Use of Blood Components In Transfusion Therapy John B. Nobiletti, M.D., Ph.D.

Objective is to provide physicians using transfusion therapy current information on: Indications, contraindications and guidelines for the most commonly used blood components Risk vs. benefit considerations for transfusion therapy Steps taken by the blood center for patient safety with respect to donor selection, collection, processing and testing of blood components

I. Risks vs. Benefits of Transfusion Therapy

Risks vs Benefits of Transfusion Therapy Your decision to or not to transfuse your patient should be based on good clinical judgment after considering both the patient’s clinical status and laboratory data Transfusion therapy involves risks associated with the use of a biological product of human origin such as transfusion transmitted infectious disease as well as an acute or delayed transfusion reaction and possible difficulty finding compatible red cells or platelets for future transfusions Under transfusion is just as bad as over transfusion

Risk of Transfusion Transmitted Infectious Disease Known diseases screened for by both laboratory testing and donor health history (HIV, HBV, WNV, HCV, syphilis, Chagas disease) Risk of a window period donation Known diseases screened for only by donor health history (malaria, gonorrhea, Babesiosis) Risk of diseases with no history questions / testing Risk of unknown infectious diseases in the blood supply such as HIV in the 1980’s

Infectious Disease Risk Based on mathematical models / actual experience is much better than that predicted by the models HIV = 1 in 1.5 million transfusions HCV = 1 in 1.1 million transfusions HBV = 1 in 1 million transfusions Improvement in established serological testing as well as the development and implementation of molecular testing

Transfusion Reactions Risk of acute transfusion reactions that vary in severity from mild, non-life threatening (febrile non-hemolytic, mild allergic) to those that can be fatal (hemolytic, septic, TRALI or anaphylatic) as well as volume overload Also delayed hemolytic

Problems With Future Transfusions Possibility of your patient making an antibody that would make finding compatible red cells or platelets difficult for future transfusions

II. Blood Center Steps For Patient Safety All stages of collection, processing, infectious disease testing, and storage have protocols that must be strictly followed with monitoring and regulatory control Donor health history Infectious disease testing with the implementation of Nucleic Acid Testing: HIV HCV HBV WNV Continuously upgrading testing technologies to address known agents and adding new tests to address new infectious disease threats

Additional Steps For Safety Universal pre-storage leukocyte reduction: leukoreduction by the blood center of all donations during or shortly after collection – highly efficient process vs bedside filtration – reduces risk of febrile non-hemolytic transfusion reactions, alloimmunization, CMV transmission Predominately male plasma to reduce risk of transfusion related acute lung injury (TRALI) Bacterial culturing of platelets to reduce risk of bacterial contamination / septic reactions

III. Blood Component Transfusion

Component Therapy One of the basic principles of Transfusion Medicine Whole blood is fractionated into its components (red cells, platelets, plasma and leukocytes) The patient is transfused with only the component that is needed Results in increased patient safety and improved inventory management

Circular of Information “Product Insert” for blood components Good source of basic information on transfusion practice Contains information on the administration of blood components and potential complications of transfusion therapy Also provides a detailed discussion of each component including indications / contraindications and component modifications that are available for unique clinical situations

ARC Compendium Of Transfusion Practice Guidelines Another excellent source of information on transfusion therapy Application can be downloaded at no charge from http://www.redcross.org/mobile-apps/transfusion-practice-guidelines-app Also hard copies available at no charge through your blood bank

Transfusion Therapy – General Concepts Indications are generally accepted reasons for transfusion (i.e., red cell transfusion to correct symptomatic anemia) Guidelines are parameters set by your transfusion committee and are used as audit criteria (i.e., red cell transfusions in patient with a Hb above a particular level are reviewed by the transfusion committee to determine if the transfusion was appropriate)

Transfusion Therapy - General Concepts (continued) However, you can transfuse you patients outside the guidelines, if clinically indicated Be sure to follow all transfusion protocols with respect to obtaining the pre-transfusion specimen, administration of the component, management of the patient during and following the transfusion and management of transfusion reactions Join or work with your transfusion committee to establish guidelines and protocols to ensure that your clinical needs are met

Transfusion Therapy - General Concepts (continued) Transfusion Medicine is a changing field with new products becoming available or changing indications for current products – therefore your decisions concerning transfusion therapy should be based on the current standards Also, unique clinical situations may require unique applications of transfusion therapy ARC physicians are available to support you and your transfusion service

