Blood Transfusion Reactions Senior talk by Isidore C. Okere

Objectives Early identification of common transfusion rxns. Early identification of common transfusion rxns. Differentiate life threatening reactions from benign transfusion rxns. Differentiate life threatening reactions from benign transfusion rxns. Manage common immunologic tranx rxns. Manage common immunologic tranx rxns.

Types of Reactions Immune mediated transfusion reactions Febrile non hemolytic tranx rxns Febrile non hemolytic tranx rxns Immune mediated hemolysis Immune mediated hemolysis --- Acute and delayed hemolytic reactions --- Acute and delayed hemolytic reactions Anaphylactic transfusion rxns Anaphylactic transfusion rxns Urticarial transfusion rxns Urticarial transfusion rxns Post-transfusion purpura Post-transfusion purpura GVHD GVHD TRALI (pulm leuko-agglutinin reactions) TRALI (pulm leuko-agglutinin reactions)

Non immune mediated reactions Physical reactions: thermal i.e. heat or cold induced Physical reactions: thermal i.e. heat or cold induced Infectious; Hepatitis B/C, malaria, HIV, CMV, Chagas dx, CJ Virus, West Nile virus Infectious; Hepatitis B/C, malaria, HIV, CMV, Chagas dx, CJ Virus, West Nile virus Chemical; citrate toxicity, hypo/hyperkalemia, iron overload Chemical; citrate toxicity, hypo/hyperkalemia, iron overload Acute hypotensive reaction: mediated by bradykinins and occurs in patients with faulty bradykinin metabolism on ACE I Acute hypotensive reaction: mediated by bradykinins and occurs in patients with faulty bradykinin metabolism on ACE I Osmotic injury Osmotic injury Congenital and acquired hemolytic anemia Congenital and acquired hemolytic anemia

Immunologic rxns classic blood tranx rxns are usually immunologic and occur 2/2 to interactions of inherited/ acquired Ab with foreign Ag from transfused blood Incidence of rxns SHOT trial (serious hazards of tranx) -most common cause is tranx of non-matched blood mostly 2/2 to clerical error -2x more common in infants than adults -more common in pxts with hematological and oncological conditions

Case scenario 1 A 35-year-old woman was hospitalized for anemia 2/2 sickle cell disease, she is receiving 2 units of PRBC. After her 1 st unit of blood she developed a temp of 38.3 °C (101.0°F). She has no other symptoms. A 35-year-old woman was hospitalized for anemia 2/2 sickle cell disease, she is receiving 2 units of PRBC. After her 1 st unit of blood she developed a temp of 38.3 °C (101.0°F). She has no other symptoms. On exam she appears anxious but her vital signs are stable with Bp 120/70mmHg, HR 80bpm 18cpm Pox 98% 0n RA On exam she appears anxious but her vital signs are stable with Bp 120/70mmHg, HR 80bpm 18cpm Pox 98% 0n RA She has no skin rash and her urine color is amber She has no skin rash and her urine color is amber What are your differential diagnosis and how would you manage this pxt?

Febrile non hemolytic tranx rxns Most common, usually benign without sequelae Most common, usually benign without sequelae Concerning because initial presentation is similar to more adverse rxns. i.e. fever, chills +/- mild dyspnea. Concerning because initial presentation is similar to more adverse rxns. i.e. fever, chills +/- mild dyspnea. 15% will have a rxn in the future with subsequent tranx 15% will have a rxn in the future with subsequent tranxEtiology 1. Class 1 HLA ab directed against contaminating wbc in red cell conc. Although these are not always found 2. 2/2 to cytokines IL-1, 6,8 and Tnf alpha generated in stored blood/products. 3. Determining factor is age of blood products Management Discontinue tranx, rule out hemolysis i.e. check labels, repeat type and cross, coombs test Antipyretics +/- 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 2 A 35-year-old woman was hospitalized for anemia 2/2 sickle cell disease, she is receiving 2 units of PRBC. Her 1 st unit of blood was transfused without events but 5minutes into her 2 nd unit, She complains of new flank pain and fever. A 35-year-old woman was hospitalized for anemia 2/2 sickle cell disease, she is receiving 2 units of PRBC. Her 1 st unit of blood was transfused without events but 5minutes into her 2 nd unit, She complains of new flank pain and fever. On exam she appears very anxious, diaphoretic and in acute distress, she is febrile to 38.8C with Bp 100/60mmHg, HR 101 bpm, 18cpm, Pox 98% 0n RA On exam she appears very anxious, diaphoretic and in acute distress, she is febrile to 38.8C with Bp 100/60mmHg, HR 101 bpm, 18cpm, Pox 98% 0n RA She has no skin rash but is oozing out of IV sites and her urine color is now reddish brown. She has no skin rash but is oozing out of IV sites and her urine color is now reddish brown. Labs: elevated Bun/creat, increased PTT, PT and decreased HCT. What is the diagnosis and how would you manage this patient? What is the diagnosis and how would you manage this patient?

