Blood transfusion

Overview
Blood transfusion is the process of transferring blood or blood-based products from one person into the circulatory system of another. Blood transfusions can be life-saving in some situations, such as massive blood loss due to trauma, or can be used to replace blood lost during surgery. Blood transfusions may also be used to treat a severe anaemia or thrombocytopenia caused by a blood disease. People suffering from hemophilia or sickle-cell disease may require frequent blood transfusions.

Early attempts
The first historical attempt at blood transfusion was described by the 15th-century chronicler Stefano Infessura. Infessura relates that, in 1492, as Pope Innocent VIII]] sank into a coma, the blood of three boys was infused into the dying pontiff (through the mouth, as the concept of circulation and methods for intravenous access did not exist at that time) at the suggestion of a physician. The boys were ten years old, and had been promised a ducat each. However, not only the pope died, but so did the three children. Some authors have discredited Infessura's account, accusing him of anti-papalism.

With Harvey's re-discovery of the circulation of the blood (which was discoverd by Ibn al-Nafis in the 13th century), more sophisticated research into blood transfusion began in the 17th century, with successful experiments in transfusion between animals. However, successive attempts on humans continued to have fatal results.

The first fully-documented human blood transfusion was administered by Dr. Jean-Baptiste Denys on June 15, 1667. He transfused the blood of a sheep into a 15-year old boy, who recovered. Denys performed another transfusion into a labourer, who also survived. Both instances were likely due to small amount of blood that was actually transfused into these people. This allowed them to withstand the allergic reaction. Then, Denys performed several transfusions into Mr. Mauroy, who on the third account had died (read Blood and Justice). Much controversy surrounded his death and his wife was accused of his murder; it's likely that the transfusion caused his death.

Richard Lower examined the effects of changes in blood volume on circulatory function and developed methods for cross-circulatory study in animals, obviating clotting by closed arteriovenous connections. His newly devised instruments eventually led to actual transfusion of blood.

"Many of his colleagues were present. . . towards the end of February 1665 when he selected one dog of medium size, opened its jugular vein, and drew off blood, until . . . its strength was nearly gone . . . Then, to make up for the great loss of this dog by the blood of a second, I introduced blood from the cervical artery of a fairly large mastiff, which had been fastened alongside the first, until this latter animal showed . . . it was overfilled . . . by the inflowing blood." After he "sewed up the jugular veins," the animal recovered "with no sign of discomfort or of displeasure."

Lower had performed the first blood transfusion between animals. He was then "requested by the Honorable Robert Boyle . . . to acquaint the Royal Society with the procedure for the whole experiment," which he did in December of 1665 in the Society’s Philosophical Transactions. On 15 June 1667 Denys, then a professor in Paris, carried out the first transfusion between humans and claimed credit for the technique, but Lower’s priority cannot be challenged.

Six months later in London, Lower performed the first human transfusion in England, where he "superintended the introduction in his [a patient’s] arm at various times of some ounces of sheep’s blood at a meeting of the Royal Society, and without any inconvenience to him." The recipient was Arthur Coga, "the subject of a harmless form of insanity." Sheep’s blood was used because of speculation about the value of blood exchange between species; it had been suggested that blood from a gentle lamb might quiet the tempestuous spirit of an agitated person and that the shy might be made outgoing by blood from more sociable creatures. Lower wanted to treat Coga several times, but his patient wisely refused. No more transfusions were performed. Shortly before, Lower had moved to London, where his growing practice soon led him to abandon research. 

The first successes
The science of blood transfusion dates to the first decade of the 19th century, with the discovery of distinct blood types leading to the practice of mixing some blood from the donor and the receiver before the transfusion (an early form of cross-matching).

In 1818, Dr. James Blundell, a British obstetrician, performed the first successful transfusion of human blood, for the treatment of postpartum hemorrhage. He used the patient's husband as a donor, and extracted four ounces of blood from his arm to transfuse into his wife. During the years 1825 and 1830, Dr. Blundell performed 10 transfusions, five of which were beneficial, and published his results. He also invented many instruments for the transfusion of blood. He made a substantial amount of money from this endeavour, roughly $50 million in real dollars.

In 1840, at St. George's Hospital Medical School in London, Samuel Armstrong Lane, aided by Dr. Blundell, performed the first successful whole blood transfusion to treat hemophilia.

George Washington Crile is credited with performing the first surgery using a direct blood transfusion at the Cleveland Clinic.

