Blood Transfusion ReactionsBlood Transfusion Reactions

Senior talk by Senior talk by Isidore C. Okere Isidore C. Okere

ObjectivesObjectives

Early identification of common Early identification of common transfusion rxns.transfusion rxns.

Differentiate life threatening Differentiate life threatening reactions from benign transfusion reactions from benign transfusion rxns.rxns.

Manage common immunologic Manage common immunologic tranx rxns.tranx rxns.

Types of ReactionsTypes of Reactions

Immune mediated transfusion reactionsImmune mediated transfusion reactions Febrile non hemolytic tranx rxnsFebrile non hemolytic tranx rxns Immune mediated hemolysis Immune mediated hemolysis ------Acute and delayed hemolytic Acute and delayed hemolytic

reactionsreactions Anaphylactic transfusion rxnsAnaphylactic transfusion rxns Urticarial transfusion rxnsUrticarial transfusion rxns Post-transfusion purpuraPost-transfusion purpura GVHD GVHD TRALI (pulm leuko-agglutinin TRALI (pulm leuko-agglutinin

reactions)reactions)

Non immune mediated Non immune mediated reactionsreactions

Physical reactions: thermal i.e. heat or cold Physical reactions: thermal i.e. heat or cold inducedinduced

Infectious; Hepatitis B/C, malaria, HIV, CMV, Infectious; Hepatitis B/C, malaria, HIV, CMV, Chagas dx, CJ Virus, West Nile virusChagas dx, CJ Virus, West Nile virus

Chemical; citrate toxicity, hypo/hyperkalemia, Chemical; citrate toxicity, hypo/hyperkalemia, iron overloadiron overload

Acute hypotensive reaction: mediated by Acute hypotensive reaction: mediated by bradykinins and occurs in patients with faulty bradykinins and occurs in patients with faulty bradykinin metabolism on ACE Ibradykinin metabolism on ACE I

Osmotic injuryOsmotic injury Congenital and acquired hemolytic anemiaCongenital and acquired hemolytic anemia

Immunologic rxnsImmunologic rxnsclassic blood tranx rxns are usually immunologic and classic blood tranx rxns are usually immunologic and occur 2/2 to interactions of inherited/ acquired Ab with occur 2/2 to interactions of inherited/ acquired Ab with foreign Ag from transfused bloodforeign Ag from transfused blood

Incidence of rxnsIncidence of rxns SHOT trial (serious hazards of tranx)SHOT trial (serious hazards of tranx)

-most common cause is tranx of non-matched -most common cause is tranx of non-matched blood mostly 2/2 to clerical errorblood mostly 2/2 to clerical error

-2x more common in infants than adults-2x more common in infants than adults

-more common in pxts with hematological and -more common in pxts with hematological and oncological conditionsoncological conditions

Case scenario 1Case scenario 1

A 35-year-old woman was hospitalized for anemia 2/2 A 35-year-old woman was hospitalized for anemia 2/2 sickle cell disease, she is receiving 2 units of PRBC. sickle cell disease, she is receiving 2 units of PRBC. After her 1After her 1stst unit of blood she developed a temp of 38.3 unit of blood she developed a temp of 38.3 °C (101.0°F). She has no other symptoms.°C (101.0°F). She has no other symptoms.

On exam she appears anxious but her vital signs are On exam she appears anxious but her vital signs are stable with Bp 120/70mmHg, HR 80bpm 18cpm Pox stable with Bp 120/70mmHg, HR 80bpm 18cpm Pox 98% 0n RA98% 0n RA

She has no skin rash and her urine color is amberShe has no skin rash and her urine color is amber

What are your differential diagnosis and how would you What are your differential diagnosis and how would you manage this pxt?manage this pxt?

