Transfusion Medicine
Last revised 19 March 2008
Last major update August 2007
Copyright (c) 2007-8, PathologyOutlines.com, Inc.
See also Coagulation chapter
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Transfusion Medicine - table of contents
Transfusion reaction: general, acute hemolytic, allergic-mild, allergic-severe, delayed hemolytic, febrile nonhemolytic, graft versus host disease, immune system modulation, nonimmune hemolysis, red blood cell alloimmunization, transfusion related acute lung injury
Transfusion side effects: circulatory overload, coagulation effects, hemoglobinopathy (apparent), hypotension, iron overload, metabolic effects, platelet antibodies, post transfusion purpura, transfusion-associated microchimerism
Transfusion transmitted disease: general, pathogen inactivation, Babesiosis, bacteria, CMV, variant Creutzfeldt–Jakob, Hepatitis B, Hepatitis C, HIV, HTLV, malaria, Parvovirus, SEN virus, syphilis, Toxoplasma, transfusion transmitted virus, Trypanosoma cruzi, West Nile virus
Standards for blood banks: general
Primary references for Transfusion Medicine
American Journal of Clinical Pathology (AJCP), January 1975 to July 2007
Archives of Pathology and Laboratory Medicine (Archives), January 1976 to August 2007
Biomed Center, 1 March 1997 to 17 August 2007
Henry’s Clinical Diagnosis and Management by Laboratory Methods (2006, 21st ed)
Journal search terms: transfusion and each disease entity listed
Please refer to these primary references for more detailed discussions and additional images
Transfusion reaction
Usually identified during or shortly after transfusion
If identified during transfusion:
- stop transfusion; keep IV line open with saline
- report to blood bank/transfusion service using standard forms
- check labels of transfused components for clerical errors
- check post-transfusion serum/plasma for hemolysis compared to pre-transfusion sample
- perform DAT (direct antiglobulin test) on post-transfusion specimen, compare it to pre-transfusion sample
- document transfusion reaction in patient’s chart
If identified after transfusion:
- determine cause, document in patient’s chart
Algorithm for patient management and blood bank investigation
Acute hemolytic transfusion reaction
By definition, presents within 24 hours of transfusion
Usually due to accidental transfusion of ABO incompatible red blood cells (see Standards section below for prevention strategies)
Less commonly due to anti-Pk, anti-Vel or rarely anti-Lea (Lewis), anti-Jka, anti-Jkb (Kidd) or anti-K1 (Kell) antibodies
May be immune mediated due to effect of drugs (cefotetan-Am J Hematol 2000;64:67, oxaliplatin chemotherapy-Transfusion 2004;44:838)
Incidence of 1 per 14-38K red cell transfusions (20 annual deaths in US)
Severity is related to volume of incompatible blood transfused
Hemolytic antibodies cause complement mediated lysis of red blood cells in peripheral circulation; extravascular hemolysis is less common
Complement activation causes release of cytokines, leading to fever (increased temperature of at least 1°C), chills, hypotension, wheezing, chest pain, nausea and vomiting, flank pain
Variable patient symptoms - 47% have none; severe reaction causes DIC, bleeding, renal failure, shock, circulatory collapse and death (2%)
Laboratory: hemoglobulinemia and hemoglobinuria; elevated LDH, bilirubin, low haptoglobin (Eur J Clin Invest 2006;36:202); may have positive direct antiglobulin test (DAT)
May also occur due to ABO incompatible plasma in platelet products (Archives 2007;131:909)
- very rare; less than 20 case reports, all involving group O platelets
- usually occurs in group A patients or those with anti-A titers greater than 1:1000
- can prevent by removing plasma from platelets, or limiting number of incompatible group O platelets in a 24 hour period
Case reports: due to antibodies - ABO incompatible platelet products #1 (AJCP 1999;111:202), #2 in a baby (J Clin Apher 2005;20:225), anti-Bg HLA antibodies (Transfusion 2003;43:753), anti-Coa (Immunohematol 2001;17:45), anti-Dombrock(a) (Transfusion 2006;46:244), anti-Fy3 in a non sickle cell disease patient (Immunohematol 2005;21:48), anti-IH in a patient with sickle cell disease (Transfusion 2000;40:828), anti-Jka not detected by polybrene screen (Ann Clin Lab Sci 2006;36:101), anti-Jra (Transfusion 2004;44:197), anti-P1 (Transfusion 1998;38:373)
due to non-antibodies - chimeric red cells in a donor who was a twin (Transfusion 2003;43:1449), sickle cell disease (Transfusion 2001;41:323)
Treatment: stop transfusion but maintain IV access; hydration and diuretics (maintain renal perfusion but avoid fluid overload), possibly dopamine (maintain blood pressure and cardiac function); possibly exchange transfusion; report to blood bank promptly since another patient may be at risk if there is a name mix up
References: Merck Manual
Allergic transfusion reaction - mild
Common (1 per 2000 transfusions); occur with all types of blood components but less common with red blood cells
