1
2	A03-35: Case History 83 year old man Chronic cholangitis with an acute exacerbation On coumadin for Atrial Fribrillation Given 1 unit of FFP to reverse a prolonged INR During transfusion, patient developed acute pulmonary edema. Died 6 hours later despite ventilation
3
4	A03-35: Lung 400x H & E CD15 (granulocyte)
5	A03-35: Antibody Evaluation Donor had a history of 6 pregnancies and 2 prior transfusions Antibodies Present: HLA Class I (PRA 74%) A2,9 (23,24),10 (25,26,34,66),28(68,69), B7,B17(57,58) HLA Class II (PRA 76%) DR2(15,16),12,17 Anti Neutrophil Abs HNA-3a (5b) Patients HLA type A32,68; B39,51; DRB1*01,11
6	FDA-reported Fatalities:
7	Why has the Transfusion Community not acted to prevent TRALI? No previous agreement on what constitutes TRALI Incidence and risk are poorly understood Continued debate over the etiology
8	Toward an understanding of transfusion-related acute lung injury:statement of a consensus panel Kleinman S, et al Transfusion 44, 1774 2004 Acute Lung Injury Hypoxemia Bilateral diffuse infiltrates on CXR Within 1-6 hours of Transfusion No evidence of circulatory overload No pre existing lung injury No temporal relationship to other causes of ALI A clinical diagnosis Majority resolve in 96 hours, 5 - 10% fatal
9	Incidence of TRALI: reviewed in Kleinman S, et al Transfusion 44, 1774 2004 Author FFP WB Plts RBCs Silliman (1990’s) 1:19,411 1:432 1:4,410 Popovsky (1980s) Kopko (2001-03) Quebec (2000-03) 1:61,006 1:9,306 1:58,279 SHOT (1996-02) 1:74,000 1:557,000 Wallis (1991-02) 1:7,896 Silliman (1990’s)
10	Transfusion-related acute lung injury and pulmonary edema in critically ill patients: a retrospective study. Rana et al. Transfusion 2006:46;1478 Consecutive pts at 4 intensive care units (ICUs) No respiratory support at the time of transfusion Identified with computer system that tracks the time of transfusion (6 hours) onset of noninvasive or invasive respiratory support. Experts blinded to specific transfusion factors categorized the cases of pulmonary edema as permeability edema (suspected or possible TRALI) or hydrostatic edema (TACO)
11	Transfusion-related acute lung injury and pulmonary edema in critically ill patients: a retrospective study. Rana et al. Transfusion 2006:46;1478 8,902 units transfused in 1,351 patients 94 required new respiratory support within 6 hours of transfusion. 49 patients with confirmed acute pulmonary edema experts identified 7 cases with suspected TRALI 17 patients with possible TRALI 25 cases with TACO The incidence of suspected TRALI 1 in 1,271 per unit transfused; Possible TRALI 1 in 534 per unit transfused; TACO 1 in 356 per unit transfused.
12
13	Etiology: Most experts agree that leukocyte antibodies in female donors exposed to fetal antigens in pregnancy are a major causative factor Anti-Granulocyte antibodies HLA Class I antibodies HLA Class II antibodies Bioactive response modifiers Final common pathway of granulocytes homing to the Lungs and causing plasma leakage into the alveolae, resulting in acute pulmonary edema
14	Why has the Transfusion Community not acted to prevent TRALI? Antibodies implicated in only 65-90% of cases Even antibodies that cause fatalities can be transfused without incident to most patients Leukocyte antibodies are common (10-20% of females donors) but TRALI is rare (~1:5,000) Exclusion policies would impact product availability
15	Strategies to Reduce TRALI Appropriate use of Blood products Selective use of Male products Donor history of transfusion or pregnancy Testing for HLA and HNA antibodies Others Pool & store platelets Platelet additive solutions Solvent detergent plasma
16	Serious Hazards of Transfusion UK (SHOT 2001-2) http://www.shotuk.org
17	The UK Solution: Based on 2001-2002 data showing FFP was involved in 60% of TRALI cases, the UK moved to predominantly male plasma in Oct 2003. No reports of TRALI due to plasma after Jan 2004. Now moved to resuspending platelet pools in male only plasma Data is strongly suggestive, but retrospective and the numbers are small. US is awaiting definitive data. SHOT 2005 data presented at ISBT and AABB in the Fall of 2006 further supported the efficacy of the use of predominantly male plasma.