Febrile non hemolytic tranx Febrile non hemolytic tranx rxnsrxns

Most common, usually benign without sequelaeMost common, usually benign without sequelae Concerning because initial presentation is similar to Concerning because initial presentation is similar to

more adverse rxns. i.e. fever, chills +/- mild dyspnea.more adverse rxns. i.e. fever, chills +/- mild dyspnea. 15% will have a rxn in the future with subsequent 15% will have a rxn in the future with subsequent

tranxtranx

EtiologyEtiology1.1. Class 1 HLA ab directed against contaminating wbc in Class 1 HLA ab directed against contaminating wbc in

red cell conc. Although these are not always foundred cell conc. Although these are not always found2.2. 2/2 to cytokines IL-1, 6,8 and Tnf alpha generated in 2/2 to cytokines IL-1, 6,8 and Tnf alpha generated in

stored blood/products.stored blood/products.3.3. Determining factor is age of blood productsDetermining factor is age of blood products

ManagementManagementDiscontinue tranx, rule out hemolysis i.e. check labels, Discontinue tranx, rule out hemolysis i.e. check labels,

repeat type and cross, coombs testrepeat type and cross, coombs testAntipyretics +/- meperidine for chills and rigorsAntipyretics +/- meperidine for chills and rigors

Prevention • Leukoreduction: evidence is scarce but few studies have shown a decrease in number of reactions.

• Although tylenol and antihistamine premedication is widely used there are no evidence to support that their use actually prevents rxn.

Case scenario 2Case scenario 2

A 35-year-old woman was hospitalized for anemia 2/2 A 35-year-old woman was hospitalized for anemia 2/2 sickle cell disease, she is receiving 2 units of PRBC. Her 1sickle cell disease, she is receiving 2 units of PRBC. Her 1stst unit of blood was transfused without events but 5minutes unit of blood was transfused without events but 5minutes into her 2into her 2ndnd unit, She complains of new flank pain and fever. unit, She complains of new flank pain and fever.

On exam she appears very anxious, diaphoretic and in acute On exam she appears very anxious, diaphoretic and in acute distress, she is febrile to 38.8C with Bp 100/60mmHg, HR distress, she is febrile to 38.8C with Bp 100/60mmHg, HR 101 bpm, 18cpm, Pox 98% 0n RA101 bpm, 18cpm, Pox 98% 0n RA

She has no skin rash but is oozing out of IV sites and her She has no skin rash but is oozing out of IV sites and her urine color is now reddish brown.urine color is now reddish brown.

Labs: elevated Bun/creat, increased PTT, PT and decreased Labs: elevated Bun/creat, increased PTT, PT and decreased HCT.HCT.

What is the diagnosis and how would you manage this What is the diagnosis and how would you manage this patient?patient?

Acute hemolytic rxnsAcute hemolytic rxns

Medical emergencyMedical emergency Occurs due to rapid transfused RBC destruction Occurs due to rapid transfused RBC destruction

by preformed recipients Absby preformed recipients Abs Mostly 2/2 to ABO incompatibility-typically type Mostly 2/2 to ABO incompatibility-typically type

O receiving non O blood. May occur with other O receiving non O blood. May occur with other blood typesblood types

IgM mediated complement fixation leading to IgM mediated complement fixation leading to rapid intra vascular hemolysisrapid intra vascular hemolysis

Most common causes are clerical or procedural Most common causes are clerical or procedural errorserrors

Complications includes DIC, shock, ARF 2/2 to Complications includes DIC, shock, ARF 2/2 to ATNATN

Clinical presentation Classic presenting triad of Fever, flank pain and reddish brown

urine from hemoglobinuria are rarely seen DIC may be presenting mode

Labs Direct Coombs +, Pink plasma, Lactate, FDP in DIC

Management1. Stop transfusion, alert blood bank to start search for clerical

error since another patient may be at risk 2. R/o tranx rxn i.e. check labels, repeat type and cross with unit,

check urine for hemoglobin 3. Supportive care; ABC +/-pressors4. cardiac monitoring because of risk of hyperkalemia5. Infuse NS to maintain BP and promote diuresis, avoid LR and

dextrose because calcium in LR will promote clotting in IV line and dextrose will increase hemolysis. Maintain urine output >100-200ml/hour

