1. Boonthorn 6 November 2009 Anaphylactic transfusion reaction

2. Case ผู้ป่วยหญิงไทยคู่อายุ 66 ปี CC: เหนื่อยเพลีย 2 สัปดาห์ PI: 3 สัปดาห์ก่อนมาร.พ. ถ่ายดำ ครั้งละครึ่งแก้ว 3 วันติดกัน จุกลิ้นปี่ หน้ามืด ล้มลงไป admit รพช.ที่ สงขลาได้แต่น้ำเกลือ ไม่ได้เลือดและยากลับบ้าน 2 สัปดาห์ ก่อนมาร.พ. เหนื่อยมากขึ้น หน้ามืดเวลาเปลี่ยนท่า มีคนทักว่าซีด ญาติจึงพามา ร.พ. จุฬา PH:Atrial fibrillation on warfarinปี 2545 , Hx of gastritis,gouty arthritis on colchicine,herbal medicine 20 d ,Hx of blood transfusion 20yrs.ago (due to TAH operation ,no complication) ปฏิเสธประวัติแพ้ยาหรืออาหาร

3. Physical examination PE: BP 100/70, PR 70 irreg Skin : no ecchymosis HEENT: moderately pale ,not icterus ,no mucosal bleed Heart:increase S 2 ,PSM gr IV at LLPSB , totally irreg Lung: normal breath sound , no adventitious sound Abd: liver 1 FB below RCM Ext.: no edema , no ecchymosis PR : no melena

4. Lab (22/09) Hct 20% wbc 6890 Plt 356,000 N52 L29 E10 PT 17.9 INR 1.6 PTT 27.9 BUN 48 Cr 2.1 uric 11 TB 0.45 DB 0.19 AST 14 ALT 9 ALP 74 UA : normal CXR : cardiomegaly EKG : atrial fibrillation Echo : moderate pulmonary HT,severe TR

5. Hospital course 1.acute anemia R/O internal organ bleeding EGD : clean based ulcer LP –PRC transfusion Off warfarin 2. acute renal failure Hydration Urine ออกดี Cr ลดลงเหลือ 1.3 คิดถึง pre renal azothemia

6. Hospital course

7. Hospital course Serum tryptase =? Repeat G/M => no mismatch Coombs’ test : negative IgA level= 311 ( 70 -400 ) จอง single donor PRC 1 uไว้ เนื่องจาก Hct stable ,ผ.ป.ไม่อยากได้ blood transfusion อีก จึงให้เป็น Fe replacement และ D/C ได้ สรุปผู้ป่วยรายนี้ underlying AF on warfarinมาด้วย bleeding GU with post hemorrhagic anemiaand prerenalazothemiaเกิดปัญหา Acute transfusion reaction ใน ward

8. Acute transfusion reaction Epidemiology Type of reaction Cause of anaphylactic transfusion reaction Management of IgA anaphylactic transfusion reaction

9. 7.9 5.1 0.2 Cumulative numbers of cases reviewed by SHOT, the UK hemovigilance system 1996-2007 (n = 4335) (Before 2006 the HTR category was referred to as delayed transfusion reactions.) ATR, acute transfusion reactions; HTR, hemolytic transfusion reaction; IBCT, incorrect blood component; PTP, post-transfusion purpura; TA-GVHD, transfusion-associated graft-versus-host disease; TRALI, transfusion-related acute lung injury; TTI, transfusion-transmitted infection Transfusion alternatives in transfusion medicine 2008

10. Transfusion Medicine Reviews ,vol 20,No4,2006:273-82

11. Acute transfusion reactions in the pediatric intensive care unit Transfusion.vol. 46 ,nov 20006.

13. Allergic transfusion reaction Allergic transfusion reactions are reported to complicate ~1- 3% of all blood transfusions.1 Severe allergic reactions ( anaphylactic shock ) incidence of 1 per 20 000 to 47 000 units of blood and components.1 Retrospective review 9 yrs.period (Cleveland) allergic reactions 273/1613 adverse reactions (17%). 2 151 male and 122 female patients. (1.2:1) 14 (5.1%) allergic reactions associated with temperature increase of 1ºC or greater 26 (9.5%) not have skin manifestations Transfusion Reactions. 2nd ed. Bethesda, Md: AABB Press; 2001:83–127. arch Patho Lab med vol 127,March 2003

