Editing Blood transfusion (section)

== Adverse effects ==
In the same way that the safety of pharmaceutical products is overseen by [[pharmacovigilance]], the safety of blood and blood products is overseen by haemovigilance. This is defined by the World Health Organization (WHO) as a system "...to identify and prevent occurrence or recurrence of transfusion related unwanted events, to increase the safety, efficacy and efficiency of blood transfusion, covering all activities of the transfusion chain from donor to recipient." The system should include monitoring, identification, reporting, investigation and analysis of adverse events, near-misses, and reactions related to transfusion and manufacturing.<ref>{{cite web|url=https://www.who.int/bloodsafety/haemovigilance/en/ |archive-url=https://web.archive.org/web/20110318122450/http://www.who.int/bloodsafety/haemovigilance/en/ |url-status=dead |archive-date=March 18, 2011 |title=WHO &#124; Haemovigilance |publisher=Who.int |date=2013-06-25 |access-date=2013-12-11}}</ref> In the UK this data is collected by an independent organisation called SHOT (Serious Hazards Of Transfusion).<ref>{{cite web |url=http://www.shotuk.org/home/shot-organisation/141-2/ |title=SHOT Terms of Reference |publisher=Shotuk.org |access-date=22 August 2014 |archive-date=30 September 2020 |archive-url=https://web.archive.org/web/20200930013157/https://www.shotuk.org/home/shot-organisation/141-2/ |url-status=dead }}</ref> Haemovigilance systems have been established in many countries with the objective of ensuring the safety of blood for transfusion, but their organisational set-up and operating principles can vary.<ref>{{Cite journal |last1=Berg |first1=P |last2=Heiden |first2=M |last3=Müller |first3=S |last4=Meyer |first4=B |last5=Witzenhausen |first5=C |last6=Ruppert-Seipp |first6=G |last7=Kehr |first7=S |last8=Funk |first8=M.B. |date=2024-06-18 |title=A national surveillance system for continuous monitoring of blood transfusion safety: German haemovigilance data |journal=Vox Sanguinis |volume=119 |issue=9 |pages=953–962 |doi=10.1111/vox.13694 |issn=0042-9007 |doi-access=free |pmid=38889998 }}</ref>

Transfusions of blood products are associated with several complications, many of which can be grouped as immunological or infectious. There is controversy on potential quality degradation during storage.<ref>Wang, SS. "What's the Shelf Life of Blood? Focus on Whether Older Donations Impair Recovery of Transfusion Recipients". ''The Wall Street Journal''. 2009 Dec. 1.</ref>

