update on blood product alternatives

1. Jodi V. Mones, M.D.
Assistant Professor of Medicine
Montefiore Medical Center
September 17, 2015

3. 1)Why treat anemia?
a) Mortality of anemia vs. Morbidity of red cell transfusion
b) Role of Hemoglobin
2)Why do we need red cell substitutes
a) Hematology Economics (supply vs. demand)
b) Clinical reasons
3)Characteristics of a RBC substitute
4)Current Possibilities
a) HBOC (hemoglobin based oxygen carriers)
1)HemeAssist
2)Polyheme
3)Hemopure
4)HBOC toxicities
b) Sanguinate
c) in vitro production
5)In the meantime…..
1) Severe anemia protocol

4. 1)Hgb 8.1-9.0 (g/dl) 0.5%
2)Hgb 7.1-8.0 1%
3)Hgb 5.1-7.0 2%
4)Hgb 3.1-5.0 11%
5)Hgb < 3.0 50%
Jo KI, Shin JW, Choi TY, Park YJ, Youm W, Kim MJ. Eight-year experience of
bloodless surgery at a tertiary care hospital in Korea. Transfusion. 2013 May;53(5):948-54
Carson JL, Berlin JA, et al. Mortality and morbidity in patients with low postop Hg
levels. Transfusion 2002; 42: 812

5. 1)TRALI
2)Hemolytic or anaphylactic reactions
3)Infectious disease contamination
4)TA- GVHD
5)NEC in prematurity

6. “Silver Tsunami”
• by the year 2020, 25% of US workforce will be over 55
• population over age 65 expected to double by 2030
• >50% transfusions go to those over 65 years
• ideal blood donor is under 75 years
Henkel-Hanke T., Oleck M. Artifiial Oxygen Carriers: A Current Review. AANA
Journal.
June 2007. Vol. 75, No. 3

7. 1)Provide oxygen and volume
a) delay or avoid transfusions
b) hemorrhage
2) Diminish tissue ischemia
a) myocardial ischemia
b) cerebral ischemia
3) Gas absorption and NO scavenging
a) the “bends”
b) treatment of hypotension in sepsis
4) Radiosensitization
Henkel-Hanke T., Oleck M. Artifiial Oxygen Carriers: A Current Review. AANA
Journal.
June 2007. Vol. 75, No. 3

8. 1)Why treat anemia?
a) Mortality of anemia vs. Morbidity of red cell transfusion
b) Role of Hemoglobin
2)Why do we need red cell substitutes
a) Hematology Economics (supply vs. demand)
b) Clinical reasons
3)Characteristics of a RBC substitute
4)Current Possibilities
a) HBOC (hemoglobin based oxygen carriers)
1)HemeAssist
2)Polyheme
3)Hemopure
4)HBOC toxicities
b) Sanguinate
c) in vitro production
5)In the meantime…..
1)Severe anemia protocol

9. 1)Oxygen transport
2)Nitric Oxide (NO) homeostasis
3)Hemostasis

10. 1)Oxygen transport
2)Minimal interaction with NO
3)Volume expansion
4)Non-infectious
5)Universally compatible
6)Storage, temperature
7)Minimal methemoglobin production

11. 1) Chemically modified cell-free hemoglobin
2) Liposomal, encapsulated artificial “red cells”
3) Flourocarbon solvents
4) Polyethylene glycol conjugated red cells
5) In vitro cRBCs
Mozzarelli, A, Bruno S et al. Haemoglobin-based oxygen carriers: research and
reality towards an alternative to blood transfusions. Blood Transf 2010; 8 Supp 3: s59

12. 1)Why treat anemia?
a) Mortality of anemia vs. Morbidity of red cell transfusion
b) Role of Hemoglobin
2)Why do we need red cell substitutes
a) Hematology Economics (supply vs. demand)
b) Clinical reasons
3)Characteristics of a RBC substitute
4)Current Possibilities
a) HBOC (hemoglobin based oxygen carriers)
1)HemeAssist
2)Polyheme
3)Hemopure
4)HBOC toxicities
b) Sanguinate
c) in vitro production
5)In the meantime…..
1)Severe anemia protocol