14. arch Patho Lab med vol 127,March 2003

15. Severe allergic reactions 21/273 patients (7.7% of allergic reaction). Overall incidence 21/1613 (1.3% of all transfusion reaction) reactions : anaphylaxis or anaphylactoid signs and symptoms and/or hypotension or decrease in oxygen saturation. 14 males and 7 females red blood cell transfusions(33.3%) platelet or FFP transfusions (66.7%) 9pts. (42.9%) associated hypotension. arch Patho Lab med vol 127,March 2003

16. 9-year study period1,125,846 blood component transfusion arch Patho Lab med vol 127,March 2003

17. Acute transfusion reaction Transfusion alternatives in tranfusion medicine 2008

18. Acute transfusion reaction Transfusion alternatives in tranfusion medicine 2008

19. Acute transfusion reaction Transfusion alternatives in tranfusion medicine 2008

20. Acute transfusion reaction Transfusion alternatives in tranfusion medicine 2008

21. Possible Mechanisms Producing Allergic Transfusion Reactions Preexisting IgE or IgGAb in recipient reacts with allergens or proteins in transfused blood (eg, drugs or chemicals [ethylene oxide, plastics]). Class- or subclass-specific anti-IgAAb in recipient reacts against IgA in transfused blood. Preexisting IgG or IgE in recipient that reacts against allotypic serum protein forms in transfused blood (eg, albumin, haptoglobin, and complement component). Passive transfer of IgE antibodies from donor to the recipient. Transfusion of complement-derived anaphylatoxins (C3a and C5a) produced during blood storage. Transfusion of cytokines, bradykinin, histamine, or other biological mediators produced during blood storage. arch Patho Lab med vol 127,March 2003

22. IgA anaphylactic transfusion reaction Incidence : no reliable estimate ( nonstandardized diagnostic criteria, lack of laboratory based F/U for severe allergic transfusion reaction) occur in 1 in 20,000 to 47,000 transfusions3 patients with a history of anaphylactic transfusion reactions, anti-IgA was detected in only 65 of 359 (18%) of patients2 Screened 32,376 healthy blood donors for registry of IgA-deficient donors, 1 in 1200 donors was found to be IgA-deficient (<0.05 mg/dL) with anti-IgA (PHA)1 at least 40 published case reports and numerous unpublished observations of severe IgA anaphylactic or anaphylactoid reactions in transfusion recipients. >75 % of the case reports of IgA anaphylactic transfusion reactions were published before 1985 when TRALI was first recognized 1.Blood 1994;84:2031-5. 2.Current Opinion in Hematology 2003, 10:419–423 3. Transfus Med Rev. 1995 Jan;9(1):1-8

23. Diagnosis of IgA deficiency in managinganaphylactic transfusion reactions diagnosis : show IgA-antibody in patient's serum Anti-IgA and anaphylactic transfusion reactions first described by Vyaset al. in 1968 AABB Press textbook on transfusion reactions :“when pt. experience anaphylactic or severe anaphylactoid transfusion reaction for first time, pretransfusion serum must be screened for anti-IgA” and “If an anti-IgA is detected, a lifelong commitment to transfusion with only IgA-deficient blood components is made” Current Opinion in Hematology 2003, 10:419–423

24. Vyaset al. :Two groups of patients with anti-IgA class specific suffered severe anaphylactic reactions No detectable serum IgA very high titers of anti-IgA reacted with all IgAparaprotein-coated red blood cells limited specificity generally multiple transfused patients only suffered urticaria or other milder reactions to blood products detectable levels of serum IgA low titers of anti-IgA Reacted with only some IgAparaprotein coats and not others Current Opinion in Hematology 2003, 10:419–423

