Fibrinogen is a blood fraction that is essential for clotting. It is decreased in two ways, both relatively uncommon: (1) by intravascular deposition of fibrin in the form of small clots (DIC) and (2) by inactivation in the presence of primary fibrinolysin. Fibrinogen concentrates used to be prepared commercially but are no longer available due to the considerable risk of hepatitis. Cryoprecipitate contains 150 mg or more of fibrinogen per bag and is the most commonly used source of therapeutic fibrinogen.
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Special Coagulation Factor Materials
Factor VIII concentrate differs from cryoprecipitate in several ways. It is prepared from a pool of donors and is lyophilized. The two major advantages are that factor VIII activity has been assayed by the manufacturer for each concentrate bag and that treatment with solvent-detergent mixtures or adequate heat (when coupled with donor testing) can virtually eliminate infectivity by hepatitis B and C virus and HIV-I. Some other viral infections can still be transmitted. Recombinant factor VIII will eliminate infection problems when it becomes widely available. Factor VIII concentrate is not reliable for therapy of von Willebrand’s disease.
Hemophilia A patients who develop factor VIII inhibitors and become refractory to ordinary factor VIII therapy have been treated with some success using a commercial product known as prothrombin complex concentrate. This was originally developed for use in factor IX deficiency. A newer product known as activated prothrombin complex concentrate (or antiinhibitor coagulant complex) is said to be more effective.
Factor IX concentrate (prothrombin complex concentrate) is available for therapy of factor IX deficiency (hemophilia B; Christmas disease). Treatment of this product by solvent-detergent mixture or adequate heat reduces risk of infection by viruses surrounded by a lipid envelope such as HIV-1, the hepatitis viruses, and CMV. However, there have been cases of DIC, thrombosis and embolization, and acute myocardial infarction.
Factor XI deficiency is usually treated with fresh frozen plasma, although some factor XI is present in all blood or blood products.
Antithrombin III (AT-III) deficiency or protein C deficiency (Chapter 8) are usually treated with fresh frozen plasma, although AT-III activity is fairly stable in plasma that is present in any blood product. Cryoprecipitate also contains AT-III, but the amount per unit is not large. Fibronectin is a plasma glycoprotein thought to play a role in phagocytosis by acting as a nonspecific opsonin. Fibronectin is said to be fairly stable in plasma contained in any blood product, but the usually recommended therapeutic source is cryoprecipitate.
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Cryoprecipitate
Cryoprecipitate is prepared from fresh frozen plasma; it is the material that does not become totally liquid when fresh frozen plasma is slowly thawed and the major part has liquefied. Cryoprecipitate contains about 50% of the original factor VIII and von Willebrand factor activity, about 20%-40% of the fibrinogen and some factor XIII. The major advantage over fresh frozen plasma is reduction in the total volume of fluid that is transfused. Transfusion of one unit of cryoprecipitate carries about the same risk of hepatitis or HIV-I infection as transfusion of one unit of fresh frozen plasma or one unit of whole blood. Cryoprecipitate can also transmit infection by cytomegalovirus and Epstein-Barr virus. The amount of factor VIII activity in each unit of cryoprecipitate is reported to be highly variable (from approximately 25-150 units), although each bag is supposed to contain at least 80 units. Each unit contains about 150 mg of fibrinogen. Cryoprecipitate is useful in treating von Willebrand’s disease as well as hemophilia A. Some reports suggest that cryoprecipitate, for unknown reasons, has some corrective activity in uremic patients with a bleeding tendency. If many units of cryoprecipitate are administered, some believe that ABO-compatible units should be used, since cryoprecipitate is a plasma preparation and could contain anti-A and anti-B antibodies. These antibodies could produce a positive direct Coombs’ test result on recipient RBC, which would be confusing. However, the need for ABO compatibility has been disputed. Large amounts of cryoprecipitate might elevate plasma fibrinogen levels and through this mechanism could produce a temporary elevation of the RBC sedimentation rate.
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Plasma
Plasma itself may be either stored or fresh frozen. Stored plasma until the early 1970s was the treatment of choice for blood volume depletion in burns and proved very useful as an initial temporary measure in hemorrhagic shock while whole blood was being typed and crossmatched. It was also useful in some cases of shock not due to hemorrhage. Stored plasma may be either from single donors, in which case it must be crossmatched before transfusion; or more commonly, from a pool of many donors. Pooled plasma dilutes any dangerous antibodies present in any one of the component plasma units, so that pooled plasma may be given without crossmatch. For many years it was thought that viral hepatitis in plasma would be inactivated after storage for 6 months at room temperature. For this reason, pooled stored plasma was widely used. In 1968 a study reported a 10% incidence of subclinical hepatitis even after storage for prescribed time periods. The National Research Council Committee On Plasma And Plasma Substitutes then recommended that 5% albumin solution be used instead of plasma whenever possible.
