There are several alternatives to blood transfusion that can help reduce its use and risks. These include treating pre-existing anemia, using medications to stimulate red blood cell production or stop bleeding, employing blood-saving surgical techniques and technologies like cell salvage machines. While blood substitutes have been studied, none have gained approval due to safety issues. Implementing strategies of patient blood management can help minimize allogenic blood transfusions.

1. Alternatives to
blood transfusion
Dr. Ashish Chauhan
Dr. Sangeeta Parmar

2. INTRODUCTION
Patient Blood Management
■ Patient Blood Management (PBM) is a multimodal, multidisciplinary
approach adopted to limit the use & need for allogeneic blood transfusion
in all at- risk patients with the aim of improving their clinical outcome
■ The term PBM was 1st used in 2005 by Prof James Isbister , an Australian
haematologist , who realised that the focus of transfusion medicine should
be changed from blood products to the patients

3. Reasons to reduce blood exposure:
Limited
resources
- Increasing
demands
New donor
selection
criteria:
donor panels
Rare blood
group
Multiple red
cell
antibodies
To reduce risks
Transfusion-
transmitted
infections (TTIs)
Immunological
complications

4. Limitations Of
Conventional Blood
Transfusions

5. Why Haematological Patients Require Transfusion
■ Bone marrow failure
– Disease or treatment
■ Peripheral cytopenias
– Reduce production or increase destruction of peripheral blood cells

6. Indication for RBC transfusion
■ Attention : Each participant had to tick one indication therefore it is possible that were patients
that had more than one reason to be transfused. i. e a patient in a chronic transfusion
programme that also had symptoms

7. Need For Alternatives To Blood Transfusion??
■ A recent meta-analysis of 19 prospective, randomised trials
supports adherence to restrictive blood transfusion
Increased mortality,
Increased length of hospital stay- related to infections and sepsis,
Multi-organ system dysfunction.
Blood
transfusions
Hospital mortality and post operative infections
More than 6000
patients
Restrictive Vs Liberal transfusions

8. ■ One in 455 had Adverse reaction
■ Risk of serious reactions (1 in 6224)
■ Transfusion-transmitted infections (1 in 225,440) was lower
18,308
transfusion-related adverse reactions
201 facilities

9. There are multiple therapeutic resources to reduce or avoid allogenic blood
transfusion
These options involve clinic strategies with medicine and/or specific
equipment to treat the patient with anemia and/or blood coagulation disorder
(for instance, low platelet).
On the other hand, there are also surgical strategies with evidences to reduce
blood loss by the patient during surgery.

10. Patient Blood Management

12. BLOODLESS MEDICINE
•Make sure patient loses as little
blood as possible
•Help patient body make best use of
o2 in blood stream
•Screen patient for anaemia & treat
it before going any further

13. Main Options And/Or Alternatives With Impact To Reduce
Blood Transfusion Are:
■ Tolerate anemia
■ Medications to treat anemia.
■ Medications of systemic usage (intravenous) to stop bleeding and avoid blood
transfusion
■ Medications of topic usage to stop bleeding and avoid blood transfusions
■ Equipment/machines which avoid blood transfusion
■ Acute normovolemic hemodilution
■ Surgical techniques
■ Avoid excessive blood collections
■ Using small tubes to collect blood
■ Early oxygen therapy/ Additional oxygen.

14. Medications To Treat Anemia..
■ Ferrous Sulphate, Folic Acid, B12 Vitamin, Erythropoietin, Darbepoietin and
CERA (continuous erythropoietin activator) are the main ones.
■ There are others in final phase of worldwide liberation which play the role
of the blood when transporting oxygen: Hemopure, Hemolink, Oxygent.

15. Medications Of Systemic Usage (Intravenous) To Stop Bleeding And
Avoid Blood Transfusion::
■ Tranexamic acid
■ Aminocaproic epsilon acid
■ Vasopressin
■ Combined estrogens
■ Octreotide
■ Somatostatin
■ Desmopressin acetate (DDAVP)
■ K vitamin (phytomenadione)
■ Activated recombined factor VII
■ Factor VIII coagulation concentrate
■ Prothrombin complex concentrate
■ Human fibrinogen concentrate
■ Human recombined factor XIII.

