Transfusion Therapy in General Practice

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[edit] Transfusion Therapy in General Practice

Irma O. Szymanski

Blood transfusion is an intrinsic part of both medical and surgical practice. To meet the nation's blood needs, about 12 million volunteer blood donations are given annually in the United States. Modern transfusion practice utilizes blood component therapy instead of whole blood transfusions to provide specific therapy. The method of preparation of blood components is discussed briefly so that the reader can appreciate the relationship between the content and function of blood components. Despite our ability to prepare sophisticated blood components, both infectious and immunologic adverse effects still occur.

The risk of transmitting infectious diseases by blood components has decreased greatly in recent years, mainly because powerful methods are used to detect infectious disease markers in donor blood. The risk of transfusion- associated (TA) infection is now so small that it is immeasurable, and the degree of risk is calculated on the basis of mathematic models, taking into account the length of the seronegative window period of various viral infections. Current estimates of the risks of TA infection are given in Table 116-1. In the near future, blood safety will increase even further since nucleic acid amplification technology (NAT) will be adapted for detection of the RNA of the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) in donor blood. Furthermore, methods to inactivate all pathogens in blood components have been introduced so that in the future the blood components will be practically sterile.

Table 116-1 Estimated Risks of TA Infections

The appropriate use of blood components has been debated greatly in the last few years. Current understanding of the use of blood components is discussed in the next section.

[edit] BLOOD COMPONENTS

[edit] Preparation

During a blood donation a donor gives about 450 ml of whole blood, which is anticoagulated with 63 ml of citrate-phosphate-dextrose anticoagulant. The whole blood is centrifugally separated within 8 hours of collection into packed red cell concentrate, random platelet concentrate, and plasma. The red cells are stored in a preservative solution (Adsol or Nutricel) for up to 42 days at 4° C. Platelet concentrates are stored at 22° C in special gas-permeable plastic bags for 5 days while being agitated. Plasma is frozen and stored at −18° C for up to 1 year.

Random platelet concentrates separated from whole blood are transfused as pools of 5 or 6 units, but a therapeutic dose of platelets (total of about 3 × 10¹¹ platelets) is obtained from a single donor using apheresis technique.

[edit] White Blood Cells in Blood Components

Centrifugally separated cellular blood components contain between 10⁸ to 10⁹ white blood cells (WBC)/unit. These “passenger” leukocytes may carry such infectious agents as cytomegalovirus (CMV), human T-cell leukemia/lymphoma virus (HTLV) I/II, and possibly the prion causing new variant Creutzfeld-Jakob disease (nvCJD). These leukocytes may also sensitize recipients to human leukocyte antigens (HLA), subsequently preventing a good response to platelet transfusions, cause graft vs. host disease (GvHD), as well as cause subtle changes in a patient's immune response (immune modulation). These complications can be avoided or minimized by using leukocyte-reduced red cells and platelets (containing less than 5 × 10⁶ WBC/unit) that are prepared by high-efficiency filtration, preferably in the laboratory under standardized conditions, either before or during the early period of storage of the blood component (Table 116-2). The effectiveness of bedside filtration is variable.

Table 116-2 “Regular” and Leukocyte-reduced (Containing <5×10⁶ WBC/Unit) Red Cell and Platelet Products

✢High-efficiency filtered.

Certain plateletpheresis techniques are designed to remove leukocytes from the product during collection (COBE Spectra LRS platelets) so that platelets prepared by this method need not be filtered.

Presently about 20% of red cell and platelet transfusions are leukocyte reduced. A change to universal leukocyte reduction of cellular blood components may occur since several European countries have recently switched to transfusing only leukocyte-reduced cellular blood components to all patients. Such a recommendation was also issued by the Blood Products Advisory Committee of the Food and Drug Administration (FDA) in September 1998, presaging the change to leukocyte-reduced blood product transfusion in the United States.

[edit] Washing, Irradiation, and Freezing of Cellular Blood Components

To prevent both allergic and anaphylactic transfusion reactions as well as TA-GvHD, cellular blood products can be further “customized” as follows:

• Washing cellular blood components prevents allergic and anaphylactic reactions caused by plasma present in components.
  
• Irradiation of blood components (about 3000 rads/unit) will prevent TA-GvHD, which may occur in susceptible patients even if they receive leukocyte-reduced blood components.
  
• Frozen red cell programs permit availability of fully typed, rare red cells and autologous red cells. Red cells can be stored at −80° C for up to 10 years.
  

Patient populations benefiting from the transfusion of customized products are listed in Table 116-3.

Table 116-3 Benefits of Customized Cellular Products (RBCs or Platelets)

[edit] INFECTIOUS DISEASE TRANSMISSION

As shown in Table 116-1, the risks of transmitting infectious diseases by blood transfusion are currently quite low because of careful donor-screening techniques. These risks can be further decreased by using autologous blood, blood substitutes, and inactivating pathogens in blood components.