18	"Transfusion-related acute lung injury surveillance..." Transfusion-related acute lung injury surveillance (2003-2005) and the potential impact of the selective use of plasma from male donors in the American Red Cross. Eder AF, Herron R, Strupp A, Dy B, Notari EP, Chambers LA, Dodd RY, Benjamin RJ. Transfusion 2007:47; 599-607
19	ARC suspected TRALI reports (2003-5)
20	Suspected TRALI Fatalities (2003-2005):
21	Independent Review of TRALI Fatalities:
22	Probable TRALI by Implicated Component:
23	Rate of Probable TRALI Fatality per 10⁶ Distributed Units
24	Plasma Production in the ARC System (2005)
25	Red Cross Pilot Program ARC instituted a pilot program to produce predominantly male plasma frozen within 24 hours (FP24) on October 1^st 2006. Program assessed the manufacturing issues, not the clinical efficacy Products were temporarily labeled with gender at collection and triaged on receipt at manufacturing. Process instituted as a business practice final product was not labeled customers were not notified used female AB plasma as needed.
26
27	Overview of Red Cross Approach FFP (<8 hrs), FP24 (<24 hrs), and Cryo Poor Plasma Selective use of male products achieving >95% male plasma distributions by November 2007 Longer term goal is 100% male plasma Leeway reserved to ensure availability Currently collect enough AB plasma to ensure 92% Male Will need to move to >80% FP24 (<24 hrs) FFP (<8 hours) will become a specialty product Final Product will not be labeled with Donor Gender Apheresis Plasma (Auto-C, excluding concurrent) Donor history + Testing (details still under evaluation) by November 2007 Apheresis Platelets and Concurrent Plasma Donor history + Testing (details still under evaluation) by November 2008
28	Overview: Impact on Customers
29	Impact on Customers
30
31	Effect of 24-hour whole blood storage on Plasma Clotting Factors:
32	Cofactors V and VIII after Endotoxin Administration to Human Volunteers
33	"Congenital Deficiencies" Congenital Deficiencies (~1%) Factors XI, V, X Not Factors VII, VIII, IX, vWF, XIII, Fibrinogen Therapeutic Plasma Exchange (~10%) TTP/HUS Multiple Factor Deficiencies (~90%) Consumption states, DIC, Massive transfusion Coumadin reversal (II, VII, IX & X, Protein C,S) Liver Failure
34	Proportion of Male Apheresis Donors
35	Issues Regarding Testing for Alloantibodies No FDA licensed assays for donor screening No suitable technology for routine Human Neutrophil Antibody (HNA) screening U.S. manufacturers are developing automated HLA class I and class II antibody screening technologies Uncertainties remain What is the appropriate screening strategy? How do we define a clinically relevant positive test? What is the appropriate donor deferral? Are product recalls and withdrawals appropriate?
36	Approach to Apheresis Products (in development) Prestorage pooled whole blood-derived platelets are being developed as an alternative We assume that we must test, though donor history may play a role REDS II LAPS alloantibody data needed to define who should screened What is the prevalence in untransfused males? If a significant proportion of untransfused males harbor antibodies, will this necessitate universal testing? What is the incremental prevalence with transfusion? What is the incremental prevalence with pregnancy?
37	Summary Prudent measures to reduce patient exposure to alloantibodies in plasma products may markedly reduce the risk of TRALI. Availability issues with AB plasma argue against product gender labeling and the use of 100% male only products. Plasma frozen within 24 hours will become the product of choice for most indications Appropriate use of plasma products remains the most important safeguard against adverse reactions, including TRALI