16. Medications of topic usage to stop bleeding and avoid blood
transfusions:
■ Oxidized cellulose haemostatic for wound compression
■ Fabric adhesive/fibrin glue/sealers
■ Fibrin or platelets gel
■ Haemostatic collagen
■ Jelly foam/sponge
■ Topic buffering of thrombin or soaked with thrombin

17. H
E
M
O
G
L
O
B
I
N
=
BEFORE SURGERY
Medications
Nutritional
supplements

18. Lancet 2013; 381: 1855–65

19. Erythropoiesis-stimulating Agents
Risk of higher rates of thrombosis (assessed with
Doppler evaluation) than patients on placebo
(4.1% vs. 2.1%)1
Management of anaemia with erythropoiesis-stimulating agents
or iron in patients under going
• Orthopaedic 2
• Cardiac surgery 3
Blood-conservation Strategy
Are erythropoiesis-stimulating agents Safe???
1. Stowell, Christopher P. MD, PhD*; et al,. Spine 34(23):p 2479-2485, November 1, 2009. 2. British Journal of Anaesthesia 106 (1): 13–22 (2011) 3. Young-Chul Yoo, Anesthesiology 2011; 115:929–937

20. Erythropoiesis-stimulating Agents: No Differences In Mortality,
Thrombotic Events, Or Serious Adverse Events
Risk of exposure to allogenic blood transfusion
(P = .007)
A substantial reduction in blood transfusions was evident.
Weltert L, D’Alessandro S, Nardella S, et al. J Thorac Cardiovasc Surg 2010; 139: 621–26.

21. Off -Label Use Of Erythropoiesis stimulating Agents In Patients
Undergoing Cardiac Or Vascular Surgery lacks evidence
Restrict the use of erythropoiesis stimulating agents for
elective surgical setting to non-vascular, non-cardiac
patients undergoing major elective surgery.
Goodnough LT, Shander A, Spence R. Bloodless medicine: clinical care without allogeneic blood transfusion. Transfusion 2003; 43: 668–76
Off- label indication

22. Erythropoiesis-stimulating agents was associated with increased morbidity (thrombosis or cardiovascular
events) and mortality

23. Indication: Erythropoiesis-stimulating agents
○ Haemoglobin concentration < 100 g/L
○ Patients with symptomatic anaemia.
Death and
thromboembolic
events
Reduced blood
transfusions
with long-term
treatment
Take into account each patient’s
clinical circumstances and
preferences.99
R
I
S
K
B
E
N
E
F
I
T
Lancet 2013; 381: 1855–65

24. Pharmacological Alternatives
To Blood Components

25. Antifibrinolytic Agents
Despite a modest reduction in the risk of massive bleeding, the
strong and consistent negative mortality trend associated
with aprotinin VS lysine analogues, precludes its use in high-risk
cardiac surgery
N Engl J Med 2008;358:2319-31

26. Tranexamic Acid Should Be Considered For Use In Bleeding Trauma Patients. Lancet 2010; 376: 23–32

27. ■ Rapid thrombelastography
Prothrombin
complex
Off –Label Use
• Trauma
• Surgical settings associated with coagulopathy
Targeted treatment with pro thrombin complex concentrates with rotation
thrombelastometry based algorithms has shown significant reductions in
transfused blood components
Lancet 2013; 381: 1855–65

28. • Special anesthesia
• Harmonic scalpel
• Cell salvage machine
• Hemoglobin monitor
DURING SURGERY

29. Equipment/Machines Which Avoid Blood Transfusion
■ It is a machine capable of recovering the patient’s blood that would be lost during surgery.
■ What is interesting is that this recovered blood has DNA from the patient themselves. It can be
reused and is not a homotoxin (“foreign body”). When not recovered, unfortunately, it goes to
the trash can together with gauze and compresses. It is a real blood recycling.
This is the best blood a patient could receive in a transfusion: their OWN BLOOD.
■ Intraoperative self-transfusion is an excellent alternative to allogenic blood, mainly due to the
benefits, like: fresh blood immediate disposal, postoperative complications diminish, reduction of
days of staying and associated infections, reduction of death, as well as diminishing the need of
homologous blood (bags).
■ The cost of this procedure is almost the same as the price of one or two blood bags, when taking
into account all the activities involved in blood transfusion.