Fresh frozen plasma. Fresh frozen plasma is prepared from fresh whole blood within 6 hours after collection. Fresh frozen plasma used to be the treatment of choice for coagulation factor deficiencies such as factor VIII (hemophilia A), von Willebrand’s disease, or fibrinogen. Since large volumes were often required for hemophilia A, methods were devised to concentrate factor VIII. Concentrated factor VIII solutions and cryoprecipitate are both available commercially and have largely superseded the use of fresh frozen plasma in hemophilia A. All of these products, unfortunately, may transmit infection by viruses, including the hepatitis viruses and HIV-I. Heat treatment in conjunction with donor testing has nearly eliminated HIV-I infectivity of factor VIII concentrate and greatly reduced hepatitis B virus infections.
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Granulocytes (Neutrophils)
WBC transfusions are being used for treatment of infections not responding to antibiotics in patients with severe leukopenia due to acute leukemia or bone marrow depression. The AABB recommends 500 granulocytes/mm3 (or per microliter) as the cutoff point defining severe leukopenia. Clinical improvement has been reported in some of these patients but not all. Most large blood banks have the equipment to offer granulocyte transfusion as a routine procedure. The granulocytes are usually collected by apheresis methods and stored at room temperature. The AABB recommends that granulocytes be transfused within 24 hours after collection. According to the AABB, a daily dose of at least 1 x 1010 functional granulocytes appears necessary. Each granulocyte concentrate dose also contains 3 x 1011 platelets. The same recommendations regarding irradiation noted above for platelet concentrates also applies to granulocytes.
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Platelets
Platelets are supplied in units that are equivalent to the number of platelets in one unit of whole blood (about 5.5 x 1010). These are obtained as single platelet units from random-donor whole blood units or as multiple platelet units from a single donor by means of platelet apheresis. Platelets are stored at room temperature up to 5 (sometimes 7) days. One single-donor unit ordinarily is expected to raise the platelet count 7,000-11,000/mm3 per square meter of body surface (equivalent to 5,000-10,000/mm3 [10-25 x 109/L] in an average-size adult). It has been suggested that platelets should be transfused as soon as possible after collection to retain maximum function and that infusions should be rapid (10 ml/min). Some also suggest a microaggregate filter (usually 40-µ size) if platelet storage has been more than 24 hours from time of collection. Platelet concentrates prepared by ordinary methods usually contain some plasma (about 50 ml/platelet unit) and some WBCs. Platelets from donors who have taken aspirin within 72 hours of donation may have deficient platelet function.
Platelet antigens. Platelets themselves contain various antigens, including ABO and HLA. Single-donor platelets can be transfused without typing (similar to random-donor platelets) or can be typed (usually ABO and HLA) for recipient compatibility before administration. Platelet ABO incompatibility usually has only a minor effect on donor platelet survival. HLA incompatibility may become a more serious problem. After repeated transfusions with random-donor nonmatched platelets about 50%-70% of patients (range, 10%-100%) become sensitized to platelet HLA antigens (or sometimes, to platelet-specific antigens), and these patients usually become refractory to additional platelet transfusions. Most can still be transfused with HLA-matched platelets. Siblings have the best chance of providing HLA-compatible blood, although nonsiblings often match adequately. Some institutions administer only HLA-matched platelets when long-term need for platelets is anticipated. However, the AABB currently recommends that patients receive non-HLA-matched platelets initially, with HLA-matched platelets reserved for those who become refractory. Some reports suggest that leukocyte depletion helps delay platelet sensitization. Some investigators perform a 1-hour and a 24-hour platelet count after transfusion. Low 1-hour recovery is said to suggest platelet antigen sensitization. When conditions that decrease platelet survival (e.g., fever, infection, or disseminated intravascular coagulation [DIC]) are present, the 1-hour count shows normal recovery but the 24-hour count is low. One report suggests that a platelet count 10 minutes after transfusion provides the same platelet values as the 1-hour count.
