Transfusion Medicine Residency Program Cases and Chapters Blood Conservation Dr. D.K. Towns June 18, 2009

Outline 1.Guideline Driven Blood Product Use 2. Pharmaceutical Preparations a) Desmopressin (DDAVP) b) Anti-fibrinolytics i) Aprotinin ii) Lysine analogues (Tranexamic acid, e-Aminocaproic acid) c) Recombinant Factor FVIIa (rFVIIa) d) Topical hemostatic agents ex. fibrin sealant e) Erythropoietin (EPO) f) Iron g) Anticoagulation reversal

Outline (continued) 3. Autologous a) Pre-operative deposit b) Cell salvage i) intraoperative ii) postoperative c) Acute Normovolemic Hemodilution 4. Multi-Disciplinary Approach to Blood Management a) Preoperative b) Intraoperative i) Surgical ii) Anesthetic c) Postoperative

Outline (continued) 6. Blood "Substitutes" a) Perfluorochemicals b) Hemoglobin based oxygen carriers (HBOC's) c) Liposome-encapsulated hemoglobin 7. Case presentations

1. Guideline Driven Blood Product Use Creating transfusion criteria decreases the likelihood of transfusion Should be created by a multidisciplinary team based on evidence Evidence is key Audit before and after implementation

2. Pharmaceutical Preparations a) Desmopression (DDAVP) -increases circulating levels of FVIII and VWF -a Cochrane review of adult elective surgery without bleeding disorders concluded that it doesn't decrease RBC loss, risk of allogeneic transfusion, volume of RBC transfused, or mortality -it is associated with 2-4 x increased risk of myocardial infarction in cardiac surgery patients -bottom line - its use should be restricted to the management of patients with Hemophilia A and von Willebrand's Disease

b) Antifibrinolytics i) Aprotinin -direct inhibitor of plasmin (a fibrinolytic enzyme) -anaphylaxis possible, especially with repeat doses -decreases the need for allogeneic blood transfusion, bleeding, and re-exploration in cardiac surgery -not extensively studied in non-cardiac surgery -several meta-analyses have shown favourable outcomes in reducing mortality, risk of stroke, and need for repeat surgery in massive bleeding -observational study in 2007 (Mangano, NEJM) reported that aprotinin use was associated with 2x risk of renal failure in cardiac surgery, and, 55% increase in the risk of MI or heart failure, and 181% increase in the risk of stroke or encephalopathy

ii) Lysine analogues - Tranexamic acid - Cyklokapron (+ e-Aminocaproic acid - Amicar) -bind to plasminogen and inhibit its finding to fibrin, thus impairing fibrinolysis -appear to show less safety concerns but contraindicated if patient is at risk of thrombosis -fewer randomized trials than with Aprotinin cheaper than Aprotinin

Most recently, the Blood Conservation using Antifibrinolytics in a Randomized Trial Investigators (Fergusson, Hebert, Mazer - NEJM 2008) published the findings of their multi- centre RCT of aprotinin and lysibne analogues in high risk cardiac surgery The study was terminated because of a strong and consistent negative mortality trend associated with aprotinin as compared with lysine analogues November, 2007 Bayer and Nordic Pharma suspended global marketing of aprotinin Brown et al (Circulation 2007) published a meta-analysis of randomized trials which confirmed the effectiveness in decreasing blood loss and transfusion, but suggested no significant risks or benefits for mortality, stroke, MI; (it did suggest an association of aprotinin and risk of renal dysfunction)

c) Recombinant factor VIIa Binds to tissue factor at the site of tissue injury and vascular wall disruption, generating thrombin and activating platelets rFVIIa acts on the platelet surface, which generates a thrombin burst, leading to the conversion of fibrinogen to fibrin As well, rFVIIa results in clot stabilization by inhibition of fibrinolysis

Major indication is perioperative prophylaxis and treatment of bleeding episodes in hemophiliac patients with inhibitors against factors VIII and IX, and for patients with acquired hemophilia, coagulation VII deficiency, and Glanzmann's thrombasthenia “Off-label" use has increased in patients with severe acquired coagulopathy and uncontrollable nonsurgical bleeding associated with surgery and trauma Concerns about intravascular thrombosis leading to increased morbidity and mortality A recent systematic review (Ranucci et al, Arch Surg 2008) found that it was effective in decreasing blood transfusion (in major blood loss surgery) with no major safety concerns Awaiting publication of recent RCT's It is expensive

d) Topical Hemostatic agents - ex. fibrin sealant (Tisseel) Fibrin sealant - combination of thrombin and fibrinogen mixed with calcium to form fibrin commercially available, or, can be produced from autologous plasma

e) Erythropoietin Primary regulator of the production of RBC's by stimulating erythryopoiesis with hypoxia being its major stimulus Used to replenish RBC volume in patients undergoing preop autologous donation, or in patients with refractory anemia Effect is rapid (2-3 days) Equivalent of one unit of blood is seen in 7 days, although 2-4 weeks is necessary for adequate erythropoiesis to occur Adverse events include thrombotic events, hypertension, seizures, and rare cases of red cell aplasia Patients benefited the most had a hemoglobin below 13.5 g/dL Iron supplementation maximizes its benefit Used in combination with other blood conservation strategies

f) Iron Iron deficiency anemia should ideally be corrected prior to elective surgery Iron therapy is not beneficial in non-iron deficient patients without corresponding use of EPO

g) Anticoagulation reversal Patient factors should be taken into considered when discontinuing, or modifying anticoagulation Warfarin - Vitamin K (Octaplex in setting of blood conservation, if emergency surgery) Heparin - Protamine ASA - discontinue 2 days prior to surgery (7 days preferable) Plavix - discontinue 5 days prior to surgery (7 days preferable) Other NSAIDS - discontinue "5 half-lives" prior to surgery

