A nurse calls to report chills and fever partway through a unit. For every suspected transfusion reaction, stop the transfusion and start a defined laboratory investigation. Donor screening, testing, and pathogen reduction reduce the infection risk of transfused components but do not eliminate it. The laboratory has two roles. It determines whether a reaction caused harm, and it determines whether an implicated donor or component puts other recipients at risk.
Immediate response and basic workup
The bedside team stops the transfusion, checks the patient, paperwork, and unit, and notifies the transfusion service. The clinical team stabilizes and treats the patient. The transfusion service technologist performs the laboratory 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 has four steps:
- 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 a postreaction urine specimen for hemoglobinuria, and the postreaction blood specimen 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. 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 (BNP).1
When hemolysis is suspected, compare the patient specimen with residual component and administration tubing samples, using collection methods that avoid introducing hemolysis. Free hemoglobin already present in the bag supports injury before administration. A rise confined to the tubing directs investigation toward the administration equipment, temperature, pressure, and simultaneous fluids. This comparison localizes a possible source of injury. A negative DAT alone does not establish a nonimmune cause.2
Acute reactions
Acute reactions begin during transfusion or within 24 hours.1
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| Reaction | Mechanism | Key findings | Immediate response and laboratory action | 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 and notify the transfusion service; perform the clerical and hemolysis workup while the clinical team stabilizes the patient | 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; inspect the component and equipment and investigate handling | 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; culture the patient and component, perform a component Gram stain, and notify the collecting facility while the clinical team treats suspected sepsis | 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 | Fever of at least 38 °C with a rise of at least 1 °C from the pretransfusion temperature, or chills or rigors, during transfusion or within 4 hours after it ends, in the absence of another pyretic stimulus; a diagnosis of exclusion after hemolysis and bacterial contamination are ruled out, and a concerning reaction is assessed even when it does not meet the formal case definition | Stop transfusion and exclude hemolysis and sepsis; the clinical team treats symptoms | Prestorage leukoreduction for recurrent reactors |
| Allergic reaction, mild | IgE-mediated mast-cell degranulation against a plasma allergen | Urticaria, pruritus, erythema | Pause the transfusion and notify the clinical team; resumption requires a clinical assessment that symptoms remain isolated | Washed cellular components for recurrent severe reactions under transfusion-service policy |
| 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 the transfusion and activate the emergency clinical response; investigate the implicated component after stabilization | Washed cellular components or other product-specific support for a documented plasma-protein mechanism |
| Transfusion-related acute lung injury (TRALI) | 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; distinguish TRALI from circulatory overload and report the implicated donation while the clinical team provides respiratory support | Plasma and platelet donor policies favoring male donors or HLA-antibody-screened donors |
| Transfusion-associated circulatory overload (TACO) | Volume exceeds cardiovascular reserve | New or worsening respiratory distress or pulmonary edema during or within 12 hours after transfusion, together with supporting findings such as clinical or radiographic volume overload, hypertension, jugular venous distension, and elevated BNP or NT-proBNP; the combination of findings defines the reaction, and an elevated BNP alone does not | Stop transfusion and assess the circulatory-overload pattern; the clinical team provides treatment | Transfusion-service consultation on rate and component volume for recipients at risk |
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.1,3 Report suspected TRALI and posttransfusion sepsis to the blood collection facility immediately, so other components from the involved donations can be retrieved.3
The 2019 consensus distinguishes two forms of transfusion-related acute lung injury (TRALI). Type I occurs without an acute respiratory distress syndrome (ARDS) risk factor. Type II permits an ARDS risk factor or existing mild ARDS when respiratory status was stable during the 12 hours before transfusion and the subsequent deterioration is judged transfusion related. Both require the acute hypoxemia and pulmonary-edema findings, with onset during or within 6 hours of transfusion and hydrostatic edema not the main explanation. The respiratory course before transfusion is therefore part of the classification. An ARDS risk factor does not exclude TRALI. Classification combines the clinical and transfusion-service assessment. Record any uncertainty or concurrent circulatory overload.4
Delayed reactions
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| Reaction | Mechanism | Key findings | Management and prevention |
|---|---|---|---|
| Delayed serologic transfusion reaction | Newly demonstrable clinically significant red-cell antibody after transfusion; IgG rises 2 to 14 days after re-exposure | Serologic change without demonstrated hemolysis; review hemoglobin and hemolysis markers against baseline | Preserve the new antibody history and select compatible units for future transfusion |
| Delayed hemolytic transfusion reaction | Often an anamnestic response to a non-ABO antigen, classically Rh, Kidd, Duffy, or Kell; IgG rises 2 to 14 days after re-exposure | Serologic evidence with red-cell destruction, such as an unexplained hemoglobin fall, increased bilirubin or lactate dehydrogenase, and reduced haptoglobin | Investigate the implicated transfusion and select antigen-negative, antiglobulin-crossmatched units for the relevant antibody |
| 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 | Report the urgent platelet fall and perform or refer the HPA antibody workup; future component selection follows the identified antibody and the transfusion-service plan |
| 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 | Trend ferritin with the transfusion history and report the cumulative pattern; the clinical service manages treatment |
A positive DAT or newly identified alloantibody establishes a serologic finding. Hemolysis requires separate evidence. The National Healthcare Safety Network (NHSN) January 2026 protocol retains delayed serologic and delayed hemolytic definitions in its previous-classifications section. Those categories are no longer part of its routinely requested data. A laboratory can still use them for a clearly identified internal classification process.5
Nonimmune hemolysis, transfusion-associated sepsis, circulatory overload, and iron overload do not involve an antibody. The other reactions in both tables depend on antibody or another immune mediator.