Indications for platelet transfusion. Platelet transfusion can be therapeutic or prophylactic. Therapeutic transfusions are indicated when severe acute bleeding occurs and the patient is severely thrombocytopenic (<50,000 platelets/mm3 or µL). When the patient has thrombocytopenia but has very minor bleeding or is not bleeding, the question of prophylactic platelet transfusion may arise. The decision is usually based on the degree of risk and the type of disorder being treated. Until 1993, most authorities considered patients to be high-risk if their platelet counts were less than 20,000/mm3 or µL (some used a cutoff value of 10,000/mm3); moderate-risk patients (transfusion only if clinically indicated) were those with counts of 20,000-50,000mm3; and low-risk patients included those with counts over 50,000mm3. Based on more recent studies, investigators are now proposing 5,000mm3 (or µL) as the threshold “trigger” value for prophylactic platelet transfusion (rather than 20,000 or even 10,000). The bleeding time has also been used as a guide to therapy; a bleeding time value of less than twice the upper limit of the reference range would not ordinarily need platelet transfusion. In patients with conditions that require multiple platelet transfusions over relatively long time periods, an additional consideration is the probability of developing antiplatelet antibodies that would interfere with therapy if actual bleeding developed later. In idiopathic thrombocytopenic purpura, antiplatelet antibodies that destroy donor platelets are already present, so that transfusion is useless unless the patient is actively bleeding. In drug-induced thrombocytopenia, transfusion is useless if the drug is still being given; after medication has been discontinued, transfusion can be helpful since a normal platelet count will usually return in about 1 week and transfused platelets survive about 1 week.
Platelet concentrates given to bone marrow transplant patients, severely immunodeficient or immunosuppressed patients, and blood relatives of the donor should have the platelet unit irradiated with at least 25 Gy to avoid graft-vs.-host disease.
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Leukocyte-Poor Blood Products
There are several indications for leukocyte removal. The most frequent reason is development of an immune reaction to antigens on “foreign” transfused leukocytes that constitutes the great majority of febrile nonhemolytic transfusion reactions and by far the most common overall transfusion reaction, especially in multitransfused patients. Second, removal of leukocytes helps prevent microaggregates (miniclots) of WBC, fibrin, platelets, and RBC debris that form in stored blood. These microaggregates have been implicated as one cause for adult respiratory distress syndrome. Another indication is to prevent immunization and subsequent reaction to class II (D-locus) HLA antigens present on lymphocytes. This may also cause nonhemolytic febrile reactions, but assumes greatest importance in patients who may need tissue transplants. Another indication is to help prevent or delay sensitization to platelets, which carry HLA class I (A, B, C loci) antigens. Leukocyte removal also helps prevent transmission of cytomegalovirus that infects lymphocytes. This is most important in neonates and in immunocompromised patients. However, the most common use of leukocyte removal is in multiply transfused patients with febrile reactions.
Leukocyte removal is most easily accomplished in older blood units (in which some degree of spontaneous leukocyte microaggregation takes place). The original and still used method is centrifugation of the blood unit and removal of the leukocyte-rich layer (“buffy coat”). This removes about 70%-80% of the leukocytes. If the remaining blood is passed through a 20-40 micron depth-type microaggregate filter, this increases WBC removal to 90%-94%. Special granulocyte filters are now commercially available that can remove as much as 99.9% of the leucocytes; these filters can be used at the patient’s bedside. About 25% of the RBCs are lost during special leukocyte filtration. Age of the blood does not matter. When the object is to prevent immunization, there are differences in performance between commercially available filters.
Other methods of leukocyte removal are the washing of red cells or as a side effect of preparing frozen RBCs. These are discussed separately since these methods accomplish other purposes besides only leukocyte removal.
Washed red blood cells. Washed RBCs are packed cells that have received several washes with saline, followed by centrifugation. This removes more than 90% of the WBCs with most of the platelets and plasma proteins. About 10%-20% of the RBCs are lost. Indications for washed cells are relatively few. Cell washing removes donor antibodies and is useful in IgA immune reactions. Washed RBCs are traditionally used in patients with paroxysmal nocturnal hemoglobinuria. Washed cell methods remove 70%-93% of total WBCs and are reported to cause fewer leukoagglutinin reactions than ordinary centrifuged leukocyte-poor RBCs. However, current leukocyte filters remove more leukocytes than cell washing. The saline wash process reduces but does not completely eliminate the risk of viral hepatitis.
Washed RBCs must be discarded if not transfused within 24 hours after preparation (washing). No more units should be ordered than definitely will be used.
