Transfusion Practice
Transfusion Reactions and Transfusion-Transmitted Infections
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Every suspected transfusion reaction stops the transfusion and starts a defined laboratory investigation, and every transfused component carries a residual infection risk that donor screening, testing, and pathogen reduction reduce without eliminating. The laboratory role is twofold: determine whether a reaction caused harm, and determine whether an implicated donor or component threatens other recipients.
Immediate response and basic workup
Recognition and treatment require a multidisciplinary response. The bedside team stops the transfusion, maintains intravenous access with 0.9% sodium chloride, treats the patient, performs a clerical check of the patient, paperwork, and unit, and notifies the transfusion service. The transfusion service technologist performs the basic workup, and the transfusion service physician interprets the results and recommends the approach for future transfusion. Investigation, documentation, and any additional state, accreditation, or facility reporting follow the applicable requirements, and the FDA, AABB, and CAP roles remain distinct.1
The basic workup follows one logic:
- Check for a clerical discrepancy first. A wrong patient or wrong sample is the single most preventable cause of a hemolytic reaction.
- Inspect the postreaction plasma or serum for visible hemolysis and compare the color with a prereaction specimen when one exists.
- Perform a direct antiglobulin test (DAT) on the postreaction specimen and repeat ABO testing on the postreaction sample and the implicated unit.
- Test the postreaction specimen for urinalysis hemoglobinuria and for lactate dehydrogenase, bilirubin, and haptoglobin changes as the clinical picture requires.
A negative DAT does not exclude immune hemolysis when incompatible cells have already been cleared, when too few coated cells remain, or when the coating is below the assay’s sensitivity. A DAT that is stronger on the postreaction specimen than the prereaction specimen, or a mixed-field DAT, suggests circulating incompatible transfused cells and prompts DAT with separate IgG and C3d reagents plus an eluate to identify the antibody coating the cells.1 The clinical picture may prompt secondary testing, including a repeat antibody screen or crossmatch, eluate studies, cultures, HLA or HNA antibody testing, chest imaging, or B-type natriuretic peptide.1
Acute reactions
Acute reactions begin during transfusion or within 24 hours.1
| Reaction | Mechanism | Key findings | Immediate management | Prevention |
|---|---|---|---|---|
| Acute hemolytic transfusion reaction, immune | Preformed IgM or IgG, most severely ABO antibody, binds donor antigen; complement activation produces intravascular hemolysis, vasoactive amine and cytokine release, and coagulation activation | Fever, chills, flank, back, or infusion-site pain, hemoglobinemia, hemoglobinuria, hypotension, disseminated intravascular coagulation, renal failure; as little as 10 mL of incompatible blood can trigger it | Stop transfusion, maintain IV access, support blood pressure and renal perfusion, treat coagulopathy | Positive patient and sample identification at every step |
| Acute hemolytic transfusion reaction, nonimmune | Mechanical or thermal red-cell damage from improper storage or warming temperature, small-bore needles, pressure infusers, or incomplete deglycerolization | Hemoglobinuria most commonly, often asymptomatic; DAT negative | Stop transfusion; hydrate | Correct handling and equipment technique |
| Transfusion-associated sepsis | Bacterial growth in the component, platelets far more often than red cells because of room-temperature storage | High fever with a temperature rise of 2 °C or more, severe chills, hypotension, or circulatory collapse during or shortly after transfusion; gram-positive contamination may present hours later | Stop transfusion, begin broad-spectrum antimicrobials, culture patient and component with Gram stain, notify the collecting facility | Skin antisepsis, diversion pouch, and platelet bacterial-risk control or pathogen reduction |