=== Immunologic reaction ===
* [[Acute hemolytic transfusion reaction|Acute hemolytic reactions]] are defined according to Serious Hazards of Transfusion (SHOT) as "fever and other symptoms/signs of haemolysis within 24 hours of transfusion; confirmed by one or more of the following: a fall of Hb, rise in lactate dehydrogenase (LDH), positive direct antiglobulin test (DAT), positive crossmatch"<ref name=":1">{{Cite book|title = The 2014 Annual SHOT Report (2015)| vauthors = Bolton-Maggs PH, Poles D |publisher = SHOT|year = 2015|isbn = 978-0-9558648-7-2 |collaboration = Serious Hazards of Transfusion (SHOT) Steering Group|url = http://www.shotuk.org/wp-content/uploads/report-2014.pdf|access-date = 2016-01-21|archive-url = https://web.archive.org/web/20160127114949/http://www.shotuk.org/wp-content/uploads/report-2014.pdf|archive-date = 2016-01-27|url-status = dead}}</ref> This is due to destruction of donor red blood cells by preformed recipient antibodies. Most often this occurs because of clerical errors or improper [[ABO blood group system|ABO blood typing]] and crossmatching resulting in a mismatch in ABO blood type between the donor and the recipient. Symptoms include fever, chills, chest pain, back pain,<ref name="LauraDean"/> hemorrhage, [[tachycardia|increased heart rate]], shortness of breath, and [[hypotension|rapid drop in blood pressure]]. When suspected, transfusion should be stopped immediately, and blood sent for tests to evaluate for presence of hemolysis. Treatment is supportive. Kidney injury may occur because of the effects of the hemolytic reaction (pigment nephropathy).<ref name=":2">{{cite web|url = https://www.hhs.gov/ash/bloodsafety/2011-nbcus.pdf|title = The 2011 National Blood Collection and Utilization Survey Report|access-date = 21 January 2016|publisher = Department of Health and Human Services|archive-date = 19 March 2016|archive-url = https://web.archive.org/web/20160319015943/http://www.hhs.gov/ash/bloodsafety/2011-nbcus.pdf|url-status = dead}}</ref> The severity of the transfusion reaction is depended upon amount of donor's antigen transfused, nature of the donor's antigens, the nature and the amount of recipient antibodies.<ref name="LauraDean"/>
* [[Delayed hemolytic transfusion reaction|Delayed hemolytic reactions]] occur more than 24 hours after a transfusion. They usually occur within 28 days of a transfusion. They can be due to either a low level of antibodies present prior to the start of the transfusion, which are not detectable on pre-transfusion testing; or development of a new antibody against an antigen in the transfused blood. Therefore, delayed haemolytic reaction does not manifest until after 24 hours when enough antibodies are available to cause a reaction. The red blood cells are removed by macrophages from the blood circulation into liver and spleen to be destroyed, which leads to extravascular haemolysis. This process usually mediated by anti-Rh and anti-Kidd antibodies. However, this type of transfusion reaction is less severe when compared to acute haemolytic transfusion reaction.<ref name="LauraDean"/>
* [[Febrile non-hemolytic transfusion reaction|Febrile nonhemolytic reactions]] are, along with allergic transfusion reactions, the most common type of blood transfusion reaction and occur because of the release of [[cytokine|inflammatory chemical signals]] released by white blood cells in stored donor blood<ref name=":3" /> or attack on donor's white blood cells by recipient's antibodies.<ref name="LauraDean">{{cite book|vauthors=Laura D|title=Blood Groups and Red Cell Antigens|date=2005|publisher=National Center for Biotechnology Information|location=Bethesda, United States|url=https://www.ncbi.nlm.nih.gov/books/NBK2261/|access-date=4 October 2017|archive-date=25 March 2021|archive-url=https://web.archive.org/web/20210325083706/https://www.ncbi.nlm.nih.gov/books/NBK2261/|url-status=live}}</ref> This type of reaction occurs in about 7% of transfusions. Fever is generally short lived and is treated with [[antipyretic]]s, and transfusions may be finished as long as an acute hemolytic reaction is excluded. This is a reason for the now-widespread use of leukoreduction — the filtration of donor white cells from red cell product units.<ref name=":3" />
* [[Allergic transfusion reaction]]s are caused by IgE anti-allergen antibodies. When antibodies are bound to its antigens, [[histamine]] is released from [[mast cell]]s and [[basophil]]s. Either IgE antibodies from the donor's or recipient's side can cause the allergic reaction. It is more common in patients who have allergic conditions such as [[hay fever]]. Patient may feel itchy or having hives but the symptoms are usually mild and can be controlled by stopping the transfusion and giving [[antihistamine]]s.<ref name="LauraDean"/>
* Anaphylactic reactions are rare life-threatening allergic conditions caused by IgA anti-plasma protein antibodies. For patients who have [[selective immunoglobulin A deficiency]], the reaction is presumed to be caused by IgA antibodies in the donor's plasma. The patient may present with symptoms of fever, wheezing, coughing, shortness of breath, and [[shock (circulatory)|circulatory shock]]. Urgent treatment with [[epinephrine (medication)|epinephrine]] is needed.<ref name="LauraDean"/>
* [[Post-transfusion purpura]] is an extremely rare complication that occurs after blood product transfusion and is associated with the presence of antibodies in the patient's blood directed against both the donor's and recipient's platelets HPA (human platelet antigen). Recipients who lack this protein develop sensitization to this protein from prior transfusions or previous pregnancies, can develop thrombocytopenia, bleeding into the skin, and can display purplish discolouration of skin which is known as [[purpura]]. Intravenous immunoglobulin (IVIG) is treatment of choice.<ref name="LauraDean"/><ref>{{Cite book|title = Practical Transfusion Medicine| vauthors = Murphy M |publisher = Wiley-Blackwell|year = 2013|pages = 127–130|chapter = Post-transfusion purpura|edition = 4th| veditors = Murphy M, Pamphilon D, Heddle N }}</ref>
* [[Transfusion-related acute lung injury]] (TRALI) is a syndrome that is similar to [[acute respiratory distress syndrome]] (ARDS), which develops during or within 6 hours of transfusion of a plasma-containing blood product. Fever, hypotension, shortness of breath, and tachycardia often occurs in this type of reaction. For a definitive diagnosis to be made, symptoms must occur within 6 hours of transfusion, hypoxemia must be present, there must be radiographic evidence of bilateral infiltrates and there must be no evidence of left atrial hypertension (fluid overload).<ref name=":5">{{cite web |url=https://www.cdc.gov/nhsn/biovigilance/blood-safety/ |title=Blood Safety |publisher=National Healthcare Safety Network (NHSN), Centers for Disease Control and Prevention |date=July 2024 }}</ref> It occurs in 15% of the transfused patient with mortality rate of 5 to 10%. Recipient risk factors includes: end-stage liver disease, sepsis, haematological malignancies, sepsis, and ventilated patients. Antibodies to human neutrophil antigens (HNA)  and human leukocyte antigens (HLA) have been associated with this type of transfusion reaction. Donor's antibodies interacting with antigen positive recipient tissue result in release of inflammatory cytokines, resulting in pulmonary capillary leakage. The treatment is supportive.<ref>{{cite journal | vauthors = Kim J, Na S | title = Transfusion-related acute lung injury; clinical perspectives | journal = Korean Journal of Anesthesiology | volume = 68 | issue = 2 | pages = 101–5 | date = April 2015 | pmid = 25844126 | pmc = 4384395 | doi = 10.4097/kjae.2015.68.2.101 }}</ref>
* [[Transfusion associated circulatory overload|Transfusion associated circulatory overload (TACO)]] is a common, yet underdiagnosed, reaction to blood product transfusion consisting of the new onset or exacerbation of three of the following within 6 hours of cessation of transfusion: acute respiratory distress, elevated brain natriuretic peptide (BNP), elevated central venous pressure (CVP), evidence of left heart failure, evidence of positive fluid balance, and/or radiographic evidence of pulmonary vascular congestion.<ref name=":5" /> Patients with [[congestive heart failure]] or kidney disease are more susceptible to volume overload.  For especially vulnerable patients, a standard RBC unit could be split by sterile technique in the blood bank and administered over 8 hours instead of the standard 4 hours.  Plasma transfusion is especially prone to causing TACO because large volumes are usually required to give any therapeutic benefit.
* [[Transfusion-associated graft versus host disease]] frequently occurs in immunodeficient patients where recipient's body failed to eliminate donor's T cells. Instead, donor's T cells attack the recipient's cells. It occurs one week after transfusion.<ref name="LauraDean"/> Fever, rash, diarrhoea are often associated with this type of transfusion reaction. Mortality rate is high, with 89.7% of the patients dead after 24 days. Immunosuppressive treatment is the most common way of treatment.<ref>{{cite journal | vauthors = Kopolovic I, Ostro J, Tsubota H, Lin Y, Cserti-Gazdewich CM, Messner HA, Keir AK, DenHollander N, Dzik WS, Callum J | display-authors = 6 | title = A systematic review of transfusion-associated graft-versus-host disease | journal = Blood | volume = 126 | issue = 3 | pages = 406–414 | date = July 2015 | pmid = 25931584 | doi = 10.1182/blood-2015-01-620872 | doi-access = free }}</ref> Irradiation and leukoreduction of blood products is necessary for high risk patients to prevent T cells from attacking recipient cells.<ref name="LauraDean"/>