Frozen red blood cells. Fresh citrate-anticoagulated RBCs may have their storage life greatly prolonged by freezing. Glycerol is added to packed RBCs to protect them during freezing; this substance prevents intracellular fluid from becoming ice. The blood is slowly frozen and is maintained at below-zero temperatures until ready for use. Thereafter it must be thawed, after which the glycerol is removed (to avoid osmotic hemolysis), and the cells are suspended in saline. This technique will maintain packed RBCs for up to 5 years. Advantages to the blood bank include the ability to maintain a much larger inventory of blood types without fear of outdating and better control over temporary fluctuations in donor supply or recipient demand. It also permits stockpiling of rare RBC antigen types. Advantages to the patient include approximately 95% elimination of leukocytes, platelets, and plasma proteins, thus removing sources of immunization and febrile reactions; removal of most potassium, ammonium, and citrate, three substances that might be undesirable in large quantities; and considerable reduction of risk for viral hepatitis. Unfortunately, risk of viral hepatitis or HIV-I (HTLV-III) infection is not completely eliminated. Transfused frozen RBCs contain less plasma than washed RBCs.
Disadvantages include considerably greater cost; significant time lost in thawing and preparing the RBCs (1 hour or more); equipment limitation on the number of units that can be prepared simultaneously, which might cause difficulty in emergencies; the fact that once thawed, cells must be used within 24 hours (by current AABB rules; some data suggest this period could be extended to 7 days using a special plastic bag closed system to remove the glycerine); and the presence of variable amounts of free Hb, which might be of sufficient quantity to be troublesome if tests are needed for possible hemolytic transfusion reaction.
Frozen RBCs are becoming more widely available as larger blood banks acquire the necessary equipment. In addition to use in persons with rare blood types, current practice favors their use in some circumstances with greater risk of certain types of immunohematologic sensitization. These include circumstances in which reactions to plasma proteins may occur (e.g., IgA-deficient persons or persons already sensitized to IgA or other serum proteins). Some advocate frozen RBCs as therapy for paroxysmal nocturnal hemoglobinuria. The new leukocyte filters are more effective in removing WBCs than are frozen RBCs. RBCs containing sickle Hb are difficult to deglycerolize and require special techniques.
Irradiated red blood cells. Donor lymphocytes can induce the graft-vs.-host reaction (Chapter 11) in recipients who are severely immunocompromised or are blood relatives of the donor. Gamma radiation (at doses of 25 Gy, equivalent to 2500 rads) affects lymphocytes but not RBCs, granulocytes, or platelets. Such radiation substantially reduces the risk of graft-vs.-host reaction. Radiation of this magnitude will not inactivate viral hepatitis or HIV-I. If blood product irradiation is necessary, all blood products that contain any lymphocytes must be irradiated; these include whole blood, the various RBC preparations (including frozen RBCs), platelet concentrates, and granulocyte concentrates.
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Packed Red Blood Cells
Packed RBCs consist of refrigerated stored blood with about three fourths of the plasma removed. Packed cells help avoid the problem of overloading the patient’s blood volume and instigating pulmonary edema. This is especially useful in patients with anemias due to destruction or poor production of RBCs, when the plasma volume does not need replacement. In fact, when anemia is due to pure RBC deficiency, plasma volume becomes greater than usual, because extracellular fluid tends to replace the missing RBC volume to maintain total blood volume. Packed cells are sometimes used when the donor RBCs type satisfactorily but antibodies are present in donor plasma. Packed cell administration also helps diminish some of the other problems of stored blood, such as elevated plasma potassium or ammonium levels. Packed RBCs retain about 20%-25% of the plasma and most of the white blood cells (WBCs) and platelets. Preserved in CPDA-1, on day 1 plasma potassium averages about 5.1 mEq/L (mmolL) and on day 35 averages about 78.5 mEq/L (mmolL), due in part to the small amount of plasma remaining with the RBC. Plasma Hb on day 1 averages about 78 mg/L and on day 35 averages about 658 mg/L (also partially due to small plasma volume).
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Blood Donation
The standard time interval between blood donations is 8 weeks. However, most healthy persons can donate one unit every 5-7 days for limited periods of time (1-2 months), assisted by oral iron supplements.
Since the use of blood transfusion has increased dramatically over the years, maintenance of adequate donor sources has been a constant problem. In Russia, cadaver blood apparently has been used to a limited extent. If collected less than 6 hours postmortem, it does not differ significantly from stored (bank) blood, except that anticoagulation is not required. A few experimental studies have been done in the United States, with favorable results.
