Whole blood

Approximately 75 million units of whole blood are collected worldwide, but this almost certainly does not meet worldwide needs. The organizations and systems that collect and provide blood vary greatly throughout the world. Most developed countries, with the exception of the United States, have some form of a national blood program.³ The program may be operated by that country’s Red Cross or by its government. The extent to which this program is structured, the mechanisms of funding, and the effectiveness of the national blood program in meeting the total blood needs for that country also vary greatly throughout the world. In many developing countries the blood supply may be inadequate to meet the needs, and the blood that is available has a high likelihood of transmitting infectious disease.⁴

The US blood system is operated by multiple organizations.⁵ Approximately 15 million units of whole blood are collected each year primarily in regional or community blood centers.⁶ Hospitals collect less than 10% of the US blood supply. The American Red Cross is the largest blood collecting organization in the US, accounting for about 45% of the blood supply. Other regional or community blood centers are non-profit organizations governed by local volunteer boards of directors.

It is policy of the International Society for Blood Transfusion and the World Health Organization that blood should be donated voluntarily. The reason for advocating volunteerism in blood donation is not only based on the moral principle of not selling body parts or tissues but also because blood from paid donors has a much higher risk of disease transmission.⁷ When a financial payment is involved, there is an incentive for the potential donor to be dishonest about his or her medical history. Despite the increased sophistication of laboratory testing of donated blood, some infectious units of blood will not be detected by present tests.⁸ Thus, if the donor is dishonest about his or her medical history, there is more likelihood that the unit may be infectious.

In developed countries, the collection, processing, testing and preparation of blood components is subject to some form of regulation. Although blood is a biological, and thus different from a pharmaceutical, some form of pharmaceutical-type regulation is applied.⁵ Thus, there are requirements for donor eligibility, laboratory testing of donated blood, blood preservation and the minimum content of various blood components. Usually these requirements define procedures, records, staff proficiency, specific testing and donor medical requirements that blood banks must follow. In the US, additional standards have been promulgated by the American Association of Blood Banks – a voluntary organization that accredits blood banks as a way of assuring high quality and providing continued education for blood bank professionals.^9,10

Blood donor recruitment

In developed countries, whether or not there is a national blood program, blood is collected from volunteer donors. The costs that are incurred in collection, testing, production and distribution of blood components are covered in a variety of ways depending on the method of financing healthcare in each country. In some countries, these costs are part of the national health service budget and the funds may be provided to hospitals to purchase blood from the national blood program or the Red Cross. In other countries, the funds may be provided directly to the national blood program or the Red Cross and the blood is then supplied without charge to the hospitals. In many parts of the world, especially in areas without a structured blood system and where individual hospitals must attempt to meet their own blood requirements, patients and their families may be required to obtain a certain number of donors or units of blood before procedures involving blood loss will be undertaken. This requirement may even lead to families paying individuals to donate blood on their behalf. The payment then creates the difficulties of a paid-donor system described earlier.

In developed countries, most people will require a blood transfusion at some time in their lives. The blood supply comes from a small group of dedicated donors. In the US, blood donors differ from the general population in that they are more likely to be male, aged 30–50, more highly educated, employed and Caucasian.¹¹ Although there have been some studies of the social psychology and motivation of blood donors,¹² the process is not well understood and is likely to vary for different ethnic or cultural groups or countries.¹² A recent developing concern is that with the increasingly stringent donor requirements resulting from the AIDS epidemic, a larger portion of the population is being excluded as potential donors. In addition, as the population in many developed countries ages, there is a decreasing portion of the population available for blood donation. In the US, only about a third of the population meets all the donor requirements.¹³

Plasma

A large number of therapeutic products such as albumin, intramuscular and intravenous immune globulin, and coagulation factor concentrates are prepared from plasma by using large-scale manufacturing processes. The plasma to serve as raw material may be obtained from individual units of whole blood or by plasmapheresis. Worldwide, the demand for these plasma derivatives exceeds that provided from plasma obtained from whole blood donations. Thus, a large amount of the plasma that serves as raw material for the production of derivatives is obtained by plasmapheresis. Plasmapheresis donation requires more time than whole blood donation, and because red cells are not removed from the donor, the donor can donate plasma more frequently than whole blood; in some countries, plasmapheresis donors are paid.

In the US, the plasmapheresis collection and plasma fractionation system is separate from the whole blood collection system. This plasma system is operated by large commercial companies that pay donors and produce plasma derivatives for profit. Thus, it differs in many ways from the whole blood collection system which relies on volunteer donors and is operated by non-profit organizations. In most other developed countries, the plasma system is operated as a not-for-profit system, often as part of the regular, whole blood collection system. Some countries operate their own plasma fractionation plant while others contract with plants operated in other countries. Plasma fractionation involves the processing of up to 10 000 liters of plasma, which may be pooled from as many as 50 000 donors. Thus, the potential for infectivity is substantial. Since the AIDS epidemic, the plasma fractionation industry has introduced pathogen inactivation systems and today most, if not all, plasma derivatives are free of transmission of most viral diseases. Presently many coagulation factor concentrates are manufactured using recombinant DNA technology and thus are free of disease transmission.

The AIDS epidemic has had a major impact on blood banking and transfusion medicine. Although blood bank professionals believe they acted properly, with reasonable speed, and with the public’s interest in mind to balance blood safety and blood availability, in many countries the public was not satisfied with this response. The plasma industry was subjected to even more severe criticism, particularly from the hemophilia community. Because plasma derivatives, including coagulation factor concentrates, are prepared from large pools of plasma containing plasma from many donors, a large proportion of these derivatives was contaminated with HIV and many hemophiliacs were infected. Although the plasma industry moved expeditiously to introduce pathogen inactivation steps into the manufacturing process, there was a widely held belief that these companies should have implemented these steps sooner. In addition, in some countries, criminal actions were taken successfully against leaders of the blood programs for failure to take certain actions that might have helped to mitigate the impact of the AIDS epidemic on transfusion recipients. As a result of the AIDS epidemic, there has been a substantial increase in the eligibility requirements for blood donors and increase in the number and specificity of questions about donor’s medical history and activities that might place them at risk of being infected with transfusion-transmitted diseases. In addition, the number of tests performed on donated blood has increased and there has also been a fundamental shift in the regulatory philosophy. In most developed countries, the expectation developed that blood donor screening, collection, processing and component production would be carried out much like a pharmaceutical manufacturing process.^5,10 In addition, the use of blood products also changed dramatically. Physicians became much more conservative in prescribing blood and more extensive use of guidelines and monitoring of transfusions has occurred.

Medical history

Selection of blood donors involves ensuring the safety of the donor and obtaining a blood component that is high in quality and has the least possible chance of transmitting disease. This is accomplished by using volunteer blood donors, questioning donors about their general health and medical history, carrying out a brief physical examination of each donor, and laboratory testing the donated blood. The questions used in each country will differ to reflect the kinds of disease exposure donors are most likely to encounter. The general principles will apply, however: questions intended to protect the donor from risks of blood donation and questions (primarily related to infectious diseases) intended to protect the recipient by identifying and excluding donors whose blood might be infectious.

Examples of questions in the medical history designed to protect the donor include whether the donor is under the care of a physician or has a history of cardiovascular or lung disease, seizures, present or recent pregnancy, recent donation of blood or plasma, recent major illness or surgery, unexplained weight loss, unusual bleeding, or is taking medications. Questions about medications help to identify any diseases or illnesses that might make blood donation a risk for the donor.

Most of the questions designed to protect the recipient deal with exposure to infectious diseases. Examples of these questions are the occurrence of or exposure to hepatitis or other liver disease, HIV (or symptoms of AIDS), Chagas disease or babesiosis; use of injected drugs; receipt of growth hormone, coagulation factor concentrates, blood transfusion, recent immunizations, tattoo, acupuncture, ear piercing, or an organ or tissue transplant; travel to areas endemic for malaria; presence of a major illness or surgery; or previous notice of a positive test for a transmissible disease. Examples of questions related to HIV risk behavior include whether the potential donor has had sex with anyone with AIDS, has given or received money or drugs for sex, (for males) has had sex with another male, (for females) has had sex with a male who has had sex with another male.