3. Autologous i) Pre-operative deposit Not for all surgeries - should have at least a 10% chance of requiring blood Not all patients are eligible Optimal timing is days prior to surgery, 1 week apart, therefore maximum 3-4 units ? epo/iron 50% wastage rate; usage markedly declining in Canada, and worldwide Reduction in likelihood of allogeneic transfusion, but increased likelihood of any transfusion

ii) Cell Salvage Usually contraindicated if risk that blood may be contaminated (infection, tumour, topical disinfectants) Induce some degree of mechanical injury to the red cells Intra-operative –cardiac surgery has largest average number of units recovered

Two types of devices: –Simpler, less expensive, canister type - blood is anti-coagulated and aspirated using a vacuum supply into a disposable liner bag with a filter –Blood can be concentrated and washed in the blood bank or directly re-infused –Potential for inflammatory "soup" + particulate matter to be transfused - although few untoward consequences (?coagulion abnormalities) –Not useful for large volumes Automated -Centrifuge assisted semi-continuous flow; requires technical expertise; -Anticoagulates, washes, and concentrates the red cells before re-infusion Postoperative -Several devices are available -Red cells should be washed prior to re-infusion and infused through a microaggregate filter within 6 hr of starting the procedure

iii) Acute Normovolemic Hemodilution Removal of whole blood from the patient immediately before surgery along with simultaneously of crystalloid or colloid Collected in standard blood bags containing citrate anticoagulant Target hematocrit is about V = EBC x initial Hct - desired Hct average Hct Rationale - blood loss occurs at a lower hematocrit Contraindications - significant coronary, pulmonary, renal, or liver disease, infection Efficacy is dubious

CSA Standards Z Blood and Blood Components 12.5 Perioperative collection (pages 57, 58) (includes intraoperative + postoperative cell salvage and ANH) "The blood centre or transfusion service should be involved in the development of the policies and procedures used in the management of the perioperative blood recovery program."

4. Multi-disciplinary Approach Pre-op - maximize patient's hemoglobin - correct impaired hemostasis - nutritional status Intra-op - Anesthetic controlled hypotension (minimal benefit shown; risk of end organ ischemia) regional anesthetic techniques normothermia (?benefit) - Surgical careful ligation of blood vessels, and other "good surgical technique" laparascopic techniques optimize cautery topical thrombogenic agents as appropriate Post-op - minimize blood draw - worst in ICU, and with arterial line in place

5. Blood Substitutes Red Cell Substitutes - usually refer to oxygen carrying solutions that can both expand the blood volume and oxygenate tissues

Wish list for "ideal" substitute is long … –small molecule –delivers O 2 efficiently –universal compatibility –sterilized –no risk of disease transmission –no immunosuppressive effects, or interaction with the immune system –maintenance of arterial blood pressure and pH –abundant supply –long shelf-life at room temp –reconstitutes easily –cost-effective –no toxicity –ease of administration –no interference with capillary circulation –ability to access all areas of the body including ischemic tissue –in vivo half-life similar to the red blood cell –rapid metabolization and elimination in vivo

3 general classes 1)Perfluorochemicals 2)Hemoglobin-based oxygen carriers (HBOC's) 3) Liposome encapsulated hemoglobin

6. Case Presentations Case #1 14 year old female, 50 kg, otherwise healthy, for anterior/posterior correction of idiopathic scoliosis. What intra-operative modalities would you consider to decrease transfusion? What postoperative therapies would you consider?

How would you investigate this patient’s anemia? How would you treat? What is your target? (Assuming iron deficiency, or mixed iron deficiency/ACD): –Oral iron: How much? What kind? How long to effect? How do you deal with side effects? –IV iron: Who’s a candidate? How much? How often? How long to effect? EPO? Who’s a candidate? How much? How often? What do you tell patients about the potential for adverse effects? Case #2 84 year old woman for revision hip arthroplasty, seen pre- op for Hb 100.

Assume we’ve decided to do just one knee – How does management of this patient differ from others? An opportunity to discuss accepted vs. unaccepted modalities in these patients. Case #3 Jehovah’s Witness patient for bilateral total knee arthroplasty. Management?

How do you treat this patient? Essentially it was an epo/iv fe resuscitation – I could probably scare up more details on this case if you like. Case #4 Or (one of our recent cases here): JW waiting to have primary knee arthroplasty done, sprouted a GI bleed and was admitted to hospital with Hb 56.

Management? No family members who were In-B negative. One unit of autologous blood donated – I can’t remember when in the pregnancy it was donated, but it was definitely frozen. So maybe combine this case with something like a placenta previa – then discuss autologous in pregnancy and issues of timing, as well as the use of cell saver during c-section. Case #5 Obstetrics! We recently had a case of a pregnant woman with an Anti-InB (high-incidence antigen) – no risk to baby but potential risk of hemolytic reaction if antigen positive blood transfused.

Case #6 67 year old male, JW. Admitted to ER with rectal bleeding. CBC shows Hgb 57, WBC 0.7 and plt 9. Bone marrow aspirate and biopsy consistent with aplastic anemia.