Autologous donations currently constitute a little more than 3% of total units, but they are feasible only before surgical procedures. Patients with bacteremia, severe aortic stenosis, and significant left coronary artery disease do not qualify. Since it is difficult to predict accurately the need of blood transfusion during surgery, only about 50% of the autologous blood is transfused. For safety reasons it is recommended that autologous blood not be “crossed over” to other patients. Thus autologous blood tends to be more expensive than homologous blood.

Various hemoglobin preparations have been tested in laboratory and in clinical settings. Due to their relatively short half-life and vasotoxicity, they have not yet been accepted in routine use. Perfluorocarbons are still being perfected, but the current preparations function only when recipients breathe 100% oxygen.

The desire to further reduce the risks of allogeneic blood transfusions has produced the following FDA-approved approaches:

• Solvent/detergent (S/D) treatment ofpooled fresh frozen plasma (FFP) (pool size about 2500 units). The S/D process destroys lipid envelope viruses including HIV, HCV, and HBV, but not hepatitis A virus (HAV), or human parvovirus B19. The final product is expensive, and questions remain about the use of pooled product. Therefore many transfusion services have not adopted the routine use of S/D FFP.
  
• In the “delayed release” method, each individual unit of FFP is released for use only after a second donation from the same individual (given a minimum of 112 days after the first) tests negative for infectious disease markers.
  

Several methods of inactivation have shown promise but are not used routinely in clinical setting. Baxter/Fenwal introduced the use of methylene blue for destruction of viral RNA or DNA in FFP. This approach avoids using pools of plasma because the dye is added to individual units of FFP.

A photochemical treatment (PCT) using Psoralen S-59 with activation by long–wavelength ultraviolet A light (UVA) is a promising nucleic acid–targeted approach to inactivate pathogens in platelet concentrates. PCT requires 3 minutes of UVA exposure, is compatible with single-donor and pooled platelet concentrates, and inactivates high titers of enveloped and nonenveloped viruses, bacteria, and protozoa. In addition, leukocytes, including T cells, are inactivated in the process, with inhibition of proliferation and cytokine synthesis. A passive adsorption process of the S-59 is needed before transfusion. Clinical trials are currently ongoing.

Frangible anchor linker effectors (FRALEs) are being developed to inactivate pathogens in red cell concentrates. These agents cross-link nucleic acids without the need for light inactivation. A compound, S-303, is being evaluated for clinical use.

[edit] TRANSFUSION THERAPY

[edit] Acute Blood Loss

After acute blood loss the most important, immediate therapeutic goal is to restore the blood volume (Table 116-4). This can be accomplished with crystalloid or colloid infusion. However, recent studies have indicated that albumin use in critically ill patients is associated with higher mortality than is the case in patients who did not receive albumin. Patients who are treated in intensive care units tend to get red cells, FFP, and platelets. All of these products are probably over-used. A recent published study showed that liberal use of RBCs to maintain hemoglobin concentration between 10 and 12 gm/dl by transfusion was associated with higher in-hospital mortality than was the case when a patient's hemoglobin was kept between 7 and 9 gm/dl. The reason for this adverse effect was not clear, but it could be related to the poorly understood adverse effects of red cell transfusions such as passenger leukocytes or the large number of nonviable red cells in the stored red cell product, compromising the function of the reticuloendothelial system of these patients. Some of the principles of blood component transfusion after acute blood loss are as follows.

Table 116-4 Blood Component Transfusion During Acute Blood Loss

Crystalloid infusions should be given as first-line therapy when acute blood loss exceeds 10% of blood volume. The treatment can be considered effective when vital signs have normalized. Red cell transfusions are helpful if blood loss exceeds 15% of the blood volume. In addition to increasing red cell mass and oxygen delivery capacity, red cell transfusions also increase plasma volume, by recruiting plasma proteins and extracellular fluid into the vascular compartment.

In most cases crystalloids and red cell transfusions are sufficient to correct all adverse effect of the blood loss. FFP transfusion might be useful if coagulation abnormalities exist (international normalized ratio [INR] >1.5 and PTT >60 sec).

[edit] Chronic Anemia

Long-term red cell transfusions are required for patients with bone marrow failure or when the purpose of the transfusions is to suppress bone marrow (as is in the case of thalassemia), or if patient's chronic hemolytic anemia does not respond to other therapy. Some principles of transfusion therapy in these cases include: leukocyte-reduced red cells should be given to chronically transfused patients, and, if possible, it would be helpful to limit the number of donors (using the same, dedicated donors repeatedly). Complete blood typing (for the minor antigens) may be helpful to avoid immunization to them.