=== Infection ===

The use of greater amount of red blood cells has been suggested to increase the risk of infections, not only transfusion-transmitted infections, but also due to a phenomenon known as transfusion-related immunomodulation (TRIM). TRIM may be caused by macrophages and their byproducts.<ref name="u083">{{cite journal | last1=Youssef | first1=Lyla A. | last2=Spitalnik | first2=Steven L. | title=Transfusion-related immunomodulation: a reappraisal | journal=Current Opinion in Hematology | volume=24 | issue=6 | date=2017 | pmid=28806274 | pmc=5755702 | doi=10.1097/MOH.0000000000000376 | pages=551–7}}</ref> In those who were given red blood cells only with significant anemia ("restrictive" strategy), serious infection rates were 10.6% while in those who were given red blood at milder levels of anemia ("liberal" strategy), serious infection rates were 12.7%.<ref>{{cite journal | vauthors = Rohde JM, Dimcheff DE, Blumberg N, Saint S, Langa KM, Kuhn L, Hickner A, Rogers MA | display-authors = 6 | title = Health care-associated infection after red blood cell transfusion: a systematic review and meta-analysis | journal = JAMA | volume = 311 | issue = 13 | pages = 1317–26 | date = April 2014 | pmid = 24691607 | pmc = 4289152 | doi = 10.1001/jama.2014.2726 }}</ref>

On rare occasions, blood products are contaminated with bacteria. This can result in a life-threatening infection known as transfusion-transmitted bacterial infection. The risk of severe bacterial infection is estimated, {{as of|2020|lc=y}}, at about 1 in 2,500 platelet transfusions, and 1 in 2,000,000 red blood cell transfusions.<ref name="r896">{{cite journal | last1=Ackfeld | first1=Theresa | last2=Schmutz | first2=Thomas | last3=Guechi | first3=Youcef | last4=Le Terrier | first4=Christophe | title=Blood Transfusion Reactions-A Comprehensive Review of the Literature including a Swiss Perspective | journal=Journal of Clinical Medicine | volume=11 | issue=10 | date=2022-05-19 | pmid=35628985 | pmc=9144124 | doi=10.3390/jcm11102859 | doi-access=free | page=2859}}</ref> Blood product contamination, while rare, is still more common than actual infection. The reason platelets are more often contaminated than other blood products is that they are stored at room temperature for short periods of time. Contamination is also more common with longer duration of storage, especially if that means more than 5 days. Sources of contaminants include the donor's blood, donor's skin, phlebotomist's skin, and containers. Contaminating organisms vary greatly, and include skin flora, gut flora, and environmental organisms. There are many strategies in place at blood donation centers and laboratories to reduce the risk of contamination. A definite diagnosis of transfusion-transmitted bacterial infection includes the identification of a positive culture in the recipient (without an alternative diagnosis) as well as the identification of the same organism in the donor blood.