Acute hemolytic rxns Medical emergency Medical emergency Occurs due to rapid transfused RBC destruction by preformed recipients Abs Occurs due to rapid transfused RBC destruction by preformed recipients Abs Mostly 2/2 to ABO incompatibility-typically type O receiving non O blood. May occur with other blood types Mostly 2/2 to ABO incompatibility-typically type O receiving non O blood. May occur with other blood types IgM mediated complement fixation leading to rapid intra vascular hemolysis IgM mediated complement fixation leading to rapid intra vascular hemolysis Most common causes are clerical or procedural errors Most common causes are clerical or procedural errors Complications includes DIC, shock, ARF 2/2 to ATN Complications includes DIC, shock, ARF 2/2 to ATN

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 Management 1.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 +/-pressors 4.cardiac monitoring because of risk of hyperkalemia 5.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 > ml/hour 6.With DIC early heparinization 10u/kg/hr may be beneficial

Delayed hemolytic transfusion rxns Generally occurs within 2-10 days of tranx Usually due to senescent Ab response on re-exposure to a foreign red cell Ag History of previous pregnancy, transfusion or transplant Usually extra vascular and is less severe than acute Other Abs often Rh and Kidd Clinical presentation Falling HCT, low grade fever, slight increase in indirect bili, spherocytes on blood smear Diagnosis New +DAT and new Ab test when new blood is ordered Txt None in the absence of rapid hemolysis Avoid 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 thousand Mechanism Presence of class specific IgG and anti IgA abs in pxts who are IgA def -Selective IgA def is fairly common, occurring in 1/ people but majority of them do not develop Abs -Ahaptoglobinemia with antihaptoglobin Abs is similar and occur primarily in East Asian Treatment As in all cases of anaphylaxis: stop tranx, epi 0.3ml of soln IM Consider IV epinephrine drip ABC +/- pressor support

Prevention Establish diagnosis: usually after the fact Use 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 3 30 year old kidney transplant recipient on chronic Immunosupressive therapy admitted for anemia and received 2 units of non irradiated PRBC from his sister 3 days ago develops skin bullae, diarrhea and abdominal cramps 30 year old kidney transplant recipient on chronic Immunosupressive therapy admitted for anemia and received 2 units of non irradiated PRBC from his sister 3 days ago develops skin bullae, diarrhea and abdominal cramps VS: notable for low grade fever of 37.9C otherwise normal VS: notable for low grade fever of 37.9C otherwise normal PE: Jaundice, swollen skin with multiple bulla PE: Jaundice, swollen skin with multiple bulla Labs; new thrombocytopenia, elevated LFT, increased bilirubin. Labs; new thrombocytopenia, elevated LFT, increased bilirubin. What is your diagnosis?

Very rare (0.1-1%) complication seen in Immuno-compromised individuals esp in solid tumor cancer pxts on chemo, but can occur with acute/chronic leukemia, lymphomas, new borne with erythroblastosis fetalis and transplant pxts Very rare (0.1-1%) complication seen in Immuno-compromised individuals esp in solid tumor cancer pxts on chemo, but can occur with acute/chronic leukemia, lymphomas, new borne with erythroblastosis fetalis and transplant pxts Different from transplant GVHD by its effect on bone marrow (BM aplasia) Different from transplant GVHD by its effect on bone marrow (BM aplasia) It occurs in immuno-compromised recipients of blood products from donors with identical HLA haplotypes. They are heterozygous for a HLA haplotype for which the donor is homozygous.e.g. genetically identical relatives It occurs in immuno-compromised recipients of blood products from donors with identical HLA haplotypes. They are heterozygous for a HLA haplotype for which the donor is homozygous.e.g. genetically identical relatives HLA ag are shared by donor and recipient, thus donor lymphocyte are engrafted by recipient because they are the only Ag seen by the host. HLA ag are shared by donor and recipient, thus donor lymphocyte are engrafted by recipient because they are the only Ag seen by the host. On the flip side the donor lymphocytes view the recipients tissues as foreign leading to immunologic activation and GVHD. On the flip side the donor lymphocytes view the recipients tissues as foreign leading to immunologic activation and GVHD. Bone marrow aplasia is the primary cause of death Bone marrow aplasia is the primary cause of death Transfusion associated GVHD

Clinical presentation Skin: Swollen, erythroderma and bullae formation- most common GI: Diarrhea and abdominal cramps Liver: Elevated LFT and Hyperbilirubinemia Heme: Bone marrow aplasia, persistent thrombocytopenia Skin manifestation of GVHD Generalized swelling, erythroderma and bullous formation

Non Irradiated whole blood Non Irradiated whole blood PRBC PRBC Platelets Platelets Granulocytes Granulocytes Fresh non frozen plasma Fresh non frozen plasma It has not been seen with frozen deglycerolized RBC, FFP or Cryoprecipitate Treatment Poor response to standard immunosuppressive therapies, Thalidomide has been tried with variable success. Prevention Key since response to treatment is poor Gamma irradiation and leuko-reduction of products Avoid blood products from genetically identical donors Implicated products