Development of blood banking
While the first transfusions had to be made directly from donor to receiver before coagulation, in the 1910s it was discovered that by adding anticoagulant and refrigerating the blood it was possible to store it for some days, thus opening the way for blood banks. The first non-direct transfusion was performed on March 27, 1914 by the Belgian doctor Albert Hustin, who used sodium citrate as an anticoagulant. The first blood transfusion using blood that had been stored and cooled was performed on January 1,1916. Oswald Hope Robertson, a medical researcher and U.S. Army officer, is generally credited with establishing the first blood bank while serving in France during World War I.

The first academic institution devoted to the science of blood transfusion was founded by Alexander Bogdanov in Moscow in 1925. Bogdanov was motivated, at least in part, by a search for eternal youth, and remarked with satisfaction on the improvement of his eyesight, suspension of balding, and other positive symptoms after receiving 11 transfusions of whole blood.

In fact, following the death of Vladimir Lenin, Bogdanov was entrusted with the study of Lenin's brain, with a view toward resuscitating the deceased Bolshevik leader. Tragically, but perhaps not unforeseeably, Bogdanov lost his life in 1928 as a result of one of his experiments, when the blood of a student suffering from malaria and tuberculosis was given to him in a transfusion. Some scholars (e.g. Loren Graham) have speculated that his death may have been a suicide, while others attribute it to blood type incompatibility, which was still incompletely understood at the time.

The modern era
Following Bogdanov's lead, the Soviet Union set up a national system of blood banks in the 1930s. News of the Soviet experience traveled to America, where in 1937 Bernard Fantus, director of therapeutics at the Cook County Hospital in Chicago, established the first hospital blood bank in the United States. In creating a hospital laboratory that preserved and stored donor blood, Fantus originated the term "blood bank". Within a few years, hospital and community blood banks were established across the United States.

In the late 1930s and early 1940s, Dr. Charles R. Drew's research led to the discovery that blood could be separated into blood plasma and red blood cells, and that the components could be frozen separately. Blood stored in this way lasted longer and was less likely to become contaminated.

Another important breakthrough came in 1939-40 when Karl Landsteiner, Alex Wiener, Philip Levine, and R.E. Stetson discovered the Rhesus blood group system, which was found to be the cause of the majority of transfusion reactions up to that time. Three years later, the introduction by J.F. Loutit and Patrick L. Mollison of acid-citrate-dextrose (ACD) solution, which reduces the volume of anticoagulant, permitted transfusions of greater volumes of blood and allowed longer term storage.

Carl Walter and W.P. Murphy, Jr., introduced the plastic bag for blood collection in 1950. Replacing breakable glass bottles with durable plastic bags allowed for the evolution of a collection system capable of safe and easy preparation of multiple blood components from a single unit of whole blood. Further extending the shelf life of stored blood was an anticoagulant preservative, CPDA-1, introduced in 1979, which increased the blood supply and facilitated resource-sharing among blood banks.

Compatibility
Great care is taken in cross-matching to ensure that the recipient's immune system will not attack the donor blood. In addition to the familiar human blood types (A, B, AB and O) and Rh factor (positive or negative) classifications, other minor red cell antigens are known to play a role in compatibility. These other types can become increasingly important in people who receive many blood transfusions, as their bodies develop increasing resistance to blood from other people via a process of alloimmunization.

Screening for infection
A number of infectious diseases (such as HIV, syphilis, hepatitis B and hepatitis C, among others) can be passed from the donor to recipient. This has led to strict human blood transfusion standards in developed countries. Standards include screening for potential risk factors and health problems among donors by determining donor hemoglobin levels, administering a set of standard oral and written questions to donors, and laboratory testing of donated units for infection. The lack of such standards in places like rural China, where desperate villagers donated plasma for money and had others' red blood cells reinjected, has produced entire villages infected with HIV.

As of mid-2005, all donated blood in the United States is screened for the following infectious agents:
 * HIV-1 and HIV-2
 * Human T-lymphotropic virus (HTLV-1 and HTLV-2)
 * Hepatitis C virus
 * Hepatitis B virus
 * West Nile virus
 * Treponema pallidum (the causative agent of syphilis, usually used as more of a screening test for high risk lifestyle, the last case of transfusion transmitted syphilis was in 1965.)

When a person's need for a transfusion can be anticipated, as in the case of scheduled surgery, autologous donation can be used to protect against disease transmission and eliminate the problem of blood type compatibility.