30. Cell salvage in orthopedic
surgery decreases the need for
allogeneic blood transfusion
perioperatively, but
postoperative cell salvage is
only marginally effective in
cardiac surgery.
(Anesth Analg 1999;89:861–9)

31. Preoperative Autologous Donation- Rise and fall of
interest in PABD
■ Due to
• Increased cost - additional cost of $758 per patient.
• Reduced risk of infection associated with allogeneic blood transfusions,
• Advanced surgical techniques to reduce blood loss
Appropriate for substantial procedures
(eg, total hip revision or scoliosis repair) and
for patients with serologic alloantibodies to
blood.
Poorly cost effective.

32. Management of blood loss anaemia
Perioperative autologous blood procurement
Acute normovolaemic haemodilution
■ Blood collected by acute normovolaemic haemodilution is stored at
room temperature in the operating room and is returned to the
patient within 8 h of collection, platelets and coagulation factors
remain functional.
■ Cheaper
■ Selected clinical settings (eg, patients with a high preoperative Hb
concentration undergoing a surgical procedure with a high expected
blood loss such as a revision hip replacement), for reduction of
allogeneic blood transfusions.1
■ Low volume acute normovolaemic haemodilution did not reduce
allogeneic blood for patients undergoing cardiac value
replacement surgery.2
1. N Engl J Med 1999; 340: 525–33.
2. Ann Card Anaesth 2010; 13: 34–38

33. Early Oxygen Therapy/ Additional Oxygen
■ Tolerance to anemia can be increased by ventilating the patient with a high inspired
fraction of oxygen (FiO2).
■ While maintaining normovolemia , hyperoxid ventilation (offer 100% oxygen) can be
considered a salvation therapy when facing an important bleeding associated with
severe acute anemia with risk of Ventilating with 100% oxygen results in fast increase
in the continent of arterial oxygen, assuring oxygenation of tissues even with very
low hemoglobin (severe anemia) and shows an important strategy to reduce
allogenic transfusion

34. Blood Substitutes
Ideal
Properties Of
Blood
Substitute
Lack
antigenicity
Oxygen
delivery
Store at
room
temperature
Long half-
life

35. Blood Substitutes Types
First-
Generation
Stroma-Free
Hemoglobin
Next-
Generation
Blood
Substitutes

36. First-Generation
Perfluorocarbon emulsions
Fluosol-DA
Oxygent
Oxycyte
- FDA approved for percutaneous
transluminal coronary angioplasty.
- Withdrawn from the market:
 A short effective half-life
 Low oxygen-carrying capacity
 Acute complement activation
Phase III trials -
increased incidence
of stroke and trials
have been halted.[6]
Entering phase II trials

37. Stroma-Free Hemoglobin
■ Ability to withstand sterilization and a shelf life of approximately 2 years at room temperature for some
products.
ADR: Hypertension
 Diaspirin cross-linked hemoglobin (DCLHb)
 Recombinant hemoglobin product, rHb 1.1
 rHb 2.0
 PolyHeme
N= 720, phase III trial in trauma patients I
The difference in mortality between the 2 groups at 30 days was not significant.

38. Next-Generation Blood Substitutes
MP4OX, is a PEG-conjugated human hemoglobin
Hemospan
•Phase II study- At relatively low concentrations, is capable of transporting large
amounts of oxygen.
Percentage of hypotensive episodes in the Hemospan (MP4OX) group was about
45% lesser when compared to 87% among controls.
Cross-linked
Polyhemoglobin
•Cross-linked with catalase and superoxide dismutase to form a compound that, in
animal models can not only carry oxygen but also remove oxygen radicals that are
responsible for ischemia reperfusion injuries.
Cross-linked with tyrosinase to form a soluble complex that can carry oxygen and
decrease the systemic levels of tyrosine. This agent has been shown to delay
tumor growth without having significant adverse effects in a melanoma model