6. With DIC early heparinization 10u/kg/hr may be beneficial

Delayed hemolytic transfusion rxns

Generally occurs within 2-10 days of tranxUsually due to senescent Ab response on re-exposure to a foreign red cell Ag History of previous pregnancy, transfusion or transplantUsually extra vascular and is less severe than acuteOther Abs often Rh and Kidd

Clinical presentationFalling HCT, low grade fever, slight increase in indirect bili, spherocytes on blood smear

DiagnosisNew +DAT and new Ab test when new blood is ordered

Txt None in the absence of rapid hemolysisAvoid offending Ag in future tranx

Anaphylactic reactions-life threatening emergency-Occurs within a few seconds to minutes following tranx-Characterized by rapid onset of anaphylaxis -Can occur with all blood products but generally unseen with serum albumin, plasma protein fractions or coagulation factors

Incidence 1 in 20-50 thousand

MechanismPresence of class specific IgG and anti IgA abs in pxts who are IgA def -Selective IgA def is fairly common, occurring in 1/300-500 people but majority of them do not develop Abs -Ahaptoglobinemia with antihaptoglobin Abs is similar and occur primarily in East Asian

TreatmentAs in all cases of anaphylaxis: stop tranx, epi 0.3ml of 1.1000 soln IMConsider IV epinephrine dripABC +/- pressor support

PreventionEstablish diagnosis: usually after the factUse IgA def products for all further tranx (extra washed red cells or platelets)

Urticarial reactions-Allergenic products in blood products activates IgE in recipient leading to histamine release from mast cells and basophils-Only rxn in which tranx can be resumed-Give benadryl 25-50mg IV/PO if urticaria is extensive

Case scenario 3Case scenario 3

30 year old kidney 30 year old kidney transplanttransplant recipientrecipient on on chronic chronic ImmunosupressiveImmunosupressive therapy admitted for anemia and therapy admitted for anemia and received 2 units of received 2 units of non irradiated PRBCnon irradiated PRBC from his from his sistersister 3 days ago develops skin bullae, diarrhea and 3 days ago develops skin bullae, diarrhea and abdominal crampsabdominal cramps

VS: notable for low grade fever of 37.9C otherwise VS: notable for low grade fever of 37.9C otherwise normal normal

PE: Jaundice, swollen skin with multiple bullaPE: Jaundice, swollen skin with multiple bulla

Labs; new thrombocytopenia, elevated LFT, increased Labs; new thrombocytopenia, elevated LFT, increased bilirubin.bilirubin.

What is your diagnosis?What is your diagnosis?

Very rareVery rare (0.1-1%) complication seen in Immuno-compromised (0.1-1%) complication seen in Immuno-compromised individuals esp in solid tumor cancer pxts on chemo, but can occur individuals esp in solid tumor cancer pxts on chemo, but can occur with acute/chronic leukemia, lymphomas, new borne with with acute/chronic leukemia, lymphomas, new borne with erythroblastosis fetalis and transplant pxts erythroblastosis fetalis and transplant pxts

Different from transplant GVHD by it’s effect on bone marrow (BM Different from transplant GVHD by it’s effect on bone marrow (BM aplasia)aplasia)

It occurs in immuno-compromised recipients of blood products from It occurs in immuno-compromised recipients of blood products from donors with identical HLA haplotypes. They are heterozygous for a donors with identical HLA haplotypes. They are heterozygous for a HLA haplotype for which the donor is homozygous .e.g. genetically HLA haplotype for which the donor is homozygous .e.g. genetically identical relativesidentical relatives

HLA ag are shared by donor and recipient, thus donor lymphocyte HLA ag are shared by donor and recipient, thus donor lymphocyte are engrafted by recipient because they are the only Ag seen by the are engrafted by recipient because they are the only Ag seen by the host.host.

On the flip side the donor lymphocytes view the recipient’s tissues On the flip side the donor lymphocytes view the recipient’s tissues as foreign leading to immunologic activationas foreign leading to immunologic activation and GVHD. and GVHD.

