Blood donor screening: Overview of recipient and donor protections

INTRODUCTION — Multiple layers of safety are needed to approach the desired level of zero risk to the recipient of a blood transfusion and to protect the safety of the blood donor.

This topic will provide an overview of the procedures and processes involved in blood donor screening for allogeneic transfusion directed at enhancing the safety of the recipient and the donor. Separate topics review the components of the blood donor history, post-donation laboratory testing, and autologous blood donation:

●Donor history – (See "Blood donor screening: Medical history".)

●Laboratory testing – (See "Blood donor screening: Laboratory testing".)

●Autologous donation – (See "Surgical blood conservation: Preoperative autologous blood donation".)

APPROACHES TO MAXIMIZING SAFETY — There are several cornerstone approaches to maximizing the safety of blood transfusion and blood donation [1-4].

●Recipient protections

•Avoiding financial incentives to prospective donors for donating.

•Not collecting blood in prisons due to increased infectious risks of prisoners [5,6].

•Providing educational materials to donors at the donation site so that they can self-defer before donation.

•Obtaining a medical history to identify potential infectious or other risks.

•Establishing deferral criteria for certain medical conditions (cancer) and infectious disease exposures (HIV, malaria, prion diseases).

•Testing blood for various infectious pathogens.

•Collecting post-donation information from donors that will result in the quarantine and destruction of the donated unit if appropriate. (See 'Post-donation screening' below.)

•Pre-storage leukoreduction of cellular blood components (red blood cell and platelet units).

•Application of licensed pathogen reduction technologies to specific blood components (at discretion of the hospital transfusion services and blood collecting organization).

•Establishing procedures for storage conditions, testing, administration, and pathogen reduction technologies.

Leukoreduction and pathogen reduction are discussed separately. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Pre-storage leukoreduction' and "Pathogen inactivation of blood products".)

●Donor protections

•Limiting donation frequency.

•Establishing age and weight eligibility criteria.

•Excluding donors with certain medical conditions (heart disease, lung disease, pregnancy, recent surgery).

•Testing pre-donation vital signs and hemoglobin level.

•Monitoring during donation.

•Providing liquids before and after donation to avoid hypovolemia.

•Providing appropriate follow-up if donor or product infectious disease testing reveals a health risk (eg, positive viral testing).

Although viral testing may lead to donor notification about a potential risk, donation centers emphasize that blood donation should not be used as a means of obtaining this testing, as that may place the recipient at increased risk. (See 'Other incentives' below.)

Over time, organizations such as the Association for the Advancement of Blood & Biotherapies (AABB), the US Food and Drug administration, and the European Medicines Agency (EMA), continue to assess infectious and other risks and make recommendations to blood collection establishments and/or establish requirements regarding screening and deferral criteria.

When it is first suspected that an infectious agent may be transmitted by transfusion, the initial response is to develop donor deferral policies using epidemiologic data. After this initial step, subsequent review often leads to the nationwide implementation of a particular donor screening procedure following recommendations of these agencies [7,8].

In the past, when such procedures were implemented, they tended to become permanent, even if their efficacy could not be established. However, certain requirements have subsequently been modified, either in response to acquiring additional epidemiologic data or for extraordinary circumstances such as during the coronavirus disease 2019 (COVID-19) pandemic [9-12]. Zika virus testing is an example in which testing was implemented when there was concern about infections among donors that were acquired during travel, and for which testing was removed when this risk became negligible. (See "Blood donor screening: Medical history", section on 'COVID-19 pandemic considerations'.)

PROTECTION OF THE RECIPIENT

Pre-donation procedures and processes

Donor motivations — One of the major motivations for donation is altruism, based on a sense of societal responsibility and/or personal awareness of the benefits of donation [13-15].

Elimination of financial incentives — Historically, monetary payment for blood donation has been associated with increased infectious disease risks.

●Data collected in the United States from the 1970s showed higher rates of hepatitis B surface antigen (HBsAg) positivity in paid donors, higher rates of hepatitis in recipients of paid versus volunteer donor blood, and a substantial decrease in cases of post-transfusion hepatitis in transfusion recipients following elimination of financial incentives for blood donation [16-18].

●In 1978, the US Food and Drug Administration (FDA) instituted regulations that required the labeling of a blood unit as either from a volunteer or a paid donor, and several states passed legislation prohibiting the use of blood donated in exchange for payment [19]. The result has been the almost total elimination of paid donors from the whole blood collection system in the United States.

Since the late 1970s, almost all blood components in the United States (whole blood, red blood cells [RBCs], platelets, and plasma for transfusion) come from volunteer donors [20]; an exception has been a small number of platelet apheresis units [21].

Distinct from blood donation is plasma donation for the production of plasma derivatives. Donors of this type of plasma donation are frequently paid in some countries including the United States, although not in others. Safety is maintained in manufactured plasma derivatives such as albumin, immune globulin, and clotting factors because they undergo multiple processing steps that inactivate infectious organisms (these include cold ethanol purification, affinity chromatography, nanofiltration, solvent/detergent treatment, pasteurization). (See "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'Purification methods' and "Pathogen inactivation of blood products".)

In Europe, the European Medicines Agency (EMA) provides oversight for plasma-derived products. Both the EMA and the World Health Organization recommend that two distinct steps with different mechanisms be used to inactivate viruses in plasma derivatives or a manufacturing process be used that reliably inactivates enveloped and non-enveloped viruses [22].

Other incentives — In addition to relying on donor altruism, some blood collection agencies also use incentives other than the direct payment of cash; these include compensation for time missed from work, gifts, monetary credit, and free laboratory screenings for analytes of potential health significance [23,24]. Research into the effectiveness of incentives shows differing results as summarized in a systematic review of this subject [25].

Although there has been concern that incentives may have an adverse influence on blood safety, several reports suggest that well-selected incentives given to first-time or repeat donors do not have an adverse effect on blood safety, as monitored by donor infectious disease testing results [23,26-29].

