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Brian Poirier, MD Medical Director, Collections BloodSource

Using Blood Wisely: Evidence-Based Transfusion Indications. Brian Poirier, MD Medical Director, Collections BloodSource. Using Blood Wisely: Evidence-Based Transfusion Indications. Objective

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Brian Poirier, MD Medical Director, Collections BloodSource

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  1. Using Blood Wisely: Evidence-Based Transfusion Indications Brian Poirier, MD Medical Director, Collections BloodSource

  2. Using Blood Wisely: Evidence-Based Transfusion Indications Objective At the conclusion of this presentation, participants will be able to identify key steps in the development of evidence-based criteria for the transfusion of blood components. Conflicts of Interest I have no conflicts to disclose.

  3. Using Blood Wisely: Evidence-Based Transfusion Indications Outline (5 Minutes): What, Exactly Is In the Blood Components I Issue or Transfuse? (30 minutes): Evidence-Based Transfusion Indications for: RBCs Plasma Platelets Cryoprecipitate Primary focus will be on the transfusion of adults

  4. Using Blood Wisely: Evidence-Based Transfusion Indications The Manufacture of Blood Components

  5. How We Make Blood Components From Whole Blood Multi-bag whole blood collection kits Flow of whole blood into primary bag

  6. How We Make Blood Components Centrifuge used for component manufacture Platelet-rich plasma being expressed into secondary bags (on countertop) Interior compartment of component centrifuge

  7. Blood Component Manufacture from Whole Blood (as it’s done in USA) RBCs Platelet-Rich Plasma + Plasma Platelets Centrifuge (low g forces) Freeze Fresh Frozen Plasma (FFP) or “Plasma Frozen with 24 hours” Centrifuge (higher g forces) Freeze Recovered Plasma Freeze (usually) Liquid Plasma + • Leukoreduce • Possibly irradiate • Other (e.g., wash) …

  8. Thaw (4° C) Centrifuge Blood Component Manufacture from Whole Blood • Single dose Cryo contains – 80 IU FVIII, 150 mg Fibrinogen Fresh Frozen Plasma (FFP) Cryoprecipitate + Cryo-Reduced Plasma

  9. The Principles of Apheresis Plasma Platelets Mononuclear Cells Granulocytes Red Blood Cells Whole Blood Whole Blood Anticoagulant added Remaining blood constituents returned (vein) (vein) Blood constituents separated by centrifuge and selectively collected

  10. How We Make Blood Components From Apheresis Collections Using apheresis technology to collect platelets, plasma, RBCs, etc.

  11. e - Platelets per apheresis unit = 3 x 1011 Whole Blood-Derived Platelets Plateletpheresis Unit

  12. Plasma Collected Via Apheresis Predictable Volumes of 200 or 400 mL (etc.) FFP Made from Apheresis

  13. Using the “Leftovers” Wisely Plasma (of any kind) Sent for further processing Plasma Derivatives • Albumin • Factor VIII • Immune globulin • etc.

  14. “Shotgun” Approach vs. Component Therapy Blood can be utilized optimally via the transfusion of specifically required components, instead ofwhole blood

  15. Using Blood Wisely Transfusion Indications for Blood Components – The Evidence Basis

  16. Red Blood Cells (RBCs)

  17. P.E. Marik and H.L. Corwin. Efficacy of red blood cell transfusion in the critically ill: A systematic review of the literatureCrit Care Med 2008; 36: 2667 – 74 • Methods • Meta-analysis of 45 observational studies assessing independent effects of RBC transfusions on patient outcomes • Included 687 adult ICU, trauma, and surgery patients • Outcome measures • Mortality • Infections • Multi-organ dysfunction syndrome • Acute respiratory distress syndrome • Results: … (next three slides) …

  18. P.E. Marik and H.L. Corwin. Efficacy of red blood cell transfusion in the critically ill: A systematic review of the literatureCrit Care Med 2008; 36: 2667 – 74 Association Between RBC Transfusions & Mortality

  19. P.E. Marik and H.L. Corwin. Efficacy of red blood cell transfusion in the critically ill: A systematic review of the literatureCrit Care Med 2008; 36: 2667 – 74 Association Between RBC Transfusions & ARDS

  20. P.E. Marik and H.L. Corwin. Efficacy of red blood cell transfusion in the critically ill: A systematic review of the literatureCrit Care Med 2008; 36: 2667 – 74 Association Between RBC Transfusions & Infectious Complications