Bone marrow aplasia is the primary cause of deathBone marrow aplasia is the primary cause of death

Transfusion associated Transfusion associated GVHDGVHD

Clinical presentationClinical presentation

SkinSkin: Swollen, erythroderma and bullae formation- most : Swollen, erythroderma and bullae formation- most common common

GIGI: Diarrhea and abdominal cramps: Diarrhea and abdominal cramps

Liver:Liver: Elevated LFT and Hyperbilirubinemia Elevated LFT and Hyperbilirubinemia

HemeHeme: Bone marrow aplasia, persistent : Bone marrow aplasia, persistent thrombocytopeniathrombocytopenia

Skin manifestation of GVHD Generalized swelling, erythroderma and bullous formation

Non Irradiated whole bloodNon Irradiated whole blood PRBCPRBC PlateletsPlatelets Granulocytes Granulocytes Fresh non frozen plasmaFresh non frozen plasmaIt has not been seen with frozen deglycerolized RBC, FFP or It has not been seen with frozen deglycerolized RBC, FFP or

CryoprecipitateCryoprecipitate

Treatment Treatment Poor response to standard immunosuppressive therapies,Poor response to standard immunosuppressive therapies,Thalidomide has been tried with variable success.Thalidomide has been tried with variable success.

PreventionPreventionKey since response to treatment is poor Key since response to treatment is poor Gamma irradiation and leuko-reduction of productsGamma irradiation and leuko-reduction of productsAvoid blood products from genetically identical donorsAvoid blood products from genetically identical donors

Implicated productsImplicated products

Case scenario 4Case scenario 4

A 35-year-old woman was hospitalized for thrombotic A 35-year-old woman was hospitalized for thrombotic thrombocytopenic purpura for which she underwent therapeutic thrombocytopenic purpura for which she underwent therapeutic plasma exchange with fresh frozen plasma. After 7 days of treatment, plasma exchange with fresh frozen plasma. After 7 days of treatment, she had improved sufficiently to allow for weaning from daily she had improved sufficiently to allow for weaning from daily transfusions; however, at the conclusion of plasma exchange, she transfusions; however, at the conclusion of plasma exchange, she developed a cough and a temperature of 38.3 °C (101.0 °F), with developed a cough and a temperature of 38.3 °C (101.0 °F), with progression of respiratory symptoms to severe dyspnea, with some progression of respiratory symptoms to severe dyspnea, with some wheezing. wheezing.

On physical examination, the blood pressure is 120/80 mm Hg. There On physical examination, the blood pressure is 120/80 mm Hg. There is no rash or hives. She is tachycardic and cyanotic on is no rash or hives. She is tachycardic and cyanotic on cardiopulmonary examination. Oxygen saturation is 80% on room air, cardiopulmonary examination. Oxygen saturation is 80% on room air, and a blood gas study shows an arterial PO2 of 55 mm Hg. A chest and a blood gas study shows an arterial PO2 of 55 mm Hg. A chest radiograph reveals diffuse opacifications of both lungs and a normal-radiograph reveals diffuse opacifications of both lungs and a normal-sized heart and no pleural effusion. sized heart and no pleural effusion.

Which of the following is the most likely cause for this patient's Which of the following is the most likely cause for this patient's reaction?reaction?

1.1. Pulmonary embolism Pulmonary embolism 2.2. Antileukocyte antibodies Antileukocyte antibodies 3.3. Allergy to donor plasma proteins Allergy to donor plasma proteins 4.4. Circulatory overloadCirculatory overload

Transfusion related Transfusion related acute lung injuryacute lung injury New acute lung injury occurring during or New acute lung injury occurring during or

within 6 hour of blood product tranxwithin 6 hour of blood product tranx All blood products have been implicatedAll blood products have been implicated May progress to ARDsMay progress to ARDs Immune mediated non cardiogenic pulm Immune mediated non cardiogenic pulm

edemaedema

Risk factors Risk factors No definite risk factors but prolonged storage No definite risk factors but prolonged storage

of blood products, massive tranx, cytokine txt, of blood products, massive tranx, cytokine txt, multiparity, thrombocytopenia and active multiparity, thrombocytopenia and active infections have been implicated in a number infections have been implicated in a number of studies.of studies.

