Blood Products and Bloodless Medicine

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1 Blood Products and Bloodless Medicine
Sujani Surakanti, MD Duke University Hospital Medicine, Hematology, Medical Oncology

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3 Bloodless Medicine Objection to blood products
Religious Personal Challenges with taking blood products Adverse reactions Allo-antibodies

4 Question 1 What Blood Products are not acceptable to all Jehovah’s Witnesses? Whole Blood, Packed RBCs Platelets, FFP Cryoprecipitate, IVIG A, B, and C A and B

5 What blood products are not acceptable to all Jehovah's witnesses?

6 For the Jehovah’s Witness
Although Jehovah's Witness (JW) patients refuse transfusion of primary blood components (above dotted line) as directed by the Watch Tower Society, acceptance of other components or blood substitutes (below dotted line) has been left to the individual patient. The Annals of Thoracic Surgery  , 19-25DOI: ( /j.athoracsur ) Copyright © 2012 The Society of Thoracic Surgeons Terms and Conditions

7 Blood Component Separation
Whole Blood Slow Centrifuge Packed Red Blood Cells Platelet Rich Plasma Fast Centrifuge Platelet Concentrate Fresh Frozen Plasma Thaw FFP Centrifuge Cryoprecipitate Apheresis for platelets or plasma.

8 Components Plasma components Cellular Components Plasma Derivatives
Red Cell Platelets Granulocytes Plasma components Fresh Frozen Plasma Cryoprecipitate Cryopoor plasma Stored plasma Plasma Derivatives Albumin Immunoglobulin Coagulation Factors

9 Whole Blood Unit 450ml No functional platelets
No labile coagulation factors Rarely used (exception: massive transfusion protocol, acute trauma with blood loss)

10 Red Cell Concentrates, aka Packed RBCs
Platelets and plasma removed Unit ml, Hct 60% Stored at 4⁰C for up to six weeks One unit expected to raise Hgb by 1g/dL (Hct by 3%) in average size adult

11 Packed Red Blood Cells Indication: symptomatic anemia Common triggers
Hgb < 7 mg/dL or symptomatic Hgb < 10 mg/dL for cardiac or pulmonary disease Hemorrhage with >30% total blood loss Sickle cell anemia Transfusion or exchange to decrease Hgb S <30%

12 Platelets Random donor: 4-6 units of platelets from multiple donors
Apheresis: Single donor Stored at room temperature for up to 5 days Cold storage decreases platelet function Long storage time increases infection risk Raise plate count by 20,000-30,000/µL

13 Platelets Indications: decreased platelet count and/or function
Common triggers Plts < 10,000 Plts < 20,000 with fever or sepsis Plts < 50,000 prior to major surgery Plts < 100,000 prior to neurosurgery or ophthalmologic surgery Active bleeding with known platelet dysfunction

14 FFP Frozen within 8 hours of collection at -18⁰C Stored up to 1 year
Volume = 200 ml 1 IU/ml of each factor To increase factor levels by 20-30% - give 10 to 20 ml/kg (4 to 6 units)

15 Cryoprecipitate Cold-insoluble portion of plasma containing high molecular weight glycoproteins Stored at -18⁰C for 1 year Unit is 25 ml ≥ 150 mg fibrinogen ≥ 80 IU of Factor VIII 30% of factor XIII of original plasma 10 units to raise fibrinogen 100 mg/dL

16 Cryoprecipitate Indications: decreased or dysfunctional fibrinogen, vWF, Factor XIII, Factor VIII Common triggers Fibrinogen < 100 mg/dL Dysfibrinogenemia Factor XIII deficiency Uremic platelet dysfunction with bleeding vWD if DDAVP contraindicated (type 2B or type 3) and active bleeding

17 Conversation & Conservation
Although Jehovah's Witness (JW) patients refuse transfusion of primary blood components (above dotted line) as directed by the Watch Tower Society, acceptance of other components or blood substitutes (below dotted line) has been left to the individual patient. The Annals of Thoracic Surgery  , 19-25DOI: ( /j.athoracsur ) Copyright © 2012 The Society of Thoracic Surgeons Terms and Conditions

18 Blood Conservation Blood conservation may provide particular benefit to: Blood refusal patients Patients with sickle cell disease or other hematologic disorders (hemolytic anemia) Transplant recipients or patients waiting for transplants

19 Question 2 You are the nocturnist, called on a 32 yo female patient with vasoocclusive crisis with Hgb SS. A page from RN states that the patient developed a fever to 38.1, hypotensive to 80/50, and severe respiratory distress with RR of 30/min and SPO2 of 81%. Before going to evaluate you review her last progress note. Her baseline Hgb runs about 6 g/dL. She has ongoing problems with iron deficiency from menorrhagia from multiple large uterine fibroids. Now during this admission, she is actively menstruating. Her hemoglobin dropped to 3 g/dL and she was lethargic and dizzy. She was given her 1U RBC earlier today, with improvement in symptoms. You go evaluate the patient and her sats continue to drop and her breathing is very labored.