  21. P.E. Marik and H.L. Corwin. Efficacy of red blood cell transfusion in the critically ill: A systematic review of the literatureCrit Care Med 2008; 36: 2667 – 74 • Conclusions • Authors acknowledged “inherent limitations* in the analysis of cohort studies” – still … • … Their meta-analysis showed that RBC transfusions were associated with increased morbidity and mortality • Authors’ Take-Home Message: “[C]urrent transfusion practices may require reevaluation.” *Even though the authors analyzed the best studies available to them, none of these studies controlled for confounding variables in the way that a randomized controlled clinical trial would have. Products were generally not leukoreduced.

  22. PC Hebert et al. A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical CareNEJM 1999; 340: 409-417 • Background: To determine if restrictive vs. liberal transfusion strategies in critically ill patients yield equivalent results • Methods: 838 euvolemic, critically ill patients were randomly assigned to receive transfusions only if: • Hgb < 7 (afterwards, maintained at 7-9 g/dL) or • Hgb < 10 (afterwards, maintained at 10-12 g/dL)

  23. PC Hebert et al. A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care NEJM 1999; 340: 409-417 • Results • 30-day mortality rates were similar in the two groups • 18.7% for restrictive vs. … • 23.3% for liberal group (p = 0.11), but … • Mortality rates in restrictive group were significantly lower in two specific subgroups – e.g., among: • “Patients who were less acutely ill” (8.7% for restrictive vs. 16.1% for liberal; p = 0.03) • Patients < 55 years old (5.7 in restrictive vs. 13.0% for liberal; p = 0.02) • No difference was seen in patients with clinically significant heart disease (20.5 vs. 22.9%; p = 0.69)

  24. J. Lacroix et al. Transfusion Strategies for Patients in Pediatric Intensive Care UnitsNEJM 2007; 356: 1609 – 1619 • Methods • Multicenter, non-inferiority study (USA and Canada) • 637 stable pediatric ICU patients (3 days to 14 years) • Randomized to be transfused at: • Hgb < 7.0 g/dL (restrictive study group) versus • Hgb < 9.5 g/dL (liberal study group)

  25. J. Lacroix et al. Transfusion Strategies for Patients in Pediatric Intensive Care UnitsNEJM 2007; 356: 1609 – 1619 • Results • No differences between two groups in rates of: • New or progressive multi-organ failure (12% for each) • All causes of 28-day mortality (4% for each) • Nosocomial infections (20% vs. 25% for restrictive vs. liberal; p = 0.16) • Big differences seen in transfusion rates … • Restrictive group had 44% fewer transfusions (with 54% not transfused at all) • Only 2% of liberal group avoided transfusions • Conclusion: The authors demonstrated noninferiority of the restrictive transfusion strategy

  26. LA Hajjar et al. Transfusion Requirements After Cardiac Surgery: The TRACS Randomized Controlled TrialJAMA 2010; 304:1559-1567 • Objective: To define whether a restrictive perioperative red blood cell transfusion strategy is as safe as a liberal strategy in patients undergoing elective cardiac surgery. • Design, Setting, and Patients • Prospective, randomized, controlled clinical noninferiority trial • Conducted between February 2009 and February 2010 in an intensive care unit at a university hospital cardiac surgery referral center in Brazil. • Consecutive adult patients (n=502) who underwent cardiac surgery with cardiopulmonary bypass were included • Analysis was by intention-to-treat.

  27. LA Hajjar et al. Transfusion Requirements After Cardiac Surgery: The TRACS Randomized Controlled TrialJAMA 2010; 304:1559-1567 • Intervention: Patients were randomly assigned to a: • Liberal strategy of RBC transfusion (to maintain Hct of 30%) or • Restrictive strategy (to maintain Hct of 24%). • Main Outcome Measure: Composite end point of 30-day all-cause mortality and severe morbidity … • Cardiogenic shock • Acute respiratory distress syndrome, or • Acute renal injury requiring dialysis or hemofiltration occurring during the hospital stay