Pathogenesis Pathogenesis -Abs against HLA -Abs against HLA -2 hit hypothesis: -2 hit hypothesis: 11stst hit is an underlying pulm pathology that leads to hit is an underlying pulm pathology that leads to

localization of neutrophils in the pulm vasculature 2localization of neutrophils in the pulm vasculature 2ndnd hit is the transfusion of blood products containing hit is the transfusion of blood products containing sensitized neutrophils Ab leading to release of sensitized neutrophils Ab leading to release of vasoactive Cytokine and pulm edemavasoactive Cytokine and pulm edema

Leading cause of transfusion related fatalities in the USA

1 case for every 1000-2400 units transfused 6-9% mortality rate

Epidemiology

Clinical presentationClinical presentation

Acute onset of respiratory distress (hypoxemia) during or Acute onset of respiratory distress (hypoxemia) during or shortly after blood tranx. On the average within 1-2 hours shortly after blood tranx. On the average within 1-2 hours post tranxpost tranx

Fever, tachycardia, tachypnea, +/-hypotension Fever, tachycardia, tachypnea, +/-hypotension In intubated pxts; elevated peak airway pressures, pink In intubated pxts; elevated peak airway pressures, pink

frothy airway secretion frothy airway secretion CXR bilateral patchy alveolar infiltrates, normal cardiac CXR bilateral patchy alveolar infiltrates, normal cardiac

picturepicture Labs; eosinophilia and transient drop in neutrophils, Leuko-Labs; eosinophilia and transient drop in neutrophils, Leuko-

agglutinin testingagglutinin testing

DiagnosisDiagnosisClinical presentation and CXR findingsClinical presentation and CXR findings-Labs; granulocyte/ leuko-agglutinating abs, decline in C3 or C5 -Labs; granulocyte/ leuko-agglutinating abs, decline in C3 or C5

levels 12-36 hours after onset of symptoms followed by rise levels 12-36 hours after onset of symptoms followed by rise 4-7 days later4-7 days later

(a) Bilateral patchy alveolar infiltrate in TRAL (b) Complete resolution

a b

Criteria for the diagnosis of TRALI• No acute lung injury immediately before transfusion• New acute lung injury: 1. acute onset lung injury, 2. no circulatory overload or PA pressures <18mmHg, 3. bilateral pulm infiltrate on Cxr, 4. Hypoxemia:Pa02/FiO2 <300, or sat <90% on RA.• Onset within 6 hours after transfusion • No temporal relation to an alternate risk factor for acute lung injury

Popovsky TP et al TRALI; definition and review. Crit care Med 2005

Ddx includesDdx includes Acute fluid overload: Acute fluid overload: ↑ ↑ JVP, JVP, ↑SBP and widened pulse ↑SBP and widened pulse

pressure during dyspneic episode, ↑ pulm vascular markings pressure during dyspneic episode, ↑ pulm vascular markings on CXRon CXR

Hemolytic transfusion rxns Hemolytic transfusion rxns IgA mediated anaphylaxis in IgA def patientsIgA mediated anaphylaxis in IgA def patients

Management -Mostly supportive with abrupt resolution in symptoms within a few days-A majority of patients may require mechanical ventilation-Diuretics play no role in management since it is microvascular damage and not due to volume. It has been shown to actually worsen TRALI

PrognosisIncreased risk of recurrence if they receive products from the implicated donor but no risk from other donors

Conclusion Conclusion

Transfusion reactions are mostly due to Transfusion reactions are mostly due to clerical errors and can range from benign clerical errors and can range from benign reactions to life threatening emergenciesreactions to life threatening emergencies

Early detection, discontinuation of Early detection, discontinuation of transfusion and instituting supportive transfusion and instituting supportive care are key to management.care are key to management.

Reporting of all reactions helps to Reporting of all reactions helps to improve standard practices and reduce improve standard practices and reduce future occurrences.future occurrences.