Processing of blood prior to transfusion
Donated blood is sometimes subjected to processing after it is collected, to make it suitable for use in specific patient populations. Examples include:
 * Leukoreduction, or the removal of stray white blood cells from the blood product by filtration. Leukoreduced blood is less likely to cause alloimmunization (development of antibodies against specific blood types), and less likely to cause febrile transfusion reactions. Also, leukoreduction greatly reduces the chance of cytomegalovirus (CMV) transmission. Leukoreduced blood is appropriate for:
 * Chronically transfused patients
 * Potential transplant recipients
 * Patients with previous febrile nonhemolytic transfusion reactions
 * CMV seronegative at-risk patients for whom seronegative components are not available
 * Irradiation. In patients who are severely immunosuppressed and at risk for transfusion-associated graft-versus-host disease, transfused red cells may be subjected to irradiation with at least 25 Gy to prevent the donor T lymphocytes from dividing in the recipient. Irradiated blood products are appropriate for:
 * Patients with hereditary immune deficiencies
 * Patients receiving blood transfusions from relatives in directed-donation programs
 * Patients receiving large doses of chemotherapy, undergoing stem cell transplantation, or with AIDS (controversial).
 * CMV screening. Cytomegalovirus, or CMV, is a virus which infects white blood cells. Many people are asymptomatic carriers. In patients with significant immune suppression (e.g. recipients of stem cell transplants) who have not previously been exposed to CMV, blood products that are CMV-negative are preferred. Leukoreduced blood products can substitute for CMV-negative products, since the complete removal of white blood cells removes the source of CMV transmission (see leukoreduction above).

Neonatal transfusion
To ensure the safety of blood transfusion to pediatric patients, hospitals are taking additional precaution to avoid infection and prefer to use specially tested pediatric blood units that are guaranteed negative for Cytomegalovirus. It is uncertain whether leukodepletion can be adequate for the prevention of CMV, and therefore most guidelines recommend the provision of CMV-negative blood components for newborns or low birthweight infants in whom the immune system is not fully developed. These specific requirements place additional restrictions on blood donors who can donate to babies.

Terminology
The terms type and screen are used for the testing that (1) determines the blood group (ABO compatibility) and (2) checks for alloantibodies. It takes about 45 minutes to complete.

If time allows more extensive testing, a large number of antibodies are screened. This is known as group & screen and can take up to a day.

If there is no time the blood is called "uncross-matched blood". Uncross-matched blood is O-positive or O-negative. O-negative is usually used for children and women of childbearing age.

Procedure
Blood transfusions can be grouped into two main types depending on their source:
 * Homologous transfusions, or transfusions using the stored blood of others.
 * Autologous transfusions, or transfusions using one's own stored blood.

Blood can only be administered intravenously. It therefore requires the insertion of a cannula of suitable caliber. Before the blood is administered, the personal details of the patient are matched with the blood to be transfused, to minimize risk of transfusion reactions. With the recognition that clerical error (eg administering the wrong unit of blood) is a significant source of transfusion reactions, attempts have been made to build redundancy into the matching process that takes place at the bedside.

A unit (up to 500 ml) is typically administered over 4 hours. In patients at risk of congestive heart failure, many doctors administer furosemide to prevent fluid overload. Acetaminophen and/or an antihistamine such as diphenhydramine are sometimes given before the transfusion to prevent a transfusion reaction.

Blood donation
Blood is most commonly donated as whole blood by inserting a catheter into a vein and collecting it in a plastic bag (mixed with anticoagulant) via gravity. Collected blood is then separated into components to make the best use of it. Aside from red blood cells, plasma, and platelets, the resulting blood component products also include albumin protein, clotting factor concentrates, cryoprecipitate, fibrinogen concentrate, and immunoglobulins (antibodies). Red cells, plasma and platelets can also be donated individually via a more complex process called apheresis.

Donations are usually anonymous to the recipient, but products in a blood bank are always individually traceable through the whole cycle of donation, testing, separation into components, storage, and administration to the recipient. This enables management and investigation of any suspected transfusion related disease transmission or transfusion reaction.

Contraindications to being a blood donor
Blood donation centers in different countries may have different guidelines about who can serve as a blood donor. Common contraindications to being a blood donor fall into two main groups: conditions which might cause a problem for the recipient and conditions which might cause a problem for the donor. A donor who is found ineligible is "deferred" from donation, though in some cases this may be a permanent deferral and the donor is not expected to return.