Potential donors should be advised that donation should not be used as a means of obtaining testing for HIV or other infectious diseases, which was a motivation for some donors in the 1980s during the early days of the HIV epidemic [30-33]. Some centers have adopted additional approaches such as specifically asking donors if they are donating to get an HIV test or offering free HIV testing to people who desire it without requiring that a blood donation be made.

Screening at the donation site

Donor medical history — The major procedure for screening donors at the donation site is the medical history interview, which includes questions about potential infectious risks and donor characteristics that might increase the risk of transfusion reactions.

●Infectious diseases – Risk of infections is assessed by questions about risk factors for HIV, history of infections, travel history, and vaccinations. For some disorders including variant Creutzfeldt-Jacob disease (CJD) and malaria, non-laboratory donor screening procedures are the only method available for increasing transfusion safety [34-37]. For other infections for which laboratory screening tests are available such as HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV), the medical history may reveal infections that are in the window period that precedes development of a positive laboratory test. (See "Blood donor screening: Medical history" and "Blood donor screening: Laboratory testing".)

●TRALI – Individuals with a previous history of their donations causing transfusion-related acute lung injury (TRALI) are deferred from apheresis platelet and plasma donations; some blood collection centers defer them from all donations. The risk of TRALI from different blood components and the mitigation strategies used for each component are presented separately. (See "Transfusion-related acute lung injury (TRALI)", section on 'Prevention'.)

While there are distinct advantages to eliminating donors with possible risks of disease transmission, there are also negative consequences of this approach [38]. Donor deferral criteria often have poor specificity, and as a result, a large number of donors will be deferred who could have safely donated [39]. This is especially concerning when the blood supply is limited, such as during the coronavirus disease 2019 (COVID-19) pandemic, when there have been concerns that donations would be reduced and the blood supply would be insufficient. The FDA altered some donor eligibility and deferral criteria during the pandemic to increase the donor pool. (See "Blood donor screening: Medical history", section on 'COVID-19 pandemic considerations'.)

There is no available algorithm to decide if a given procedure or screening question should be implemented. Such decisions must attempt to balance the extent of disease transmission, the severity of the consequences to the recipient, the expected sensitivity (effectiveness) of the procedure, and the number of donors lost by implementation of the procedure.

Although cost-effectiveness analyses of some donor interventions have been performed, there has not been any consensus on how to use these analyses to guide decision-making [40-43].

Donor deferrals and a registry of deferred donors — Temporary or permanent deferral of donors serves to protect recipients.

Reasons for temporary deferrals for certain high-risk exposures include:

●Certain high-risk behaviors or travel histories related to risk of contracting HIV, malaria, prion diseases, or other infectious diseases

●Receipt of certain live vaccines

●Cancer (some types)

●Certain medications that could cause adverse effects in the recipient

Other factors may permanently disqualify a donor. Among many reasons for permanent or indefinite deferral, examples are:

●Ever tested positive for HIV or hepatitis B surface antigen (HBsAg)

●Ever received bovine insulin or human growth hormone derived from pituitary glands due to concern for Creutzfeldt-Jakob disease (CJD)

●History of certain infectious diseases (such as HIV/AIDS)

Further details about donor deferral are presented separately. (See "Blood donor screening: Medical history".)

Another tool related to donor deferral is the use of a computerized registry of deferred donors; this allows identification of donors from whom blood (or blood components) should not be collected or used for transfusions [44]. Such deferral registries are composed of data obtained during a successful or unsuccessful prior donation attempt that resulted in a donor being permanently or indefinitely deferred, for reasons such as those noted above. When such registries are used prior to donation, they can ensure that blood from such high-risk donors is not collected.

There is no single national blood service in the United States. Instead, blood collection is conducted by many organizations, including the American Red Cross, America's Blood Centers, OneBlood, New York Blood Center, Versiti, Vitalant, and others. These organizations have multiple locations widely distributed across the country, and registry information present in one organization's database may not be available to other blood collection organizations.

Pre-donation deferral avoids the costs and burdens of phlebotomy and reduces the risk that a unit from a deferred donor might be transfused to a recipient. If a unit is collected from a deferred donor and this information is not discovered until post-donation (see 'Post-donation screening' below), the unit is retrieved, quarantined, and destroyed.

Post-donation screening — The primary post-donation procedure for enhancing recipient safety is laboratory testing of the donated unit for multiple infectious disease markers. These are listed separately. (See "Blood donor screening: Laboratory testing".)

A second safety procedure is the telephone callback. At the time of blood donation, donors receive instructions that they may call the blood center sometime after the donation to report additional pertinent medical history information. Telephone callbacks fall into two prominent categories:

●Donors may call back to report the development of an acute illness, such as fever, upper respiratory tract infection, or a gastrointestinal disorder, occurring up to several days post-donation.

●Donors may call back to indicate risk factors for HIV or other infectious diseases that might not have been disclosed at the time of donation.

Blood centers are required to have established policies for managing post-donation telephone callback information. In general, if post-donation information would have caused the donor to be deferred, blood centers will quarantine and destroy any components that have not yet been shipped and will transmit pertinent information to the hospital transfusion services that have received components from the donation. The transfusion service will retrieve any components that are still in their inventory and either return them to the blood center or destroy them. If the unit has already been transfused, information is conveyed to the patient's clinicians who will then determine (often in consultation with the blood center's medical director) if recipient notification and testing is required. Post-donation information that affects the eligibility evaluation of the donor must be reported by licensed blood establishments to the FDA.

Hereditary hemochromatosis — Hereditary hemochromatosis (HH) is a genetic condition caused by homozygosity for the C282Y variant in the HFE gene that can lead to increased iron absorption. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis" and "HFE and other hemochromatosis genes".)