IV. Blood Components

1. Red Cells

Adsol Preserved Red Cells 300-400mL of red cells in Adsol with a HCT of 55 – 65% Adsol is a solution containing salts, sugars and adenine that preserves red cell viability and allows a shelf life of 42 days 1 unit of Adsol red cells raises the hematocrit by approximately 3 percentage points and the hemoglobin by approximately 1 gm/dL depending on the clinical situation

Red Cell Indications / Contraindications - treatment of the symptomatic deficit of oxygen carrying capacity - exchange transfusions Contraindications - asymptomatic anemia that can be corrected by pharmacological means - used to increase blood pressure or volume only

Red Cell: Typical Transfusion Guidelines Guidelines: - Hb less than 8 gm/dL, not due to chronic anemia - symptomatic anemia - significant and symptomatic acute blood loss - exchange transfusion

Universal Donor (O Rh negative) Red Cells Valuable resource to be used appropriately – only 8% of the population is O Rh negative which can limit availability Needed to meet needs of both O Rh negative patients as well as patients needing emergency transfusion when their ABO and Rh status have not yet been determined by the lab

Rh Status: Rh Antigen System vs D Antigen Rh antigen system has multiple antigens including the “D” antigen Rh status usually refers to presence or absence of the D antigen on red cell: 85% are Rh positive, that is, express the D antigen while 15% are Rh negative, that is, do not express the D antigen

Universal Donor Red Cells Universal red cell donor is O Rh negative blood group “O” can be given to patients regardless of their ABO group Using Rh (D) negative red cells prevents formation of antibodies against the D antigen in an Rh negative patient and prevents a hemolytic reaction to the D antigen in a patient with anti-D

Emergency Use of O negative Red Cells Use of O negative red cells still has risk of a hemolytic reaction if the patient has unexpected red cell antibodies against other red cell antigens – D antigen is one of hundreds of antigens on red cells Emergency transfusion: immediately provide the blood bank with a pre-transfusion specimen for typing and screening and be prepared to switch once the blood type has been determined

Autologous Red Cells Patient must be able to both safely donate and receive their red cells Autologous donations may be appropriate for patients who: 1) are hard to match and require rare blood (consider blood relatives but not all blood relatives are suitable donors) or 2) have a strong psychological aversion to receiving red cells from the blood supply ARC physician is available for consultation

2. Platelets

Available Platelet Products Apheresis platelets units are collected from a single donor and have the advantages of giving your patient 1 donor exposure per platelet transfusion as well as the ability to specifically match your patient’s HLA or platelet antigens Pooled platelets consist of a pool of usually 6 platelet concentrates obtained from 6 whole blood donations and can not be matched to your patient Platelet dose: one apheresis unit or 1 platelet pool

Platelet: Indications and Contraindications Indications: - treatment of bleeding secondary to thrombocytopenia or platelet dysfunction - patients on anti-platelet medications with a risk of bleeding due to pending procedure or surgery - prophylactic platelet transfusions for rapidly falling or low platelet counts Contraindications: - TTP or ITP or HIT unless life threatening bleeding – consult a hematologist - bleeding NOT secondary to thrombocytopenia or platelet dysfunction

Platelets: Typical Guidelines Guidelines: - platelet count less than 10,000/uL NO ITP or TTP or HIT - platelet count less than 20,000/uL with fever, sepsis, coagulopathy, other hemostatic defect or falling platelet count NO ITP or TTP or HIT - platelet less than 50,000/uL with bleeding or a planned invasive procedure - platelet less than 100,000/uL with life threatening bleeding - Pt on anti-platelet meds, if clinically necessary

Platelets (continued) Dose: one apheresis platelet bag or one platelet pool both of which contain greater than 3.0 X 1011 platelets in approximately 250mL of plasma Patients that are bleeding or are on platelet aggregation inhibitors may require multiple doses

Expected Response to Platelet Transfusion One platelet dose should increase the patient’s platelet count by 30,000 to 50,000 CCI or corrected count increment is a mathematical formula used to assess a patient’s response to platelet transfusion and is based on a platelet count drawn at 10 minutes to one hour following transfusion CCI should be greater than 7,500 with a sample drawn at 10 minutes to one hour post transfusion and above 4,500 at 24 hours post transfusion