20 Question 2 (cont) You call an RRT. She is intubated.
What will she need next? Continue Supportive care Diuretics RBC exchange IV antibiotics

21 You call and RRT. She is intubated. What will she need next?

22 Benefits of Transfusion Avoidance
Infectious risks TRALI/ TACO Immune suppression Administration error/ transfusion reactions Limited resource Cost Most common major complication is TRALI/TACO- probably under reported

23 Cost of Blood Products Acquisition Costs, American Red Cross 2016
PRBCs - $212.73 Platelet pheresis unit - $514.00 FFP - $49.98 Cryoprecipitate pool (5 bags) - $315.67 

24 Cost of Transfusion Tasks and resource consumption (materials, labor, third-party services, capital) related to blood administration RBC-unit costs averaged $761 ± 294 Did not include treatment of complications associated with transfusion-transmissible disease, litigation or reimbursement/indemnification for adverse events Cost exceeded acquistion cost by 3-4 fold Impact on LOS not evaluated Shander, A et al. Transfusion, 2010; 50:

25 Restrictive Transfusions
Hebert, et. al. A MC, RCT of Transfusion Requirements in CC. NEJM 1999; 340:

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27 No GPS, Yet Growing number of Bloodless Medicine and Surgery programs across the nation No standard, established guidelines Not many studies to inform optimal treatment

28 Common Methods Minimizing lab testing
Low volume microtainers for phlebotomy Tolerating lower Hgb levels Dx and treat anemia and other cytopenias

29 Preoperative Perform thorough history and physical exam to evaluate for potential causes of anemia or blood loss Referral back to PCP or GI for colonoscopy if suspected GI bleed (iron deficiency) Hematology referral for complex anemia (hemolysis, neutropenia or thrombocytopenia, etc) Delay surgery to allow for treatment of anemia Early evaluation Hold anticoagulants appropriately Consultation of cardiologist, neurologist as needed Wait several weeks after cath

30 Intraoperative Treatment
Surgical techniques Minimally invasive techniques, tissue coagulants, minimize cooling Ensure “maximum hemostasis” Perfusion Techniques RAP, smaller circuit volume Normovolemic hemodilution Cell salvage Pharmacotherapy (DDAVP, Antifibrinolytics, etc) Minimize crystalloid Hemodilution of clotting factors Minimally invasive surgery, use of tissue coagulants (surgicel, pro-seal, etc) Minimize crystalloid Ensure “maximum hemostasis”-something we can’t measure

31 Normovolemic Hemodilution

32 Cell Saver

33 Question 3 Neurosurgery consulted you for medical co-management on a 65 yo male with HTN admitted to undergo elective lumbar spinal fusion. He is a Jehovah’s Witness. His surgery goes well. Post-op day 2, the patient is hypotensive and mildly dyspneic. You note in the Anesthesia log that Factor VIIa was not given during the case. The OP note says that hemostasis was judiciously maintained. Preadmission testing Hgb was 9 g/dL. Today Hgb is 5.8 g/dL. You page the primary team to recommend the following: Reassess your patient and consider taking back to the OR Call Hematology to get recombinant Factor VIIa approved to give now Start IV iron and erythropoeitin Check CBC, coags, and DIC panel q6hours and replete factors accordingly

34 Neurosurgery consulted you for medical co-management of HTN on a 65 yo male admitted to undergo elective lumbar spinal fusion… you page the primary team to recommend the following.