May occur with autologous blood products (Archives 2003;127:316)
Symptoms: pruritis, urticaria, erythema, cutaneous flushing, angioedema, nausea, vomiting, diarrhea, abdominal pain; 10% have only pulmonary symptoms
Prevention: pretreatment with diphenhydramine is common but controversial (Transfus Med Rev 2007;21:1, Br J Haematol 2005;130:781), removal of plasma because reaction may be due to antibodies to donor plasma proteins; washing red blood cells and platelets, but not if only cutaneous allergic reaction
Treatment: stop transfusion immediately and maintain IV access; intubate or administer oxygen if necessary; diphenhydramine (50-100 mg) is usually effective; may need epinephrine for severe reactions
Can restart the transfusion if reaction is mild; if reaction is severe, do not restart
Allergic transfusion reaction - severe / major (anaphylactic)
Symptoms similar to anaphylaxis
Occurs in 1 per 30,000 transfusions
Causes: IgA deficiency (< 0.05 mg/dL) plus anti-IgA antibodies (obtain quantitative IgA levels) causes <20% of cases (Immunohematol 2004;20:226); haptoglobin deficiency due to IgG or IgE antihaptoglobin (more common in Japan); also plasma proteins, chemicals used to sterilize tubing, penicillin or other drugs; cause is often unknown (Curr Opin Hematol 2003;10:419)
Symptoms: those of mild allergic reaction (above) plus hypotension, tachycardia, chest pain, loss of consciousness, arrhythmia, shock, cardiac arrest, dyspnea or stridor, wheezing; no fever
Prevention: premedication with antihistamines or corticosteroids; if IgA deficiency, use IgA deficient plasma or wash red cells and platelets; resuspending platelets in a nonprotein storage solution instead of fresh frozen plasma may be helpful (Transfusion 2002;42:556)
Case reports: 4 year old girl receiving blood from mother (Acta Anaesthesiol Scand 2002;46:1276)
Treatment: stop transfusion but maintain IV access; intubation, oxygen, IV fluids, epinephrine as needed, antihistamines as needed, particularly if urticaria, aminophylline for bronchospasm; steroids for chronic symptoms
Delayed hemolytic transfusion reaction
By definition, occurs 24 hours or more after transfusion, usually within 2 weeks
Due to anamnestic immune response in patients previously alloimmunized by certain RBC antigens; hemolysis is usually extravascular
Cannot be detected by pretransfusion antibody screening tests or crossmatches because antibodies are present in low concentrations, have low affinity for antigen or indicator antigen is missing from test red cells
Antibodies are usually IgG reactive at 37°C, fix complement; Duffy (Fya) and Kidd (Jka) are most likely
Associated with prolonged intervals between initial and subsequent transfusions, as antibodies decrease to undetectable levels
Rarely is due to a primary immune response with no prior exposure (Immunohematol 2004;20:184)
Symptoms: usually mild hemolysis, fever, falling hematocrit, jaundice; may have “bystander hemolysis” affecting non-transfused red cells, due to complement activation and deposition of C3d on non-transfused red cells
Sickle cell patients usually have non-severe symptoms (Transfusion 2002;42:37), but may have acute pain syndrome with life threatening anemia due to bystander hemolysis (hyperhemolysis, Pediatrics 2003;111:e661)
Laboratory: anemia, mild hemolysis, reticulocytes, hyperbilirubinemia (unconjugated), increased serum LDH and WBCs, low haptoglobin, positive DAT, new RBC antibody present, spherocytes due to removal of portions of red cell membranes by splenic phagocytic cells
Prevention: accurate recordkeeping of prior red cell alloantibodies and avoiding reexposure; obtain accurate patient history of other transfusions and contact those institutions for their records; minimize transfusions; sickle cell patients should have their extended red cell antigen phenotype determined (ABO, Rh, Kell, Kidd, Duffy, Lewis, MNS) before transfusion therapy and receive units phenotypically matched for C, E, and Kell (Transfusion 2001;41:1086)
Case reports: severe reaction due to anti-At(a) (Transfusion 1999;39:834), due to anti-D (Transfusion 1998;38:459), due to anti-Go(a) (Am J Hematol 1996;53:248), due to anti-Jk(a) (Acta Chir Iugosl 2005;52:111), due to anti-Jk3 after massive postpartum hemorrhage requiring transfusion (Archives 1999;123:949), multiple episodes due to different antibodies (Transfus Sci 2000;23:107)
sickle cell patients - due to anti-c (Sao Paulo Med J 1999;117 n.1), due to anti-Js(a) (AJCP 1997;108:658), due to anti-s (J Pediatr Hematol Oncol 1999;21:70), with pregnancy (Obstet Gynecol 2007;110:471), with Serratia marcescens infection and death (J Natl Med Assoc 2006;98:1697)
Treatment: usually careful followup only; may need exchange transfusion if large number of antigen positive red cells; IV immunoglobulin may prevent transfusion reactions if compatible blood cannot be obtained
Febrile nonhemolytic transfusion reaction