| Febrile nonhemolytic transfusion reaction | Recipient antibody against donor leukocytes, or cytokines released by leukocytes during storage | Temperature rise of at least 1 °C or chills or rigors within 4 hours, in the absence of another pyretic stimulus; a diagnosis of exclusion after hemolysis and sepsis are ruled out | Antipyretics; meperidine treats rigors, with respiratory-depression caution | Prestorage leukoreduction for recurrent reactors |
| Allergic reaction, mild | IgE-mediated mast-cell degranulation against a plasma allergen | Urticaria, pruritus, erythema | Pause transfusion, give antihistamine, resume if symptoms resolve and no other symptom appears | Premedication for recurrent reactors |
| Anaphylactoid or anaphylactic reaction | More extensive mediator release; reported in IgA-deficient patients with anti-IgA and in haptoglobin deficiency, though most cases are idiopathic | Bronchospasm, angioedema, hypotension, gastrointestinal symptoms, collapse; rare, below about 10 per 100,000 units | Stop transfusion permanently; intramuscular epinephrine in the mid-anterolateral thigh is the immediate drug, repeated per the anaphylaxis protocol; support airway, oxygenation, and circulation | Washed cellular components, IgA-deficient components, and IgA-deficient immune globulin for documented anti-IgA |
| Transfusion-related acute lung injury | Donor anti-HLA or anti-HNA antibodies, stored-blood proinflammatory mediators, or both acting with patient factors injure the alveolar-capillary membrane | Acute hypoxemia and bilateral infiltrates within 6 hours, with pulmonary edema that circulatory overload does not explain | Stop transfusion; provide oxygen and ventilatory support and assess for circulatory overload | Plasma and platelet donor policies favoring male donors or HLA-antibody-screened donors |
| Transfusion-associated circulatory overload | Volume exceeds cardiovascular reserve | New or worsening respiratory distress with clinical or radiographic volume overload, hypertension, jugular distension, and elevated BNP or NT-proBNP | Upright positioning, oxygen, diuresis | Slower rate and smaller-volume aliquots in very young, elderly, cardiac, or renal patients |
Hypotension without circulatory-overload evidence supports TRALI; hypertension, elevated BNP or NT-proBNP, cardiovascular changes, and fluid-overload evidence support TACO. No single feature is definitive, and overlap occurs.1,2 Suspected TRALI and posttransfusion sepsis are reported to the blood collection facility immediately so other components from the involved donations can be retrieved.2
Delayed reactions
| Reaction | Mechanism | Key findings | Management and prevention |
|---|---|---|---|
| Delayed serologic or hemolytic transfusion reaction | Anamnestic antibody response to a non-ABO antigen, classically Rh, Kidd, Duffy, or Kell, from prior transfusion or pregnancy; IgG rises 2 to 14 days after re-exposure | Unexplained falling hemoglobin, rising LDH and bilirubin, falling haptoglobin; DAT often positive; serologic reactions may be asymptomatic, hemolytic reactions add jaundice and malaise | Antigen-negative, antiglobulin-crossmatched units for future transfusion; prevention depends on accurate history and record keeping |
| Posttransfusion purpura | Anamnestic antibody against a platelet antigen, classically HPA-1a, destroying transfused and autologous platelets | Abrupt severe thrombocytopenia, typically 7 to 10 days after transfusion, with bleeding; high-dose IVIG corrects the thrombocytopenia | HPA antigen-negative platelets for future transfusion; the Leukocyte and Platelet Antigen Testing page covers the HPA workup |
| Iron overload | Cumulative iron from chronic red-cell transfusion, about 250 mg per unit, with significant accumulation possible after 10 to 20 units | Multiorgan liver, heart, and endocrine dysfunction with elevated ferritin | Serial ferritin follow-up; chelation, exchange transfusion, or phlebotomy as indicated |