Since the advent of HIV testing of donor blood in the mid/later 1980s, ex. 1985's [[ELISA]], the [[AIDS#Body fluids|transmission of HIV during transfusion]] has dropped dramatically. Prior testing of donor blood only included testing for antibodies to HIV. However, because of latent infection (the "window period" in which an individual is infectious, but has not had time to develop antibodies) many cases of HIV seropositive blood were missed. The development of a nucleic acid test for the HIV-1 RNA has dramatically lowered the rate of donor blood seropositivity to about 1 in 3 million units. As transmittance of HIV does not necessarily mean HIV infection, the latter could still occur at an even lower rate.

The transmission of hepatitis C via transfusion currently stands at a rate of about 1 in 2 million units. As with HIV, this low rate has been attributed to the ability to screen for both antibodies as well as viral RNA nucleic acid testing in donor blood.

Other rare transmissible infections include [[hepatitis B]], [[syphilis]], [[Chagas disease]], [[cytomegalovirus]] infections (in immunocompromised recipients), [[HTLV]], and [[Babesia]].

===Comparison table===
{|class="wikitable"
|+ Comparison of symptoms of blood transfusion reactions characterized by fever.<ref name="Transfusion reactions / M.A. Popovsky 1996 p.">Unless otherwise specified in boxes, reference is: {{cite book | title=Transfusion reactions / M.A. Popovsky | publisher=Karger | location=Basel | year=1996 | isbn=978-3-8055-6509-7 | oclc=40288753 }}</ref>
|colspan=5| + =Occasionally present &nbsp; ++ =Frequently present
|-
!  !! [[Febrile non-hemolytic transfusion reaction|Febrile nonhemolytic]] !! [[Transfusion-related acute lung injury|TRALI]] !! [[Acute hemolytic transfusion reaction|Acute hemolytic]] !! Bacterial contamination
|-
! Appearance of symptoms during or after transfusion
| Usually toward end.<br>5–10% appear up to 2 hours after. || Early (after 10–15 ml) || Early (after 50–100 ml) || Up to 8 hours after transfusion
|-
! Fever
| + || ++ || ++ || ++
|-
! Chills
| ++ || ++ || ++ || +++
|-
! Cold
| ++ || - || + || -
|-
! Discomfort
| ++ || - || - || -
|-
! Rigors
| + || - || - || -
|-
! Headache
| + || - || + || -
|-
! Nausea and/or vomiting
| + || - || ++ || -
|-
! Dyspnea
| + || ++ || ++ || -
|-
! Cyanosis
| - || ++ || ++ || -
|-
! Hypotension / [[circulatory shock]]
| - || ++ || ++ || ++
|-
! [[Disseminated intravascular coagulation]]
| - || - || ++ || ++
|-
! [[Hemoglobinuria]]
| - || - || ++ || +
|-
! [[Renal failure]]
| - || - || ++ || ++
|-
! Back pain
| - || - || ++ || -
|}

=== Inefficacy ===
Transfusion inefficacy or insufficient efficacy of a given unit(s) of blood product, while not itself a "complication" ''per se'', can nonetheless indirectly lead to complications – in addition to causing a transfusion to fully or partly fail to achieve its clinical purpose. This can be especially significant for certain patient groups such as critical-care or neonatals.