  28. LA Hajjar et al. Transfusion Requirements After Cardiac Surgery: The TRACS Randomized Controlled TrialJAMA 2010; 304:1559-1567 • Results • Hemoglobin concentrations were maintained at a mean of: • 10.5 g/dL in the liberal-strategy group and • 9.1 g/dL in the restrictive-strategy group (P.001) • RBCs transfusion occurred in: • 198 of 253 patients (78%) in the liberal-strategy group and • 118 of 249 (47%) in the restrictive-strategy group (p = .001) • Occurrence of the primary end point was similar between groups • 10% liberal vs. … • 11% restrictive (p =0.85) • Independent of transfusion strategy, the number of transfused red blood cell units was an independent risk factor for clinical complications or death at 30 days (hazard ratio for each additional unit transfused, 1.2 (p = 0.002)

  29. LA Hajjar et al. Transfusion Requirements After Cardiac Surgery: The TRACS Randomized Controlled TrialJAMA 2010; 304:1559-1567 Conclusion: “[T]he use of a restrictive perioperative transfusion strategy compared with a more liberal strategy resulted in noninferior rates of the combined outcome of 30-day all-cause mortality and severe morbidity.”

  30. More To Come: FOCUS Trial • Multicenter Study: USA and Canada • Patients with Hip Fracture and Cardiovascular Disease or Risk Factors • 2016 patients (from about 14k enrolled) • 75% women, avg age = 81yo • Randomized to: • Liberal (“10/30”) transfusion policy or • Restrictive – no transfusion unless symptomatic anemia, optional if Hgb < 8.0 g/dL • To Be Published…

  31. Accepted Clinical Indications for RBCs (Adults) • Clinical Indications: To restore O2-carrying capacity in clinically significant anemias • Asymptomatic anemia: In most cases wait until Hgb drops below 7 g/dL before considering transfusion • Symptomatic anemia:(More controversial)Consider a higherHgb threshold (e.g., up to 8 g/dL) • Bleeding: Transfuse at physician’s discretion • Occasional exceptionsexist …

  32. Platelets

  33. Clinical Indications for PlateletsThe Earliest Days … 1910: Duke first demonstrated that platelets from transfused fresh whole blood decrease bleeding time and control bleeding. Duke WW. JAMA 1910; 55: 1185-92.

  34. All Bleeding Skin & Epistaxis Excluded Grossly Visible Bleeding (hematuria, melena, hematemesis) Relationship BetweenPlatelet Count and Hemorrhage 100 90 80 70 60 % Days With Hemorrhage 50 40 30 20 10 0 <1,000 1-3,000 3-5,000 5-10,000 10-20,000 20-50,000 >100,000 50-100,000 Platelets / L Gaydos, et al.; NEJM 1962; 266: 905.

  35. 100 80 60 Stool Blood Loss (ml/days) 40 20 25 5 10 15 20 Platelet Count x 103/ l Fecal Blood Loss vs Degree of Thrombocytopenia Slichter & Harker. Clin Haematol 1978;7:523.

  36. SJ Slichter et al. Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage NEJM 2010; 362: 600 – 13 • Background: Randomized clinical trial investigating effect of prophylactic platelet transfusions • Methods: Involved patients hospitalized for: • Hematopoietic stem cell transplants, or • Chemotherapy treatment for hematologic cancers or solid tumors

  37. SJ Slichter et al. Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage NEJM 2010; 362: 600 – 13 • Methods (continued): Three dosage arms: • Low (1.1 x 1011 platelets/meter2 body surface area) • Medium (2.2 x 1011 platelets/m2 BSA) • High (4.4 x 1011 platelets/m2 BSA) • Primary endpoint was > grade 2 bleeding (WHO definition = mild, clinically significant bleeding)

  38. SJ Slichter et al. Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage NEJM 2010; 362: 600 – 13 • Results (n = 1,272 patients) • Primary endpoint (> grade 2 bleeding) was reached in 71%, 69%, and 70% of low-, medium-, and high-dose groups (no statistically significant differences between groups) • Median number of platelets transfused per group: • Low-dose: 9.25 x 1011 • Medium-dose: 11.25 x 1011 • High-dose: 19.63 x 1011 • But … median number of platelet units transfused per patient was significantly higher in: • low-dose group (5 units) versus • medium- and high-dose groups (3 units each)

  39. SJ Slichter et al. Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage NEJM 2010; 362: 600 – 13 • Conclusions • Low-dose prophylactic transfusions led to: • Fewer platelets given, but … • More transfusions (due to ↓’d interval between transfusions) • “At doses between 1.1 x 1011 and 4.4 x 1011 platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding.”

