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InternalMed_Harrison. I system antigens are also oligosaccharides related to H, A, B, and Le. I and i are not allelic pairs but are carbohydrate antigens that differ only in the extent of branching. The i antigen is an unbranched chain that is converted by the I gene product, a glycosyltransferase, into a branched chain. The branching process affects all the ABH antigens, which become progressively more branched in the first 2 years of life. Some patients with cold agglutinin disease or lymphomas can produce anti-I autoantibodies that cause RBC destruction. Occasional patients with mononucleosis or Mycoplasma pneumonia may develop cold agglutinins of either anti-I or anti-i specificity. Most adults lack i Rh (D, C/c, E/e) RBC protein IgG HTR, HDN Lewis (Lea , Leb) Oligosaccharide IgM/IgG Rare HTR Kell (K/k) RBC protein IgG HTR, HDN Duffy (Fya/Fyb) RBC protein IgG HTR, HDN Kidd (Jka/Jkb) RBC protein IgG HTR (often delayed), MNSsU RBC protein IgM/IgG Anti-M rare HDN, anti- S, -s, and -U HDN, HTR


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InternalMed_Harrison. MNSsU RBC protein IgM/IgG Anti-M rare HDN, anti- S, -s, and -U HDN, HTR Abbreviations: HDN, hemolytic disease of the newborn; HTR, hemolytic transfusion reac tion; RBC, red blood cell. expression; thus, finding a donor for patients with anti-i is not difficult. Even though most adults express I antigen, binding is generally low at body temperature. Thus, administration of warm blood prevents isoagglutination. The P system is another group of carbohydrate antigens controlled by specific glycosyltransferases. Its clinical significance is in rare cases of syphilis and viral infection that lead to paroxysmal cold hemoglobinuria. In these cases, an unusual autoantibody to P is produced that binds to RBCs in the cold and fixes complement upon warming. Antibodies with these biphasic properties are called Donath-Landsteiner antibodies. The P antigen is the cellular receptor of parvovirus B19 and also may be a receptor for Escherichia coli binding to urothelial cells.


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InternalMed_Harrison. The MNSsU system is regulated by genes on chromosome 4. M and N are determinants on glycophorin A, an RBC membrane protein, and S and s are determinants on glycophorin B. Anti-S and anti-s IgG antibodies may develop after pregnancy or transfusion and lead to hemolysis. Anti-U antibodies are rare but problematic; virtually every donor is incompatible because nearly all persons express U.


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InternalMed_Harrison. The Kell protein is very large (720 amino acids), and its secondary structure contains many different antigenic epitopes. The immunogenicity of Kell is third behind the ABO and Rh systems. The absence of the Kell precursor protein (controlled by a gene on X) is associated with acanthocytosis, shortened RBC survival, and a progressive form of muscular dystrophy that includes cardiac defects. This rare condition is called the McLeod phenotype. The Kx gene is linked to the 91-kDa component of the NADPH-oxidase on the X chromosome, deletion or mutation of which accounts for about 60% of cases of chronic granulomatous disease. The Duffy antigens are codominant alleles, Fya and Fyb, that also serve as receptors for Plasmodium vivax. More than 70% of persons in malaria-endemic areas lack these antigens, probably from selective influences of the infection on the population. For unknown reasons, the lack of the Duffy antigen receptor for cytokines (DARC) is associated with mild neutropenia.


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InternalMed_Harrison. The Kidd antigens, Jka and Jkb, may elicit antibodies transiently. A delayed hemolytic transfusion reaction that occurs with blood tested as compatible is often related to delayed appearance of anti-Jka. Pretransfusion testing of a potential recipient consists of the “type and screen.” The “forward type” determines the ABO and Rh phenotype of the recipient’s RBC by using antisera directed against the A, B, and D antigens. The “reverse type” detects isoagglutinins in the patient’s serum and should correlate with the ABO phenotype, or forward type. The alloantibody screen identifies antibodies directed against other RBC antigens. The alloantibody screen is performed by mixing patient serum with type O RBCs that contain the major antigens of most blood group systems and whose extended phenotype is known. The specificity of the alloantibody is identified by correlating the presence or absence of antigen with the results of the agglutination.