Not all C282Y homozygotes develop iron overload; those who do require therapeutic phlebotomy to remove iron and reduce the risk of organ damage from excess iron. Red blood cells from individuals with HH are normal, and many of these individuals wish to donate blood removed by phlebotomy rather than have it be discarded. (See "Management and prognosis of hereditary hemochromatosis".)

Blood centers in the United States can make individual decisions about whether to accept donations from persons with HH; if they choose to accept such donations, they must adhere to the following regulatory requirements:

●The donor with HH must meet all qualification criteria for donating blood (with the exception of the eight-week inter-donation interval).

●A clinician must provide an order for therapeutic phlebotomy for HH.

●The blood center making the collection must perform therapeutic phlebotomies for any patient with HH at no charge, regardless of whether they meet all blood donor qualification criteria.

These requirements are intended to remove any monetary incentive for a patient with HH to be a blood donor. If these criteria are met, the collected unit of blood does not require special labeling. If therapeutic phlebotomy is required more frequently than an eight-week interval (the minimum inter-donation interval for allogeneic blood donors), such donated units also may be used for transfusion provided all other criteria are met.

Evidence regarding the safety of blood donated from individuals with HH includes the following:

●A systematic review from 2012 evaluated the relative safety of blood from donors with HH and found no evidence to suggest that their blood would present a greater risk to recipients than blood from the general population [45]. However, there were few available studies, and the quality of the evidence was low.

●A study from 2001 that used an anonymous mail survey found that donors with HH had similar rates of risk factors for transfusion-transmitted infections (2.0 percent, versus 3.1 percent for the general population) and similar rates of positive laboratory screenings (1.3 percent, versus 1.6 percent for the general population) [46].

●An in vitro study of the properties of donated blood from 12 donors with HH and 10 random non-HH donors found similar properties of the RBCs in both groups [47].

An international survey from 2013 that queried blood services in 33 countries found that approximately two-thirds of respondents would accept donors known to have an HH genotype, and one-quarter would accept patients who were diagnosed with and being treated for HH [48]. Not all blood centers in the United States collect donations from individuals with HH, despite performing therapeutic phlebotomies.

In contrast to HH, individuals who undergo therapeutic phlebotomy for certain other conditions such as polycythemia vera, a myeloproliferative neoplasm, are not eligible to be blood donors.

PROTECTION OF THE DONOR — Each prospective blood donor is evaluated to reduce the risk of adverse reactions related to the donation [49].

Risks to the donor from blood donation are very small for healthy individuals; however, complications may occur in individuals whose cardiovascular status does not permit adequate compensation for volume depletion or anemia [8]. Thus, deferral criteria for the protection of the donor are based upon establishing that the donor is not likely to have an increased risk of an immediate post-donation reaction, a post-donation reaction that is especially severe or prolonged, or cardiovascular factors that do not permit adequate hemodynamic compensation. Donors are asked questions about their overall state of health and cardiac and pulmonary conditions, which is intended to reduce the likelihood of complications such as myocardial ischemia or syncope related to donation.

Specific guidance regarding donation includes the following:

FDA – The US Food and Drug Administration (FDA) 21 CFR 630.10 states that a donor is not eligible to donate blood if they are not in good health and a donation could harm them. The FDA indicates that the blood center medical director or responsible clinician must determine such eligibility requirements. There are no individualized recommendations related to specific heart or lung diseases.

AABB – The Association for the Advancement of Blood & Biotherapies (AABB) Standards state that the prospective donor must be in good health and free of major organ diseases such as those affecting the heart, liver, or lungs, but AABB allows the medical director to set the specific policy for eligibility in a variety of medical conditions.

General procedures to protect the donor — Anonymity protects the donor. Recipients are not informed of the donor's age sex, skin color, ethnic background, medical history, or vaccination status [50]. A recipient cannot specify that they preferentially would like to receive units from a donor with specific characteristics unless they are part of a directed donation program. (See 'Directed donations' below.)

Age and weight cutoffs — Age cutoffs are used to ensure fully informed consent and maximal safety for donation; weight cutoffs are used to reduce the risk of hypovolemic reactions.

●Age – In the United States, each state sets the age limit for blood donation (typically age 16 or 17 years) [51]. In virtually all states that allow 16 year olds to donate, written permission from a parent or guardian is required for those between 16 and 17 years.

There is no upper age limit for blood donation in the United States; some countries do have an upper age limit. A review of available data supports the safety of blood donation by persons older than age 70 [52,53].

●Weight or blood volume – Blood centers generally defer donors who weigh less than 50 kg. The estimated blood volume (EBV) for a 50 kg adult is approximately 3500 mL, and phlebotomy of 525 mL of blood (500 mL collection plus 25 mL sample volume) would result in a 15 percent reduction in the donor's blood volume [54].

Not surprisingly, the rate of donor reactions has been demonstrated to be inversely proportional to body weight, with the highest reaction rates in donors weighing between 50 and 54 kg [55]. In a report of 11,333 apheresis collections, moderate to severe adverse events (mostly vasovagal), were seen in 53 (0.47 percent) [56]. Risk factors for these events included female sex, lower pre-donation blood volume, lower pre-donation hematocrit, and higher total red blood cell (RBC) loss.

Since 2009, rather than rely solely on the donor's weight, the American Red Cross and some other regional blood centers have implemented a selection criterion for 16 to 18 year old donors. EBV is calculated based on the donor's sex and self-reported height and weight. Donors are determined to be ineligible if their EBV is <3500 mL [57].

This safety initiative has led to decreasing complications among 16- to 18-year-old donors, such that the risk of a presyncopal or syncopal reaction for 16 year olds is no longer different from that observed for 19 year olds.

Donation frequency — Historically, blood centers limited the frequency of allogeneic whole blood donation to allow sufficient time for the hemoglobin level to return to baseline [58]. Some jurisdictions have modified their frequency criteria based on consideration of the time it takes for donors to replenish their iron stores. (See 'Anemia' below and 'Iron deficiency without anemia' below.)