For red blood cells (RBC), by far the most commonly transfused product, poor transfusion efficacy can result from units damaged by the so-called storage lesion — a range of biochemical and biomechanical changes that occur during storage. With red cells, this can decrease viability and ability for tissue oxygenation.<ref>{{cite journal | vauthors = Zubair AC | title = Clinical impact of blood storage lesions | journal = American Journal of Hematology | volume = 85 | issue = 2 | pages = 117–122 | date = February 2010 | pmid = 20052749 | doi = 10.1002/ajh.21599 | s2cid = 205293048 | doi-access = free }}</ref> Although some of the biochemical changes are reversible after the blood is transfused,<ref>{{cite journal | vauthors = Heaton A, Keegan T, Holme S | title = In vivo regeneration of red cell 2,3-diphosphoglycerate following transfusion of DPG-depleted AS-1, AS-3 and CPDA-1 red cells | journal = British Journal of Haematology | volume = 71 | issue = 1 | pages = 131–6 | date = January 1989 | pmid = 2492818 | doi = 10.1111/j.1365-2141.1989.tb06286.x | s2cid = 43303207 }}</ref> the biomechanical changes are less so,<ref>{{cite journal | vauthors = Frank SM, Abazyan B, Ono M, Hogue CW, Cohen DB, Berkowitz DE, Ness PM, Barodka VM | display-authors = 6 | title = Decreased erythrocyte deformability after transfusion and the effects of erythrocyte storage duration | journal = Anesthesia and Analgesia | volume = 116 | issue = 5 | pages = 975–981 | date = May 2013 | pmid = 23449853 | pmc = 3744176 | doi = 10.1213/ANE.0b013e31828843e6 }}</ref> and rejuvenation products are not yet able to adequately reverse this phenomenon.<ref name="pmid25053933">{{cite journal | vauthors = Barshtein G, Gural A, Manny N, Zelig O, Yedgar S, Arbell D | title = Storage-induced damage to red blood cell mechanical properties can be only partially reversed by rejuvenation | journal = Transfusion Medicine and Hemotherapy | volume = 41 | issue = 3 | pages = 197–204 | date = June 2014 | pmid = 25053933 | pmc = 4086768 | doi = 10.1159/000357986 }}</ref> There has been controversy about whether a given product unit's age is a factor in transfusion efficacy, specifically about whether "older" blood directly or indirectly increases risks of complications.<ref>{{cite news | url=http://well.blogs.nytimes.com/2013/03/11/the-shelf-life-of-donor-blood/ | work=The New York Times | vauthors=Bakalar N | title=The Shelf Life of Donor Blood | date=2013-03-11 | access-date=2013-04-05 | archive-date=2013-03-17 | archive-url=https://web.archive.org/web/20130317014828/http://well.blogs.nytimes.com/2013/03/11/the-shelf-life-of-donor-blood/ | url-status=live }}</ref><ref>{{cite news | url=https://www.wsj.com/articles/SB10001424052748703939404574567771148801570 | work=The Wall Street Journal | title=What's the Shelf Life of Blood? | vauthors=Wang SS | date=2009-12-01 | access-date=2017-08-03 | archive-date=2017-07-09 | archive-url=https://web.archive.org/web/20170709021358/https://www.wsj.com/articles/SB10001424052748703939404574567771148801570 | url-status=live }}</ref> Studies have not been consistent on answering this question,<ref>{{cite journal | vauthors = Aubron C, Nichol A, Cooper DJ, Bellomo R | title = Age of red blood cells and transfusion in critically ill patients | journal = Annals of Intensive Care | volume = 3 | issue = 1 | pages = 2 | date = January 2013 | pmid = 23316800 | pmc = 3575378 | doi = 10.1186/2110-5820-3-2 | doi-access = free }}</ref> with some showing that older blood is indeed less effective but with others showing no such difference;<ref name="z575">{{cite journal | last1=Fergusson | first1=Dean A. | last2=Hébert | first2=Paul | last3=Hogan | first3=Debora L. | last4=LeBel | first4=Louise | last5=Rouvinez-Bouali | first5=Nicole | last6=Smyth | first6=John A. | last7=Sankaran | first7=Koravangattu | last8=Tinmouth | first8=Alan | last9=Blajchman | first9=Morris A. | last10=Kovacs | first10=Lajos | last11=Lachance | first11=Christian | last12=Lee | first12=Shoo | last13=Walker | first13=C. Robin | last14=Hutton | first14=Brian | last15=Ducharme | first15=Robin | last16=Balchin | first16=Katelyn | last17=Ramsay | first17=Tim | last18=Ford | first18=Jason C. | last19=Kakadekar | first19=Ashok | last20=Ramesh | first20=Kuppuchipalayam | last21=Shapiro | first21=Stan | title=Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial | journal=JAMA | volume=308 | issue=14 | date=2012-10-10 | issn=1538-3598 | pmid=23045213 | doi=10.1001/2012.jama.11953 | pages=1443–51}}</ref><ref name="f112">{{cite journal | last1=Walsh | first1=Timothy S. | last2=Stanworth | first2=Simon | last3=Boyd | first3=Julia | last4=Hope | first4=David | last5=Hemmatapour | first5=Sue | last6=Burrows | first6=Helen | last7=Campbell | first7=Helen | last8=Pizzo | first8=Elena | last9=Swart | first9=Nicholas | last10=Morris | first10=Stephen | title=The Age of BLood Evaluation (ABLE) randomised controlled trial: description of the UK-funded arm of the international trial, the UK cost-utility analysis and secondary analyses exploring factors associated with health-related quality of life and health-care costs during the 12-month follow-up | journal=Health Technology Assessment  | volume=21 | issue=62 | date=2017 | pmid=29067906 | pmc=5682573 | doi=10.3310/hta21620 | pages=1–118}}</ref> these developments are being closely followed by hospital [[blood bank]]ers — who are the physicians, typically pathologists, who collect and manage inventories of transfusable blood units.