25. prevalence of IgA deficiency in north India. Methods: A sensitive enzyme linked immunosorbent assay developed in-house was used to detect IgA deficiency in a total of 3818 blood donors. Complete IgA deficiency was defined as value less than 5 mg/dl whereas partial IgA deficiency was defined as value between 5-30 mg/dl. Results: Of the 3818 blood donors screened, 3640 (95.3%) were males with a mean age of 31.2 yr. No donor was found to have complete IgA deficiency; however, 257 (6.7%) had partial IgA deficiency INDIAN J MED RES, MAY 2006

26. IgA DEFICIENCY Relative IgA deficiency plasma IgA concentration less than lab’s reference range (<5 mg/dL in most laboratories) occurs in 1:500 individuals may experience symptoms of immune deficiency absolute IgA deficiency (<0.05 mg/dL) may form class-specific alloanti-IgA,presumably, IgE anti-IgA. Such persons are at risk of an anti-IgA-mediated transfusion reaction (IgA anaphylaxis). Persons with normal or decreased concentrations of plasma IgA have been reported to have had adverse transfusion reactions attributed to subclass-specific anti-IgA1 or -IgA2. These are rare and unconfirmed events. IgA anaphylaxis has been reported to occur after the recipient’s first blood transfusion TRANSFUSION 2006;46:10-13.

27. American Red Cross National Reference Laboratory. Of 359 serum samples referred between 1978 and 1995 from patients with suspected diagnoses of IgA anaphylactic transfusion reactions, only 17.5 percent contained an IgA antibody of any serologic specificity TRANSFUSION Volume 46, January 2006

28. How I manage patients suspected of having had an IgA anaphylactic transfusion reaction Testing for anti-IgA is available in a few lab supplies of frozen IgA-deficient plasma are limited TRANSFUSION Volume 46, January 2006

29. APPROACH 1. Patients who just had an anaphylactic or anaphylactoid reaction, which is being reported to the transfusion service with the question “What do we do now?” and the statement “I need to transfuse this patient.” TRANSFUSION Volume 46, January 2006

30. presence of any IgA R/O absolute IgA deficiency, for practical purposes, excludes likelihood of anti-IgA-mediated anaphylactic reaction Careful, controlled, and monitored transfusions may be resumed. plasma IgA content cannot be performed or the result suggests a decreased, but not absolute deficiency of IgA 1) careful, controlled, and monitored transfusion with standard blood components (leukoreducedPlt& Rbc component , S/D-treated plasma) 2) transfusions of washed red blood cells (RBCs) or platelet (PLT) components (5washed step,decreasealb&Ig>95%); or 3)attempting to obtain blood components from known IgA deficient donors (reserved for high clinical suspicion of severe reactions and require additional time ) TRANSFUSION Volume 46, January 2006

31. 2. Pts. have PH of severe anaphylactic reaction, but no laboratory F/U or clinical Dx not known. As above, Dx of IgA deficiency being considered, but need for transfusions not urgent. test for plasma IgA concentration should be performed If presence of any IgA, person cannot form class-specific alloanti-IgA and IgA anaphylactic transfusion reaction is excluded. if Hx and/or lab report of IgA deficiency support Dx of IgA anaphylactic reaction, although unconfirmed by result of anti-IgA Recommended => wash RBC and PLT components or locate components from IgA deficient donor. TRANSFUSION Volume 46, January 2006

32. 3. Patients with Hx of severe anaphylactic transfusion reaction and laboratory-confirmed diagnosis of IgA deficiency. safest option is transfusing IgA deficient blood components (IgA<0.05 mg/dL) whenever transfusions are not urgent IVIG administered with IgA-depleted products (<1.2 μg/mL) TRANSFUSION Volume 46, January 2006