Physical and laboratory examination of the blood donor

The donor’s general appearance is assessed for any signs of illness or the influence of drugs or alcohol. The skin is examined for signs of intravenous drug abuse, lesions suggestive of Kaposi’s sarcoma, and local lesions that might make it difficult to decontaminate the skin and thus lead to contamination of the blood unit during venipuncture. Physical examination of the potential donor usually includes the temperature, pulse, blood pressure, weight and blood hemoglobin concentration. The specific requirements for these measures are established by the regulatory agency of each country.

Collection of whole blood

Blood is collected into plastic bags, each of which is sterile and can be used only once. Often combinations of bags are used so that whole blood can be separated into its components in a closed system, thus minimizing the chance of bacterial contamination while making storage of the components for days or weeks possible. The venipuncture site is an area free of skin lesions; it is scrubbed with a soap solution followed by an iodine solution. Because bacterial contamination of blood can be a serious or even fatal complication of transfusion,^14,15 it is important to minimize bacterial contamination by selecting a good venipuncture site and decontaminating it properly.

Special blood donations

Most blood is collected for placement in a ‘bank’ to provide for the general community and thus may be used by any patient. However, some blood donations are made intentionally to be used by a specific patient. Examples of these include autologous donation, directed donation and patient-specific donation. In some of these situations the usual regulations for blood donation may not apply.

Autologous blood donation

Autologous blood donation can be done in several ways: preoperative donation, acute normovolemic hemodilution, also known as perioperative hemodilution, intraoperative salvage, and/or postoperative salvage.

In the early 1990s, there was great excitement about the potential of autologous blood and it was estimated that in the US autologous blood could account for 20% of all blood used.²² This has not occurred because much of the autologous blood was collected from patients undergoing procedures with little likelihood of needing blood, surgeons became more skilled at minimizing blood loss, and anesthesiologists became more skilled at managing fluid administration and maintaining patients with lower hemoglobin levels. In 2004, only 3% of donation in the US was autologous.⁶

Preoperative donation. If an elective procedure is scheduled and there is a high likelihood of blood transfusion, the patient can donate blood in advance for his/her own use. Since the donor is actually a patient, they usually do not meet the regulatory requirements for normal blood donation. Thus, the blood is usually not suitable for use by someone else if it is not needed by the original donor/patient. Thus, it is important that autologous blood be collected only for procedures in which there is substantial likelihood that it will be used. Without this type of planning, there is a very high rate of wastage of autologous blood (estimated at 40.4% in the US in 2004).⁶ This amount of waste also means that the costs of autologous blood are quite high.²³

Although there are some contraindications for preoperative autologous blood donation such as bacteremia, symptomatic angina, recent seizures and symptomatic valvular heart lesions, the usual donor requirements do not apply and the final decision whether to withdraw blood from an autologous donor rests with the medical director of the blood bank. This decision may necessitate consultation between the donor’s/patient’s physician and the blood bank physician.

There are no age or weight restrictions for autologous donation. Pregnant women may donate, but donation is not recommended routinely because these patients rarely require transfusion. The autologous donor’s hemoglobin may be lower than that required for routine donors and autologous donors may donate several times within a few weeks prior to the planned surgery. However, usually it is only possible to obtain 2–4 units of blood before the hemoglobin falls to unacceptably low levels.

In most countries, autologous blood must be typed for ABO and D antigen, and at least the first unit must be tested for transmissible diseases. If any of the transmissible disease tests are positive, it may be necessary to label the unit(s) as biohazard in order to alert healthcare personnel to the hazard presented by the potentially infectious blood.

With the discovery of erythropoietin, there was great hope that it could be given to autologous blood donors to increase the number of units they could donate and substantially reduce the use of the general blood supply. Unfortunately this has not occurred because erythropoietin does not result in a meaningful increase in autologous blood units obtained from each patient.

Perioperative hemodilution (acute normovolemic hemodilution).²⁴ Perioperative hemodilution is carried out in the operating room usually after the patient has undergone general anesthesia. One to two units of whole blood are collected and replaced with an electrolyte solution at three times the volume of blood collected. The patient’s hematocrit is maintained at least at 30%. This procedure does not pose unusual risks to patients who are stable and undergoing elective surgery. If it is carried out prior to surgical procedures in which substantial expected blood loss is expected, the 2 units of freshly collected blood are kept in the operating room and can be transfused to the patient during surgery. Theoretical advantages of perioperative hemodilution, in addition to having the blood available, are that blood loss during surgery occurs at a lower hematocrit and thus there is less red cell loss, that surgery is carried out at lower hematocrit which improves blood viscosity and possibly provides better tissue oxygenation, and that the blood that is available for transfusion is fresh. Perioperative hemodilution must be carried out by a committed, knowledgeable anesthesia staff and it appears to have limited but definite value.

Intraoperative blood salvage. In elective, urgent or trauma surgery when substantial blood loss is expected, some of the shed blood can be recovered and returned to the patient. Several devices that combine suction, centrifugation and washing are available for this purpose. Because of the cost of operating these devices, intraoperative blood salvage is usually reserved for situations in which the blood loss is expected to exceed 1000 ml. The device suctions or aspirates blood from the operative site. The collected blood is centrifuged, and, in some cases, a wash solution is added. After processing, the blood is pumped out of the device into a plastic bag so it can be used for transfusion. Contraindications to intraoperative blood salvage are bacterial contamination of the operative site and surgery for malignancy. In both of these situations, transfusion of blood containing bacteria or malignant cells would be undesirable. Examples of situations in which intraoperative blood salvage is used most commonly are vascular surgery, cardiovascular surgery and some major orthopedics procedures.

Postoperative blood salvage. In some situations such as cardiovascular or orthopedic surgery, if there is extensive postoperative bleeding or draining from the surgical site, devices can be used to collect this drainage so that the shed blood can be used for transfusion. This use of postoperative blood salvage has not gained widespread acceptance because the volume of red cells that can be obtained is usually small; if substantial surgical site drainage is occurring, this often indicates a surgical problem that requires intervention. The shed blood usually contains activated coagulation factors, fibrin strands, cellular aggregates and other debris which make transfusion of this material undesirable.

Directed donor blood

Directed donors are friends or relatives who wish to give blood for a specific patient. Usually this is done because the patient hopes those donors will be ‘safer’ than regular blood donors. In some parts of the world, however, directed donation is a necessity because the general blood supply is not adequate. In the US, data do not indicate that directed donors have a lower incidence of transmissible disease markers,²⁵ and thus there is no factual rationale for these donations. Directed donors must meet all of the regulatory requirements for routine blood donation. Their blood becomes part of the community’s general blood supply if it is not used for the originally intended patient.

Therapeutic bleeding

Blood may be collected as part of the therapy for diseases such as polycythemia vera or hemochromatosis. This blood is not usually used for transfusion because the donors do not meet the FDA requirements. As the genetic basis for hemochromatosis has become known, efforts have begun to gain approval for the use of blood obtained from patients with hemochromatosis.^26,27 Limited experience suggests that a donor program could be effective, but it is not likely that blood from hemochromatosis patients would have a substantial impact on the nation’s blood supply.²⁸

Red blood cells

If whole blood is centrifuged and most of the platelets and plasma are removed, the resulting packed red cells or red cell concentrate is resuspended in a solution to optimize red cell preservation and allow storage of red cells for 42 days at 1–6°C. During the 42 days of storage, there is some loss of viability, adenosine triphosphate, membrane lipid and 2.3-DPG (causing increased affinity of hemoglobin for oxygen), reduced transmembrane transport of sodium and potassium, and accumulation of metabolites. Each unit of red cells has a volume of approximately 300 ml and contains about 200 ml of red cells. Red cells are used to provide oxygen-carrying capacity in anemic patients. The number of units given depends on the degree of anemia or blood loss.

Fresh frozen plasma

In the US, when the unit of whole blood is centrifuged, platelet-rich plasma results. The platelet-rich plasma is then centrifuged and the plasma and platelets are separated, resulting in a unit of plasma and a platelet concentrate. If this plasma is placed at −18°C or colder within 8 hours of collection it is called fresh frozen plasma. Fresh frozen plasma can be stored for up to 1 year at −18°C or colder. The unit of fresh frozen plasma has a volume of approximately 185 ml and contains all the constituents of citrated normal plasma such as the coagulation factors, the components of the complement and fibrinolytic systems, and the plasma proteins that maintain osmotic pressure and modulate immunity.