Case scenario 4 A 35-year-old woman was hospitalized for thrombotic thrombocytopenic purpura for which she underwent therapeutic plasma exchange with fresh frozen plasma. After 7 days of treatment, she had improved sufficiently to allow for weaning from daily transfusions; however, at the conclusion of plasma exchange, she developed a cough and a temperature of 38.3 °C (101.0 °F), with progression of respiratory symptoms to severe dyspnea, with some wheezing. A 35-year-old woman was hospitalized for thrombotic thrombocytopenic purpura for which she underwent therapeutic plasma exchange with fresh frozen plasma. After 7 days of treatment, she had improved sufficiently to allow for weaning from daily transfusions; however, at the conclusion of plasma exchange, she developed a cough and a temperature of 38.3 °C (101.0 °F), with progression of respiratory symptoms to severe dyspnea, with some wheezing. On physical examination, the blood pressure is 120/80 mm Hg. There is no rash or hives. She is tachycardic and cyanotic on cardiopulmonary examination. Oxygen saturation is 80% on room air, 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-sized heart and no pleural effusion. On physical examination, the blood pressure is 120/80 mm Hg. There is no rash or hives. She is tachycardic and cyanotic on cardiopulmonary examination. Oxygen saturation is 80% on room air, 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-sized heart and no pleural effusion. Which of the following is the most likely cause for this patient's reaction? 1. Pulmonary embolism 2. Antileukocyte antibodies 3. Allergy to donor plasma proteins 4. Circulatory overload

Transfusion related acute lung injury New acute lung injury occurring during or within 6 hour of blood product tranx New acute lung injury occurring during or within 6 hour of blood product tranx All blood products have been implicated All blood products have been implicated May progress to ARDs May progress to ARDs Immune mediated non cardiogenic pulm edema Immune mediated non cardiogenic pulm edema Risk factors No definite risk factors but prolonged storage of blood products, massive tranx, cytokine txt, multiparity, thrombocytopenia and active infections have been implicated in a number of studies. No definite risk factors but prolonged storage of blood products, massive tranx, cytokine txt, multiparity, thrombocytopenia and active infections have been implicated in a number of studies.

Pathogenesis -Abs against HLA -2 hit hypothesis: 1 st hit is an underlying pulm pathology that leads to localization of neutrophils in the pulm vasculature 2 nd hit is the transfusion of blood products containing sensitized neutrophils Ab leading to release of vasoactive Cytokine and pulm edema 1 st hit is an underlying pulm pathology that leads to localization of neutrophils in the pulm vasculature 2 nd hit is the transfusion of blood products containing sensitized neutrophils Ab leading to release of vasoactive Cytokine and pulm edema Leading cause of transfusion related fatalities in the USA 1 case for every units transfused 6-9% mortality rate Epidemiology

Clinical presentation Acute onset of respiratory distress (hypoxemia) during or shortly after blood tranx. On the average within 1-2 hours post tranx Acute onset of respiratory distress (hypoxemia) during or shortly after blood tranx. On the average within 1-2 hours post tranx Fever, tachycardia, tachypnea, +/-hypotension Fever, tachycardia, tachypnea, +/-hypotension In intubated pxts; elevated peak airway pressures, pink frothy airway secretion In intubated pxts; elevated peak airway pressures, pink frothy airway secretion CXR bilateral patchy alveolar infiltrates, normal cardiac picture CXR bilateral patchy alveolar infiltrates, normal cardiac picture Labs; eosinophilia and transient drop in neutrophils, Leuko-agglutinin testing Labs; eosinophilia and transient drop in neutrophils, Leuko-agglutinin testingDiagnosis Clinical presentation and CXR findings -Labs; granulocyte/ leuko-agglutinating abs, decline in C3 or C5 levels hours after onset of symptoms followed by rise 4-7 days later

(a)Bilateral patchy alveolar infiltrate in TRAL (b) Complete resolution ab 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 includes Acute fluid overload: JVP, SBP and widened pulse pressure during dyspneic episode, pulm vascular markings on CXR Acute fluid overload: JVP, SBP and widened pulse pressure during dyspneic episode, pulm vascular markings on CXR Hemolytic transfusion rxns Hemolytic transfusion rxns IgA mediated anaphylaxis in IgA def patients IgA 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 Prognosis Increased risk of recurrence if they receive products from the implicated donor but no risk from other donors

Conclusion Transfusion reactions are mostly due to clerical errors and can range from benign reactions to life threatening emergencies Transfusion reactions are mostly due to clerical errors and can range from benign reactions to life threatening emergencies Early detection, discontinuation of transfusion and instituting supportive care are key to management. Early detection, discontinuation of transfusion and instituting supportive care are key to management. Reporting of all reactions helps to improve standard practices and reduce future occurrences. Reporting of all reactions helps to improve standard practices and reduce future occurrences.

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