33. A new strategy for prevention of IgA anaphylactic transfusion reactions A 40-year-old man with CVID had previous Hx of anaphylaxis after IM Ig . His serum contained anti-IgA, and he required Ig for recurrent infections administration of IVIgG containing < 0.1 mg/ mLIgA led to anaphylactic reaction after transfusion of only 2-3 mL. same IVIgG charge was pretreated with freshly separated autologous plasma and given to pt. on three consecutive days without any reaction (1.25, 10, and 10 g each in 400 mL plasma). Anti-IgA activity did not increase, and pt. was treated again without complications Ex vivo pretreatment of IVIgG preparations with autologous plasma appears to be safe and useful in management of pts. with clinically significant anti-IgA. To achieve a significant IgA blockage, preparation to be used should not contain large amounts of IgA TRANSFUSION 2004;44:509-511

34. TRANSFUSION 2004;44:509-511

35. Haptoglobin Plasma glycoprotein , binding free Hb , chain , HP1 and HP2 alleles Asymptomatic haptoglobin deficiency 1 in 9771 healthy japanese donor1 Japanese pt. suffer from anaphylactic transfusion reactions => congenital haptoglobin deficiency associated with haptoglobin Ab2 1. SeibutsuButsuri Kagaku 1991;35:297-301. 2. Jpn J Transf Med 1983;29:221-3.

37. 71% of pts. suffered fromallergic NHTRs -367 cases(8%) of immediate-onset (within 20 min of the start of transfusion), anaphylactic NHTRs. TRANSFUSION Volume 42, June 2002

38. TRANSFUSION Volume 42, June 2002

39. TRANSFUSION Volume 42, June 2002

40. Detection of Hpdel among Thais, deleted allele of haptoglobin gene that causes congenital haptoglobin deficiency Haptoglobin gene, Hpdel, causes congenital haptoglobindeficiency, observed in other Northeast Asian populations, such as Japan ,Korean and Chinese persons. Not reported in African and European-African populations Hpdelwas detected among healthy, normal Japanese population at frequency of 0.015 prevalence of haptoglobin deficiency among Japanese population ~ 1 in 4000 ,~5 times > selective IgA deficiency(1 in 30,000) prevalence of haptoglobin deficiency among patients who experienced immediate-onset anaphylactic NHTRs ~ 1 in 60 TRANSFUSION 2007;47:2315-2321.

41. Simple PCR detection of haptoglobin gene deletion in anhaptoglobinemic patients with antihaptoglobin antibody that causes anaphylactic transfusion reactions Blood. 2000; 95:1138-1143

42. Identification of haptoglobin deficiency with simplified ELISA among 200 Thais. TRANSFUSION 2007;47:2315-2321.

43. Detection of 6 subjects heterozygous for the Hpdel allele among 200 Thais. (A) Determination of Hpdel allele with Hpdel -specific PCR (B) Determination of haptoglobin phenotype by Western blotting TRANSFUSION 2007;47:2315-2321.

45. frequency of Hpdelallele was calculated to be 0.015- prevalence of haptoglobin deficiency caused by Hpdelhomozygosity ~ 1 in 4000. (similar in Japan ) TRANSFUSION 2007;47:2315-2321.

46. Posttransfusion anaphylactic reactions in patient with severe vWD: role of complement and alloAb to vWF Serial plasma samples were collected from a patient with severe vnWillebrand disease, IgGalloAb against vWF , and a history of posttransfusion anaphylaxis. During an 18-day period the patient was treated with factor VIII-vWF concentrate and with recombinant factor VIII. Symptoms of anaphylaxis and signs of complement activation were present only when IgGAb to vWF were measurable during replacement with factor VIII-vWF concentrate (days 1 and 6). IgE, IgA, and IgM antibodies to vWF were not detectable in plasma at any time. This study indicates cause-effect relationship between formation of IgG-vWF complexes and massive complement activation in posttransfusion non-IgE-mediated anaphylactic reactions J Lab Clin Med. 1995 Mar;125(3):348-55.