Temperature rise at least 1º C, usually associated with chills or rigors, but without hemolysis
Usually during or within 1 hour of transfusion completion
Incidence of 0.1% of RBC transfusions, 0.1-1.0% of platelet transfusions
Due to pyrogenic cytokines and intracellular contents released from donor leukocytes
A particular problem with platelet transfusions because platelets are stored at room temperature, which allows contaminating leukocytes to remain functional
No complications, but costs time and money to rule out more serious transfusion reactions
Some recommend continuing the transfusion after reaction has been diagnosed to minimize number of donor exposures
Others recommend against continuing the transfusion because may have continued reaction or may have subsequent severe reaction if initial reaction was actually due to bacterial contamination or hemolysis
Patients are often pretreated for transfusions by acetaminophen and diphenhydramine, which benefits recipient but does not necessarily save money (Archives 2004;128:991, Transfus Med Rev 2007;21:1)
These reactions are underreported in cancer patients (MedGenMed 2004;6:17)
Prevention: leukocyte reduction (Transfusion 2004;44:10, Transfusion 2004;44:25, but see Transfusion 2001;41:997); pre-storage reduction may be more effective than post-storage reduction; plasma removal is also helpful
Treatment: acetaminophen (optional, fever is usually self limited), diphenhydramine (commonly used, but may have no effect)
DD: bacterial contamination, hemolytic transfusion reaction, disease related fever, rise to normal temperature in initially hypothermic patient
Graft versus host disease - transfusion related
Rare
Viable donor CD8+ T cells proliferate and attack recipient’s bone marrow cells and possibly other organs (Osaka City Med J 1999;45:37); recipient’s immune system does not attack these donor T cells
Usually 2-50 days after transfusion
Rate markedly reduced after universal leukoreduction in United Kingdom (Transfusion 2007;47:1455)
Very rare in blood stored 4+ days due to WBC inactivation (Br J Haematol 2000;111:146)
Symptoms: skin rash, diarrhea, fever, abnormal liver function tests, pancytopenia, hypoplastic marrow
Risk factors: marked cellular immunodeficiency; recipient may have normal immunity if homozygous for a HLA haplotype and donor is heterozygous with one shared haplotype, which causes donor cells to see recipient cells as foreign, but recipient cells don’t see donor cells as foreign (high risk if directed donations from first or second degree relatives); rural areas where gamma radiation is not possible (Transfusion 2007;47:1405, Indian Pediatr 2004;41:1260)
Indications for irradiating blood components to inactivate donor lymphocytes:
absolute - chemotherapy with purine analogs, congenital cellular immunodeficiency (severe combined immunodeficiency, DiGeorge syndrome), hematopoietic progenitor cell transplantation, granulocyte transfusion, Hodgkin’s lymphoma, intrauterine transfusion, neonates who have received intrauterine transfusion, transfusion from relatives
probable - infants < 1200g, non-Hodgkin’s lymphoma/leukemia (Vox Sang 2002;83:279), HLA-matched platelet concentrates, high dose chemotherapy, radiation therapy or aggressive immunotherapy
controversial - solid organ transplants, large volume or exchange transfusions in infant who did not receive intrauterine transfusion, aplastic anemia, absolute lymphopenia
NOT indicated - HIV infection, hemophilia, humoral immunodeficiency (common variable immunodeficiency), small volume transfusions in term infant who did not receive intrauterine transfusion, elderly, immunosuppression other than purine analogs, pregnancy, red cell disorders (hemoglobin, membrane or metabolic)
Diagnosis: skin biopsy
Case reports: fatal case caused by blood from unrelated HLA homozygous donor #1 (AJCP 2000;113:732), #2 (Transfusion 2006;46:885); fatal cases caused by blood from related donors - father (Indian J Pediatr 2005;72:533), first-degree relatives (J Natl Med Assoc 2005;97:418)
Treatment: 90% mortality, usually due to infection
Immune system modulation due to transfusion
Also called transfusion related immune modulation (TRIM)
Transfusion is “liquid allogeneic transplant”, causing changes to immunologic profile of recipient (Archives 2007;131:708)
Transfusions may increase nosocomial infections in critically ill patients (Crit Care Med 2002;30:2249) and overall mortality (JAMA 2002;288:1499); for ICU patients, one study found reduced mortality with lower hematocrit trigger, possibly due to fewer transfusions (N Engl J Med 1999;340:409)
However, transfusions also decrease recurrence of Crohn’s disease (Colon Rectum 1989;32:749) and enhance graft survival after HLA-DR shared blood transfusions (Hum Immunol 2002;63:902)
No reduction in infectious complications from leukoreduction (Shock 2006;26:342)
References: Chest 2005;127:295, Transfus Clin Biol 2001;8:315.