For recipient safety:
 * Donors who recently received a blood transfusion: All recipients of blood have potentially been exposed to a source of transfusion transmitted infections.  Additionally, alloimmunization can occur which can lead to positive antibody testing, which can cause significant problems in crossmatching.
 * Recent pregnancy: Pregnancy can also cause alloimmunization, and donors are deferred for the same reason.
 * History of cancer: Although no blood cancers have ever been transmitted through blood transfusions, any patient who has ever had leukemia or lymphoma or other neoplastic diseases involving blood is permanently excluded.  Other cancer patients are typically excluded for five or more years.
 * Any current infection or acute disease: Even a minor infection, such as the common cold, could be dangerous to some recipients.
 * Current disease or at high risk for a disease that can be transmitted by transfusion:
 * Malaria: Donors are considered to be at high risk for malaria if they live in or have recently traveled to a malarial risk area. This is far more difficult to implement in countries that are endemic for malaria and all residents are considered to be high risk.
 * Hepatitis (B or C): Donors are considered to be at high risk for hepatitis if they live with a person who has hepatitis, have recently had a non-sterile tattoo or piercing, or have ever used intravenous drugs (other than prescribed medications).
 * HIV: Donors are considered to be at high risk for HIV if they have ever used intravenous drugs (other than prescribed medications), have been in certain African countries where HIV is extremely common, engaged in high-risk sexual behaviors, or had sex with anyone who is in any of those risk groups. High-risk sexual behaviors include prostitution and men who have sex with men (MSM).  The deferral of every man who has had sex with another man since 1977 is controversial.  Donors who have had a recent needlestick injury are also deferred.
 * CJD and vCJD: Donors who have spent substantial time in areas at high risk for vCJD (typically the United Kingdom and Europe) are typically excluded, though like malaria this is difficult to implement in the countries that are at risk. Donors who have ever received human pituitary growth hormone are also excluded because of their higher risk for these diseases.
 * Chagas Disease, Babesiosis, and Leishmaniasis are also causes for deferral.
 * Some medications remain in the bloodstream for a long time and can cause complications for a recipient. For example, Avodart causes birth defects and transfusing a blood product containing it to a pregnant woman could have serious adverse effects.

For donor safety:
 * Donors who are not healthy enough to tolerate the process are generally excluded. Conditions of concern include cardiovascular disease, current pregnancy, high blood pressure, tuberculosis, a history of seizures, and many others.  Some blood banks will simply refuse to accept donors over a certain age because of possible health risks.
 * Before donation, a blood sample is taken to check the iron level (i.e. hematocrit) to ensure that the donor will not be made anemic by the donation. This is a common reason for deferral, especially in pre-menopausal women.
 * Younger donors are excluded from donating allogeneic blood because they cannot give legal consent for the process. Very young donors also may not understand the process and may injure themselves.

For the donor
Donating whole blood at a modern, well-run blood collection center is safe. The biggest risk is probably that of vasovagal syncope, or "passing out". A large study, involving 194,000 donations during a one-year period at an urban U.S. blood center, found 178 cases of syncope, for an incidence of 0.09%. Only 5 of these incidents required emergency room attention, and there was one long-term complication. Most syncopal episodes occurred at the refreshment table following donation, leading the authors to recommend that donors spend at least 10 minutes at the refreshment table drinking fluids after donation. A Greek study of over 12,000 blood donors found an incidence of vasovagal events of 0.89%. Another study interviewed 1,000 randomly selected blood donors 3 weeks after donation, and found the following adverse effects: None of these were severe enough to require medical attention in this study. There is no risk of acquiring an infection at a modern, well-run blood donation center.
 * Bruise at the needle site — 23 percent
 * Sore arm — 10 percent
 * Hematoma at needle site — 2 percent
 * Sensory changes in the arm used for donation (eg, burning pain, numbness, tingling) — 1 percent
 * Fatigue — 8 percent
 * Vasovagal symptoms — 5 percent
 * Nausea and vomiting — 1 percent

Donation of blood products via apheresis is a more complex procedure and can entail additional risks, although this procedure is, overall, still very safe for the donor.

For the recipient
There are risks associated with receiving a blood transfusion, and these must be balanced against the benefit which is expected. The most common adverse reaction to a blood transfusion is a febrile non-hemolytic transfusion reaction, which consists of a fever which resolves on its own and causes no lasting problems or side effects.

Hemolytic reactions include chills, headache, backache, dyspnea, cyanosis, chest pain, tachycardia and hypotension.

Blood products can rarely be contaminated with bacteria; the risk of severe bacterial infection and sepsis is estimated, as of 2002, at about 1 in 50,000 platelet transfusions, and 1 in 500,000 red blood cell transfusions.

Transmission of viral infection is a common concern with blood transfusion. As of 2006, the risk of acquiring hepatitis B via blood transfusion in the United States is about 1 in 250,000 units transfused, and the risk of acquiring HIV or hepatitis C in the U.S. via a blood transfusion is estimated at 1 per 2 million units transfused. These risks were much higher in the past before the advent of second and third generation tests for transfusion transmitted diseases. The implementation of Nucleic Acid Testing or "NAT" in the early 00's has further reduced risks, and confirmed viral infections by blood transfusion are extremely rare in the developed world.