For transfusion, fresh frozen plasma is thawed in a 37°C water bath for approximately 30 minutes. Microwave ovens usually are not used to thaw fresh frozen plasma because they create hot spots that damage the plasma proteins. Thawed plasma should be transfused as soon as possible, but at the latest within 24 hours. If not used by then, it can be relabeled as thawed plasma and stored for an additional 4 days, although it will have reduced levels of factors V and VIII.

Plasma and source plasma

Plasma can also be removed from whole blood up to 24 hours after collection and stored at −18°C or less and stored for up to 1 year. This 24 hour frozen plasma has reduced levels of factor VIII. Source plasma is collected by plasmapheresis and is intended to serve as the raw material for further manufacture into blood derivatives.

Cryoprecipitate

When previously frozen plasma is thawed at 1–6°C, an insoluble material called cryoprecipitate remains after the liquid plasma is removed. Each bag of cryoprecipitate contains about 100 units of factor VIII and 200 mg of fibrinogen and has a volume of about 10 ml. It can be stored for up to 1 year at −18°C or lower. Cryoprecipitate is thawed in a 37°C water bath, and cryoprecipitate from multiple bags is usually pooled into a single container that is dispensed by the blood bank. Cryoprecipitate is usually given in the same ABO type as the recipient. If there is a shortage, small amounts of ABO-incompatible cryoprecipitate can be given. There is usually little risk of hemolysis from small volumes of ABO-incompatible plasma because the volume of plasma from any individual donor who might have a high-titer antibody is only 10 ml. Because cryoprecipitate contains few red cells, it can be given without regard to Rh type.

Cryoprecipitate was developed originally as a source of factor VIII and was the first concentrated form of this coagulation factor available to treat hemophilia. With the development of coagulation factor concentrates that have undergone viral inactivation, the major use of cryoprecipitate currently is as a source of fibrinogen or as fibrin glue.²⁹

Whole blood-derived platelet concentrates – platelet-rich plasma method

Platelets can be produced from units of whole blood or by plateletpheresis. In the US, when platelets are prepared from whole blood, the unit of whole blood is maintained at room temperature and centrifuged, and the platelet-rich plasma is passed into a satellite bag. The platelet-rich plasma is centrifuged again, and the platelet-poor plasma is passed into another satellite bag leaving the platelet concentrate which has a volume of proximately 50 ml. At least 75% of random donor-platelet concentrates contain at least 5.5 × 10¹⁰ platelets. Four to six units of random-donor platelets are pooled to provide a therapeutic dose for transfusion. These whole blood-derived platelet concentrates may then be stored for up to 5 days at room temperature (20–24°C). The variables known to be important in platelet preservation are: temperature, method of agitation, volume of suspending plasma and type of storage container. At the end of the storage period, the intravascular recovery and half-life of the stored platelets are approximately 51% and 3.1 days.³⁰

Whole blood-derived platelet concentrates – buffy coat method

In some countries, the whole blood is centrifuged and the buffy coat containing leukocytes and platelets is removed.³¹ Buffy coats from several units are pooled, the pooled buffy coats are centrifuged, and the platelets are separated from the leukocytes to provide a platelet concentrate. This method provides a therapeutic dose of platelets and no further pooling is necessary. It is thought that this method of preparation provides better platelet function,³¹ although it has not been adopted in the US.

Platelet concentrates

Plateletpheresis usually takes about 90 minutes during which about 4000–5000 liters of the donor’s blood are processed through the blood cell separator. These platelet concentrates have a volume of about 200 ml and contain about 3.5 × 10¹¹ platelets and less than 0.5 ml of red cells. This provides a therapeutic dose of platelets for transfusion. Plateletpheresis has been used increasingly so that in the US about 80% of platelets are produced by plateletpheresis,⁶ but plateletpheresis is much less common in many other countries.

Granulocyte concentrates

Because of the small number of circulating granulocytes, it is not practical to prepare granulocyte concentrates from whole blood donations. Instead, leukapheresis is used to process 6.5–8.0 ml of donor blood during about three hours³² and obtain a granulocyte concentrate. Hydroxyethyl starch is added to the blood cell separator flow system to sediment the red cells and improve the separation of granulocytes from other blood components. To increase the donor’s peripheral blood granulocyte count, and thus increase the yield of granulocytes, dexamethasone and recently, granulocyte colony-stimulating factor (G-CSF) has been administered to granulocyte donors.³³

Mononuclear cell concentrates

Mononuclear cell collection is also done by cytapheresis. This produces a component containing approximately 1 × 10¹⁰ mononuclear cells, which are a mixture of lymphocytes and monocytes. These mononuclear cell concentrates may be used for direct transfusion such as in adoptive immunotherapy to prevent relapse of CML following stem cell transplantation or as the starting material for further processing as part of gene therapy or adoptive immunotherapy.

Plasma

Plasmapheresis can be done using sets of multiple attached bags, but this is time-consuming, cumbersome and involves disconnecting the blood bags from the donor to centrifuge and separate the plasma from the red cells. This creates the chance of returning the blood to the wrong donor. Semi-automated instruments are used that require less operator involvement than the bag systems, while producing up to 750 ml of plasma in about 30 minutes depending on the size of the donor. Because few red cells are removed, the procedure can be repeated frequently so that a donor could provide large amounts of plasma.

Peripheral blood stem cells

Hematopoietic stem cells present in the peripheral blood that are capable of providing complete hematopoietic reconstitution in humans stimulated the development of methods to collect peripheral blood stem cells by cytapheresis.^33,34 The number of peripheral blood stem cells (PBSCs) circulating under usual conditions is low but following chemotherapy there is a rebound and a large number of PBSCs can be obtained by apheresis. G-CSF is also given to patients or normal donors to increase the number of circulating PBSCs and provide an adequate dose of cells for successful reconstitution of hematopoiesis.^35,36 Usually approximately 1 × 10¹⁰ mononuclear cells and 2–6 × 10⁷ CD34⁺ cells are obtained after processing up to 15 l of the donor’s blood during 4–5 hours. The concentrate has a volume of about 200 ml.

Selection of apheresis donors

The criteria and requirements for donors of whole blood apply to the selection of donors for apheresis;³⁷ however, there are some additional requirements. These may vary in different countries, but they generally define the volume of blood that can be extracorporeal during apheresis, the volume of red cells or plasma that can be removed in a given time, the frequency of donation, and any laboratory tests in addition to those performed for whole blood donation. The laboratory testing of donors for transmissible diseases is the same as that for whole blood donation. Thus, the likelihood of disease transmission from apheresis components is the same as that from components prepared from whole blood.

Reactions in apheresis donors

In general, the types of adverse reactions that occur following cytapheresis are similar to those following whole blood donation. However, some side-effects or reactions unique to cytapheresis occur.³² These include paresthesias due to the infusion of the citrate used to anticoagulate the donor’s blood while it is in the cell separator; myalgia, arthralgia, headache, or flu-like symptoms due to G-CSF in granulocyte donors;^32,37 or headache and/or hypertension from blood volume expansion due to the sedimenting agent hydroxyethyl starch used in the cell separator to improve the granulocyte yield.

Transfusion of components containing red blood cells

Clinical indications. Red cells are transfused to improve oxygen-carrying capacity or for restoration of blood volume following blood loss. There is no specific hemoglobin value above which patients have a better outcome, feel better, or have improved wound healing. Thus, in making a decision to transfuse a patient to improve oxygen capacity, the patient’s overall condition must be considered. For instance, when anemia has developed over a long period of time, the patient adjusts to lower hemoglobin levels and may not require transfusion despite very low hemoglobin levels. Most studies that deal with the physiology of blood loss have been done in normal animals, essentially healthy humans, or military casualties, who are usually young males. Thus, the indications for transfusion in patients with cardiac disease, coronary atherosclerosis or other vascular insufficiency are not established.

In the past, some anesthesiologists and surgeons transfused patients to achieve a hemoglobin level of 10 g/dl prior to surgery. However, there is no scientific basis, nor are there clinical data, to support this practice. Many patients would not be at risk if a transfusion was withheld until the hemoglobin level was approximately 7 g/dl.^42,43

Transfusion for restoration of blood volume should not be initiated too rapidly because it is clear that in most ‘normal’ patients the loss of approximately 1000 ml of blood can be replaced by colloid or crystalloid solutions alone. The hemoglobin level may not be of value in this situation because if blood loss has been acute, the patient may have a normal or nearly normal hemoglobin level until equilibration between the intravascular and extravascular space occurs.