Alloimmunization itself is an adverse outcome even without symptoms, because it complicates future compatibility and raises delayed-hemolytic and refractoriness risk. Red-cell alloimmunization affects roughly 2% to 8% of transfused patients generally and rises sharply in chronically transfused sickle cell disease, where prevalence reaches about one third of patients under ABO and D matching alone and falls with extended Rh and K matching.1,3 In the Trial to Reduce Alloimmunization to Platelets, lymphocytotoxic antibodies developed in 45% of controls and 17% of recipients of filtered apheresis platelets, the trial result behind leukoreduction’s HLA-alloimmunization benefit.4 HPA-specific alloimmunization, which affects a small fraction of multiply transfused patients, is unaffected by leukoreduction because platelets express their own HPA antigens. Nonimmune causes account for most platelet-refractoriness cases overall.1
Sample collection errors set the ceiling on transfusion safety. Major wrong-blood-in-tube errors occur at roughly 1 in 1,200 to 1 in 2,800 samples, and minor missing-information labeling defects at roughly 1 in 71 to 1 in 165. The rates correlate: a facility with more minor errors has a higher major-error rate, which makes minor-error trending a useful leading indicator.1
Reactions to derivatives and special populations
Plasma derivatives such as albumin, immune globulin, and coagulation factor concentrates more often cause noninfectious reactions. Hypotensive reactions follow rapid albumin infusion, particularly in patients taking angiotensin-converting enzyme inhibitors, and IVIG can cause aseptic meningitis and renal dysfunction. Infection after modern viral inactivation is uncommon.1
Therapeutic apheresis with blood-component replacement fluid can itself provoke transfusion-type reactions, following the same recognition rules. Neonates rarely mount classic acute immune reactions because their immune system is immature, but they are disproportionately vulnerable to the metabolic derangements of transfusion, including hyperkalemia, hypocalcemia, and hyperglycemia or hypoglycemia, and in necrotizing enterocolitis or sepsis to T-antigen activation with polyagglutination hemolysis. Autologous transfusion eliminates infection exposure to another donor, while mistransfusion, bacterial sepsis, circulatory overload, febrile reactions, and hemolytic reactions from clerical errors remain possible under the same rules that govern allogeneic transfusion.1
Hepatitis viruses
Hepatitis is liver inflammation from any cause; the hepatitis viruses are the subset for which the liver is the primary target. Hepatitis A and E spread fecal-orally, and hepatitis B, C, D, and G spread parenterally.1
| Agent | Family and genome | Transmission | Key markers | Donor screening |
|---|---|---|---|---|
| HAV | Picornaviridae, single-stranded RNA | Fecal-oral | IgM anti-HAV marks acute infection; IgG anti-HAV marks past infection or immunity | Not routinely tested |
| HBV | Hepadnaviridae, partly double-stranded circular DNA | Parenteral, sexual, perinatal | HBsAg marks active infection; anti-HBs marks immunity; HBeAg marks high infectivity; IgM anti-HBc marks recent or acute infection and persists about 6 months; HBV DNA by NAT is the earliest marker | HBsAg, anti-HBc, and HBV NAT |
| HCV | Flaviviridae, single-stranded RNA | Parenteral; sexual and vertical transmission rare | Anti-HCV for screening; HCV RNA for confirmation and infectivity | Anti-HCV and HCV NAT |
| HDV | Defective single-stranded RNA requiring HBsAg | Parenteral, sexual | Anti-HDV and HDV RNA | Tested only indirectly; HBV screening removes it, because HDV cannot replicate without HBV |
| HEV | Hepeviridae, single-stranded RNA | Fecal-oral; transfusion transmission possible | IgM and IgG anti-HEV, HEV RNA | Routine U.S. screening absent; probable U.S. transfusion transmission has been reported |
| HGV/GBV-C | Flaviviridae, enveloped RNA | Parenteral | RNA by RT-PCR; anti-E2 marks past infection | Untested, with no demonstrated disease association |
HIV, HTLV, and West Nile virus
HIV-1 and HIV-2. These retroviruses cause AIDS; almost all U.S. cases are HIV-1, with HIV-2 associated with West Africa and rare in the United States. Every donation intended for transfusion is screened with a licensed anti-HIV-1/2 assay and HIV-1 NAT. A reactive donation is not released; supplemental testing and any donor reentry follow FDA’s December 2017 NAT guidance.2,5