Nonimmune hemolysis and transfusion
Must exclude immune causes
Hemolysis of red cells may occur from storage and handling, hyper- and hypoosmotic fluids, thermal injury
Lysed red cells may cause hemodynamic, renal and pulmonary problems, possibly death
Laboratory: hemoglobinemia, hemoglobinuria, possibly hyperkalemia (if renal failure)
Treatment: stop transfusion but maintain IV access, save blood bag, tubing and IV fluids; rule out hemolytic transfusion reaction, monitor serum potassium and urine output
DD: hemolytic transfusion reaction with no identifiable antibody, percutaneous mechanical thrombectomy (Transfusion 2005;45:1291), transfusion related infection (malaria, babesiosis)
Red blood cell alloimmunization and transfusion
Red cell antibodies occur in 3% of general population, 5-37% with thalassemia (Transfus Med 2006;16:200), 18-47% with sickle cell anemia (Transfusion 2002;42:37), 20% if prior transfusion but no hematologic or oncologic disease
Still occurs in pregnancy despite widespread antenatal and postpartum Rhesus immune globulin (RhIG), due to inadvertent failure to administer and antenatal sensitization prior to administration of RhIG (Semin Hematol 2005;42:169)
Incidence not affected by prestorage leukoreduction (Br J Haematol 2005;129:151)
Different antibodies appear at different times after transfusions (Transfusion 2006;46:250)
Recommended to match red cells for E antigens in thalassemia patients (Southeast Asian J Trop Med Public Health 2006;37:1015)
Usually no acute hemolytic transfusion reactions even if red cell antibodies present, if accurate antibody identification and component phenotyping occurs during compatibility testing
Delayed incompatibility occurs in 1 per 1500 units due to anamnestic response in previously sensitized patient; however, often no actual hemolysis and is termed delayed serologic transfusion reaction
May cause transfusion challenges in solid organ transplant patients (Transplantation 2007;84:527)
Appears to be regulated by CD4+ CD25+ T cells (Am J Hematol 2007;82:691)
Alloimmunization may be reduced by molecular testing (Curr Opin Hematol 2006;13:471, Transfusion 2006;46:841)
Transfusion related acute lung injury (TRALI)
Clinical diagnosis of acute respiratory distress, usually during or within hours of transfusion
#1 cause of death from transfusion therapy
Incidence of 1 per 5,000 units of packed RBC
Considered a subtype of ARDS, but associated with better outcome than non-TRALI ARDS
Computer screening identifies more cases of post-transfusion hypoxemia than are reported voluntarily (AJCP 2005;124:601)
Epidemiologic studies: allogeneic red blood cell transfusion is an independent risk factor for ARDS in the intensive care unit population; follows a dose-response relationship (Crit Care 2007 Jun 6;11(3):R63 [Epub ahead of print]), but see Eur J Anaesthesiol 2007;24:355; transfusions of plasma-rich blood products, FFP and platelets may have higher risk of ARDS than RBC transfusions (Chest 2007;131:1308); restrictive transfusion policies reduce late onset ARDS in trauma patients (J Trauma 2007;63:1)
Symptoms: vary from mild to life threatening; usually rapid onset of shortness of breath, severe hypoxemia (<90% pO2 on room air), tachycardia, fever, hypotension, cyanosis, noncardiogenic pulmonary edema; by definition, no findings of circulatory overload, no preexisting acute lung injury or ARDS
Chest Xray: necessary to confirm diagnosis; bilateral infiltrates resembling pulmonary edema, may persist after symptoms subside
Pathophysiology: endothelial damage likely due to donor antibodies against recipient HLA or other granulocyte antigens (Hematology Am Soc Hematol Educ Program 2006;497); testing for these antibodies is not required for diagnosis and is not predictive (Vox Sang 2007;93:70, Vox Sang 2007;92:247); granulocytes accumulate within pulmonary vasculature and extravasate into alveoli (AJCP 1999;112:216)