Whole blood. Whole blood is rarely used in the developed countries. Instead, it is converted into components to take advantage of the need for plasma and platelets. Acute blood loss is managed by transfusion of red cells and crystalloid or colloid solutions. In developing countries, most transfusions may be of whole blood since facilities for preparation of blood components are often not available.

Red blood cells. Patients with severe anemia usually do not need intravascular volume replacement and thus red cells are the component of choice. In patients with acute massive hemorrhage, who may need both intravascular volume and red cell replacement, crystalloid or colloid solutions, not human plasma, are used with red cells. Crystalloid and colloid solutions have few adverse effects and their use allows the plasma from the original unit of whole blood to be used for the production of coagulation factor concentrate.

Leukocyte reduced red cells. Leukoreduced red cells are being used increasingly throughout the world. In the past, these red cells were used primarily to prevent febrile non-hemolytic transfusion reactions in patients who received multiple transfusions. Leukocyte-reduced red cells reduce the likelihood of HLA alloimmunization and platelet refractoriness^44,45 and may have an immune modulating effect leading to decreased postoperative infection and decreased cancer reoccurrence.^46–48 The availability of filters that remove more than 99% of the leukocytes have made this the method used to prepare leukocyte-depleted red cells.

Washed red cells. When red cells are washed and resuspended in an electrolyte solution, most of the plasma, platelets and leukocytes have been removed. Thus, washed red cells are indicated for patients who have severe reactions caused by plasma. For instance, patients with IgA deficiency can have severe, often fatal, anaphylactic reactions when exposed to plasma containing IgA. Although washed red cells have been used to prevent febrile reactions due to transfused leukocytes, the availability of filters for leukocyte removal has eliminated the use of washed red cells for this purpose.

Frozen deglycerolized red blood cells. Red cells can be protected from injury during freezing by the addition of glycerol. They can then be stored for 20 years or more.⁵⁰ Because most of the plasma, platelets and leukocytes have been removed and after thawing and washing these red cells are suspended in an electrolyte solution, they can be used in a similar way to washed red cells. However, the main advantage of frozen deglycerolized red cells is that they can be stored for years, thus allowing development of a depot of red cells of rare types or of autologous red cells. Frozen deglycerolized red cells do not have a reduced likelihood of disease transmission.

Effects of red blood cell transfusion

The effects of red blood cell transfusion on the recipient’s hemoglobin and hematocrit levels will be affected by the recipient’s blood volume, pretransfusion hemoglobin level, clinical condition (stable, bleeding, etc.), and the hemoglobin content of the donor unit. In general 1 unit of red cells will increase the hemoglobin value 1 g/dl in an average-sized adult.

Transfusion of products containing coagulation factors

Blood components that can be used to replace coagulation factors are fresh frozen plasma and cryoprecipitate. Several plasma derivatives, including factor VIII, factor IX, antithrombin III, and von Willebrand factor concentrates, are available for various coagulation disorders. The plasma derivatives are most useful for single or isolated coagulation factor deficiencies and discussion of this therapy is not within the scope of this book.

Fresh frozen plasma. The most common combined coagulation factor deficiency involves the vitamin K-dependent factors. This deficiency is best managed by treating the underlying condition with or without vitamin K administration. However, if rapid reversal is necessary, fresh frozen plasma or plasma of any age can be used since these coagulation factors do not deteriorate during storage of whole blood at 1–6°C.

Recommended indications for use of fresh frozen plasma are:⁴⁹

Replacement of immunoglobulins in the treatment of immunodeficiency, such as in patients with protein-losing enteropathy or children or adults with immunodeficiency, is not recommended because of the availability of intravenous immunoglobulin preparations.

Because fresh frozen plasma is usually given to replace multiple plasma proteins, the dose is difficult to determine. The desired level of each protein may be different although for many coagulation factors, a level of 30% is considered adequate to provide hemostasis. In an average-sized adult, 5 units of fresh frozen plasma would be necessary to reach this level. This would involve transfusion of about 1000 ml of plasma; the patient’s blood volume and cardiovascular status must be considered.

Coagulation factor concentrates. Deficiency of isolated factor VIII or IX are usually treated with the appropriate factor concentrate. This allows larger doses to be given and the dose can be accurately calculated because each vial of concentrate is assayed for its content of factor.

Cryoprecipitate. Hypofibrinogenemia may occur as an isolated inherited deficiency or in obstetrical complications, disseminated intravascular coagulation, and some forms of cancer. In acquired hypofibrinogenemia, treatment should be directed toward the underlying cause of the disease rather than toward replacement of fibrinogen; however, when the fibrinogen level reaches 50 mg/ml or less, fibrinogen replacement may be necessary.^51,52 Cryoprecipitate is usually used as the source of fibrinogen.⁵³ The dose of fibrinogen for an adult is 6000–8000 mg, although this varies depending on the patient’s fibrinogen level. Usually about 30 bags of cryoprecipitate would be used. A commercially prepared fibrinogen product is now available in Europe.

Transfusion of platelets

Indications for platelet transfusion. Platelet transfusion has increased more than that of other blood components during the past decade.⁶ The most common reason for platelet transfusion is to prevent bleeding (prophylactic)^53,54 and prophylactic platelet transfusions are usually given to patients with transient thrombocytopenia due to chemotherapy for malignancy including bone marrow transplantation. Platelets can also be transfused to treat active bleeding, but this accounts for fewer transfusions.

Only a few small controlled studies of prophylactic platelet transfusion have been done, but in the absence of extensive data, it became common practice to transfuse platelets to prevent serious bleeding when the platelet count was less than 20 000/µl.⁵⁵ More recent studies have established that prophylactic transfusion can be initiated at platelet count of 10 000/µl without increased bleeding^56,57 and this is the current practice.

The usual dose of platelets for a prophylactic platelet transfusion to an average-sized adult is 1 apheresis unit or a pool of 4–5 whole blood-derived platelet concentrates prepared by either the PRP or buffy coat methods. Frequent transfusions of smaller doses result in less total platelet usage with no increase in bleeding,⁵⁴ while others believe that larger doses of platelets are a preferable transfusion strategy.⁵⁸

In a large multi-center trial the likelihood of bleeding was the same in patients who received half or twice the usual platelet dose,⁵⁴ although a separate smaller study found higher bleeding when low dose transfusions were used.⁵⁹

The optimum platelet count to achieve in a bleeding patient is not known. The bleeding time increases when the platelet count is less than 100 000/µl⁶⁰ which suggests that this number could be the goal of transfusion in actively bleeding patients. However, few studies are available to assist in this decision. It appears that bleeding may be more related to the severity of the surgical procedure than the platelet count⁶¹ and platelet transfusion is recommended for patients undergoing lumbar puncture if the platelet count is less than 20 000/µl.⁶² In actively bleeding patients, an attempt to achieve a platelet count of greater than 50 000/µl is recommended.⁶³

In patients with autoimmune thrombocytopenic purpura or drug-induced immune thrombocytopenia, platelet antibodies cause shortened survival of transfused platelets, and thus transfusion is recommended only for treatment of severe thrombocytopenia with active hemorrhage.

There is a dose-response effect from platelet transfusion. One to three hours after transfusion, the usual dose of platelets transfused should cause a platelet count increase of about 25 000 µl in an average-sized adult.^64,65 Some patients do not attain the expected post-transfusion increment in platelet count because they are alloimmunized to platelet or leukocyte antigens.^45,65 In addition, platelet survival can be affected by many clinical factors in the patient,⁶⁶ such as disseminated intravascular coagulopathy; amphotericin B administration; palpable spleen; presence of HLA antibody, platelet antibody, and fever; and status after marrow transplantation. Prevention of alloimmunization has been accomplished using single-donor (apheresis) platelets, leukocyte-depleted blood components, and UV irradiation.⁴⁵

Because platelet refractoriness is often associated with bleeding and with a poor outcome, this is a major clinical problem in transfusion medicine. Refractoriness is managed by treating clinical factors that might cause refractoriness,⁶⁶ the use of ABO-compatible platelets,⁶⁷ and the use of platelets as fresh as possible. If these measures fail, an improved response may be obtained by selecting a platelet donor whose HLA type matches that of the recipient,^68–70 although about 30% of HLA-matched transfusions do not provide a satisfactory response. Another approach is to crossmatch the patient’s serum with platelets and to select compatible donors based on this laboratory test. This approach is about as effective as the use of HLA-matched donors.^71,72

Granulocyte transfusion

Many chemotherapy and stem cell transplant regimens cause severe and prolonged granulocytopenia. These patients are at increased risk of infection, which is a major cause of death. The availability of blood cell separators and of donor-stimulation techniques have made it possible to collect large numbers of granulocytes for transfusion, especially with the use of G-CSF stimulated donors. Historically granulocyte transfusions appeared to be helpful,⁷³ but today most patients respond to antibiotics. Fungal infections, however, continue to be a major problem,⁷⁴ and granulocyte transfusions are being used in this setting and for bacterial sepsis unresponsive to antibiotics. No clinical trials have documented the effectiveness of granulocyte transfusion in these situations, but G-CSF stimulation of donors yields very high dose granulocyte concentrates³³ and this has led to a new large-scale clinical trial of granulocyte transfusion.