HTLV-I and HTLV-II. These retroviruses integrate as provirus. Transmission requires viable donor leukocytes, and plasma does not transmit HTLV. Licensed screening assays react with both types, so they are managed together. Under FDA’s February 2020 guidance, a repeatedly reactive donation receives licensed supplemental testing and the donor is deferred; a donor who is eligible can be evaluated for reentry after at least 6 months with two different licensed screening assays, both nonreactive, and a positive supplemental result permanently defers.6
West Nile virus. This mosquito-borne Flavivirus circulates between Culex mosquitoes and birds. Donor NAT screening, in minipools with reflex to individual-donation testing on a reactive pool, began in 2003 after the 1999 to 2003 U.S. outbreaks and substantially reduced transfusion-transmitted cases.1,2
Bacterial contamination
Bacterial contamination is now the leading infectious cause of transfusion-associated sepsis because donor testing has controlled the viral agents. Room-temperature-stored platelets carry a far higher risk than refrigerated red cells, and gram-positive skin flora are the organisms most often recovered. Prevention begins with validated skin antisepsis and diversion of the initial blood into a separate pouch. Under the current Circular of Information, every room-temperature platelet component has either tested negative for bacterial contamination under an FDA-recommended bacterial risk control strategy using an FDA-cleared or approved device, or been treated with FDA-approved pathogen reduction technology; culture is one compliant strategy among several.2
Red-cell contamination is rarer and favors cold-growing organisms such as Yersinia enterocolitica and citrate-using organisms, with risk rising over weeks of storage.2
Syphilis, parasites, and prions
Syphilis. Treponema pallidum testing with a licensed serologic assay is required for every donation intended for transfusion, and a reactive unit is not released. FDA’s December 2020 guidance applies additional treponemal or nontreponemal testing according to the screening assay and permits donor reentry after successful treatment completed at least 3 months earlier or after medical evaluation establishes that the original result was falsely reactive.7
Babesia microti. This tick-borne intraerythrocytic protozoan is a documented transfusion-transmitted pathogen. FDA’s May 2019 guidance recommends year-round licensed NAT in designated higher-risk jurisdictions, or an approved pathogen-reduction device where applicable, and a donor with a reactive NAT result is deferred for at least 2 years before any requalification. A patient-side diagnosis of babesiosis uses thick and thin smears, PCR, and serology under clinical authority, which is a separate question from donor testing.8
Trypanosoma cruzi. The agent of Chagas disease is an insect-vector zoonosis endemic to Central and South America that can persist asymptomatically for decades, so transfusion transmission occurs during the chronic latent phase. Licensed antibody screening is required on the current donation or at least one previous donation.2
Plasmodium species. Malaria is a rare transfusion complication in the United States. FDA’s December 2022 final guidance generally requires a 3-month deferral after qualifying travel for residents of nonendemic countries and eligible former residents, and a 3-year deferral after malaria or for specified former-resident scenarios. A 2025 FDA proposal for selective NAT in recurrent travelers remains draft guidance and is not for implementation.9
Prion disease. Classic Creutzfeldt-Jakob disease has no documented transfusion transmission; that risk remains theoretical. Four probable transfusion-transmitted variant CJD infections were reported in the United Kingdom. FDA’s May 2022 revision removed deferrals based solely on time spent in the United Kingdom during 1980 to 1996, in France, or in Ireland during 1980 to 2001, while permanent deferrals remain for diagnosed CJD or vCJD, familial prion disease, cadaveric dura mater or pituitary growth hormone exposure, and a blood relative with CJD under the current donor-eligibility guidance.10