Allowable inter-donation intervals by jurisdiction are [59-61]:

●United States – 8 weeks (longer for certain groups in some blood centers)

●United Kingdom – 16 weeks for females and 12 weeks for males

●Canada – 12 weeks for females and 8 weeks for males

A 2017 study of 45,000 blood donors in the United Kingdom that evaluated the impact of shortening the inter-donation interval indicated that shortening the interval to 8 weeks would increase the percentage of donors with iron deficiency [59]. Canada previously had an interval of 8 weeks for all donors before lengthening the interval for females [61].

Automated erythrocyte apheresis technology permits the collection of double red cell units in one sitting [62]. In the United States, donors are required to wait at least 16 weeks between apheresis RBC collections. In one series, double-unit donors not receiving iron supplementation reestablished their baseline hematocrit at two months post-phlebotomy, but their serum ferritin levels, although still within the normal range, were one-half that of pre-donation levels [63]. In some individuals, serum ferritin did not return to normal by four months post-phlebotomy. (See 'Anemia' below.)

Medical conditions — There may be some variability in specific eligibility requirements in different blood collection organizations in the United States because such specific policies are decided by the medical director of the individual blood collection organization.

The following conditions warrant consideration:

●Cardiopulmonary disease – Donors with conditions that could lead to hypoxia are generally deferred. This includes donors with significant coronary artery disease, cardiac valve disease, arrythmia, cerebrovascular disease, heart failure, or any active pulmonary disease impairing gas exchange.

●Surgery – Donors who have recently had surgery without blood transfusion are deferred until healing is complete and full activity has been resumed.

●Pregnancy – Donors who are pregnant or postpartum are deferred during pregnancy and for six weeks after delivery.

●Seizure disorder – Individuals with a seizure disorder are able to donate, provided that they have had no seizures within a defined period of time (as established by the specific blood center), with or without medications. This policy appears reasonable, as there are no data linking seizure activity to the convulsive activity that may occur secondary to ischemia from a post-donation vasovagal reaction [64].

If donor or unit testing reveals a health risk such as positive viral testing, the donor is notified. (See 'Approaches to maximizing safety' above.)

Vital signs — Other indications for donor deferral in the United States include temperature >37.5°C, blood pressure out of range (>180 or <90 mmHg systolic; >100 or <50 mmHg diastolic), pulse rate outside the established limits of 50 to 100 beats per minute, or an arrhythmia detected on pulse examination.

Exceptions to blood pressure or pulse cutoffs may be made upon the discretion of the medical director. One common exception is for athletes in whom lower pulse rates are an indication of enhanced cardiovascular conditioning.

Likelihood of complications from donating blood — Complications of blood donation are rare; serious complications are very rare. A 2008 retrospective study evaluated over 6 million donations of whole blood and hundreds of thousands of platelet and RBC apheresis donations and estimated the following rate of major complications (excluding hematomas) [65]:

●Whole blood – 7.4 per 10,000

●Apheresis platelets – 5.2 per 10,000

●Apheresis red blood cells – 3.3 per 10,000

Other studies evaluating risk factors have found slightly higher rates of adverse reactions in first-time donors and younger donors [66-71]. A systematic review also identified additional risk factors including lower resting blood pressure, reduced sleep before donation, female sex, and symptoms during previous donations [71]. Provision of a supportive individual during the donation, especially for relatively novice donors, may enhance the donation experience and increase donor retention [72].

A surveillance report of plasma donations to be used in fractionation and production of plasma derivatives performed surveillance on adverse events in >12 million donations from >1 million donors and found an overall rate of adverse events of 15.85 per 10,000 donations (0.16 percent) [73]. Approximately 90 percent were bruising or hypotension without loss of consciousness. First-time donors were 11 times more likely to experience an adverse event than repeat donors. Unlike donors of plasma for transfusion, donors of plasma for fractionation may be paid for donating.

Injuries related to the needlestick are very rare and generally resolve. To determine the frequency of these rare reactions, data from 22 million donations from six countries over a three-year period (2015 to 2017) were pooled and analyzed [74]. This analysis found that cellulitis occurred at a rate of 3.1 per million donations and deep vein thrombosis (DVT) at a rate of 0.9 per million donations. Other local complications were even rarer.

Blood donors comprise a healthy subset of the general population, as reflected by a lower mortality as well as a lower risk of cancer, cardiovascular disease, and transfusion-transmissible viral infection [75-79]. In a retrospective study of over one million blood donors who were followed for up to 35 years after their first computer-registered blood donation, mortality was 30 percent lower than the general population, and cancer incidence was 4 percent lower [79].

Complications of whole blood donation

Vasovagal and hypovolemic reactions

●Prevalence – Vasovagal and/or hypovolemic reactions occur in approximately 2 to 5 percent of blood donors, with true syncope in a smaller number (<0.1 to 0.3 percent) [66,67,70,80,81].

●Risk factors – Contributing factors include psychologic distress (ie, fear of needles, pain, and/or the sight of blood), volume removal of 450 to 500 mL of whole blood, and an orthostatic blood pressure effect superimposed on a post-donation hypovolemic state. In practice, it is difficult to distinguish between the two mechanisms (vasovagal versus hypovolemic versus a combination of both) [82].

The risk of hypovolemic reactions is greater in individuals with lower total blood volumes, and the risk of vasovagal reactions is greater in individuals who are younger, have lower body weight, and are first-time donors. Small studies focusing on high school student donors have confirmed a higher risk of reactions in this age group [68].

●Timing – Most vasovagal and hypovolemic reactions occur immediately after donation or at the refreshment table. Thus, it seems prudent to make sure the donor sits up and stands up slowly, make sure they feel well before walking to the refreshments table, and encourage them to stay at the table for 10 to 15 minutes for observation and fluid replenishment.