Blood derivatives

During the late 1930s, the technique was developed for the separation of different plasma proteins. This technique is now used to process thousands of liters of plasma in large batches to produce many plasma proteins, termed plasma derivatives, for therapeutic use. Some of the plasma for production of derivatives is obtained from units of voluntarily donated whole blood separated into components, but most of the plasma is obtained by plasmapheresis of paid donors. This aspect of the blood supply has been extremely effective in producing large amounts of important therapeutic proteins such as albumin, coagulation factor concentrates and immune globulins. However, the risk of disease transmission from paid donors was high^7,75 and this fact was tragically demonstrated with the onset of the AIDS epidemic.⁷⁶ Improvements in the manufacturing technique have now made these products free of transmission of most viruses^77,78 and most are now being produced by recombinant DNA methods. The demand for the intravenous form of immune serum globulin is large because if its use in many situations in addition to the FDA-licensed indications of primary congenital immune deficiency and autoimmune thrombocytopenia. A discussion of the use of plasma derivatives is beyond the scope of this chapter.

Transfusion of cytomegalovirus (CMV)-negative blood products

CMV can be transmitted by blood transfusion with a severe, even fatal result. Transfusion-transmitted CMV occurs in immunosuppressed patients and can be prevented by using CMV antibody-negative blood components or blood components filtered to remove the leukocytes that are thought to be the source of latent CMV. These CMV-safe blood components are indicated in neonates,⁷⁹ pregnant women,⁸⁰ patients undergoing bone marrow transplantation,^81,82 patients with AIDS or severe combined immune deficiency, and patients receiving extensive chemotherapy. There is little information available about the value of CMV-safe blood components in patients who receive solid organ transplants. Most, if not virtually all, of the CMV disease in these patients is due to reactivation of a previous infection, thus CMV-safe blood components are not usually provided to these patients.

Irradiated blood components

Viable lymphocytes contained in blood components can cause fatal graft-versus-host disease (GVHD) in immunocompromised patients. Transfusion-induced GVHD can be prevented by using blood components that have been gamma irradiated.⁸³ Irradiation with 1500–5000 Gy interferes with the ability of lymphocytes to proliferate without damaging the cell function.⁸⁴ Doses of up to 5000 Gy do not have an adverse effect on red cells, platelets or granulocytes. As the use of irradiated blood components has increased, often it is not possible to transfuse them immediately after they are irradiated. Doses of 2000 or 3000 rads to units of red cells result in potassium levels two and three times normal after storage for 4–5 days which suggests that there is some irradiation damage to the red cell membrane or the sodium-potassium pump. However, the amount of potassium in the supernatant is not considered dangerous, and the normal survival of these cells in vivo is the basis for allowing storage of irradiated red cells for the original expiration date or 28 days after irradiation, whichever comes first.

It is difficult to determine which patients should receive irradiated blood components because there are no in vitro assays of immunodeficiency that satisfactorily predict which patients are susceptible to transfusion-associated GVHD. However, several kinds of patients are so severely immunocompromised that transfusion-associated GVHD is very likely unless blood components are irradiated. These include: fetuses undergoing intrauterine or exchange transfusion, patients with severe combined immunodeficiency syndrome or Wiskott–Aldrich syndrome, and patients undergoing allogeneic or autologous hematopoietic stem cell transplantation.

Occasionally blood is irradiated for patients who are not immunocompromised. In immunocompetent patients, some cases of transfusion-associated GVHD occurred after transfusion of blood from relatives or unrelated donors who were partially HLA-matched with the patient.⁸⁵ Apparent transfusion-associated GVHD has been reported due to fresh blood transfused to two immunocompetent children who underwent cardiac surgery and received blood from donors who were homozygous for an HLA Class I antigen haplotype shared with the recipient. In these cases, the recipient would not have recognized the HLA Class I antigens on the transfused cells as foreign, but lymphocytes in the donated blood would have recognized the recipient’s cells as foreign. Because of additional reports of transfusion-associated GVHD in other immunocompetent patients,^86,87 irradiation of the blood components donated by first-degree relatives of the patient has been instituted. Because of the high frequency of certain HLA antigens in the Japanese population and the resulting likelihood that a random, unrelated donor may be partially HLA-matched with the recipient, irradiation may be used more commonly there.

There are several other clinical situations in which isolated cases of transfusion-associated GVHD have been reported and for which a few medical centers use irradiated blood components, but there is no consensus on recommended practice. These include neonates, although there is no evidence that newborns who do not have a congenital immunodeficiency are at increased risk of developing transfusion-associated GVHD; patients with hematologic malignancies, especially those receiving very severe chemotherapy regimens often with radiation; patients with aplastic anemia, although these patients usually do not have defective cellular immunity and there have not been documented cases of transfusion-associated GVHD due to transfusion of normal cells, patients with solid tumors such as neuroblastoma or glioblastoma; and patients with AIDS, although no cases of transfusion-associated GVHD have been reported.

Although irradiation of fresh frozen plasma and cryoprecipitate is probably not necessary, transfusion-associated GVHD has occurred in patients with congenital immune deficiency after transfusion of fresh, liquid plasma. Because previously frozen components contain fragments of leukocytes, but few viable lymphocytes, these components would not be expected to cause transfusion-associated GVHD. Still many blood banks irradiate these plasma components to avoid clerical errors in which a cellular blood component might not be irradiated when necessary.

Fibrin glue

Fibrin glue refers to the use of fibrinogen (in some form) and thrombin as a topical adhesive to control bleeding.^29,88 Fibrin glue is used predominantly by surgeons to stop microvascular bleeding in cardiovascular surgery and to reduce mediastinal drainage, to seal synthetic vascular grafts and bleeding surfaces of the liver or spleen, and in maxillofacial surgery to seal dura and repair peripheral nerves. During the past few years, commercial preparations of fibrin glue have become available.

Massive transfusion

The traditional approach to acute blood loss and massive transfusion was to maintain intravascular volume with crystalloid or colloid and replace platelets, coagulation factors and red cells as needed if depletion of these occurred. This approach accepts that coagulopathy may develop and an attempt is then made to correct this. Contemporary studies have shown results if frozen plasma is used immediately to prevent coagulopathy.^89,90 This has led to the development of standard massive transfusion protocols involving frozen plasma, platelets and red cells in a 4 : 1 : 4 ratio beginning very early in the event of a severe injury with substantial blood loss and use of these protocols is effective in both a military and civilian setting.

Massive transfusion is transfusion equivalent to the patient’s blood volume during a 24-hour interval. The effects of massive transfusion upon the recipient are due to the biochemical and functional characteristics of stored blood and include hypothermia, acidosis, hypocalcemia, hyperkalemia, coagulopathy and thrombocytopenia.⁹¹ In patients undergoing acute blood loss and/or massive transfusion, the issues faced are the type of replacement fluid, the kind of blood component to use, the necessity to replace coagulation factors or platelets, the speed with which red cells can be made available, and the blood bank’s ability to respond urgently.

Cardiovascular surgery

For patients undergoing cardiovascular surgery, fresh blood and routine platelet transfusions are not necessary. Patients undergoing cardiopulmonary bypass often develop thrombocytopenia and platelet function abnormalities.⁹² However, most patients do not experience unusual bleeding and the extent of bleeding is not directly related to these hemostatic abnormalities.⁹¹ Patients who bleed excessively should be managed like any other surgical patients.