Pathogen inactivation
Pathogen reduction adds a manufacturing step beyond donor testing. Heat treatment of albumin has run since 1948, and solvent-detergent and organic-solvent treatment inactivate lipid-enveloped viruses such as HIV, HBV, HCV, HTLV, EBV, CMV, and HHV-6 and HHV-8 while leaving nonenveloped viruses such as HAV and parvovirus B19 resistant. Nanofiltration and photochemical reduction add further coverage. In the United States, FDA-approved photochemical pathogen reduction for platelets and plasma products uses amotosalen with UVA light; riboflavin and UV systems are used in other jurisdictions. Prions, some bacterial spores, and high-titer nonenveloped virus remain resistant to current methods.1,2
Look-back, quarantine, and reporting
A current donation confirmed positive for HBV, HCV, HIV, or HTLV cannot be transfused, and every prior donation from that donor becomes suspect; any prior component still in date is quarantined pending supplemental testing. If a recipient is found to have acquired one of these infections from a single-donor unit, that donor is permanently deferred, and a multi-donor exposure prompts donor retesting with the implicated donors evaluated individually. Deferred donors are notified with an explanation of the result and its implications.1
Any death suspected to be related to transfusion is investigated. Under 21 CFR 606.170(b) and FDA’s August 2021 guidance, the facility notifies FDA as soon as possible after confirming that a complication of blood collection or transfusion was fatal; the collecting facility reports donor fatalities and the compatibility-testing facility reports recipient fatalities, and the written investigation report follows within 7 days after the fatality. Transfusion-related adverse events may also be reported to the CDC National Healthcare Safety Network Biovigilance Component hemovigilance module, whose surveillance protocol supplies CDC case classification criteria. The full reporting triggers and deadlines sit with quality assurance in the Blood Bank Quality Assurance page.2,11
References
- Bloch EM, Campbell-Lee S, McKenna DH Jr, Montemayor-Garcia C, Schwartz J, Shaz B, Storry J, eds. Technical Manual. 22nd ed. AABB; 2026.
- Association for the Advancement of Blood & Biotherapies, American Red Cross, America's Blood Centers, Armed Services Blood Program. Circular of Information for the Use of Human Blood and Blood Components. June 2024. Accessed August 31, 2026.
- Chou ST, Alsawas M, Fasano RM, et al. American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support. Blood Adv. 2020;4(2):327-355. doi:10.1182/bloodadvances.2019001143.
- Trial to Reduce Alloimmunization to Platelets Study Group. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med. 1997;337(26):1861-1869. doi:10.1056/NEJM199712253372601.
- US Food and Drug Administration. Nucleic Acid Testing (NAT) for Human Immunodeficiency Virus Type 1 (HIV-1) and Hepatitis C Virus (HCV): Testing, Product Disposition, and Donor Deferral and Reentry. Guidance for Industry. December 2017. Accessed August 31, 2026.
- US Food and Drug Administration. Use of Serological Tests to Reduce the Risk of Transfusion-Transmitted Human T-Lymphotropic Virus Types I and II (HTLV-I/II). Guidance for Industry. February 2020. Accessed August 31, 2026.
- US Food and Drug Administration. Recommendations for Screening, Testing, and Management of Blood Donors and Blood and Blood Components Based on Screening Tests for Syphilis. Guidance for Industry. December 2020. Accessed August 31, 2026.
- US Food and Drug Administration. Recommendations for Reducing the Risk of Transfusion-Transmitted Babesiosis. Guidance for Industry. May 2019. Accessed August 31, 2026.
- US Food and Drug Administration. Recommendations to Reduce the Risk of Transfusion-Transmitted Malaria. Guidance for Industry. December 2022. Accessed August 31, 2026.
- US Food and Drug Administration. Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components. Guidance for Industry. May 2022. Accessed August 31, 2026.
- Centers for Disease Control and Prevention. National Healthcare Safety Network. Biovigilance Component Hemovigilance Module Surveillance Protocol. Accessed August 31, 2026.