PROCEDURE OF THE DAY
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 transfusions used Whole Blood, but modern medical practice is to use only components of the blood.
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 did the pope die, but so did the three children. Some authors have discredited Infessura's account, accusing him of anti-papalism.
World War II syringe for direct interhuman blood transfusion
With Harvey's re-discovery of the circulation of the blood (which was discovered 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, eminent physician to King Louis XIV of France, 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 the small amount of blood that was actually transfused into these people. This allowed them to withstand the allergic reaction. In the winter of 1667, Denys performed several transfusions on Antoine Mauroy with calf's blood, who on the third account had died. Much controversy surrounded his death and his wife was accused for causing his death. Though it was later determined that Mauroy actually died from arsenic poisoning, Denys' experiments with animal blood provoked a heated controversy in France. Finally, in 1670 the procedure was banned. In time, the British Parliament and even the pope followed suit. Blood transfusions fell into obscurity for the next 150 years.
First successful transfusion
Cornishman 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 Britain, 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 blood 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 (about $2 million in 1827) real dollars (adjusted for inflation).
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.
Many patients had died and it was not until 1901, when the Austrian Karl Landsteiner discovered human blood groups, that blood transfusions became safer. Mixing blood from two individuals can lead to blood clumping or agglutination. The clumped red cells can crack and cause toxic reactions. This can have fatal consequences. Karl Landsteiner discovered that blood clumping was an immunological reaction which occurs when the receiver of a blood transfusion has antibodies (A, B, both A & B, or neither) against the donor blood cells. Karl Landsteiner's work made it possible to determine blood groups (A, B, AB, O) and thus paved the way for blood transfusions to be carried out safely. For this discovery he was awarded the Nobel Prize in Physiology or Medicine in 1930.
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 plasma 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.
As of 2006, there were about 15 million units of blood transfused per year in the United States.
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.
The key importance of the Rh group is its role in Hemolytic disease of the fetus and newborn. When an Rh negative mother carries a positive fetus, she can become immunized against the Rh antigen. This usually is not important during that pregnancy, but in the following pregnancies she can develop an immune response to the Rh antigen. The mother's immune system can attack the baby's red cells through the placenta. Mild cases of HDFN can lead to disability but some severe cases are fatal. Rh-D is the most commonly involved red cell antigen in HDFN, but other red cell antigens can also cause the condition. The "positive" or "negative" in heard blood types such as "O positive" is the Rh-D antigen.
HDN prevention started in the 1960s when it was noted children of pregnant women who had received anti Rh immunoglobulin did not develop the disease. From then on, Rh negative pregnant women receive immunoglobulin doses at several moments during pregnancy and after childbirth if the baby is Rh positive. In current practice, Rh negative women of fertile age will not receive a transfusion of Rh positive blood except in desperate situations when nothing else is available.
Transfusion Transmitted Infections
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 and laboratory testing of donated units for infection.
Among the diseases than can be transmitted via transfusion are:
* HIV-1 and HIV-2
* Human T-lymphotropic virus (HTLV-1 and HTLV-2)
* Hepatitis C virus
* Hepatitis B virus
* West Nile virus All units of blood in the U. S. are screened for this 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.)
* 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.
* variant Creutzfeldt-Jakob Disease or "Mad Cow Disease" has been shown to be transmissible in blood products. No test exists for this, but various measures have been taken to reduce risks.
* Some medications may be transmitted in donated blood, and this is especially a concern with pregnant women and medications such as Avodart and Propecia.
* 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.
As of mid-2005, all donated blood in the United States is screened for HIV, Hepatitis B and C, HTLV-1 and 2, West Nile Virus, and Treponema pallidum. Blood which tests positive for any of the diseases it is tested for is discarded.
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. "Directed" donations from donors known to the recipient were a common practice during the initial years of HIV. These kinds of donations are still common in developing countries.
Processing of blood prior to transfusion
Donated blood is usually subjected to processing after it is collected, to make it suitable for use in specific patient populations. Examples include:
* Component separation: red cells, plasma and platelets are separated into different containers and stored in appropriate conditions so that their use can be adapted to the patient's specific needs. Red cells work as oxygen transporters, plasma is used as a supplement of coagulation factors, and platelets are transfused when their number is very scarce or their function severely impaired. Blood components are usually prepared by centrifugation. Centrifuge force makes the red cells, leukocytes, plasma and platelets form different layers into the blood bag, according to their different densities. Then, the blood bag is processed to separate those layers into their final container. Temperature also plays a capital role into component storage: plasma must be frozen as soon as possible −18 °C (−0.4 °F) or colder, red cells must be refrigerated (1-6°C, 34-43°F) and platelets are kept in continuous shaking platforms at room temperature (20-24°C, 36-75°F). There are several component preparation techniques, but two methods are common for Whole Blood derived platelets: the platelet rich plasma separation technique (mostly used in the USA) and the buffy coat technique (outside the USA).
