylamine
(FTPA). PFD was the primary component and oxygen
carrier, whereas FTPA was to provide the much needed
stability. Each of the two components had different half-
lives, with PFD being only 3 to 6 hours, due to its rapid
clearance. FTPA on the other hand, persisted in the tissue
for months [15].
Second generation perfluorocarbons :
Fluosol had paved the path for further refinement of
PFCs. The desirable characteristics in the second
generation PFC, as advocated by Reiss and Le Blanc et
al [16] were : 1) large oxygen-dissolving capacity, 2)
faster excretion and less tissue retention, 3) lack of
significant side effects, 4) increasing purity, and 5) large
scale production and availability. The three candidates
chosen as per these criteria were PFD, perfluorooctyl
bromide (PFOB) and bis (perfluorobutyl) ethylene.
PFOB, known in its emulsion as Oxygent, was favoured
for clinical trials because of its stability and high
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excretion rate.
Linear PFCs like PFOB dissolve oxygen better than
cyclic ones like PFD. The oxygen solubility is inversely
proportional to the molecular weight and directly
proportional to the number of fluorine atoms. 90%
weight/volume emulsions of PFOB have the capacity to
contain four times the amount of oxygen as compared to
a first generation PFC. PFCs being chemically inert,
are not metabolised but are removed from the circulation,
within 4-12 hours, by the reticuloendothelial system.
They are stored in the liver and spleen and subsequently
exhaled through the lung. Reducing the particle size or
increasing the concentration leads to increased tissue
deposition and subsequent tissue damage [15,17].
Toxicity
The major problem with the first-generation PFCs
was due to complement activation. An in-vitro
comparison of lecithin-based PFD emulsions and
pluronic-based PFD emulsions, showed the latter to be
virtually non-toxic to peripheral human leukocytes,
except causing mild to moderate inhibition of endotoxininduced
cytokine production. Lecithin-based PFD
emulsion caused substantial cytotoxicity in phagocytic
cells like monocytes (60-100% after 24 hour incubation)
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and granulocytes (10-20% after 24 hour incubation).
They also suppressed endotoxin-induced cytokine
production in monocytes to more than 98% and inhibited
cell proliferation of an endothelial (ECV 304) and a
monocytic cell line (MonoMac6) to more than 95% [18].
However, an in-vivo trial of pluronic F-68 - based PFD
led to adverse effects like intolerance of initial test dose,
transient leucopenia, hypotension, chest pain, and a
syndrome consisting of fever, leucocytosis and infiltrates
on chest roentgenogram. In some cases there was an
initial reaction to the test doses.
Acute toxicities due to the more refined second-
generation PFCs, were in the form of transient facial
flushing, backache, fever and a flu-like symptom within
1 to 4 hours post-infusion. These effects were attributed
to the normal clearance of PFCs by the reticuloendothelial
system. Opsonisation and phagocytosis of
PFC droplets leads to activation of macrophages and
release of prostaglandins and cytokines by the archidonic
acid pathway [15,19]. Chronic or delayed side effects
MJAFI, Vol. 59, No. 1, 2003
were characterised by inhibition of platelet aggregation
with 90% weight/volume PFOB emulsion, and transient
thrombocytopaenia (not below 80,000/l). Owing to its
organ retention effect, temporary histologic changes like
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enlargement and appearance of vacuolated histiocytes
have been noted in liver biopsies [15,20].
Potential clinical use
Conventionally, it is recommended that, for
haemorrhages less than 600 ml, plasma expanders should
be used; for 600-1200 ml red blood cell products are
necessary; and for blood loss above this, transfusion of
plasma derivatives and / or platelet products, or whole
blood is vital. Research with blood substitutes conducted
on animal model and isolated human trials, recommends
its usage to treat haemorrhages where blood loss is
between 600-1200 ml. It should be used as an alternative
and/or supplement to homologous and autologous
transfusion, or in combination with the use of
erythropoietin [15]. Various clinical, non-clinical and
paradoxical utilisations have been envisaged (Table 1).
Table 1
Potential clinical applications of oxygen carrying solutions
1.
Therapy
(a)
Blood substitutes : hemorrhagic shock; hemorrhage (war,
surgery); anaemia.
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(b)
Whole-body rinse out : acute drug intoxication; acute hepatic
failure.
(c)
Local ischemia : acute MI; evolving MI; cardiac failure; brain
infarction; acute arterial thrombosis and embolism; PTCA of
coronary artery.
(d)
General ischemia : gas embolism; CO intoxication; HAPO;
HACO.
(e)
Aid for organ recovery : acute renal failure; acute hepatic failure;
acute pancreatitis.
(f)
Infectious disease : anaerobic and aerobic diseaes;
(g)
Adjuvant therapy : tumour radiotherapy; chemotherapy
2.
Perfusional protection of organs during surgery - cardiopulmonary
bypass, deep hypothermia, circulatory arrest, cardioplegia.
3.
Preservation of donor organ.
4.
Drug carrier - drug-conjugated haemoglobin and perfluorochemicals.