Autotransfusion (autologous transfusion) is the collection and subsequent transfusion of the patient’s own blood. This avoids all problems of transfusion reaction or transfusion-related infection, and in addition is useful in patients whose religious beliefs preclude receiving blood from others. Depending on the circumstances, one or more units may be withdrawn at appropriate intervals (every 5-7 days) before elective surgery and either preserved as whole blood, as packed RBCs, or in long-term storage as frozen RBC, depending on the time interval between processing and transfusion. Another type of autotransfusion consists of equipment that enables operating room personnel to reclaim suctioned blood from operative sites and recycle it back into the patient as a transfusion.
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Whole Blood
Useful life. Whole blood is collected in a citrate anticoagulant-preservative solution. The original acid-citrate-dextrose (ACD) formulation was replaced by citrate-phosphate-dextrose (CPD), which has a storage limit of 21 days when refrigerated between 1°C and 6°C. Addition of adenine (CPDA-1) increased the shelf-life to 35 days. More recently, other nutrient-additive solutions (e.g., AS-1, Adsol) have extended storage capability to 42 days, at which time there is at least 70% red blood cell (RBC) viability 24 hours after transfusion. AS-1 is currently approved only for packed RBCs, not for whole blood. If preserved in CPDA-1, plasma potassium on day 1 is about 4.2 mEq/L (4.2 mmo1/L) and on day 35 is 27.3 mEq/L (27.3 mmol/L). Plasma hemoglobin (Hb) on day 1 averages about 82 mg/L and on day 35 averages about 461 mg/L. It takes about 24 hours for RBCs stored more than two thirds of maximum storage life to regain all of their normal hemoglobin function (this is also true for packed RBC units).
Platelets in whole blood. Platelets devitalize rapidly on storage in refrigerated whole blood (discussed in greater detail in Chapter 11). Platelets in fresh whole blood are about 60% effective at 24 hours and almost completely ineffective after 48 hours. Ordinary stored whole blood or packed RBCs, therefore, essentially have no functioning platelets even though the platelet count may be normal. This may produce difficulty in massive transfusions using stored whole blood or packed RBCs, although there is usually no problem when administration takes place over longer periods of time.
Transfusion indications. The traditional cutoff point for transfusion, especially when a patient is undergoing surgical procedures, is a Hb level of 10.0 gm/100 ml (100 g/L) or a hematocrit of 33%. Based in part on experience from open-heart surgery, use of this level has recently been challenged, and a Hb level of 9.0 gm/100 ml (or hematocrit of 25%-30%) is being advocated to replace the old standard. Even more recently, based in part on surgical experience with Jehovah’s Witnesses who refuse transfusion on religious grounds, it was found that transfusion could be avoided in most cases without undue risk with Hb as low as 7.0 gm/100 ml or even lower. This led to a 1988 National Institutes of Health (NIH) Consensus Conference endorsement of Hb 7.0 gm as a suggested cutoff point. This in turn led to a study commissioned and adapted into guidelines by the American Academy of Physicians in 1992 that recommended “avoid an empiric automatic transfusion threshold.” The most important trigger was to be symptoms related to the need for blood that could not be corrected by other means.
Whole blood is used for restoration of blood volume due to acute simultaneous loss of both plasma and RBCs. This is most frequently seen in acute hemorrhage, both external and internal. Stored blood is adequate for this purpose in most cases. Actually, packed RBCs are being used in many of these patients.
Transfusion speed. Under usual circumstances, the American Association of Blood Banks (AABB) recommends that one unit of whole blood or packed cells be administered in 1.5 hours. The infusion rate should be slower during the first 15 minutes (100 ml/hour), during which time the patient is observed for signs and symptoms of transfusion reaction. One unit of whole blood or packed cells raises the Hb level approximately 1 gm/100 ml and hematocrit approximately 3 percentage units. (Various factors can modify these average values.) RBCs will hemolyze when directly mixed with 5% dextrose in either water or 0.25% saline or with Ringer’s solution.
Fresh whole blood is used within 2 days and preferably 1 day after collection. Platelets are still viable, and the labile coagulation factor VIII (antihemophilic globulin) and factor V still retain nearly normal activity. Most other disadvantages of prolonged storage are obviated. Obviously, donor and administrative problems greatly limit use and availability of fresh blood. Also, there is usually not sufficient time to perform screening tests for hepatitis B and C or human immunodeficiency virus-I (HIV-I) and II. Current official policy of the AABB states that there are no valid indications for specifically ordering fresh whole blood. Specific blood components would be more effective. In a few circumstances when whole blood is useful but long-term storage is undesirable (e.g., infant exchange transfusion), blood less than 4-5 days old is acceptable.