Certain regulatory measures are in place to minimize RBC storage lesion — including a maximum shelf life (currently 42 days), a maximum auto-hemolysis threshold (currently 1% in the US, 0.8% in Europe), and a minimum level of post-transfusion RBC survival ''in vivo'' (currently 75% after 24 hours).<ref>{{cite journal | vauthors = Hod EA, Zhang N, Sokol SA, Wojczyk BS, Francis RO, Ansaldi D, Francis KP, Della-Latta P, Whittier S, Sheth S, Hendrickson JE, Zimring JC, Brittenham GM, Spitalnik SL | display-authors = 6 | title = Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation | journal = Blood | volume = 115 | issue = 21 | pages = 4284–92 | date = May 2010 | pmid = 20299509 | pmc = 2879099 | doi = 10.1182/blood-2009-10-245001 }}</ref> However, all of these criteria are applied in a universal manner that does not account for differences among units of product.<ref>{{cite journal | vauthors = Hess JR | title = Scientific problems in the regulation of red blood cell products | journal = Transfusion | volume = 52 | issue = 8 | pages = 1827–35 | date = August 2012 | pmid = 22229278 | doi = 10.1111/j.1537-2995.2011.03511.x | s2cid = 24689742 }}</ref> For example, testing for the post-transfusion RBC survival ''in vivo'' is done on a sample of healthy volunteers, and then compliance is presumed for all RBC units based on universal (GMP) processing standards (RBC survival by itself does not guarantee efficacy, but it is a necessary prerequisite for cell function, and hence serves as a regulatory proxy). Opinions vary as to the "best" way to determine transfusion efficacy in a patient ''in vivo''.<ref>{{cite journal | vauthors = Pape A, Stein P, Horn O, Habler O | title = Clinical evidence of blood transfusion effectiveness | journal = Blood Transfusion = Trasfusione del Sangue | volume = 7 | issue = 4 | pages = 250–8 | date = October 2009 | pmid = 20011636 | pmc = 2782802 | doi = 10.2450/2008.0072-08 }}</ref> In general, there are not yet any ''in vitro'' tests to assess quality or predict efficacy for specific units of RBC blood product prior to their transfusion, though there is exploration of potentially relevant tests based on RBC membrane properties such as [[erythrocyte deformability]]<ref>{{cite journal | vauthors = Burns JM, Yang X, Forouzan O, Sosa JM, Shevkoplyas SS | title = Artificial microvascular network: a new tool for measuring rheologic properties of stored red blood cells | journal = Transfusion | volume = 52 | issue = 5 | pages = 1010–23 | date = May 2012 | pmid = 22043858 | doi = 10.1111/j.1537-2995.2011.03418.x | s2cid = 205724851 }}</ref> and [[erythrocyte fragility]] (mechanical).<ref>{{cite journal | vauthors = Raval JS, Waters JH, Seltsam A, Scharberg EA, Richter E, Daly AR, Kameneva MV, Yazer MH | display-authors = 6 | title = The use of the mechanical fragility test in evaluating sublethal RBC injury during storage | journal = Vox Sanguinis | volume = 99 | issue = 4 | pages = 325–331 | date = November 2010 | pmid = 20673245 | doi = 10.1111/j.1423-0410.2010.01365.x | s2cid = 41654664 }}</ref>

Physicians have adopted a so-called "restrictive protocol" — whereby transfusion is held to a minimum — in part because of the noted uncertainties surrounding storage lesion, in addition to the very high direct and indirect costs of transfusions.<ref name="Missingor">{{cite journal | vauthors = Shander A, Hofmann A, Gombotz H, Theusinger OM, Spahn DR | title = Estimating the cost of blood: past, present, and future directions | journal = Best Practice & Research. Clinical Anaesthesiology | volume = 21 | issue = 2 | pages = 271–289 | date = June 2007 | pmid = 17650777 | doi = 10.1016/j.bpa.2007.01.002 }}</ref><ref>{{cite web
 | title = Transfusion Overuse: Exposing an International Problem and Patient Safety Issue
 | url = https://patientsafetymovement.org/wp-content/uploads/2022/03/Action-Plan-RBC-Overuse-January-13-2013.pdf
 | website = Patient Safety Movement Foundation
 | date = 2013
 | access-date = 15 March 2022
 | archive-date = 1 April 2022
 | archive-url = https://web.archive.org/web/20220401033720/https://patientsafetymovement.org/wp-content/uploads/2022/03/Action-Plan-RBC-Overuse-January-13-2013.pdf
 | url-status = dead
 }}</ref><ref>{{cite web|url=http://www.cap.org/apps/cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt{actionForm.contentReference}=cap_today%2F0409%2F0409d_easy_does_it.html&_state=maximized&_pageLabel=cntvwr |publisher=College of American Pathologists |title=Easy does it — showing caution with RBC transfusions |date=April 2009 |access-date=22 August 2014}}</ref> However, the restrictive protocol is not an option with some especially vulnerable patients who may require the best possible efforts to rapidly restore tissue oxygenation.