Alloimmunization is an adverse outcome even without symptoms, because it complicates future compatibility testing and increases the risk of delayed hemolytic reactions and platelet refractoriness. 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.1,6 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 that supports leukoreduction to reduce HLA alloimmunization.7 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 are a major limit 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, so trending minor errors gives early warning of major errors.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 can 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 cause transfusion reactions, which are recognized and investigated by the same rules. Neonates rarely mount classic acute immune reactions because their immune system is immature. 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 removes infection exposure to another donor. Mistransfusion, bacterial sepsis, circulatory overload, febrile reactions, and hemolytic reactions from clerical errors remain possible, so the same rules apply as for 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, and D spread parenterally, as does HGV/GBV-C.1
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| 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 | No separate routine US donor assay; HBV donor screening reduces the opportunity for HDV transmission because HDV requires HBV, and some risk remains3,8 |
| HEV | Hepeviridae, single-stranded RNA | Fecal-oral; transfusion transmission possible | IgM and IgG anti-HEV, HEV RNA | No routine US screening; probable US transfusion transmission has been reported |
| HGV/GBV-C | Flaviviridae, enveloped RNA | Parenteral | RNA by RT-PCR; anti-E2 marks past infection | Not tested. No disease association has been demonstrated |
HIV, HTLV, and West Nile virus
HIV-1 and HIV-2. These retroviruses cause AIDS. Almost all US 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.3,9
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. A donor with a positive supplemental result is permanently deferred.10
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 US outbreaks and substantially reduced transfusion-transmitted cases.1,3
Bacterial contamination
Bacterial contamination is now the leading infectious cause of transfusion-associated sepsis because donor testing has greatly reduced transmission of the viral agents. Room-temperature-stored platelets have 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.3
Red-cell contamination is rarer and more often involves cold-growing organisms such as Yersinia enterocolitica and citrate-using organisms, with risk rising over weeks of storage.3
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.11
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. Laboratory testing of a patient for babesiosis uses thick and thin blood films, PCR, and serology. Patient diagnostic testing is separate from donor testing.12
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.3
Plasmodium species. Malaria is a rare transfusion complication in the United States. FDA's December 2022 final guidance recommends 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 January 2025 FDA draft guidance, not for implementation, proposes selective malaria NAT of donations from donors with malaria risk (travel to a malaria-endemic country in the past 12 months, prior residence in an endemic country, or a history of malaria). Under the draft, these donors are tested and no longer deferred.13,14
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. Permanent deferral remains for a donor diagnosed with vCJD, CJD, or another prion disease, a donor with a blood relative diagnosed with a familial prion disease (familial CJD, Gerstmann-Sträussler-Scheinker syndrome, or fatal familial insomnia), and a donor who received cadaveric pituitary growth hormone or a cadaveric dura mater transplant.15
Pathogen inactivation
Pathogen reduction adds a manufacturing step beyond donor testing. Heat treatment of albumin has been used since 1948. Solvent-detergent and organic-solvent treatment inactivate lipid-enveloped viruses such as HIV, HBV, HCV, HTLV, EBV, CMV, and HHV-6 and HHV-8. Nonenveloped viruses such as HAV and parvovirus B19 are resistant to these treatments. Nanofiltration and photochemical reduction extend coverage to additional agents. 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.1,3
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
A suspected transfusion-transmitted infection requires prompt communication to the transfusion service and collecting facility while donor linkage remains under investigation. In the NHSN January 2026 framework, a listed pathogen detected in a recipient with transfusion in the preceding 30 days can trigger a TTI Rapid Alert. CDC recommends submitting that alert within 72 hours of identifying a potential TTI and entering investigation information as it becomes available. Final proof of donor transmission is not a prerequisite for that alert. The laboratory records what is known, what remains uncertain, and subsequent findings. Separate state and federal reporting requirements also apply.5
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 are covered in the Blood Bank Quality Assurance lesson. When a reaction is reported, confirm that the transfusion has been stopped, check patient and unit identification, and retain every specimen, bag, and tubing set for the investigation.5,16
Practice
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. Back to text
- Strobel E. Hemolytic transfusion reactions. Transfus Med Hemother. 2008;35(5):346-353. doi:10.1159/000154811 Back to text
- 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. Back to text
- Vlaar APJ, Toy P, Fung M, et al. A consensus redefinition of transfusion-related acute lung injury. Transfusion. 2019;59(7):2465-2476. doi:10.1111/trf.15311 Back to text
- Centers for Disease Control and Prevention. National Healthcare Safety Network. Biovigilance Component Hemovigilance Module Protocol. Version 3.0. January 2026. Accessed September 7, 2026. Back to text
- 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 Back to text
- 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 Back to text
- Centers for Disease Control and Prevention. Hepatitis D basics. Updated April 24, 2024. Accessed August 31, 2026. Back to text
- 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. Back to text
- 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. Back to text
- 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. Back to text
- US Food and Drug Administration. Recommendations for Reducing the Risk of Transfusion-Transmitted Babesiosis. Guidance for Industry. May 2019. Accessed August 31, 2026. Back to text
- US Food and Drug Administration. Recommendations to Reduce the Risk of Transfusion-Transmitted Malaria. Guidance for Industry. December 2022. Accessed August 31, 2026. Back to text
- US Food and Drug Administration. Recommendations to Reduce the Risk of Transfusion-Transmitted Malaria. Draft Guidance for Industry. January 2025. Accessed August 31, 2026. Back to text
- 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. Back to text
- US Food and Drug Administration. Notifying FDA of Fatalities Related to Blood Collection or Transfusion. Guidance for Industry. August 2021. Accessed August 31, 2026. Back to text