Risk factors: plasma from female donors (Transfusion 2007;47:599), particularly in critically ill patients (Crit Care Med 2007;35:1645), sepsis, chronic alcohol abuse; possibly presence of donor antigranulocyte or HLA class II antibodies (Am J Respir Crit Care Med 2007 [Epub ahead of print]), increasing number of units of whole blood transfused (AJCP 2007;128:128)
Case reports: transfusions between mother and daughter (AJCP 2004;121:590), 2 cases in children (Transfus Med 2006;16:343), 67 year old man with transfusion for iron deficiency anemia (CMAJ 2007;177:149), recurrence 2 years later (Transfus Med 2007;17:192)
Treatment: stop transfusion, maintain IV access and consult blood bank; antipyretics and fluids (for fever and hypotension), oxygen; ventilation if needed; usually resolves within 2-4 days but 20% die
DD: fluid overload from transfusion, bacterial contamination, allergic reaction, ARDS, pulmonary embolism, pulmonary hemorrhage
References: Transfusion 2004;44:1774 (consensus panel), summary of consensus panel, ASH update, Blood 2005;105:2266
Transfusion side effects
Circulatory (fluid / volume) overload due to transfusion
Also called transfusion associated circulatory overload (TACO)
Occurs when transfusion volume exceeds cardiovascular capacity
Common; 1 per 2,000 red cell transfusions, 1 per 400 red cell transfusions in ICU (Transfusion 2006;46:1478); 1% of elderly patients with total knee or hip replacement (Immunohematol 1996;12:87), 1 per 6,000 platelet pool recipients
May occur after only 1-2 units of red cells
Prevent by slowing rate of transfusion (longer infusion or breaking component into smaller aliquots and giving them over time)
Risk factors: compromised cardiovascular function, current volume overload, small intravascular volume (elderly, young children), severe chronic anemia
Symptoms: dyspnea, hypoxemia, elevated venous pressure, pulmonary edema and rales, orthopnea, possible congestive heart failure
Chest Xray: pulmonary edema, distended pulmonary artery, cardiomegaly
Laboratory: elevated B-natriuretic peptide (BNP) is 81% sensitive and 89% specific (Transfusion 2005;45:1056)
Case reports: 84 year old man with respiratory distress after receiving fresh frozen plasma
Treatment: diuresis
DD: TRALI (usually no cardiovascular history, difficult to distinguish in critically ill patients-Crit Care Med 2006;34:S109), allergic reaction, other causes of congestive heart failure
References: Archives 2007;131:708
Coagulation effects of transfusion
Due to dilution of patient’s blood with red blood cells lacking platelets and coagulation factors, and possibly also to direct effects of trauma or surgery itself
Massive transfusion
Transfusion greater than 1 blood volume (70 mL/kg in adults, 85-100 mL/kg in neonates) or 10 units of blood in an adult in 24 hours
Onset and severity may differ in elective surgery versus trauma (Vox Sang 2005;89:123)
Causes decrease in fibrinogen
May cause hypothermia if red cells are not warmed prior to transfusion, leading to prolongation of PT and PTT and impaired platelet function
See also Metabolic effects of transfusion, below
May cause metabolic acidosis and hypokalemia due to citrate in red blood cell units
May cause hyperkalemia due to red cell damage from storage or irradiation
Complex coagulopathy occurs in trauma patients with hypothermia, shock, tissue anoxia, DIC
Treatment: sufficient RBC for adequate oxygen delivery, keep platelet count > 50K, plasma to replace plasma factors (early may be better, J Trauma 2007;62:112), cryoprecipitate for fibrinogen, possibly early recombinant factor VIIa (J Trauma 2007;62:1095); 1:1:1 ratio of red