13. •Mass produced
•Chloride ions in addition to 2,3 bpg
•Oxygenate tissues at very low hct
Mullon J, Dillard, T. et al. Transfusions of Polymerized Bovine Hemoglobin in
A patient with AIHA. NEJM 2000 342(22) 1638

14. Mozzarelli, A, Bruno S et al. Haemoglobin-based oxygen carriers: research and
reality towards an alternative to blood transfusions. Blood Transf 2010; 8 Supp 3: s59

16. Product type Product Name Status
Cross-linked Hg HemAssist DC ; safety concerns
Polymerized Hg Hemopure (HBOC-201)
Polyheme
DC; approved S. Africa
and Russia
DC; no efficacy
Conjugated Sanguinate Clinical trials; orphan
drug approval
Hemospan DC; no efficacy
Posluszny JA Jr. Napolitano Lena M. How do we treat life-threatening anemia
in a Jehovah’s Witness patient? Transfusion vol 54 Dec 2014; 3026
Mozzarelli, A, Bruno S et al. Haemoglobin-based oxygen carriers: research and
reality towards an alternative to blood transfusions. Blood Transf 2010; 8 Supp 3: s59

17. Chen JY, Scerbo M, Kramer G. A review of blood substitutes: history, clinical trial
results, and ethics of hemoglobin-based oxygen carriers. Clinics. 2009;64(8):803-
13.
HemAssist Human blood
Half-life 6-12 hours 37 days
Storage <5 C 1-6 C
Shelf life 1 year 42 days
P50 32mmHg P50 27mmHg
Hemoglobin concentration 10G/dL

18. Polyheme Human blood
Half-life 24 hours 37 days
Storage 4-8 C 1-6 C
Shelf life 1 year 42 days
P50 20mmHg P50 27mmHg
Hemoglobin concentration 13G/dL
Chen JY, Scerbo M, Kramer G. A review of blood substitutes: history, clinical trial
results, and ethics of hemoglobin-based oxygen carriers. Clinics. 2009;64(8):803-13

19. Hemopure Human blood
Half-life 19 hours 37 days
Storage 1-38 C 1-6 C
Shelf life 2-3 years 42 days
P50 43mmHg P50 27mmHg
Hemoglobin 30 g/unit
Posluszny JA Jr. Napolitano Lena M. How do we treat life-threatening anemia
in a Jehovah’s Witness patient? Transfusion vol 54 Dec 2014; 3026
Mullon J, Dillard, T. et al. Transfusions of Polymerized Bovine Hemoglobin in
A patient with AIHA. NEJM 2000 342(22) 1638

20. Expanded Access Study of Hemopure for
the Treatment of Life-Threatening Anemia
•Primary Outcome Measures: survival
[ Time Frame: 1 week ]
Englewood Hospital and Medical Center
Englewood, New Jersey
Contact: Jamie Ketas 201-894-3418
Principal Investigator: Aryeh Shander, MD

21. •Inclusion Criteria:
hemoglobin < = 8g/dL with active bleeding,
physiologic evidence of critical tissue ischemia, for example:
elevated troponins, altered mental status, acute renal failure,
lactic acidosis
•Exclusion Criteria:
hypersensitivity or allergy to beef products
pre-existing uncontrolled hypertension, heart failure,
circulatory hypervolemia
Patients > 80 years of age

22. Posluszny JA Jr. Napolitano Lena M. How do we treat life-threatening anemia
in a Jehovah’s Witness patient? Transfusion vol 54 Dec 2014; 3026
Natanson C, Lurie P et al. Cell-free hemoglobin based substitutes : a meta-analysis.
JAMA 2008;299: 2304.
Scavenging of NO
vasoconstriction – hypertension, pulmonary hypertension,
decreased cardiac output, myocardial infarction
GI distress – esophageal spasm, pain, nausea
Methemoglobinemia