In a study involving 194,000 donations, there were 178 such reactions that led to a syncopal episode (incidence of 0.09 percent) [70]. Of these, most occurred in the donation center before, during, or after donation (mostly in the refreshment area); only 19 occurred off-site. Five individuals hit their head and were seen in the emergency department; none were admitted to the hospital. It is these rarer delayed reactions that occur after the donor has left the donation site that have the potential to lead to more severe injury.

●Prevention – Pre-donation screenings and deferrals based on age, weight, blood volume, and vital signs are intended to reduce the risk of hypovolemic and vasovagal reactions. (See 'Age and weight cutoffs' above and 'Vital signs' above.)

Additional preventive measures taken by various blood collection organizations for individuals who are eligible to donate include a combination of some of the following [82]:

•Drink water (500 mL 30 minutes before donation; 300 mL 15 minutes before donation; 16 ounces [473 mL] before donation) [83-86].

•Consume salty snacks or isotonic drinks (eg, sports drinks).

•Encourage applied muscle tension during donation.

•Restrict donation to <15 percent of the EBV in young donors (decline donations from donors <23 years old with an EBV <3500 mL).

●Treatment – If a vasovagal or hypovolemic reaction occurs, such as presyncope, syncope, nausea, or lightheadedness, various blood collection agencies recommend some or all of the following are appropriate [70]:

•If the donor is on a reclining blood donation bed, lower the head and raise the feet.

•If the donor is in the refreshment area, sit the donor in a forward-leaning position with feet on the floor and forearms or elbows on a table. If symptoms persist, arrange for the donor to lie down, and if possible, raise the legs.

•Drink fluids if able.

•If the donor is hyperventilating, encourage the donor to take slow breaths or have the donor breathe into a paper bag.

Anemia — Each donated unit of whole blood contains approximately 525 mL of blood and approximately 240 to 265 mg of iron [87,88]. Blood donation leads to a transient reduction in the hemoglobin mass of approximately 10 percent (approximately 1.4 grams/dL).

Hemoglobin levels will be gradually restored over the following weeks, with a shorter interval in persons with adequate iron stores and in those who are taking oral iron supplementation. The replenishment of iron stores is a slower process (measured in months) than is the increase in hemoglobin, especially in individuals whose pre-donation iron stores are low. Oral iron supplementation enhances the rate of iron store repletion [87,88]. (See "Approach to the patient with suspected iron overload", section on 'Normal iron stores' and "Regulation of iron balance", section on 'Ferritin'.)

The donor's hemoglobin concentration is estimated prior to donation using a fingerstick blood sample. Donors are deferred for preexisting anemia; the acceptable minimal hemoglobin level for blood donation in the United States is 12.5 g/dL for females and 13.0 g/dL for males, as mandated by US Food and Drug Administration (FDA) requirements [7]. These criteria differ slightly from those used in other medical contexts where anemia usually is defined as a hemoglobin of 12.0 g/dL for females and 13.5 g/dL for males. (See "Diagnostic approach to anemia in adults", section on 'Anemia definitions'.)

This process also ensures that the recipient will receive an adequate therapeutic dose of RBCs and hemoglobin from the unit of packed RBCs [89-91].

Blood centers have varying policies for recommending whether donors with anemia should seek medical attention. In general, individuals are informed that they have anemia and referred for evaluation if the anemia is severe and the donor would not be expected to be anemic (eg, a first-time male donor). (See "Diagnostic approach to anemia in adults" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

Iron deficiency without anemia

●Prevalence – It is estimated that approximately 25 to 35 percent of regular blood donors develop iron deficiency, which may make them temporarily ineligible for future donations. Iron deficiency occurs at higher rates in teenage donors than in older adult donors (odds ratios of 2.1 to 4.7 depending on the level of iron depletion) [92].

●Iron supplements – Use of low-dose oral iron supplements has been explored as a means of mitigating iron deficiency in blood donors; this will enhance the ability of some donors to make frequent donations. There is controversy regarding whether iron deficiency in the absence of anemia is associated with significant symptoms in a healthy blood donor population [93,94]. Because of the lack of data collected specifically in blood donor populations, the use of oral iron supplements as a source of post-donation iron replacement is not standard practice in most countries, including the United States [60,95-99].

A survey conducted in 2016 in one United States collection center found that 21 percent of presenting donors took iron supplements, mostly in the form of a multivitamin for general health and wellness reasons rather than to compensate for iron loss during blood donation [100]. Some blood centers recommend that certain groups of donors such as premenopausal females or frequent repeat donors consider taking oral iron supplements to restore their pre-donation iron levels. Donors with concerns or those who experience side effects from oral iron can elect not to take the supplements.

Supporting evidence includes:

•A trial from 2015 randomly assigned 215 blood donors to receive one tablet of ferrous gluconate (equivalent to 37.5 mg of elemental iron) once daily or no iron for 24 weeks after donating a unit of blood [87]. Individuals in the iron supplement group had a shorter time to recovery of baseline hemoglobin levels and ferritin levels (indicator of iron stores).

•A trial from 2016 randomly assigned 692 blood donors to one of several interventions that included different doses of oral iron or placebo (38, 19, or 0 mg elemental iron once daily for two months), or monitoring of ferritin levels with a feedback letter to the donor versus no letter [101]. Follow-up lasted two years, and only 393 participants continued on the trial for the entire two-year period. Of those who completed the trial, both of the iron supplement groups had an increase in hemoglobin of approximately 0.6 g/dL, and the iron status letter group had no change in hemoglobin. Both control groups were most likely to have low or decreased ferritin.

•A trial from 2004 randomly assigned 526 regular blood donors to receive 40, 20, or 0 mg of elemental iron once daily for six months, during which one unit of blood was collected four times (males) or three times (females) [102]. In both the 40 and 20 mg of iron groups, males had stable iron stores and females had increased storage iron. The rate of gastrointestinal side effects was only slightly higher in the iron groups than the placebo group.

•Other trials have reported similar findings [103,104].