At what level of hemoglobin should the patients be kept? In thalassemia, hypertransfusion requires that the hemoglobin is maintained above 10 gm/dl (hematocrit[Hct] >30%). In other conditions, patients might remain asymptomatic when hemoglobin concentration is at least 8 g/dl (Hct 24%). Erythropoietin has replaced transfusion therapy in patients suffering from chronic renal disease. Iron overload is a severe complication of chronic red cell transfusion therapy. It should be treated with iron chelators.

[edit] Platelet Transfusions

Guidelines for platelet transfusion are given in Table 116-5. Although the transfusion trigger is based on platelet count, a low platelet count by itself is not an indication for platelet transfusion. Before initiation of platelet transfusions the etiology of thrombocytopenia must be established. The best results are obtained in patients whose platelet production is impaired. If it is likely that the reason for thrombocytopenia is accelerated peripheral destruction of platelets, the cause should be elucidated (Table 116-6). Useful principles of platelet transfusion are as follows:

• The response to platelet transfusion should be evaluated by measuring the change in platelet count 1 hour and 24 hours after completion of the transfusion. Corrected count increment (CCI) is a measure of the effectiveness of the platelet transfusion.
  CCI = (ΔPl)×BSA/(#Pl)
  where ΔPl = change in platelet count (#/μl), BSA = body surface area (m²), and #P1 = total number of platelets transfused.
  
• CCI of 7500 or higher is considered a good response.
  
• Since there is a negative correlation between anemia and platelet function, as measured by bleeding time, patients with low platelet counts should be kept at higher Hct values (about 30%) to improve the functional status of platelets and minimize the need to transfuse platelets.
  

Table 116-5 Indications for Prophylactic Platelet Transfusions

Table 116-6 Reasons for Accelerated Platelet Destruction

[edit] Transfusion of Plasma and Plasma Products

The use and properties of plasma products and derivatives are presented in Table 116-7. FFP transfusions should not be given for plasma volume expansion, but to correct coagulation factor deficiencies. Patients with abnormal liver function should be transfused with FFP if INR > 1.5, when surgery or an invasive procedure is planned. Plasma exchange, in which a volume of the patient's plasma is removed and replaced with an equal volume of donor FFP, is used to correct coagulation factor deficiencies in patients who cannot tolerate increases in plasma volume. An overdose of Coumadin can be corrected by transfusion of FFP (10 to 20 ml/kg).

Table 116-7 Use and Properties of Plasma Products and Derivatives

Patients with thrombotic thrombocytopenic purpura are treated either with FFP infusions or with plasma exchange using FFP as a replacement fluid. FFP from which cryoprecipitate has been removed, is also an acceptable, and maybe even a superior, replacement fluid for this purpose. Patients with disseminated intravascular coagulation (DIC) will benefit from infusions of cryoprecipitate, FFP, and additionally, if platelet counts are low, from platelet transfusions. It might be beneficial to give AT III infusions when the levels are very low (below 25%). Patients with hemophilia A are treated with purified coagulation factors. The current preparations are safe because they are either prepared with recombinant methods or treated with solvent/detergent. Patients with von Willebrands disease may be treated with cryoprecipitate or with purified coagulation factors containing vWF (Humate P or Alphanate). Purified AT III is now available to treat patients with congenital deficiency of AT III who undergo surgery. Albumin transfusions are much overused. A recent meta-analysis showed that critically ill patients who received albumin infusions had 6% higher mortality rate than similar patients who received crystalloid infusions.

[edit] TRANSFUSION REACTIONS

The incidence of noninfectious transfusion reactions is shown in Table 116-8. A brief description of various types of transfusion reactions follows.

Table 116-8 Etiology and Frequency of Immunologic Complications of Transfusion

[edit] Hemolytic Transfusion Reactions

Acute reactions occur during transfusion or within a few hours afterward. Delayed reactions occur within days to weeks after transfusion, and often go unnoticed. Donor red cells hemolyze intravascularly or extravascularly when patient's serum contains antibodies that combine with antigens on donor red cells. Complement binding antibodies (e.g., anti-A/B, anti-Kell, or anti-Jk^a) produce the most severe reactions. A common cause of a hemolytic transfusion reaction is an inability of the health care personnel to identify correctly the patient or the blood component. Transfusion reactions may be unavoidable when the antibody titer is too low to be detectable at the time of cross-match, or when the antibody is nonreactive by the normally used screening techniques. The symptoms of hemolytic transfusion reaction may include shock, DIC, and kidney failure. The principles of treatment of the patient who has hemolytic transfusion reaction are as follows:

• Monitor the vital signs frequently.
  
• Administer IV fluid to normalize vital signs.
  
• Do not give the patient epinephrine because it can increase the chance of kidney damage. Dopamine is acceptable.
  