Although transfusions of platelets are far less numerous (relative to RBC), platelet storage lesion and resulting efficacy loss is also a concern.<ref>{{cite journal | vauthors = Devine DV, Serrano K | title = The platelet storage lesion | journal = Clinics in Laboratory Medicine | volume = 30 | issue = 2 | pages = 475–487 | date = June 2010 | pmid = 20513565 | doi = 10.1016/j.cll.2010.02.002 }}</ref>

=== Other ===
* A relationship between intra-operative blood transfusion and cancer recurrence has been observed in colorectal cancer.<ref>{{cite journal | vauthors = Cata JP, Wang H, Gottumukkala V, Reuben J, Sessler DI | title = Inflammatory response, immunosuppression, and cancer recurrence after perioperative blood transfusions | journal = British Journal of Anaesthesia | volume = 110 | issue = 5 | pages = 690–701 | date = May 2013 | pmid = 23599512 | pmc = 3630286 | doi = 10.1093/bja/aet068 }}</ref> In lung cancer intra-operative blood transfusion has been associated with earlier recurrence of cancer, worse survival rates and poorer outcomes after lung resection.<ref>{{cite journal | vauthors = Wang T, Luo L, Huang H, Yu J, Pan C, Cai X, Hu B, Yin X | display-authors = 6 | title = Perioperative blood transfusion is associated with worse clinical outcomes in resected lung cancer | journal = The Annals of Thoracic Surgery | volume = 97 | issue = 5 | pages = 1827–37 | date = May 2014 | pmid = 24674755 | doi = 10.1016/j.athoracsur.2013.12.044 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Churchhouse AM, Mathews TJ, McBride OM, Dunning J | title = Does blood transfusion increase the chance of recurrence in patients undergoing surgery for lung cancer? | journal = Interactive Cardiovascular and Thoracic Surgery | volume = 14 | issue = 1 | pages = 85–90 | date = January 2012 | pmid = 22108935 | pmc = 3420304 | doi = 10.1093/icvts/ivr025 }}</ref> Suppression of the [[immune system]] by blood transfusion has been implicated as playing a role in more than 10 different [[cancer]] types, through mechanisms involving the innate and adaptive immune system.<ref name="Transfusion and Apheresis Science">{{cite journal | vauthors = Kormi SM, Seghatchian J | title = Taming the immune system through transfusion in oncology patients | journal = Transfusion and Apheresis Science | volume = 56 | issue = 3 | pages = 310–6 | date = June 2017 | pmid = 28651910 | doi = 10.1016/j.transci.2017.05.017 }}</ref> Five major mechanisms for this include the [[T Lymphocyte|lymphocyte-T]] set, myeloid-derived suppressor cells (MDSCs), [[tumor-associated macrophage]]s (TAMs), [[natural killer cells]] (NKCs), and [[dendritic cells]] (DCs). Blood transfusion may modulate the activity of [[antitumor]] [[CD8+]] [[cytotoxic T lymphocytes]] (CD8+/CTL), temporal response of [[Tregs]], and the [[STAT3]] signaling pathway.  The role of the antitumor [[immune response]] in cancer therapeutics was explored historically through the use of [[bacteria]] to enhance the antitumor [[immune response]] and more recently  in cellular [[Immunotherapy]].<ref name="Transfusion and Apheresis Science" /> However, the impact of transfusion-related immunomodulation (TRIM) on cancer progression has not been definitively established and requires further study.<ref name="o019">{{cite journal | last1=Abou Daher | first1=Layal | last2=Heppell | first2=Olivia | last3=Lopez-Plaza | first3=Ileana | last4=Guerra-Londono | first4=Carlos E. | title=Perioperative Blood Transfusions and Cancer Progression: A Narrative Review | journal=Current Oncology Reports | volume=26 | issue=8 | date=2024 | issn=1534-6269 | pmid=38847973 | doi=10.1007/s11912-024-01552-3 | pages=880–9}}</ref>
*In retrospective studies, blood transfusion has been associated with worse outcomes after [[cytoreductive surgery]] and [[Hyperthermic intraperitoneal chemotherapy|HIPEC]].<ref>{{cite journal | vauthors = Soldevila-Verdeguer C, Segura-Sampedro JJ, Pineño-Flores C, Sanchís-Cortés P, González-Argente X, Morales-Soriano R | title = Hepatic resection and blood transfusion increase morbidity after cytoreductive surgery and HIPEC for colorectal carcinomatosis | journal = Clinical & Translational Oncology | volume = 22 | issue = 11 | pages = 2032–9 | date = November 2020 | pmid = 32277348 | doi = 10.1007/s12094-020-02346-2 | s2cid = 215724889 }}</ref> However, correlation does not prove causation, and transfused patients often have more complicated surgeries and more underlying cardiopulmonary disease compared to untransfused patients; conclusions should be based on prospective [[randomized controlled trial]]s.