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InternalMed_Harrison. Cross-matching is ordered when there is a high probability that the patient will require a packed RBC (PRBC) transfusion. Blood selected for cross-matching must be ABO compatible and lack antigens for which the patient has alloantibodies. Nonreactive cross-matching confirms the absence of any major incompatibility and reserves that unit for the patient. In the case of Rh-negative patients, every attempt must be made to provide Rh-negative blood components to prevent alloimmunization to the D antigen. In an emergency, Rh-positive blood can be safely transfused to an Rh-negative patient who lacks anti-D; however, the recipient is likely to become alloimmunized and produce anti-D. Rh-negative women of childbearing age who are transfused with products containing Rh-positive RBCs should receive passive immunization with anti-D (RhoGam or WinRho) to reduce or prevent sensitization.


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InternalMed_Harrison. Blood products intended for transfusion are routinely collected as whole blood (450 mL) in various anticoagulants. Most donated blood is processed into components: PRBCs, platelets, and fresh-frozen plasma (FFP) or cryoprecipitate (Table 138e-2). Whole blood is first separated into PRBCs and platelet-rich plasma by slow centrifugation. The platelet-rich plasma is then centrifuged at high speed to yield one unit of random donor (RD) platelets and one unit of FFP. Cryoprecipitate is produced by thawing FFP to precipitate the plasma proteins and then separated by centrifugation. Apheresis technology is used for the collection of multiple units of platelets from a single donor. These single-donor apheresis platelets (SDAP) contain the equivalent of at least six units of RD platelets and have fewer contaminating leukocytes than pooled RD platelets.


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InternalMed_Harrison. Plasma may also be collected by apheresis. Plasma derivatives such as albumin, intravenous immunoglobulin, antithrombin, and coagulation factor concentrates are prepared from pooled plasma from many donors and are treated to eliminate infectious agents. Whole blood provides both oxygen-carrying capacity and volume expansion. It is the ideal component for patients who have sustained acute hemorrhage of ≥25% total blood volume loss. Whole blood is stored at 4°C to maintain erythrocyte viability, but platelet dysfunction and degradation of some coagulation factors occurs. In addition, 2,3-bisphosphoglycerate levels fall over time, leading to an increase in the oxygen affinity of the hemoglobin and a decreased capacity to deliver oxygen to the tissues, a problem with all red cell storage. Fresh whole blood avoids these problems, but it is typically used only in emergency settings (i.e., military). Whole blood is not readily available, because it is routinely processed into components.


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InternalMed_Harrison. This product increases oxygen-carrying capacity in the anemic patient. Adequate oxygenation can be maintained with a hemoglobin content of 70 g/L in the normovolemic patient without cardiac disease; however, comorbid factors may necessitate transfusion at a higher threshold. The decision to transfuse should be guided by the clinical situation and not by an arbitrary laboratory value. In the critical care setting, liberal use of transfusions to maintain near-normal levels of hemoglobin has not proven advantageous. In most patients requiring transfusion, levels of hemoglobin of 100 g/L are sufficient to keep oxygen supply from being critically low.


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InternalMed_Harrison. PRBCs may be modified to prevent certain adverse reactions. The majority of cellular blood products are now leukocyte reduced, and universal prestorage leukocyte reduction has been recommended. Prestorage filtration appears superior to bedside filtration as smaller amounts of cytokines are generated in the stored product. These PRBC units contain <5 × 106 donor white blood cells (WBCs), and their use Component Volume, mL Content Clinical Response RBCs with variable leukocyte content and small amount of plasma 5.5 × 1010/RD unit Plasma proteins—coagulation factors, proteins C and S, antithrombin Cold-insoluble plasma proteins, fibrinogen, factor VIII, VWF Increase platelet count 5000–10,000/μL CCI ≥10 × 109/L within 1 h and ≥7.5 × 109/L within 24 h posttransfusion Topical fibrin glue, also 80 IU factor VIII


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InternalMed_Harrison. Increase platelet count 5000–10,000/μL CCI ≥10 × 109/L within 1 h and ≥7.5 × 109/L within 24 h posttransfusion Topical fibrin glue, also 80 IU factor VIII Abbreviations: CCI, corrected count increment; FFP, fresh-frozen plasma; PRBC, packed red blood cells; RBC, red blood cell; RD, random donor; SDAP, single-donor apheresis platelets; VWF, von Willebrand factor. lowers the incidence of posttransfusion fever, cytomegalovirus (CMV) infections, and alloimmunization. Other theoretical benefits include less immunosuppression in the recipient and lower risk of infections. Plasma, which may cause allergic reactions, can be removed from cellular blood components by washing.