35 Postoperative Early recognition of surgical bleeding
Low tolerance to re-operate Labs to recognize and correct coagulopathy, point-of-care testing ACT (inadequate heparin reversal), TEG/ ROTEM Minimize blood draws Minimize myocardial demand Tolerance of anemia Pediatric tubes for labs Supplemental O2

36 Optimizing Coagulation
Assess for coagulopathy early Utilize point-of-care tests (ROTEM) By avoiding/ treating coagulopathy may transfuse less total products overall Minimize hemodilution of platelets and clotting factors (For massive transfusion, aim for 1:1:1 ratio to mimic whole blood) Pharmacotherapy Prevent fibrinolysis, improve platelet function, provide clotting factors

37 Pharmacotherapy Preoperative Perioperative IV or oral Iron B12, folate
ESAs If vWD: Desmopressin (DDAVP) cryoprecipitate Humate-P Tranexamic acid Epsilon aminocaproic acid Recombinant factor VIIa Prothrombin complex concentrate (ex: Kcentra) Calcium (optimize ionized calcium ) Development of artificial oxygen carriers has had a long, tortuous, and difficult road. Baxter terminated the program of their HBOC (DCLHb; diaspirin cross-linked hemoglobin) after 20 years of development and substantial cost after a clinical trauma trial that resulted in higher mortality of the patients treated with HBOC than those not so treated11 and terminated the clinical program of the recombinant hemoglobin products (rHb1.1, Optro®; and rHb2.0) that had been developed by Somatogen.14–17 That trauma trial was the first to be approved under the provisions of 21CFR50.24,13 exception from informed consent, and thus produced considerable consternation. Earlier this year, Northfield Laboratories announced that it would “wind down its business operations”** after their large phase III clinical trial of its HBOC, PolyHeme®, in a setting of prehospital and initial 12 hours of hospitalization, administered to patients with major trauma failed to successfully achieve its dual primary end point of superiority/noninferiority of mortality (compared with expected mortality in a rural setting with longer transit times to hospital and availability of blood).12 Northfield Laboratories reported that this resulted in the FDA determining that the failure to “meet the prespecified primary efficacy end point” in the phase III clinical trial together with “the safety data of all controlled studies reveal that the administration of PolyHeme places the patients at a higher risk of significant adverse events,” and that “therefore, in the absence of clinical benefit, the risk:benefit assessment of the product in trauma is unfavorable.”† In a similar action, Biopure filed for bankruptcy protection on July 16, 2009‡ likely owing to their HBOC having been on prolonged “clinical hold” with no clear path for continued development, because of concerns by the FDA regarding the product's safety.§ The company's assets have been sold and, as of the date of this writing (July 30, 2009), there has been no announcement suggesting a continuation of the clinical program, although further attempts at development remain possible. Other HBOCs have had similar fates. For example, Hemosol (Mississauga, ON, Canada) halted clinical development of their HBOC, Hemolink®, because of a higher incidence of myocardial damage in patients given their HBOC than in those not given their HBOC in a phase III randomized trial of patients undergoing cardiopulmonary bypass for cardiac surgery.∥ Sangart continues to develop its HBOC, Hemospan®, in Europe for an apparently different indication(s).18

38 Hgb-based O2 Carriers (HBOCs)
HBOC-201 (hemoglobin glutamer-250 (bovine), Hemopure (Biopure Corporation)

39 HBOC-201, Hemopure Carries and off-loads oxygen
demonstrated efficacy in a variety of animal models does not require crossmatching stored at room temperature, up to 3 years. proof of efficacy in clinical trials has been less consistent limited intravascular half-life, generally <1 day challenging trial design (either continued therapy or replacement with erythrocytes) only postpones transfusion

40 Postpone vs. Eliminate Need?
RCT (single blind), multinational study Q: can HBOC-201 eliminate the need for PRBC transfusion in adults undergoing elective orthopedic surgery? 688 patients (mean age, 61) with hemoglobin concentrations <10.5 g/dL who required transfusions randomized: treatment with HBOC-201 or PRBCs. J Trauma 2008 Jun; 64:1484

41 The HBOC group had significantly higher rates of AEs
loading dose of 65 g of hemoglobin infused in 500 mL (equivalent to 1U PRBCs) additional doses were administered for up to 6 days to a maximum of 325 g (2500 mL) after which need for additional oxygen-carrying capacity was met by transfusion of PRBCs. subsequent transfusions, if at least one present: P ≥100 bpm, SBP <90 mm Hg, ECG evidence of myocardial ischemia, base deficit ≥4, acute blood loss >7 mL/kg within 2 hours, oliguria, and significant weakness or dizziness. Overall, 59% of patients in the HBOC group did not require PRBC transfusion. The HBOC group had significantly higher rates of AEs elevated blood pressure RR 8.5 vs. 5.9 per patient cardiac events and strokes; RR 0.34 vs per patient risk greatest in patients > 80 yo, had volume overload, and were undertreated J Trauma 2008 Jun; 64:1484