23. •Ferrous (+2) to ferric (3+)
•Usually asymptomatic until levels >13%, unless other
abnormal Hg present
Headache, fatigue, altered mental status
Seizure, coma and death (levels >70%)
•Treatment
Methylene blue IV – acute toxicity
Oral methylene blue - daily in congenital cases

24. •36, female, Jehovah’s Witness
•B- ALL
•Induction chemotherapy with cytoxan, daunorubicin,
vincristine decadron, L – asparaginase
•Admission - Hg 7.2
•Day 8 - Hg 3.6
•Hypotensive, dizzy, tachycardic
Donahue,L, Greenburg, G. et al. Management of anemia in a JW patient with ALL with
Polymerized bovine hemoglobin-based oxygen carrier: a case report. Tranfusion.July
2010 Vol 50: 1561

25. •Hemopure by emergency IND
•15 doses
•Discharge Hg – 4.5
•Intensification courses: Epoetin alfa 40,000 units weekly
nadir Hg 7.5
Donahue,L, Greenburg, G. et al. Management of anemia in a JW patient with ALL with
Polymerized bovine hemoglobin-based oxygen carrier: a case report. Tranfusion.July
2010 Vol 50: 1561

26. Days of Induction Chemotherapy
Hglevel(g/dl)
Donahue,L, Greenburg, G. et al. Management of anemia in a JW patient with ALL with
Polymerized bovine hemoglobin-based oxygen carrier: a case report. Tranfusion.July
2010 Vol 50: 1561

27. Donahue,L, Greenburg, G. et al. Management of anemia in a JW patient with ALL with
Polymerized bovine hemoglobin-based oxygen carrier: a case report. Tranfusion.July
2010 Vol 50: 1561
Methemoglobin%
Induction chemotherapy

28. Donahue,L, Greenburg, G. et al. Management of anemia in a JW patient with ALL with
Polymerized bovine hemoglobin-based oxygen carrier: a case report. Transfusion .July
2010 Vol 50: 1561Mullon J, Dillard, T. et al. Transfusions of Polymerized Bovine
Hemoglobin in A patient with AIHA. NEJM 2000 342(22) 1638

29. 1)Why treat anemia?
a) Mortality of anemia vs. Morbidity of red cell transfusion
b) Role of Hemoglobin
2)Why do we need red cell substitutes
a) Hematology Economics (supply vs. demand)
b) Clinical reasons
3)Characteristics of a RBC substitute
4)Current Possibilities
a) HBOC (hemoglobin based oxygen carriers)
1)HemeAssist
2)Polyheme
3)Hemopure
4)HBOC toxicities
b) Sanguinate
c) in vitro production
5)In the meantime…..
1)Severe anemia protocol

30. Bovine Hemoglobin
PEG CO
decreased immunogenicity
increases t ½ - 35 hours
large – prevents extravasation
anti-vasoconstrictive
reduces NO depletion
Misra H, Kazo F, Newmark JA. Toxicology and Safety Determination for a Novel
Therapeutic Dual Carbon Monoxide and Oxygen Delivery Agent. J Clin Toxicol 2014;
4: 205
Misra H, Abuchowski A et.al. PEGylated Carboxyhemoglobin Bovine (SANGUINATE):
Results of a Phase I Trial. Artificial Organs 2014, 38(8): 702
P50: 7-16mm Hg

31. Neurotransmission Anti-inflammation
Anti-apoptosis Vasodilation

32. Misra H, Abuchowski A et.al. PEGylated Carboxyhemoglobin Bovine (SANGUINATE):
Results of a Phase I Trial. Artificial Organs 2014, 38(8): 702
•Lethargy
•Dizziness
•Decreased haptoglobin
•Increased blood pressure