• Monitor the patient for the laboratory signs of DIC.
  
• Treat the DIC, if necessary, with component therapy (cryoprecipitate, FFP, possibly platelet transfusions).
  
• If the patient becomes anemic, do not hesitate to give compatible red cell transfusions.
  
• Heparin therapy is rarely indicated, particularly in a postoperative patient. In order to prevent kidney damage, give the patient IV furosemide as soon as the transfusion reaction is identified. Monitor the urine output.
  

Patients in whose serum blood group antibodies are once detected must always receive red cell transfusions that are negative for the corresponding antigens.

[edit] Allergic Reactions

Allergic reactions occur in patients who receive donor plasma. The reactions can manifest themselves as local urticaria or as severe geographic urticaria, with joint involvement, laryngeal edema, pulmonary signs reminiscent of asthma, abdominal pains, and headaches. Depending on the severity of symptoms, the treatment may require antihistamines, corticosteroids, or epinephrine. In mild cases the transfusion can be started again after administering antihistamines.

[edit] Anaphylactic Reactions

Anaphylactic reactions occur within minutes of initiating a transfusion containing plasma or immunoglobulins. The symptoms include severe flushing of the skin, severe anxiety, laryngospasm, and shock. These types of reactions occur in IgA-deficient patients (frequency about 1/500) who have developed anti-IgA. The treatment may include intravenous fluids, epinephrine, and corticosteroids.

[edit] Febrile Nonhemolytic Transfusion Reactions

FNHTR occur after red cell and platelet transfusions. The risk is highest after platelet transfusions. FNHTR usually manifest themselves as fever above the baseline value (increase of at least 2° F), chills, and slight elevation of blood pressure. Occasionally, respiratory symptoms may occur.

Although most FNHTR are mild, some are life- threatening. The symptoms occur during or within 2 hours of transfusion. Treatment includes administration of a fever-lowering drug such as acetaminophen. It was previously assumed that FNHTR are caused by interactions between alloantibodies in the recipient's plasma and donor WBC, but now it appears more likely that they are mediated by bioreactive substances produced by WBC during blood component storage. Progressive increases in IL-1β, IL-6, IL-8, and TNF-α have been documented in platelet concentrates during storage. These increases are prevented by removal of leukocytes from platelet concentrates prior to storage.

[edit] Transfusion-related Acute Lung Injury (TRALI)

TRALI, a respiratory distress syndrome, occurs in patients within 4 hours after receiving plasma products, often derived from the blood of multiparous women. It is characterized by development of acute respiratory distress, severe hypoxemia, acute bilateral pulmonary edema, hypotension, and fever. There is no evidence of heart failure. In many cases of TRALI, HLA or granulocyte antibodies can be demonstrated in donor plasma, with specificity to antigenic determinants on patients' WBC. Recently, reactive lipid products that arise during storage of blood products have been implicated in the pathophysiology of TRALI. The complement reacting nature of these HLA or WBC antibodies results in generation of complement component C5a, which causes WBC clumping in pulmonary vasculature and increase in vascular permeability. TRALI is potentially life-threatening, but with prompt and vigorous respiratory support, at least 90% of patients recover.

[edit] Transfusion-associated Graft vs. Host Disease

Patients with impaired cellular immunity, and healthy patients who receive blood from relatives or from donors whose HLA type is homozygous and identical to one of the haplotypes of the patient, are at risk for developing TA-GvHD. Normally after transfusion the patient's immune system destroys donor lymphocytes. If, for reasons mentioned above, this does not occur, the donor lymphocytes may mount an immune attack against the patient's tissues. Within 5 to 30 days after transfusion the patient develops intractable skin rash, diarrhea, liver involvement, bone marrow failure, and eventually multiorgan failure. TA-GvHD is uniformly fatal. However, it can be prevented by irradiating blood products given to patients who are susceptible to this complication.

[edit] ADDITIONAL READINGS

• American College of Physicians: Practice strategies for elective red blood cell transfusion. Ann Intern Med 1992; 116:403 - 406.
• LT Goodnough, ME Brecher, MH Kanter,et al.: Medical progress in transfusion medicine—blood transfusion. N Engl J Med 1999; 340:438 - 447.
• PC Hebert, G Wells, MA Blajchman,et al.: A multicenter, randomized, controlled clinical trial of transfusion requirement in critical care. N Engl J Med 1999; 340:409 - 417.
• B Horowitz, AM Prince, J Hamman,et al.: Viral safety of solvent/detergent-treated blood products. Blood Coag Fibrin 1994; 5:521 - 528.
• G Schierrhout, I Roberts: Fluid resuscitation with colloid or crystalloid solutions in critically ill patients. Br Med J 1998; 316:961 - 964.