●Monitoring iron stores – There is consensus that serum ferritin is the best tool to monitor iron stores in donors [105,106]. However, in the United States, there are no point-of-care ferritin tests that can be used at the donation site. Although routine monitoring of iron stores in all donors is not performed, many United States blood centers obtain a post-donation ferritin test for specific subpopulations of donors such as repeat donors or teenage donors (ages 16 or 17 to 18 or 19). Teenage donors with a low serum ferritin are subsequently deferred for 6 to 12 months [107]. (See "Regulation of iron balance", section on 'Ferritin' and "Iron requirements and iron deficiency in adolescents", section on 'Evaluation and presumptive diagnosis'.)

Considerations regarding iron deficiency during pregnancy may also apply; these are discussed separately. (See "Anemia in pregnancy", section on 'Prevention of iron deficiency' and "Anemia in pregnancy", section on 'Screening during pregnancy'.)

Complications of apheresis — In contrast to standard whole blood donation, apheresis donation is performed as a way to collect platelets or plasma without removing red blood cells (RBCs). Two intravenous catheters are connected to an apheresis machine that collects plasma or platelets and returns the remaining blood to the patient. Apheresis donations allow significantly more plasma or platelets to be collected from a single donor, and the procedure can be performed more frequently than whole blood donation.

Thrombocytopenia — Apheresis platelet donation can remove 3 to 4 billion platelets, which in a single donation will not make the donor thrombocytopenic but carries a theoretical risk of thrombocytopenia over the long term [108,109]. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Dose'.)

To reduce the risk of thrombocytopenia over time, FDA regulations limit platelet apheresis donations to 24 donations in a 12-month period.

Evidence regarding the safety of this approach includes the following:

●In a study that tracked platelet counts in 939 donors over a four-year period during which they underwent 11,464 apheresis platelet collections, a significant decrease in platelet count occurred in all groups of donors, with a mean decrease of 40,000 per microL from baseline in the frequent-donor subgroup [110]. Deferral for low platelet count was required in 84 individuals (9 percent); most returned to donate after an interval (temporary: <150,000/microL; permanent: <100,000/microL). Of eight donors who were permanently deferred for a platelet count <100,000/microL, three were found to have an underlying hematologic disorder.

●In a single center study of 60 donors who had provided 24 platelet donations during calendar year 2005, there was no clinically or statistically significant difference in mean platelet counts from the first through the 24^th donation; none of these 60 repeat donors was ever deferred for a platelet count <150,000/microL during this period [111].

●In a study of 471 repeat apheresis platelet donors followed over 2.5 years, the platelet count actually increased slightly for each platelet product donated, and no deferrals due to a platelet count <150,000/microL occurred [112].

Lymphopenia — There are accumulating data that lymphopenia may occur in frequent platelet apheresis donors (donation frequency 20 to 24 plateletpheresis sessions in a 365-day period). A cross-sectional study observed of donors with this donation frequency found lower CD4-positive lymphocyte counts (<200 cells/microL) in 6 of 20 (30 percent) [113]. There were minor changes in other lymphocyte subsets. Subsequently, the same group of investigators found that CD4-positive lymphocytopenia persisted in 3 of 15 former frequent apheresis platelet donors who had ceased platelet donation for more than 1 year [114]. In these studies, all donors underwent apheresis using the same platelet collection system (Trima Accel, which uses a leukocyte reduction chamber). A second study failed to find a similar finding in frequent platelet apheresis donors using a different apheresis collection device (Fenwal Amicus) [115].

More difficult to ascertain is whether these reduced CD4-positive lymphocyte counts have clinical consequences. In the follow-up study discussed above, there was no evidence that this lymphocytopenia predisposed to opportunistic infections or to malignancies associated with immune dysregulation [114]. These initial observations prompted other investigators to query a very large database that included almost 75,000 apheresis donors (either platelet or plasma apheresis) [116]. Though many confounders were present and few infections were observed, statistical analysis suggested that there was an increase in infections (bacterial or other).

A commentary synthesizing the data from these studies concluded that it is increasingly confirmed that very frequent or prolonged donation on the Trima platform likely does result in lower baseline lymphocyte counts, in at least some proportion of donors [117]. While the vast majority of donors do not appear to be clinically affected, there is a concerning signal that a slight increased risk may be present. It is unclear whether the existing data will lead to any actionable changes in the allowable donation frequency.

Citrate toxicity — During the course of a standard plateletpheresis procedure, a donor may receive up to 10 grams (53 mmol) of citrate intravenously over 90 to 120 minutes [118]. This may result in symptoms. Citrate is also used in other apheresis procedures (RBC apheresis collection, plasma apheresis collection, combined component procedures), so symptoms secondary to infused citrate are also possible with these procedures.

Citrate acts as a chelating agent and may decrease serum calcium, magnesium, and phosphate [119]. Complications may include symptoms of hypocalcemia such as paresthesias, muscle cramping, and nausea, as well as prolongation of the QT interval [120]. (See "Clinical manifestations of hypocalcemia", section on 'Acute manifestations' and "Therapeutic apheresis (plasma exchange or cytapheresis): Complications", section on 'Citrate-induced hypocalcemia'.)

In a study of 19,736 apheresis procedures, 159 (0.8 percent) were associated with adverse events; rates of adverse events were slightly higher in first-time apheresis donors (1.09 percent) [121]. Of the 159 adverse events, 70 were hemodynamic or citrate related and 73 were related to venipuncture. Seven serious adverse events required evaluation in the emergency department and two required hospitalization. Two venipuncture-related events required neurologic evaluation.

The usual treatment for symptoms related to hypocalcemia is to decrease the rate of citrate infusion, to give oral calcium-containing agents, or both [122]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications", section on 'Citrate-induced hypocalcemia'.)