33. Study of SANGUINATE In the Treatment of Sickle Cell
Disease Patients With Vaso-Occlusive Crisis
Study of SANGUINATE Versus Hydroxyurea in Sickle Cell
Disease (SCD) Patients
Safety and Effect of SANGUINATE Infusion in Patients at
Risk of Delayed Cerebral Ischemia (DCI) Following
Subarachnoid Hemorrhage (SAH)
Clinicaltrials.gov; Prolong Pharmaceuticals

34. 1)Why treat anemia?
a) Mortality of anemia vs. Morbidity of red cell transfusion
b) Role of Hemoglobin
2)Why do we need red cell substitutes
a) Hematology Economics (supply vs. demand)
b) Clinical reasons
3)Characteristics of a RBC substitute
4)Current Possibilities
a) HBOC (hemoglobin based oxygen carriers)
1)HemeAssist
2)Polyheme
3)Hemopure
4)HBOC toxicities
b) Sanguinate
c) in vitro production
5)In the meantime…..
1)Severe anemia protocol

35. Giarratana, MC, Douay, L et al. Proof of principle for transfusion of in vitro-
generated red blood cells. Blood. Nov 10 2011 vol 118 (19): 5071
Hb%
Time (min.)

36. LOG (PO2, mmHg)
Fractionalsaturation
Giarratana, MC, Douay, L et al. Proof of principle for transfusion of in vitro-
generated red blood cells. Blood. Nov 10 2011 vol 118 (19): 5071

37. 1)Why treat anemia?
a) Mortality of anemia vs. Morbidity of red cell transfusion
b) Role of Hemoglobin
2)Why do we need red cell substitutes
a) Hematology Economics (supply vs. demand)
b) Clinical reasons
3)Characteristics of a RBC substitute
4)Current Possibilities
a) HBOC (hemoglobin based oxygen carriers)
1)HemeAssist
2)Polyheme
3)Hemopure
4)HBOC toxicities
b) Sanguinate
c) in vitro production
5)In the meantime…..
1)Severe anemia protocol

38. •Epoetin alfa 40,000 units daily until Hg >7 g/dl
then 40,000 weekly
•Iron sucrose 100 mg IV daily for 10 days
then oral dosing
•Folic acid 1mg daily
•B12
•Vitamin C 500mg TID except renal failure (daily)
Posluszny JA Jr. Napolitano Lena M. How do we treat life-threatening anemia
in a Jehovah’s Witness patient? Transfusion vol 54 Dec 2014; 3026

39. Thank you…..

40. •Reduction of tissue hypoxia
•Radiosensitization
Head and neck squamous cell carcinomas
1) allogeneic blood transfusions
2) oxygen mimetics
3) erythropoetic stimulation
•Support during chemotherapy and HSCT
Li Zenghong, J. Wong, T.S. ISRN Otolaryngology.2012 Vol. 2012:
doi:10.5402/2012/708974

41. • Hepatitis B:
•1 in 1.0M
•Hepatitis C
•1 in 1.2 M
•HIV
•1 in 1.5 M
•Others
•Creuzfeldt-Jakob, HTLV, Coronavirus, bacterial
contamination
Henkel-Hanke T., Oleck M. Artifiial Oxygen Carriers: A Current Review. AANA Journal.
June 2007. Vol. 75, No. 3
Zou S, Dodd RY et.al. Donor testing and risk: Current prevelance, incidence and residual risk of
Transfusin. Transfus Med Rev 2012;26:119.

42. •Oxygnenation linearly related to P02 of patient
•In vivo t1/2 – 12 hours
•Shelf life 2 years
•Stored at 4 C
•Massive hepatosplenomegaly
•Cytokine release
•Chemical pneumonitis
Henkel-Hanke T., Oleck M. Artifiial Oxygen Carriers: A Current Review. AANA Journal.
June 2007. Vol. 75, No.