Currently there is debate about whether blood stored longer before transfusion is detrimental to these patients.^93,94 This issue is not resolved and several large studies of the effects of red cells stored for different times are underway.

Transplantation

In patients undergoing hematopoietic stem cell transplantation consideration must be given to transfusion strategies before and after transplantation and in ABO- and Rh-incompatible transplants.⁹⁵ In solid organ transplantation, routine blood components are usually used for patients receiving kidney and heart transplants, but liver transplant recipients are treated more like patients undergoing massive transfusion.

Neonates

Neonates have special transfusion requirements including pre-transfusion testing, need for CMV-negative blood, and/or irradiated blood components and exchange transfusion. Larger pediatric patients are usually managed similarly to adults. Smaller pediatric patients may require special infusion devices and adjusted doses of components.⁹⁶

Hemophilia

The management of hemophilia patients is a complex subject and will not be covered here.

Provision of red cells in urgent situations

The speed and methods of making blood available are crucial in several clinical situations. Where transfusion is or may be urgent, a blood specimen should be obtained and sent to the blood bank for emergency type and crossmatch. An ABO and Rh type can be performed in about 5 minutes and blood of the same type as the patient selected for transfusion. If necessary, this blood can be released without a full crossmatch. The crossmatch procedure can be shortened to detect only ABO incompatibility since that is usually the most disastrous kind of transfusion reaction. Blood of the patient’s ABO type can be available usually in about 15 minutes using this shortened crossmatch. Usually Rh-positive blood would be chosen, but Rh-negative blood may be used if the patient is a young female. When the patient’s ABO type is not known, group O red cells are used. This practice has led to the designation of group O, Rh-negative individuals as universal donors because group O, Rh-negative red cells would not be hemolyzed by either anti-A, anti-B, or anti-D if present and would not immunize recipients to D. Group O, Rh-negative (universal donor) red cells do not avoid the potential risk that the recipient may have a red cell antibody other than anti-D or a red cell autoantibody, and hemolysis or transfusion reactions can occur after transfusion of O-negative red cells. Stocking group O, Rh-negative red cells routinely in emergency departments is inappropriate. The red cells may not be stored properly, and there may not be a system of checks for releasing the units; these are practices that can lead to serious problems. Techniques of fluid management and resuscitation are so highly developed today that patients can be maintained for the time required to obtain red cells from the blood bank. Blood bank personnel are aware that there may be situations in which there is an urgent need for blood and each blood bank should have a procedure for the rapid release of red cells.

Exchange transfusion of the neonate

The indications for exchange transfusion in the neonate are: hyperbilirubinemia, sepsis, disseminated intravascular coagulopathy, polycythemia, respiratory distress syndrome, hyperammonemia, anemia, toxin removal, thrombocytopenia and sickle cell disease. The exchange transfusion can be done via the umbilical vein for newborns or a peripheral vein for other neonates or children. Exchange of one blood volume should remove about 65% of the original intravascular constituent, and an exchange of two blood volumes should remove about 85%.³² Exchange transfusion is usually done with red cells that are only a few days old. If necessary, because of coagulopathy, fresh frozen plasma can be used with the red cells to provide coagulation factors during the exchange transfusion. The potential complications of exchange transfusion are: infection, rebound hypoglycemia, hypocalcemia (due to citrate anticoagulant in the transfused blood), hyperkalemia (if older red cells are used), late onset alkalosis, volume overload, hemolysis, thrombocytopenia, neutropenia, coagulopathy, GVHD and hypothermia. These complications can be avoided or minimized by careful technique and good general patient care, although because many of these patients are quite ill and unstable, exchange transfusion can be a risky procedure.

Autoimmune hemolytic anemia

Patients with autoimmune hemolytic anemia present a special problem for the blood bank because the patient’s serum usually reacts with red cells from all donors because of the broad spectrum of reactivity of the autoantibody. This autoantibody reactivity may obscure alloantibodies present in the patient’s serum and it may not be possible to obtain red cells for transfusion that are serologically compatible (negative crossmatch). The decision to transfuse a patient with autoimmune hemolytic anemia should be based on the severity of the anemia, whether the anemia is rapidly progressive, and the associated clinical findings.⁹⁷ In newly diagnosed patients with autoimmune hemolytic anemia, the hemoglobin should be measured frequently to determine whether the anemia is stable or progressing. Transfusion is not recommended unless the hemoglobin is in the 5–8 g/dl range. Many of these patients will compensate for their anemia, especially on bed rest in the hospital, and transfusion is not necessary. Although autoimmune hemolytic anemia patients are experiencing hemolysis, they usually do not experience signs or symptoms of an acute hemolytic transfusion reaction. In addition to the usual complications associated with transfusion, patients with autoimmune hemolytic anemia may experience increased hemolysis and/or congestive heart failure.

If transfusion is necessary, the two goals of compatibility testing are to select red cells that will survive at least as long as the patient’s own cells and to avoid transfusing red cells that are incompatible with any clinically significant alloantibodies the patient may have. There are several serologic strategies to accomplish these goals.⁹⁷

The autoantibodies usually cause the red cells from all donors to have shortened post-transfusion survival. Despite this ongoing hemolysis, patients with autoimmune hemolytic anemia do not require special red cell components. It is advisable to choose units that are in the first week or two of their storage life to obtain the maximum benefit from the transfusion. Packed red cells are satisfactory although leukocyte-depleted red cells are preferable to avoid a possible febrile transfusion reaction, which might be confused with a hemolytic transfusion reaction. There is no reason to use frozen deglycerolized red cells for autoimmune anemia patients.

Pregnant women

Anemia is common during pregnancy; however, transfusion is rarely necessary. If so, it is usually because of some other complicating factor and the choice of blood components should be based on the specific reason for the transfusion (i.e., acute blood loss, sickle cell disease). Pregnant patients receive CMV-safe blood components to prevent acute CMV infection that might cause birth defects in the child.⁸⁰

Autoimmune thrombocytopenia

Most patients with autoimmune thrombocytopenia do not require platelet transfusion despite very low platelet counts. These patients have platelet autoantibodies that severely shorten the intravascular survival of transfused platelets. The transfused platelets survive for only a few minutes or hours⁹⁸ and a beneficial effect may not be obtained. If autoimmune thrombocytopenic patients do experience serious hemorrhage, platelet transfusions should be given.

Neonatal alloimmune thrombocytopenia

Neonatal alloimmune thrombocytopenia is the platelet analogue of hemolytic disease of the newborn. That is, the mother becomes immunized to an antigen that she lacks but that the fetus has inherited from the father. Maternal IgG platelet antibodies then cross the placenta and cause thrombocytopenia in the fetus. The antibodies can be detected in the mother;⁹⁹ HPA-1 (formerly known as Pl^A1) is the most common. If the neonate requires transfusion, platelets lacking the offending antigen should be used. Alternatively, an exchange transfusion can be done to remove the offending antibody. Alternatively, platelets lacking the antigen can be obtained from the mother, although the plasma containing the antibody should be removed before transfusion and the platelets should be resuspended in saline or group AB plasma. If the mother is not available or cannot donate platelets, most large blood banks have a few HPA-1 negative donors available to provide compatible platelets. The half-life of IgG is approximately 21 days; therefore, more than one platelet transfusion may be necessary in severely affected infants.

Neonatal alloimmune neutropenia

This is the neutrophil analog of hemolytic disease of the newborn and of neonatal alloimmune thrombocytopenia. Patients are usually discovered because they develop an infection at the circumcision site or in the perineal area. Cases due to several different neutrophil-specific antibodies have been reported.¹⁰⁰ Although these infants can be given granulocytes attained from a whole blood donation by the mother, the very short half-life of granulocytes limits the effectiveness of this approach. Thus, exchange transfusion is the recommended for these patients if there is a serious infection.

Rare blood types

There is no universal definition of a rare blood type. This term usually refers to an individual who lacks a blood group antigen that is present in a very high frequency in the normal population (see Chapter 37). This means that the individual will almost certainly be exposed to the antigen if they are pregnant or receive a transfusion. First, it is necessary to determine whether the antibody is clinically significant and likely to cause accelerated destruction of red cells. If the antibody is clinically significant, efforts should be made to obtain red cells that lack the antigen. Most countries have a rare donor registry that can be consulted. Considerable planning may be necessary to obtain the red cells, especially if the donors live in other cities or if the transfusion is to replace blood loss during elective surgery. Red cells from most rare donors may be available only in the frozen state which may create additional problems if the transfusion is for anticipated but uncertain blood loss. If transfusion is needed urgently, close communication is necessary between the blood bank physician and the patient’s attending physician to determine a course of action. For instance, if the antibody may cause shortened red cell survival but little or no acute hemolysis, the decision might be made to use incompatible red cells while the search continues for red cells that lack the antigen.