* Leukoreduction, also known as Leukodepletion is the removal of 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:
o Chronically transfused patients
o Potential transplant recipients
o Patients with previous febrile nonhemolytic transfusion reactions
o CMV seronegative at-risk patients for whom seronegative components are not available
Some blood banks routinely leukoreduce all collected blood. There is some evidence that this reduces the risk of CJD transmission.
* 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 a targeted dose of 25 Gy, at least 15 Gy, to prevent the donor T lymphocytes from dividing in the recipient. Irradiated blood products are appropriate for:
o Patients with hereditary immune deficiencies
o Patients receiving blood transfusions from relatives in directed-donation programs
o 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 sometimes substitute for CMV-negative products, since the removal of white blood cells removes the source of CMV transmission (see leukoreduction above). The target for leukoreduction is <5x10^6 residual leukocytes for a full unit of Red Blood Cells, and the same amount of unfiltered blood has on the order of 10^9 leukocytes, so this reduces but does not elimate the risk.
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. Most guidelines recommend the provision of CMV-negative blood components and not simply leukoreduced 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 for neonatal use. Neonatal transfusions are usually top-up transfusions, exchange transfusions, partial exchange transfusions. Top-up transfusions are for investigational losses and correction of mild degrees of anemias, up to 5-15 ml/kg. Exchange transfusions are done for correction of anemia, removal of bilirubin, removal of antibodies and replacement of red cells. Ideally plasma-reduced red cells that are not older than 5 days are used.
The terms type and screen are used for the testing that (1) determines the blood group (ABO compatibility) and (2) screens for alloantibodies. It takes about 45 minutes to complete (depending on the method used). The blood bank technologist also checks for special requirements of the patient (eg. need for washed, irradiated or CMV negative blood) and the history of the patient to see if they have a previously identified antibody.
A positive screen warrants an antibody panel/investigation. An antibody panel consists of commercially prepared group O red cell suspensions from donors that have been phenotyped for commonly encountered and clinically significant alloantibodies. Donor cells may have homozygous (e.g. K+k-), heterozygous (K+k+) expression or no expression of various antigens (K-k+). The phenotypes of all the donor cells being tested are shown in a chart. The patient's serum is tested against the various donor cells using an enhancement method, eg Gel or LISS. Based on the reactions of the patient's serum against the donor cells, a pattern will emerge to confirm the presence of one or more antibodies. Not all antibodies are clinically significant (i.e. cause transfusion reactions, HDN, etc). Once the patient has developed a clinically significant antibody it is vital that the patient receive antigen negative phenotyped red blood cells to prevent future transfusion reactions. A direct antiglobulin test (DAT) is also performed as part of the antibody investigation.
Once the type and screen has been completed, potential donor units will be selected based on compatibility with the patient's blood group, special requirements (eg CMV negative, irradiated or washed) and antigen negative (in the case of an antibody). If there is no antibody present or suspected, the immediate spin or CAC (computer assisted crossmatch) method may be used.
In the immediate spin method, two drops of patient serum are tested against a drop of 3-5% suspension of donor cells in a test tube and spun in a serofuge. Agglutination or hemolysis in the test tube is a positive reaction and the unit should not be transfused.
If an antibody is suspected, potential donor units must first be screened for the corresponding antigen by phenotyping them. Antigen negative units are then tested against the patient plasma using an antiglobulin/indirect crossmatch technique at 37 degrees Celsius to enhance reactivity and make the test easier to read.
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. It is preferable for the laboratory to obtain a pre-transfusion sample in these cases so a type and screen can be performed to determine the actual blood group of the patient and to check for alloantibodies.
Blood transfusions can be grouped into two main types depending on their source:
* Homologous transfusions, or transfusions using the stored blood of others. These are often called Allogeneic instead of homologous.
* Autologous transfusions, or transfusions using the patient's own stored blood.
Donor units of blood must be kept refrigerated to prevent bacterial growth and to slow cellular metabolism. The transfusion must begin within 30 minutes after the unit has been taken out of controlled storage.
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. Clerical error is a significant source of transfusion reactions and 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 a diuretic to prevent fluid overload, a condition called Transfusion Associated Circulatory Overload or TACO. Acetaminophen and/or an antihistamine such as diphenhydramine are sometimes given before the transfusion to prevent other types of transfusion reactions.
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.
In developed countries, 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. In developing countries the donor is sometimes specifically recruited by or for the recipient, typically a family member, and the donation immediately before the transfusion.
Risks to 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.
There is a risk that a given blood transfusion will transmit a viral infection to its recipient. 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%.. Although the cause of TRALI is not clear, it has been consistently associated with anti HLA antibodies. Because anti HLA strongly correlate with pregnancy, several transfusion organisations (Blood and Tissues Bank of Cantabria, Spain, National Health Service in Britain) have decided to use only plasma from men for transfusion.
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 - they believe that blood is sacred; 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 known 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 2008, there are no widely 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. Hemopure, a hemoglobin-based therapy, is approved for use in South Africa.