Kleinman S, Caulfield T, Chan P, Davenport R, McFarland J, McPhedran S, et alKleinman S, Caulfield T, Chan P, Davenport R, McFarland J, McPhedran S, et al. Toward an . Toward an understanding of transfusion-related acute lung injury: statement of a consensus panel. Transfusion. understanding of transfusion-related acute lung injury: statement of a consensus panel. Transfusion. 2004;44:1774-89. [PMID: 15584994] [2004;44:1774-89. [PMID: 15584994] [PubMedPubMed] ]

Beauregard P et alBeauregard P et al. Hemolytic and pseudo- hemolytic reactions: AN overview of hemolytic reactions and . Hemolytic and pseudo- hemolytic reactions: AN overview of hemolytic reactions and the clinical conditions that mimic them. Transfus Med Rev 1994; 8:184the clinical conditions that mimic them. Transfus Med Rev 1994; 8:184

Brittingham, TE et alBrittingham, TE et al. Febrile transfusion reactions caused by sensitivity to donor leukocytes and platelets J . Febrile transfusion reactions caused by sensitivity to donor leukocytes and platelets J Am Med Assoc 1957 165:819Am Med Assoc 1957 165:819

Sanders RPSanders RP et al. A revised classification scheme for acute transfusion reactions. Transfusion 2007 47;621. et al. A revised classification scheme for acute transfusion reactions. Transfusion 2007 47;621. Stack G et al; Cytokine generation in stored platelet concentrates; Transfusion 1994Stack G et al; Cytokine generation in stored platelet concentrates; Transfusion 1994 Uhlmann ET et alUhlmann ET et al. Prestorage universal WBC reduction of RBC units does not affect the incidence of . Prestorage universal WBC reduction of RBC units does not affect the incidence of

transfusion reactions. Transfusion 2001 41; 997transfusion reactions. Transfusion 2001 41; 997 Tobian AA et alTobian AA et al. Transfusion premedication: a growing practice not based on evidence.. Transfusion 2007; . Transfusion premedication: a growing practice not based on evidence.. Transfusion 2007;

78;133778;1337 Murphy MP et alMurphy MP et al. Prevention of bedside errors in transfusion medicine (PROBE-TM) study: a cluster-. Prevention of bedside errors in transfusion medicine (PROBE-TM) study: a cluster-

randomized, matched-paired clinical areas trial of a simple intervention to reduce errors in the pre randomized, matched-paired clinical areas trial of a simple intervention to reduce errors in the pre transfusion bedside check. Transfusion 2007 47:771transfusion bedside check. Transfusion 2007 47:771

Shimada E et alShimada E et al. Anaphylactic transfusion reactions in haptoglobin-deficient patients with anti-haptoglobin . Anaphylactic transfusion reactions in haptoglobin-deficient patients with anti-haptoglobin Abs. Transfusion 2002Abs. Transfusion 2002

Vassallo RRVassallo RR: Review IgA anaphylactic transfusion reactions Part 1. Lab diagnosis, incidence and supply of : Review IgA anaphylactic transfusion reactions Part 1. Lab diagnosis, incidence and supply of IgA def products. Immune hematol 2004IgA def products. Immune hematol 2004

Kopko PM, Marshall CS, MacKenzie MR, Holland PV, Popovsky MAKopko PM, Marshall CS, MacKenzie MR, Holland PV, Popovsky MA. Transfusion-related acute lung . Transfusion-related acute lung injury: report of a clinical look-back investigation. JAMA 2002;287:1968-71. [PMID: 11960539] [injury: report of a clinical look-back investigation. JAMA 2002;287:1968-71. [PMID: 11960539] [PubMedPubMed

Toy, P Popovsky et alToy, P Popovsky et al, Transfusion-related acute lung injury; Definition and review. Crit Care Med 2005: , Transfusion-related acute lung injury; Definition and review. Crit Care Med 2005: 33:72133:721

References

Thank God this nightmare is over!!!!!!!Thank God this nightmare is over!!!!!!!