Transfusion reactions

The cause, severity and outcome of a transfusion reaction are difficult to predict from the presenting signs and symptoms. Therefore, all patients who exhibit signs or symptoms during or within several hours after platelet transfusion should be managed initially as if a transfusion reaction was occurring. When a transfusion reaction is suspected, the transfusion should be stopped immediately, the needle should be left in the vein and normal saline should be infused while vital signs are obtained and a brief physical examination is carried out. A new blood sample should be obtained for repeat red blood cell compatibility testing and inspection of the plasma for evidence of hemolysis, and a urine sample should be obtained if the patient can void. If pulmonary symptoms are prominent, a chest X-ray should be obtained. Based on these actions, a preliminary assessment of the situation can be made and definitive treatment initiated.

Hemolytic transfusion reactions. The most dangerous immunologic complication of transfusion is a hemolytic transfusion reaction which responsible for about 22% of fatalities in the US.¹⁰² This means that in the US, about 13 patients/year die, giving an apparent incidence of fatal hemolytic transfusion of about 1/1 000 000 units of red cells or 1/300 000 patients transfused.

ABO incompatibility causes severe hemolytic transfusion reactions because the patient has IgM ABO antibodies that bind complement and cause activation of the complement system release of cytokines and red cell lysis. The signs and symptoms of a hemolytic transfusion reaction are due to complement activation and also to the effects of cytokines.^105,106 The severity of the symptoms does not correlate with the volume of ABO-incompatible red cells transfused or the ultimate outcome of the transfusion reaction.^107,108 The signs of a hemolytic transfusion reaction are well known and include fever, chills, flushing, low back pain, hypotension, dyspnea, abdominal pain, vomiting, diarrhea, chest pain or unexpected bleeding. The most common signs and symptoms are fever, chest pain and hypotension. In a hemolytic transfusion reaction, the coagulation system may be activated and these patients may develop a coagulopathy and/or disseminated intravascular coagulation. Oliguria and renal failure may also be part of a hemolytic transfusion reaction because a variety of factors such as kinens, intravascular coagulation and microthrombi lead to reduced renal blood flow and damage.

There is a classic pattern of alteration in laboratory tests in a hemolytic transfusion reaction. In an acute hemolytic transfusion reaction, the common findings are hemoglobinemia and/or hemoglobinuria, reduced serum haptoglobin, elevated serum bilirubin, a positive direct antiglobulin test and the presence of unexpected red cell antibodies.¹⁰⁷ Laboratory testing should make the diagnosis of hemolysis and identify the red cell antibody involved.

Febrile reactions. These reactions occur in association with about 0.5–1.0% of transfusions. They are due to the patient’s leukocyte antibodies, which react with leukocytes present in the transfused components¹⁰⁹ or cytokines contained in the donor blood component.¹¹⁰ The severity of the reaction is directly related to the number of leukocytes in the blood component¹⁰⁹ or cytokine levels. These febrile reactions can be prevented by removing leukocytes from the blood components. Antipyretics have been used to prevent reactions, but the value is not evidence-based¹¹¹ and at most these should be used only in patients who have experienced a reaction. Corticosteroids are used for patients with severe reactions. With the increasing use of leukoreduced components, the problem of febrile transfusion reactions has decreased but continues to be a problem for some patients.

Allergic reactions. Allergic reactions manifested by hives but with no other symptoms occur following 1–2% of transfusions. When this occurs, the transfusion should be stopped; if it is then established that hemolysis is not occurring and there are no other signs or symptoms, the patient can be given an antihistamine and after about 30 minutes the transfusion can be restarted.

Pulmonary reactions. Patients may have several pulmonary reactions to transfusions called transfusion-related acute lung injury (TRALI). TRALI is now the most common cause of transfusion-related fatality,¹⁰² accounting for more than half of the deaths. These reactions are acute, sometimes fatal, usually occur up to 6 hours after the transfusion and are characterized by acute respiratory distress, severe hypoxemia, bilateral pulmonary edema, hypotension, fever and diffuse bilateral infiltrates on chest X-ray.^112,113 Cyanosis may or may not be present. The frequency of these reactions is estimated at between 1/300 and 1/5000 transfusions of plasma-containing components.¹¹³ They are probably more common than previously believed.¹¹² The reactions are thought to be due to transfusion of HLA- or granulocyte-specific antibodies in the donor unit that react with the patient’s leukocytes and also the transfusion of inflammatory mediators.¹¹⁴ In either situation, it is likely that leukocytes, endothelial cells and lipid and protein inflammatory mediators are involved and lead to endothelial damage, increased cell membrane permeability, increased neutrophil adhesion to endothelium and release of cytokines. These patients can be successfully managed if there is prompt recognition of the reaction and initiation of supportive treatment. The use of plasma products from male donors should decrease the incidence of TRALI.^115–117

Anaphylactic reactions. Patients who are IgA-deficient and who have IgA antibodies may experience dramatic and rapidly fatal anaphylactic reaction if they receive blood components containing IgA.^118,119 The treatment is the same as for any anaphylactic reaction. The reactions can be prevented by using red cells or platelet concentrates washed to remove plasma IgA and by using plasma components prepared from IgA-deficient donors.

Reactions to platelets

Transfusion reactions can occur during platelet transfusion. These reactions present as chills and fever similar to those seen in a non-hemolytic febrile transfusion reaction. Platelet transfusion reactions are caused by cytokines that accumulate in the platelet concentrate during storage¹¹⁰ or by the patient’s platelet or HLA antibodies that react with leukocytes contained in the platelet concentrates. These reactions can be prevented by removing the leukocytes before storage of platelets.¹¹⁰ The most common signs and symptoms of a transfusion reaction to platelets are chills, fever and urticaria.

Graft-versus-host disease (GVHD)

Blood components contain viable lymphocytes and can cause GVHD in patients who are severely immunocompromised. Transfusion-associated GVHD can also occur in immunocompetent patients if they receive blood from an HLA-matched (usually homozygous) donor.^85–87 The syndrome characterized by fever, liver dysfunction, skin rash, diarrhea and marrow hypoplasia begins less than 30 days following transfusions and is fatal in approximately 90% of patients. Transfusion-associated GVHD can be prevented by irradiating the blood components prior to transfusions.⁸³

Other complications of blood transfusion

Immunization to blood group antigens, iron overload, microemboli, citrate toxicity, hypocalcemia, hyperkalemia, acidosis, alkalosis and cardiac arrhythmias due to cold blood can occur following transfusion.

Post-transfusion hepatitis

Post-transfusion hepatitis is the most common disease transmitted by blood transfusion and it has a major health impact. Post-transfusion hepatitis can be due to hepatitis C virus, hepatitis B virus, hepatitis A virus, CMV or Epstein–Barr virus. The incidence varies in different parts of the world. In the US there are about 90–111 cases of post-transfusion hepatitis C and 66–153 of post-transfusion hepatitis B annually per million units of laboratory tested blood.^122–124

Hepatitis A usually has a short period of viremia and generally does not involve a carrier state. Thus, post-transfusion hepatitis A is rare, although it can occur if an individual donates blood during the short period of viremia before symptoms develop.^125,126 Donated blood is not tested for hepatitis A because hepatitis A antibodies are not present at this early stage of infection, there is no practical screening test for the virus itself, and post-transfusion hepatitis A is rare.

Most individuals infected with the hepatitis B virus are asymptomatic but about 10% develop persistent viremia and chronic hepatitis B. Thus, an infectious, but apparently healthy, individual may meet all of the donor medical history criteria and donate a unit of infectious blood. Routine screening of blood donors for hepatitis B surface antigen has reduced the previous high incidence of post-transfusion hepatitis B.