Transfusion-associated acute lung injury (TRALI) is an increasingly recognized adverse event associated with blood transfusion. TRALI is a syndrome of acute respiratory distress, often associated with fever, non-cardiogenic pulmonary edema, and hypotension, which may occur as often as 1 in 2000 transfusions. Symptoms can range from mild to life-threatening, but most patients recover fully within 96 hours, and the mortality rate from this condition is less than 10%.

Other risks associated with receiving a blood transfusion include volume overload, iron overload (with multiple red blood cell transfusions), transfusion-associated graft-vs.-host disease, anaphylactic reactions (in people with IgA deficiency), and acute hemolytic reactions (most commonly due to the administration of mismatched blood types).

Transformation from one type to another
Scientists working at the University of Copenhagen reported in the journal Nature Biotechnology in April 2007 of discovering enzymes, which potentially enable blood from groups A, B and AB to be converted into group O. These enzymes do not affect the Rh group of the blood.

Objections to blood transfusion
Objections to blood transfusions may arise for personal, medical, or religious reasons. For example, Jehovah's Witnesses object to blood transfusion primarily on religious grounds, although they have also highlighted possible complications associated with transfusion.

Animal blood transfusion
Veterinarians also administer transfusions to animals. Various species require different levels of testing to ensure a compatible match. For example, cats have 3 blood types, cattle have 11, dogs have 12, pigs 16 and horses have 34. However, in many species (especially horses and dogs), cross matching is not required before the first transfusion, as antibodies against non-self cell surface antigens are not expressed constitutively - i.e. the animal has to be sensitized before it will mount an immune response against the transfused blood.

The rare and experimental practice of inter-species blood transfusions is a form of xenograft.

Blood transfusion substitutes
As of mid-2006, there are no clinically utilized oxygen-carrying blood substitutes for humans; however, there are widely available non-blood volume expanders and other blood-saving techniques. These are helping doctors and surgeons avoid the risks of disease transmission and immune suppression, address the chronic blood donor shortage, and address the concerns of Jehovah's Witnesses and others who have religious objections to receiving transfused blood.

A number of blood substitutes are currently in the clinical evaluation stage. Most attempts to find a suitable alternative to blood thus far have concentrated on cell-free hemoglobin solutions. Blood substitutes could make transfusions more readily available in emergency medicine and in pre-hospital EMS care. If successful, such a blood substitute could save many lives, particularly in trauma where massive blood loss results.

Blood transfusion safety
As mentioned above, the major risks that the patient (donors and receivers) may have encountered are the transmission of HIV or hepatitis and immunological transfusion reactions. Most of these problems are risky possibilities and cannot always be effectively treated with appropriate medical care. In many cases, donors are either screened to reduce risks of these contaminations, the blood is tested, or both.


 * Hepatitis A and Hepatitis E can be transmitted in blood. Unlike B and C, however, the donor will be obviously ill at the time of donation.  Note that Hepatitis D or "Delta Agent" can be transmitted in blood, but the donor will also have Hepatitis B and screening for B adequately addresses this risk.
 * Malaria - Donors in the United States and Europe are screened for travel to malarial risk countries, and in Australia donors are tested for malaria.
 * Chagas Disease - A screening test has been implemented for this disease in the United States, but is not yet required.
 * Babesiosis
 * Leishmaniasis
 * Simian foamy virus - While this virus can be transmitted by blood transfusion, there is no evidence that it causes disease in humans.
 * Myocardial ischaemia - if the patient has a non-ST-segment elevation acute coronary syndromes (NSTE-ACS).
 * Some medications may be transmitted in donated blood, and this is especially a concern with pregnant women and medications such as Avodart and Propecia.
 * vCJD or "Mad Cow Disease" has been shown to be transmissible in blood products. Potential donors who have spent time in the United Kingdom or Europe may not be allowed to donate due to this risk.
 * Creutzfeldt-Jakob Disease or CJD is a separate disease from vCJD that is extremely rare.
 * Bacterial contamination is a concern with any intravenous product, and is especially problematic with blood products stored at room temperature (i.e. platelets).
 * Cytomegalovirus or CMV is a major problem for patients with compromised immune systems and for neonates, but is not generally a concern for most recipients.
 * Epstein-Barr Virus or EBV is very common, but rarely causes clinical symptoms.

Academic resources

 * Transfusion, ISSN: 1537-2995 (electronic) 0041-1132 (paper)