47. infusion of vWF-containing preparations into patients C.K. andG.T. led to formation of IgG-vWF complexes, release of complementanaphylatoxins The journal of Immunology, 1996, 156: 1256-1 261.

48. Adverse transfusion reactions associated with precipitating anti-C4 antibody of anti-Rodgers specificity. patient suffer from chronic hepatitis exhibited severe transfusion reactions after administration of FFP and prothrombin complex conc. 1 month before these reactions, she received FFP patient's serum obtained 1 wk and 6 mo. IgG class present in sera reacted with purified preparation of C4 Ab limited specificity and reacted only with C4 of Rodgers specificity Phenotype of patient's C4 group : Chido positive and Rodgers negative. patient had neither detectable anti-IgA nor other anti-IgAb coexistence of precipitating anti-C4 Ab and adverse transfusion reactions to plasma fractions containing large amounts of C4 indicates that in the absence of Ab of other specificities, this Ab can be considered as the cause of the transfusion reaction. Vox Sang. 1984;47(3):242-9

49. Severe anaphylactic reactions following transfusions of platelets to patient with anti-Ch Report : anti-Ch (and anti-Rg) not cause hemolytic transfusion reactions Ab did not cause red cell destruction, but did cause a life-threatening anaphylactic reaction during transfusion of plasma proteins in pooled platelets. Ab was of the IgG4 subclass and might have caused a short-term, sensitizing anaphylactic response. This case (transfusion reaction caused by anti-Ch ), and one previously reported in which patient with anti-Rg experienced a severe reaction to FFP and plasma derivative these Ab can cause severe, life-threatening reactions in patients who receive plasma-containing components Transfusion. 1992 Jul-Aug;32(6):576-9.

50. Activated platelet membranes orplatelet-derived microparticles as possiblecause of anaphylactic transfusion reactions platelet membrane-derived microparticles (PMPs) may be responsible for high incidence of reactions to platelet concentrates study of acute reactions in pediatric patients, there was a 5% incidence of allergic reactions to standard platelets and a 6% incidence to pre-storage WBC-reduced platelets1 study in adult patients there was a 4.1 and 4.8% incidence of allergic reactions to pre-storage WBC reduced whole blood derived and apheresis platelets respectively2 negatively charged surfaces ( externalized phosphatidyl serine and phosphatidyl ethanolamine on surface ) like ionic contrast media management option for patients who need FFP would be solvent-detergent treated plasma (SD Plasma) Transfusion 2002, 42:753–758 Transfusion 2002, 42:556–566

51. Platelets expressing P-selectin and platelet-derived microparticles in stored platelet concentrates bind to PSGL-1 on filtrated leukocytes. levels of IL-6 & platelet-derived microparticles (PMPs) were measured in 137 patients with SE from PC transfusion with leukocyte removal filtration 203 transfusions 84 patients with hematologic disease 53 patients with nonhematologic disease urticaria (75.9%), erythema (18.7%), and fever (17.2%), but no anaphylactic reactions. levels of interleukin-6 and PMP correlated in both groups, and were significantly higher in the hematologic disease group than in the nonhematologic disease group. The level of PMP, but not interleukin-6, was significantly higher for patients testing positive for allergic reaction than for those testing negative. In the stored PC prior to filtration, the level of interleukin-6 was normal. The level of P-selectin-expressing platelets and PMPs was elevated before filtration, but was significantly lower after filtration. Taken together, the results suggest that PMP is involved in the generation of transfusion reactions, and indicate that both platelets and PMP displaying P-selectin bind to P-selectin glycoprotein ligand-1 of leukocytes retained by the leukocyte filter. ClinApplThrombHemost. 2000 Oct;6(4):213-21.

52. Conclusion Anaphylactic transfusion reactions are rare Possible mechanisms are Ab to plasma donor (eg.IgA,haptoglobin,complement,coagulation factor) Management : Treatment of anaphylaxis Exclude other cause of acute transfusion reaction prevention for recurrent anaphylaxis by special blood component ( IgA blood donor,not available in Thailand?) , washed Rbc