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update on blood product alternatives

update on blood product alternatives

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update on blood product alternatives

  1. 1. Jodi V. Mones, M.D. Assistant Professor of Medicine Montefiore Medical Center September 17, 2015
  2. 2. 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
  3. 3. 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
  4. 4. 1)TRALI 2)Hemolytic or anaphylactic reactions 3)Infectious disease contamination 4)TA- GVHD 5)NEC in prematurity
  5. 5. “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
  6. 6. 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
  7. 7. 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
  8. 8. 1)Oxygen transport 2)Nitric Oxide (NO) homeostasis 3)Hemostasis
  9. 9. 1)Oxygen transport 2)Minimal interaction with NO 3)Volume expansion 4)Non-infectious 5)Universally compatible 6)Storage, temperature 7)Minimal methemoglobin production
  10. 10. 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
  11. 11. 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
  12. 12. •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
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. •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
  20. 20. 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
  21. 21. •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
  22. 22. •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
  23. 23. •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
  24. 24. 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
  25. 25. 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
  26. 26. 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
  27. 27. 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
  28. 28. 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
  29. 29. Neurotransmission Anti-inflammation Anti-apoptosis Vasodilation
  30. 30. 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
  31. 31. 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
  32. 32. 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
  33. 33. 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.)
  34. 34. 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
  35. 35. 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
  36. 36. •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
  37. 37. Thank you…..
  38. 38. •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
  39. 39. • 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.
  40. 40. •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.

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