39. Hemoglobin-based oxygen carriers (HBOCs)
Recombinant Hemoglobin Production
■ Escherichia coli was the first choice as production workhorse.
■ The alterations were identified to be caused by reduced Bohr effect and 2,3-BPG effects of the
produced recombinant hemoglobin compared to normal human hemoglobin (Hoffman et al.,
1990)
Production model shifted yeast Saccharomyces cerevisiae.
New production hosts are designed with an increased and
more efficient production capacity

40. Key Issues- HBOC
Sustained
Hemoglobin Supply
Safety Concerns Cost Effectiveness
Hemoglobin extravasation
across the blood vessel wall
Scavenging of
endothelial nitric
oxide
Oversupply of
oxygen
Oxidative side
reactions (Alayash,
2014).
As a result, the regulatory agencies in the United States and the European Union have not yet approved any
HBOCs (Meng et al., 2018)
-$11/g
- With operating cost included =
≥$200/g
High cost

41. The Design-Build-
Test-Learn cycle
(DBTL-cycle)
Recombinant HBOC

42. Artificial Blood VS Blood Substitutes
Singh, IRJP 2012

43. Summary Of Key Blood Substitutes Approved, In Clinical Trials,
Or Withdrawn
Blood Substitute Blood Substitute
Class
Clinical Trials Approval
Fluosol-DA-20 PFC Clinical Trials completed in 1980s: Discontinued
due to side effects
Approved in 1989;Withdrawn in
1994
Oxygent PFC Phase Clinical III trials: Increased risk of stroke No Approval; Phase III trials
stopped
Perftoran PFC Completed (Russia) Approved in Russia, Mexico
Oxycyte PFC Phase II Clinical Trials (traumatic brain injury)
umderway in Switzerland and Israel No Approval; Further research
needed
PHER-O2 PFC Pre-clinical Trials umderway
Oxyglobin HBOC Trials completed by late 1990s: Canine anemia Approved: Veterinary Medicine
Hemopure HBOC Completed (South Africa) Approved (South Africa); May be
withdrawn
PolyHeme HBOC Phase III Trial (U.S.): Increased side effects in
treatment group; no difference in 30=-day
survival rate No Approval; Further research
needed
MP4OX (Hemospan) HBOC Phase II Trials (U.S.): Raised oxygen levels
without serious side effects
Hemotech HBOC Phase I Trials: No toxicity

44. Americans Are More Likely To Be Worried Than Enthusiastic About Synthetic Blood
A Minority Of Americans Wants Synthetic Blood For Improved Physical Abilities
https://www.pewresearch.org/science/2016/07/26/the-publics-views-on-the-future-use-of-synthetic-blood-substitutes/
US Survey , 2016

45. ■ Results :- Treating anemia and thrombocytopenia, suspending anticoagulants and
antiplatelet agents, reducing routine phlebotomies, utilizing less traumatic surgical
techniques with moderate hypothermia and hypotension, meticulous hemostasis, use of
topical and systemic hemostatic agents, acute normovolemic hemodilution, cell salvage,
anemia tolerance (supplementary oxygen and normothermia), as well as various other
therapeutic options have proved to be effective strategies for reducing allogeneic blood
transfusions.

47. Take Home Message
■ There is an urgent need to spread awareness & implement patient blood management program
globally ( “ Our own blood is still the best thing to have in our vein “)
■ Blood substitutes (“artificial blood”), better termed as oxygen therapeutic agents (OTAs), have
been in development for many decades
■ The development of OTAs has taken two main approaches: 1. perfluorocarbon-based substitutes
and 2. hemoglobin-based oxygen carriers
■ Currently, there are no Food and Drug Administration (FDA)-approved OTAs given the toxicities
of these agents, though some OTAs are used clinically outside of the United States
■ Therefore, continued work on HBOCs is warranted and, despite multiple setbacks with trials and
products, it makes sense that further work be funded and continued, on the most promising
products

48. Thank You !