Complications of G-CSF and glucocorticoids (granulocyte donors) — Donors of granulocytes may be given dexamethasone and/or granulocyte colony-stimulating factor (G-CSF) on the day prior to the pheresis procedure to increase the yield of harvested granulocytes. A history of hypertension, diabetes, gastrointestinal ulcers, glaucoma, tuberculosis, or any fungal infections may be contraindications to glucocorticoid administration.

Side effects associated with the use of dexamethasone, G-CSF, or both are common but usually minor and include headache, arthralgias, bone pain, fatigue, and insomnia. Allergic reactions have been documented, as has fever. Long-term safety has not yet been definitively established, but the estimated risk is very low. (See "Granulocyte transfusions", section on 'Donor issues'.)

DIRECTED DONATIONS

Indications and uses of directed donations — Prior to 1983, recipient-specific donations were considered medically indicated in a limited number of situations such as kidney transplantation or platelet transfusions for individuals with refractoriness to transfusion or infants with isoimmune neonatal thrombocytopenia.

During the height of the AIDS epidemic, directed donations increased dramatically in direct response to concerns about blood safety. Subsequently, directed donations have declined to <1 percent of whole blood donations; one report cited 0.12 percent of donations in 2010, and an updated report cited 0.15 percent in 2017 [123,124]. While any blood component (red blood cells, plasma, cryoprecipitate, platelets, or granulocytes) can be directed towards a particular patient, the vast majority of directed donations are for red blood cells (RBCs).

Because directed donation requires that the donation be routed to a specific designated recipient, the logistics and scheduling of collections for designated donations is more difficult than for general allogeneic donations. Allogenic blood transfusions are one of the most common and also safest hospital procedures. Thus, many hospitals strongly discourage directed donation.

A potential use of directed donations is for a family member to donate when the patient has an alloantibody to a high-frequency red cell or platelet antigen; a family member would have a higher chance of being negative for the antigen than would the general donor population.

In some cases a directed (designated) donor is used as a means of reducing recipient exposure to certain antigens present on RBCs or platelets [125] by providing repeated donations of specific components for a single recipient, thereby reducing or obviating the need for that patient to receive components from multiple donors. This latter use of directed donations was more prominent in the 1980s and 1990s than in the 2000s.

Each institution offering directed donations should be able to perform RBC typing of potential directed donors to determine if the blood is compatible with the recipient. The recipient's clinicians should be responsible for requesting directed donations and should be kept informed as to the status of all blood collected. Community blood centers may not provide directed donation capabilities.

For standard allogenic donations, recipients cannot specify any donor characteristics (age, sex, skin color, medical conditions, or vaccination status) [50].

A discussion of autologous donation is presented separately. (See "Surgical blood conservation: Preoperative autologous blood donation".)

Potential risks — The directed donor and intended recipient should be informed about the details of the directed donor program including considerations of confidentiality and potential risks and benefits. Informed consent should be obtained, preferably from both donor and recipient. In addition to being informed about infectious disease screening, directed donors should also be aware that blood not used by the intended recipient may be made available to others. (See 'Infectious diseases (comparable to standard allogeneic blood)' below.)

Directed donors must meet all the criteria for protection of the recipient that are used for community volunteer donors. They must undergo the same medical history screening, and they must be aware that their blood will be subjected to the same infectious disease tests used to screen volunteer blood. With exceedingly rare exceptions (perhaps when a parent is donating for their child and has a nonsignificant viral marker such as anti-HBc), directed donor blood that has a positive infectious diseases screening test is discarded. Directed donors are also accorded the same patient confidentiality protections as any patient; thus, if screening reveals an infectious or other risk, the recipient will not be notified. (See "Blood donor screening: Medical history" and "Blood donor screening: Laboratory testing".)

The aggregate data suggest that blood from directed donors is neither safer nor measurably less safe than blood from volunteer donors in the community, and the thorough screening of the donor and donated blood allows blood not used by the intended recipient to be made available for others. Crossover of directed donor blood is common practice, although some collection facilities and hospital transfusion services discard unused directed donor blood. This differs from autologous blood donations, which generally are not released to other recipients. (See "Surgical blood conservation: Preoperative autologous blood donation", section on 'Crossover (release to other recipients) is no longer used'.)

Infectious diseases (comparable to standard allogeneic blood) — The rate of positive infectious disease screening tests (and hence the risk of infectious disease transmission) with directed donations is considered comparable to the general allogeneic pool when adjusted for the greater percentage of first time or parental donors in the directed donor population.

The relative safety of directed donor blood versus voluntary donations in the general pool have been addressed in studies comparing infectious disease makers:

●All directed donors – A study from the American Red Cross evaluated nearly 70,000 directed donations and over 38 million volunteer donations between 2005 and 2010 for viral markers (HIV, hepatitis B and C viruses [HBV and HCV], human T-cell lymphotropic virus [HTLV]) [123]. Directed donors were more likely to be making a first-time (rather than repeat) donation and to be older than volunteer donors. By multivariable regression analysis, the likelihood of positive testing was only slightly but not statistically significantly greater in directed donors for HIV (odds ratio [OR] 1.1; 95% CI 0.41-3.0), HBV (OR 1.1; 95% CI 0.7-1.7), and HTLV (OR 1.7; 95% CI 0.9-3.3). It was lower and statistically significant for HCV (OR 0.7; 95% CI 0.5-0.9).

●Parental donors – A study using data accumulated from 1997 to 2008 compared infectious disease screening test results on 1532 directed donations from parents to their children (parental donations), 4910 non-parental directed donations, and 17,423 allogeneic community donations [126]. Infectious disease screening was positive in 9 percent of first-time parental donors and 1 percent of repeat donors. For non-parental donors, screening was positive in 1 percent of first-time donors and 0 percent of repeat donors. For community donors, screening was positive in 3 percent of first-time donors and 0.5 percent of repeat donors. The authors concluded that first-time parental blood donation should be discouraged.