  40. Clinical Indications for Platelets • Major indications include: • Decreased Production • Leukemias • Chemotherapy • Congenital disorders • Increased Destruction/Loss • DIC • Massive transfusions • Platelet Function Defects • Myeloproliferative disorders • Aspirin/Plavix • Glanzmann’s thrombasthenia

  41. Accepted Clinical Indications for Platelets A. Guidelines for Prophylactic Platelet Transfusions • No Clinical Factors – Most advocate maintaining platelet count:a. > 10,000/uL (Adults) b. > 50,000/uL (Neonates) 2. Significant Clinical Factors (e.g., sepsis, DIC,VOD, GVHD) – Perhaps maintain platelet count > 20,000/uL (Adults) B. If Patient is Bleeding or Pre-Surgery –Maintain platelet count > 50,000/uL C. Exceptions … To be discussed (sometimes/rarely may be better to keep platelet count closer to 100,000/uL)

  42. H. Wandt et al. A therapeutic platelet transfusion strategy is safe and feasible in patients after autologous peripheral blood stem cell transplantationBone Marrow Transpl 2006; 37: 387 – 92 • Methods • 106 consecutive cases of patients who underwent 140 autologous PBSCs • Used therapeutic (not prophylactic) regimen for clinically stable patients • Transfused platelets only for bleeding greater than just petechial • Results • 26 patients had mild to moderate bleeding (never severe or life-threatening) • Platelet use (compared to control) was reduced by 50% • Conclusions: “This therapeutic platelet transfusion strategy can be performed safely resulting in a considerable reduction in prophylactic platelet transfusions.” Controversial!!!

  43. H. Wandt et al. Experience with a TherapeuticPlatelet Transfusion Strategy in Acute Myeloid Leukemia: Preliminary Results of a Randomized Multicenter Study After Enrolment of 175 Patients. Blood 2009; 114: Abstract 20 • Methods – Multicenter, randomized trial involving AML patients, comparing: • Therapeutic platelet transfusions (given only for bleeding worse than petechiae) vs. … • Prophylactic platelet transfusions (given for platelet count < 10,000/uL) • Results (n = 161 patients) • In therapeutic arm – 7 cerebral bleeds (5 minor, which resolved with transfusions; 2 major, leading to death) vs. … • No cerebral bleeds in prophylactic arm

  44. H. Wandt et al. Experience with a TherapeuticPlatelet Transfusion Strategy in Acute Myeloid Leukemia: Preliminary Results of a Randomized Multicenter Study After Enrolment of 175 Patients. Blood 2009; 114: Abstract 20 • Conclusions • “A therapeutic platelet transfusion strategy according to our protocol is feasible in AML pts during intensive chemotherapy and can reduce the number of platelet transfusions significantly. • An increased risk of fatal cerebral bleeding cannot be excluded by this study. • An international collaboration would be necessary to set up a study large enough to determine the final safety.” Should this study be done?

  45. Dosing Platelets A. For Infants/Children:5-10 mL platelets/kg B. For Adults (> 40 kg):1 plateletpheresis unit (rarely 2) • Expected Platelet Increment ≈Platelet Dose  BV x 0.67* *0.67 = correction factor for patients with spleens

  46. Dosing Platelets – Example For a 70 kg male transfused with 3.0 x 1011 platelets Expected Platelet Increment ≈ 3.0 x 1011[70 kg x 70 mL/kg] x 0.67 ≈ 40,000/uL i.e., BV

  47. Dosing Platelets • Expectations:Ideally, an appropriate dose of platelets will raise the platelet count by 30,000-60,000/uL • Post-Transfusion Assessment:Obtain a platelet count within 10 minutes to 1 hour post-transfusion – especially if refractoriness is suspected (VERY IMPORTANT) • Managing Refractory Patients: A whole ‘nother discussion

  48. S Vadhan-Raj. Management of Chemotherapy-Induced Thrombocytopenia: Current Status of Thrombopoietic AgentsSeminars in Hematology 2009; 46: S26-S32 • “That Was Then (i.e., about 10 years ago) …” • The use of recombinant thrombopoietins in nonmyeloablative clinical settings appeared promising; however … • “[F]urther clinical development was halted due to evidence of neutralizing antibodies to pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF).” Ch’ ch’ changes in store … ?

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