5.
Contrast agent - (Perfluoro-octylbromide)
Non-Clinical Applications
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1.
Culture medium
2.
Chemical examination - oxygen sensor; standard solution for oxygen
calibrator
3. Bioreactor
Paradoxical Utilisations (of high-oxygen affinity)
1.
Oxygen absorbent
2.
Oxygen pulse therapy for malignant tumour in combination with
radiotherapy or chemotherapy.
Clinical Use : The efficacy of Hb solutions in
managing haemorrhagic shock and anaemia with low
haematocrit, is better than crystalloid and colloid
solutions. These have been used to preserve isolated
organs, as cardioplegic agent, and as adjunct to
preoperative autologous donation. A trial of bovine Hb
Goorha, et al
solution in children with sickle cell anaemia, showed
clinical improvement without any adverse effects. It has
been tried in cases of organ recovery during organ
failure, in infectious diseases, and as adjuvants in tumour
therapies. PolyHb, DCLHb and recombinant Hb have
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been used in clinical trials of trauma patients [15,21,22].
Based on the effect of preserving aerobic metabolism
during ischaemia and improving peripheral circulation
by the oxygen carrying solution, these agents have been
tried for perfusional protection of organs, Hb molecules
and perfluorochemicals can be used to reach the blocked
capillary beds, while increasing the drug sensitivity of
the peripheral tissues by oxygenation. Perfluoro
octylbromide can be used as a new contrast agent with
oxygen carrying capability in ultrasound, CT scan,
angiography, MRI, liver and spleen imaging and tumour
imaging [8,22-25].
Non clinical applications : The oxygen carrying
solution can be used in culture media of the tissues and
bacteria (aerobes); in chemical examination such as an
indicator for oxygen sensor, and a standard solution for
oxygen calibrator; and in some kinds of bioreactor [25].
Paradoxical utilisations : If the oxygen affinity of the
artificial red cells can be controlled, they can be used as
an oxygen absorbent agent paradoxically. This can pave
the way for a new form of tumour therapy ie. oxygen
pulse therapy combined with radiotherapy and
chemotherapy. This would be in two stages. In the
first stage, low oxygen affinity solution, will be used
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as an adjuvant therapy of radiation to deliver the oxygen
to the tumours to increase radiosensitivity. The second
stage would comprise high oxygen affinity solution,
namely oxygen absorbent, delivered selectively to the
feeding artery of the tumour expecting anoxic necrosis
of the tumour [25].
Present status
Red cell substitutes are being developed for use in
blood replacement therapies, either for perioperative
haemodilution or for resuscitation from haemorrhagic
blood loss [26]. There is an urgent need for these
products because of risks associated with blood
transfusions and pending worldwide blood shortages.
Research in this field has benefited from development
of new technologies in protein engineering. Clinical trials
are being conducted to ascertain the safety and efficacy
of these newly developed products [1,2,7,15]. Although
cross-linked and polymerised products have been found
to be safe in preclinical and early phase I/II clinical trials,
they have had difficulty in proving efficacy. The primary
adverse effect for the majority of cross-linked or
polymerised products is a haemodynamic response,
leading to increased vascular resistance to blood flow.
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The physiological mechanisms are still incompletely
understood, so that safety and efficacy cannot be
completely dissociated. New understandings on the mode
of action of these products will help to define their utility
and application [27]. Only one product, a PFC
compound, Fluosol (Green Cross, Osaka, Japan), has
gained regulatory approval for limited use. Considerable
progress has been made in developing platelet substitutes
also. Lyophilised platelet, infusible platelet membranes,
red cells bearing arginine-glycine-aspartic acid ligands,
fibrinogen-coated albumin microcapsules and liposomebased
agents have been developed as putative alternatives
to the use of allogeneic donor platelet, to augment the
function of existing platelets and/or provide a
procoagulant material capable of achieving primary
haemostasis in patients with thrombocytopenia [28].
Conclusion
The final goal of any transfusion service is to create
a transfusion system with no side effects and with more
effective medical care. The current system of
homologous blood, although is marred by many
problems, like allosensitisation and transfusion
transmittable diseases, is working well with low cost,
acceptable efficacy and relatively less side-effects.
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Even so, the technologies of the future promise to
generate an effective blood substitute, which will
definitely have an impact on transfusion medicine and
the transfusion services. Presently, the prospect of using
artificial blood is difficult to envision owing to problems
of short half life, prolonged tissue retention, potential
toxicity, and issues of cost, cost relative benefits,
availability of raw materials and strict FDA regulations.
This may cause a temporary shift of focus from
completely replacing blood cells, to that of using this as
an adjunct to homologous transfusion. However, in pre-
hospital or battlefield resuscitation, or in countries where
supply of safe blood is affected by potential threat of
HIV infection, the role of blood substitutes will
undoubtedly be of immense value. And it is absolutely
certain that a new system of blood service with artificial
blood and blood substitutes, including artificial oxygen
carriers and recombinant plasma components, will be
developed in the near future, which will confer a new
dimension to transfusion medicine.
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