Avoiding RBC alloantibody development to prevent hemolytic disease of the fetus and newborn — It is prudent to avoid blood from an individual for a partner who may become pregnant. This is because the donor's red blood cells (RBCs) may contain antigens to which the recipient has not been exposed but which may be present on RBCs of a future fetus. As an example, if a female who is Kell (K)-negative receives a transfusion from a partner who is K-positive, she may develop alloantibodies to K; if she then conceives a child with the K-positive individual and the fetus also expresses K, her alloantibodies can cross the placenta and cause severe immune-mediated hemolytic anemia in the fetus. (See "Red blood cell antigens and antibodies" and "Management of non-RhD red blood cell alloantibodies during pregnancy" and "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management".)

ta-GVHD and need for irradiation — Transfusion-associated graft-versus-host disease (ta-GVHD) is a life-threatening complication of transfusion in which donor leukocytes recognize the recipient as foreign and mount an immune response that destroys the recipient's bone marrow and attacks other recipient tissues (skin, gastrointestinal tract); it is usually fatal. There is essentially no effective treatment except immediate hematopoietic stem cell transplant. (See "Transfusion-associated graft-versus-host disease".)

Fully immunocompetent individuals can develop ta-GVHD. Risk factors include partial human leukocyte antigen (HLA) matching, which is especially common with related donors. Any transfusion from a related donor must be irradiated to prevent ta-GVHD. (See "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Irradiated red blood cells' and "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Irradiation'.)

Directed donation parameters (frequency, timing) — As with allogeneic donors, directed donors should be restricted to donation schedules that meet US Food and Drug Administration and Association for the Advancement of Blood & Biotherapies (AABB) standards for safety to the donor. Compressed schedules, appropriate for autologous donors, are generally not applicable to directed donors. (See 'Donation frequency' above.)

One potential exception occurs when, in the opinion of the medical director, a component of truly enhanced safety can be provided by the directed donor (as with parent to infant or HLA-matched sibling to sibling). With repeated transfusion from a parent to an infant, for example, small quantities of relatively fresh blood are required at stable intervals. In this setting, it may be prudent to draw less than full units at shorter intervals than the established standard. This approach protects the donor from iron depletion and the recipient from exposure to multiple donors.

With the establishment of apheresis technologies, directed donors can, if eligible, donate double red blood cell units, thereby doubling the contribution from a donor without the need for a compressed donation schedule.

Directed donor blood cannot be used for emergency transfusion, given the need to collect and test the blood. Since complete testing usually takes approximately 48 hours (plus time for administrative paperwork, delivery to the hospital, and perhaps time to seek a replacement donor should the first donor be disqualified for any reason), it would make sense to have a directed donor's blood drawn approximately one week prior to a scheduled elective surgical procedure. The shortest time frame in which this could occur would be 48 to 72 hours, as long as there are no unexpected delays.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Transfusion and patient blood management".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Blood donation (giving blood) (The Basics)")

●Beyond the Basics topics (see "Patient education: Blood donation and transfusion (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – There are several approaches to maximizing safety of the blood supply and blood donation, including avoidance of financial incentives, screening donors for potential infectious risks, deferring certain donors, and providing support and hydration during donation. (See 'Approaches to maximizing safety' above.)

●Recipient protections – Recipient protections include incentivizing altruistic motivations for blood donation, conducting a donor medical history interview, maintaining donor deferral registries, allowing donors to provide additional medical history after the donation, infectious disease testing of donated blood, and using leukoreduction and/or pathogen inactivation procedures after collection. (See 'Protection of the recipient' above.)

●Hereditary hemochromatosis – Blood from individuals with hereditary hemochromatosis (HH) is considered safe provided the donor and the donated blood components undergo all the same screening procedures as community donations. In the United States, the blood center must perform therapeutic phlebotomies for HH at no charge, removing the financial incentive for donation. (See 'Hereditary hemochromatosis' above.)

●Donor protections – Donors are excluded if they are <16 years or <17 years depending on the state, <50 kg, or have an estimated blood volume <3500 mL. Donation frequency is limited to allow sufficient time for the hemoglobin to return to baseline. Certain medical conditions preclude donation (heart or lung disease, pregnancy, recent surgery), as do vital signs outside of normal ranges. (See 'General procedures to protect the donor' above.)

●Complications of whole blood donation – Two main complications of whole blood donation are volume-related or vasovagal reactions and anemia. Measures to reduce vasovagal reactions include providing water, ensuring the donor feels well before walking to the refreshment table, and encouraging them to stay at the table for 10 to 15 minutes. Measures to reduce anemia and iron deficiency include hemoglobin testing prior to donation and limiting donation frequency. Routine iron supplementation is not used but may be appropriate for premenopausal females, teenage donors, and/or repeat donors. Routine iron stores monitoring is not consistently performed, but many United States blood centers obtain a post-donation ferritin level for repeat and teenage donors. (See 'Likelihood of complications from donating blood' above and 'Complications of whole blood donation' above.)

●Complications of apheresis donation – Apheresis platelet donation can cause thrombocytopenia and is limited to 24 donations over a one-year period. Apheresis can cause hypocalcemia due to citrate exposure, which is treated by lowering the rate of citrate infusion and/or administering calcium-containing agents. (See 'Complications of apheresis' above.)

●Directed donations – Directed donations increased dramatically during the early AIDS epidemic but have since declined to <0.2 percent. Directed donations generally do not provide a benefit for recipients, and they carry increased administrative burdens. However, they may be appropriate in select circumstances (when a recipient has antibodies to high-frequency antigens or when there is a need to reduce recipient exposure to certain antigens on red blood cells or platelets). Donations from a male should not be used for a female who may become pregnant with his child due to the increased risk of hemolytic disease of the fetus and newborn (HDFN). Any directed donation from a related individual must be irradiated to prevent transfusion-associated graft-versus-host disease (ta-GVHD), an almost universally fatal complication. (See 'Directed donations' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff gratefully acknowledges the extensive contributions of Arthur J Silvergleid, MD to earlier versions of this and many other topic reviews.