In the late 1980s, the hepatitis C virus was discovered^127,128 and this virus accounts for almost all cases of non-A, non-B hepatitis. Testing for antibodies to hepatitis C virus was introduced in the early 1990s and has greatly reduced post-transfusion hepatitis C. Because the screening test for hepatitis C detects antibody to the virus, there is a ‘window’ period during which the individual has viremia and is infectious, but during which the test for antibodies to hepatitis C virus is negative. Blood donation by asymptomatic individuals during this window period accounts for much of the remaining post-transfusion hepatitis. This delay in antibody production had led to the development of tests to screen donated blood by detection of viral DNA or RNA. This method has been referred to as nucleic acid amplification testing (NAT) and will be discussed later.

HIV infection and AIDS

When the epidemiology of HIV infection became known and when it was clear that transfusion-transmitted AIDS did occur, blood banks altered their medical screening practices to defer potential donors from AIDS risk groups; and when the HIV-1 virus was shown to be the cause of AIDS, blood banks initiated routine testing of all donated blood for antibodies to HIV-1 (anti-HIV-1). These two steps greatly improved blood safety and reduced the risk of acquiring HIV infection following transfusion from up to 91% to very low levels. When a blood donor is found to be anti-HIV-1 positive on the initial screening test, confirmatory testing is done by the Western blot method.

Despite the effectiveness of the medical history questioning and laboratory testing of donated blood, there is a remaining risk of acquiring HIV-1 by transfusion. This risk decreased to about 1 in 500 000 units of blood,^129–131 but this meant that up to about 20 people may become infected with HIV-1 annually by transfusion of donated blood which was negative for anti-HIV-1 antibodies. The reasons for the continued risk of transfusion-transmitted HIV-1 are: 1) failure of some infected individuals to develop antibody; 2) lack of representation of variant viral strains of test reagents; 3) laboratory testing errors; and 4) the window phase of infection.¹³² Because the window phase accounts for almost all transfusion-transmitted HIV in developed countries, testing for the HIV antigen itself was attempted. Although it was predicted to shorten the window period and further reduce the likelihood of HIV-1 transmission, the method was not sufficiently sensitive to detect many infectious HIV-1 seronegative donors^133,134 and so it was never adopted. Subsequently, methods that amplify HIV-1 DNA sequences have been applied to blood donor testing, thus making it possible to detect minute amounts of viral DNA or RNA.¹³⁵

Because of the complexity and cost of NAT, sera from multiple donors are tested in a pool, but this technology detects a level of HCV or HIV viral particles/ml at the levels that occur during the window phase of infection. In the US, NAT reduced the HIV-1 window phase period from 22 to 10 days or less and the hepatitis C window phase period from 70 to about 41 days or less.¹³⁶ This reduction prevented approximately 2–15 cases of transfusion-transmitted HIV-1 and 40–60 cases of hepatitis C annually in the US.¹³²

Other transfusion-transmitted infectious diseases (Table 38.1)

Malaria can be transmitted by transfusion, but this is rare in North America and Western Europe. Most cases involve Plasmodium malariae. Donors who might transmit malaria undergo screening by medical history, although this screening method is becoming increasingly difficult as worldwide travel increases. Laboratory testing of donors for malaria is not practical or cost-effective in the US but may be done in parts of the world where malaria is endemic. Transmission of syphilis by blood transfusion was common years ago but now it is extremely rare.¹³⁷ The treponema that causes syphilis can survive in refrigerated blood for 48 hours¹³⁸ and at room temperature and, thus, can be transmitted from red cell components stored for only a few days or from platelet concentrates stored at room temperature. Although all blood donors are tested for syphilis, this is not a very effective method of preventing transfusion-transmitted syphilis because the serologic tests do not closely coincide with periods of infectivity.

Mosquito borne West Nile virus appeared in the US several years ago and was quickly recognized as a transfusion-transmitted infection.¹³⁹ Since deferring donors with a history of mosquito bites is not feasible, a nucleic acid amplification test has been incorporated into the existing NAT systems for HIV and HCV in North America.¹⁴⁰ This has greatly reduced transfusion-transmitted West Nile virus infection but rare cases still occur.¹⁴¹

CMV is a herpes virus that is common in the general population and can be transmitted by blood transfusion to both immunocompetent or immunodeficient patients. A large proportion of blood donors have been infected with CMV. There is no practical laboratory test to determine which patients previously infected with CMV but presently healthy enough to donate blood may transmit the virus. Transfusion-transmitted CMV can be prevented by using blood that lacks antibody to CMV or by removing the leukocytes from cellular components.^81,82

Transmission of HTLV-I via blood transfusion does occur,¹⁴² although no cases of transfusion-transmitted adult T-cell leukemia or tropical spastic parapheresis have been identified in the US. All donated blood in the US is tested for antibodies to HTLV-I. Trypanosoma cruzi, the organism that causes Chagas disease, can survive in refrigerated blood and can be transmitted by transfusion. Cases of transfusion-transmitted Chagas disease are rare in North America.¹⁴³ Attempts to identify donors potentially infectious for T. cruzi by medical history have not been effective.¹⁴⁴ Therefore, a test has been developed¹⁴⁵ and is being implemented to detect carriers of T. cruzi. Babesia microti can be transmitted by blood donated by asymptomatic infected donors.¹⁴⁶ The ticks that carry this parasite are prevalent in the Northeast, Mid-Atlantic, and Upper Midwest. There is no suitable laboratory screening test for B. microti. Some blood banks defer individuals from heavily tick-infested areas during the summer months.

Borrelia burgdorferi, a spirochete transmitted by ticks to humans, can survive in stored blood for up to 45 days.¹⁴⁷ Although transmission of B. burgdorferi by transfusion is theoretically possible, it has not been reported. A serologic test is available, but it is not suitable for donor screening. The widespread prevalence of the host tick makes it impractical to defer donors from endemic areas. Parvovirus B19 has been transmitted by blood transfusion.^148,149 No steps are taken to prevent transfusion-transmission of parvovirus B19, but a recent case of transmission by pooled, solvent/detergent-treated plasma¹⁴⁹ led to the screening of lots of this plasma to minimize the likelihood of infection. Theoretically, any disease in which microbes circulate in the blood and survive for a few days in stored blood components could be transmitted by transfusion. However, the diseases of most concern have been discussed. A few other diseases that almost never occur due to transfusions in North America are toxoplasmosis, dengue, chickungunya, leishmaniasis, microfilaria and African trypanosomiasis.

Erythropoietin

The availability of hematopoietic growth factors opened a new era in transfusion medicine. The first of these, erythropoietin, eliminated the need for red cell transfusions in most patients with end-stage renal failure.¹⁵⁰ It has been estimated nationally that this eliminated as many as 500 000 transfusions in the US. The use of erythropoietin would make these red cell units available for other patients and yet allow patients with renal failure to maintain higher hemoglobin levels and improved quality of life¹⁵¹ and to avoid the complications of transfusions. Erythropoietin has been used in forms of anemia not due to erythropoietin deficiency, especially cancer which has become the largest use of erythropoietin.

In patients undergoing chemotherapy, erythropoietin is used to increase the hemoglobin to 11 or even 12 g/dl to provide greater stamina and physical energy.¹⁵² However, it has been suggested that use of erythropoietin in these patients may lead to shorter survival due to complications and cancer recurrence.^153,154 Currently, this issue is unresolved.³³ Erythropoietin has also been used to increase autologous blood donation or reduce the homologous blood requirements of patients undergoing elective surgery but is of only limited benefit. This exciting drug has now taken its place in red cell transfusion practices.

Granulocyte-macrophage colony simulating factor (GM-CSF)

G or GM-CSF may decrease the period of chemotherapy-induced leukopenia in patients with malignancy or in those undergoing bone marrow transplantation.³³ Although this reduction may reduce the morbidity and mortality of these procedures, it probably will not greatly alter transfusion therapy in the near future because leukocyte replacement is not widely practiced. However, reducing the incidence and/or severity of infection could modify transfusion therapy if sepsis and disseminated intravascular coagulopathy are avoided with a resulting decline in the use of platelets and fresh frozen plasma. The use of G-CSF to stimulate donors for the collection of peripheral blood stem cells or granulocytes for transfusion has been discussed earlier.

Platelet growth factor

Platelet growth factors shorten the period of thrombocytopenia and elevate the platelet nadir in patients with solid tumors,³³ but these patients do not require many platelet transfusions and so there is little impact on platelet demand. No beneficial effect on platelet recovery has been found in patients undergoing hematopoietic stem cell transplantation.³³ Thus, despite the exciting development of the availability of platelet growth factors, they have had little impact on transfusion medicine.