42 Non-surgical Patient? Mullon, et al. NEJM 2000; 342:

43 Because it is in its experimental stages, the drug is only available under investigational status through the FDA expanded access program to qualifying patients under specific circumstances. To use it, U.S. institutions must get approval from HbO2 Therapeutics, the local Human Safety Institutional Review Board, and the US Food & Drug Administration. The institution and the treating physician must follow a specific treatment protocol, and they must submit an Investigational New Drug form agreeing to physician accountability and use of the drug in accordance with the treatment protocol.

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46 Question 4 Your work day today includes seeing new admits to a rehab center. You see a 71 yo female with h/o ITP s/p prednisone in past. She was recently given IVIG as an inpatient with good response to her platelet count, now about 50K. PT and OT consulted and suggested rehab given ongoing steroid myopathy and general weakness from prior treatments. When you see her at rehab, she is icteric and Hgb is 5 and has dropped by 3 g/dL in last 24 hours. Platelets are about 40K and she has no active sign of bleeding. You arrange for transport to ED with plans for transfusion, but in ED she refuses a transfusion and is quite disagreeable. She says she is “done with blood products.” The ED calls you saying they don’t see the point of admission and plan to let her discharge AMA, unless rehab will take her back in this state. You state that she should still be admitted. You advise the ED to: Review the smear for shistocytes, this now looks more like TTP Send a G6PD Call the blood bank and see if they carry Hemopure Send a Coomb’s test and if positive: supportive management alone

47 71 yo F with h/o ITP in the past s/p prednisone in the past… you advise the ED to:

48 Outcomes of Protocol-Driven Care of Critically Ill Severely Anemic Patients for Whom Blood Transfusion Is Not an Option*. Shander, Aryeh; Javidroozi, Mazyar; MD, PhD; Gianatiempo, Carmine; Gandhi, Nisha; Lui, John; Califano, Frank; Kaufman, Margit; Naqvi, Sajjad; Syed, Faraz; Aregbeyen, Oshuare Critical Care Medicine. 44(6): , June 2016. DOI: /CCM Figure 2 . Mortality rates in propensity score-matched transfused and bloodless patients according to the lowest hemoglobin (Hb) level within first 24 hr of ICU admission (A) and lowest Hb level during ICU stay (B). In each column, the lower (light gray) part represents mortality during ICU stay and the upper (dark gray) part represents mortality occurring during hospital stay out of ICU. Numbers in parentheses are the total number of cases in each category. Star symbol indicates p < 0.5 comparing total mortality rate between the bloodless and transfused patients. Copyright © by 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. Published by Lippincott Williams & Wilkins, Inc. 2

49 For Your Next Ill Patient, Unable to Transfuse
Iron Dextran (Infed) 100mg IVP daily x 10 days (test dose for 1st timers) Or Iron sucrose (Venofer) 100mg IVP daily x 10 days Folic acid 1mg IVPB daily Vitamin C (ascorbic acid) 500mg po q12hours Vitamin B12 (Cyanocobalamin) 1000 mcg IM x 1 Hgb > 7 g/dL: Epoetin alfa (Procrit) 40,000U SubQ weekly Hgb 5-7 g/dL: Epoetin alfa 20,00U SubQ daily x 5 days if weekly corrected Reticulocyte count , 6%, then redose as 40,000U SC daily x 4 days Hgb < 5 g/dL: Epoetin alfa 20,000U IV q12 x 5 days if weekly corrected Reticulocyte count , 6%, then redose as 40,000U IV q12 x 5days

50 Other Practical Measures
Supplemental O2 Aggressive nutritional support Aggressive management of infection SCDs for DVT prophylaxis GI Stress ulcer prevention Monitor for tissue dysoxia: daily EKG, q4h Neuro checks, metabolic acidosis, progressive AKI despite euvolemia Consider decr oxygen utilization: strict bed rest, non-selective beta-blocker (e.g. propanolol) as tolerated Goal HR , keep euthermic (ex: active cooling) Reduce intrapulmonary shunt: HOB > 30 degrees, standing bronchodilator therapy, chest PT, IS Early intubation, sedation, ventilation with 100% O2

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