Refractoriness to Platelet Transfusion Failure to achieve a CCI of 7,500 at 10 minutes to one hour or maintain platelets at 24 hours Can have many causes, both immunological and non-immunological Immunological: patient antibodies against HLA Class I antigens or platelet antigens on the donor platelets Non-immunological include: splenomegally, DIC, medications, fever, continued bleeding, sepsis

Management of Refractoriness Be sure to get platelet counts at both the 10 minute to 1 hour time period as well as at 24 hours following the transfusion Low CCI with the 10 minute to 1 hour post transfusion sample is c/w immunological cause Expected CCI with the 10 minute to 1 hour sample and low CCI at 24 hours is c/w other, non-immunological causes ARC physician and laboratory can help diagnose cause and provide matched platelets, if necessary

3. Plasma

Available Plasma Products Approximately 250mL of plasma frozen to -18o C within either 8 hours (FFP) or 24 hours of collection (FP 24) Freezing to preserve plasma protein activity Plasma transfusion therapy is aimed at replacing or increasing the levels of an absent or deficient coagulation factor or other plasma protein

Plasma: Indications Patients who are actively bleeding or at risk of bleeding (i.e., preoperative patients) and require the replacement of multiple coagulations factors Massive transfusion protocol Coumadin reversal, as per hospital protocol Plasma exchange for TTP or HUS patients Treatment of patient with specific coagulation factor deficiencies or specific plasma protein deficiencies for which factor concentrates or protein preparations are not available

Plasma: Contraindications When alternatives such as specific factor concentrates or pharmacological therapy are available or the factor deficiency can be treated more effectively with cryoprecipitate Volume replacement only or as a source of nutrition or albumin Mildly prolonged PT and or PTT in the absence of bleeding FP 24 should not be used when specific Factor V or Factor VIII replacement is needed as these factors may be reduced as compared to FFP

Plasma: Typical Guidelines And Dose Bleeding, risk of bleeding or planned invasive procedure with PT increased 1.5 over the mid-point of the normal range and/or PTT greater than 1.5 X the normal upper limit and/or factor assay less than 25% of normal Rapid reversal of coumadin Dose is generally 10 to 20 mL per kg Plasma exchange for TTP or HUS

4. Cryoprecipitate

Cryoprecipitate Preparation Prepared from thawed Fresh Frozen Plasma (FFP) Contains coagulation Factors VIII and XIII, fibrinogen, von Willebrand factor and fibronectin

Cryoprecipitate: Indications Source of fibrinogen for patients with hypo-fibrinogenemia (less than 100 mg/dL) or dysfibrinogenemia – 1 bag per 10kg body weight should raise fibrinogen by 50mg/dL in the absence of bleeding or consumption Fibrin sealant Uremic bleeding – DDAVP or desmopressin (1 desamino 8 D arginine vasopressin) is preferred over cryo-precipitate Factor XIII deficiency – bleeding or prophylaxis (virus inactivated Factor XIII concentrates are preferred but may not be readily available)

Cryoprecipitate: Contraindications Hemophilia A and von Willebrand Disease: second line therapy for these diseases and should only be used if the appropriate factor concentrates are not available – DDAVP can also be used to treat vonWillebrand Disease (preferred for Type I, contraindicated for Type IIb and not effective for Type III)

Cryoprecipitate: Typical Guidelines Confirm that cryoprecipitate is indicated by reviewing laboratory data and medical history Consider DDAVP first for uremia, mild to moderate Hemophilia A and von Willebrand Disease (DDAVP is contraindicated for Type IIb and not useful for Type III von Willebrand Disease) Consider factor concentrates before cryoprecipitate for Hemophilia A and von Willebrand Disease

Cryoprecipitate: Dose Calculations for fibrinogen and Factor VIII are based on 80 IU Factor VIII and 150mg fibrinogen per bag von Willebrand Disease: clinical response Fibrin glue: usually 1 or 2 bags

Conclusion Be sure that your patient has the appropriate indications and that you have considered the risk vs. benefit when you make the decision to transfuse your patient – also be sure to follow your local guidelines and protocols Transfusion Medicine is a changing field with new products becoming available or new indications for current products – your decision to or not to transfuse should be based on the current standards ARC physician available for consultation