* Hypothermia can occur with transfusions with large quantities of blood products which normally are stored at cold temperatures. Core body temperature can go down as low as 32&nbsp;°C and can produce physiologic disturbances. Prevention should be done with warming the blood to ambient temperature prior to transfusions.  Blood warming devices are available to avoid the hemolysis that would occur from unsafe practices such as microwaving.<ref name="g135">{{cite journal | last1=Poder | first1=Thomas G. | last2=Nonkani | first2=Wendyam G. | last3=Tsakeu Leponkouo | first3=Élyonore | title=Blood Warming and Hemolysis: A Systematic Review With Meta-Analysis | journal=Transfusion Medicine Reviews | volume=29 | issue=3 | date=2015 | issn=1532-9496 | pmid=25840802 | doi=10.1016/j.tmrv.2015.03.002 | pages=172–180}}</ref>
* Transfusions with large amounts of red blood cells, whether due to severe hemorrhaging and/or transfusion inefficacy (see above), can lead to an inclination for bleeding. The mechanism is thought to be due to disseminated intravascular coagulation, along with dilution of recipient platelets and coagulation factors. Close monitoring and transfusions with platelets and plasma is indicated when necessary.  Progressive hemorrhagic injury (PHI) in traumatic brain injured patients may be worsened by liberal transfusion strategies.<ref name="i975">{{cite journal | last1=Vedantam | first1=Aditya | last2=Yamal | first2=Jose-Miguel | last3=Rubin | first3=Maria Laura | last4=Robertson | first4=Claudia S. | last5=Gopinath | first5=Shankar P. | title=Progressive hemorrhagic injury after severe traumatic brain injury: effect of hemoglobin transfusion thresholds | journal=Journal of Neurosurgery | volume=125 | issue=5 | date=2016 | pmid=26943843 | pmc=5065393 | doi=10.3171/2015.11.JNS151515 | pages=1229–34}}</ref>
* Metabolic alkalosis can occur with massive blood transfusions because of the breakdown of citrate stored in blood into bicarbonate. However, acidemia is common in massively transfused patients, and acid-base balance is affected by complex factors.<ref name="j156">{{cite journal | last1=Schriner | first1=Jacob B. | last2=Van Gent | first2=J. Michael | last3=Meledeo | first3=M. Adam | last4=Olson | first4=Scott D. | last5=Cotton | first5=Bryan A. | last6=Cox | first6=Charles S. | last7=Gill | first7=Brijesh S. | title=Impact of Transfused Citrate on Pathophysiology in Massive Transfusion | journal=Critical Care Explorations | volume=5 | issue=6 | date=2023 | pmid=37275654 | pmc=10234463 | doi=10.1097/CCE.0000000000000925 | page=e0925}}</ref>
* Hypocalcemia can also occur with massive blood transfusions because of the complex of citrate with serum calcium. Calcium levels below 0.9&nbsp;mmol/L should be treated.<ref>{{cite web | vauthors = Sklar R |title=Damage Control Resuscitation and Management in Severe Hemorrage/Shock in the Prehospital Setting|url=https://internationaltraumalifesupport.remote-learner.net/pluginfile.php/8291/mod_resource/content/1/Position%20Paper%20-%20Damage%20Control%20Resuscitation%20-%202019.pdf |archive-url=https://ghostarchive.org/archive/20221009/https://internationaltraumalifesupport.remote-learner.net/pluginfile.php/8291/mod_resource/content/1/Position%20Paper%20-%20Damage%20Control%20Resuscitation%20-%202019.pdf |archive-date=2022-10-09 |url-status=live |website=internationaltraumalifesupport.remote-learner.net |publisher=ITLA |date=May 2019}}</ref>
* [[Blood doping]] has been used by athletes to increase physical stamina.<ref name="q308">{{cite journal | last1=Marchand | first1=Alexandre | last2=Roulland | first2=Ingrid | last3=Semence | first3=Florian | last4=Jaffredo | first4=Franck | last5=Dehainault | first5=Catherine | last6=Le Guiner | first6=Soizic | last7=Le Pajolec | first7=Marie-Gaëlle | last8=Donati | first8=Francesco | last9=Mekacher | first9=Lamine Redouane | last10=Lamek | first10=Kahina | last11=Ericsson | first11=Magnus | title=Evaluation of the detection of the homologous transfusion of a red blood cell concentrate in vivo for antidoping | journal=Drug Testing and Analysis | volume=15 | issue=11–12 | date=2023 | issn=1942-7611 | pmid=36709998 | doi=10.1002/dta.3448 | pages=1417–29| doi-access=free }}</ref> A lack of knowledge and insufficient experience can turn a blood transfusion into a dangerous event. For example, improper storage involving freezing and thawing, or minor antigen incompatibility, could lead to hemolysis.