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InternalMed_Harrison. Thrombocytopenia is a risk factor for hemorrhage, and platelet transfusion reduces the incidence of bleeding. The threshold for prophylactic platelet transfusion is 10,000/μL. In patients without fever or infections, a threshold of 5000/μL may be sufficient to prevent spontaneous hemorrhage. For invasive procedures, the usual target level is 50,000/μL platelets.


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InternalMed_Harrison. Platelets are given either as pools prepared from RDs or as SDAPs from a single donor. In an unsensitized patient without increased platelet consumption (splenomegaly, fever, disseminated intravascular coagulation [DIC]), two units of transfused RD per square-meter body surface area (BSA) is anticipated to increase the platelet count by approximately 10,000/μL. Patients who have received multiple transfusions may be alloimmunized to many HLAand platelet-specific antigens and have little or no increase in their posttransfusion platelet counts. Patients who may require multiple transfusions are best served by receiving SDAP and leukocyte-reduced components to lower the risk of alloimmunization.


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InternalMed_Harrison. Refractoriness to platelet transfusion may be evaluated using the corrected count increment (CCI): where BSA is body surface area measured in square meters. The platelet count performed 1 h after the transfusion is acceptable if the CCI is 10 × 109/mL, and after 18–24 h an increment of 7.5 × 109/mL is expected. Patients who have suboptimal responses are likely to have received multiple transfusions and have antibodies directed against class I HLA antigens. Refractoriness can be investigated by detecting anti-HLA antibodies in the recipient’s serum. Patients who are sensitized will often react with 100% of the lymphocytes used for the HLA-antibody screen, and HLA-matched SDAPs should be considered for patients who require transfusion. Although ABO-identical HLA-matched SDAPs provide the best chance for increasing the platelet count, locating these products is difficult. Platelet cross-matching is available in some centers. Additional clinical causes for a low platelet CCI include


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InternalMed_Harrison. best chance for increasing the platelet count, locating these products is difficult. Platelet cross-matching is available in some centers. Additional clinical causes for a low platelet CCI include fever, bleeding, splenomegaly, DIC, or medications in the recipient.


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InternalMed_Harrison. FFP contains stable coagulation factors and plasma proteins: fibrinogen, antithrombin, albumin, and proteins C and S. Indications for FFP include correction of coagulopathies, including the rapid reversal of warfarin; supplying deficient plasma proteins; and treatment of thrombotic thrombocytopenic purpura. FFP should not be routinely used to expand blood volume. FFP is an acellular component and does not transmit intracellular infections, e.g., CMV. Patients who are IgA-deficient and require plasma support should receive FFP from IgA-deficient donors to prevent anaphylaxis (see below).


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InternalMed_Harrison. Cryoprecipitate is a source of fibrinogen, factor VIII, and von Willebrand factor (VWF). It is ideal for supplying fibrinogen to the volume-sensitive patient. When factor VIII concentrates are not available, cryoprecipitate may be used because each unit contains approximately 80 units of factor VIII. Cryoprecipitate may also supply VWF to patients with dysfunctional (type II) or absent (type III) von Willebrand’s disease. Plasma from thousands of donors may be pooled to derive specific protein concentrates, including albumin, intravenous immunoglobulin, antithrombin, and coagulation factors. In addition, donors who have high-titer antibodies to specific agents or antigens provide hyper-138e-3 immune globulins, such as anti-D (RhoGam, WinRho), and antisera to hepatitis B virus (HBV), varicella-zoster virus, CMV, and other infectious agents.


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InternalMed_Harrison. Adverse reactions to transfused blood components occur despite multiple tests, inspections, and checks. Fortunately, the most common reactions are not life threatening, although serious reactions can present with mild symptoms and signs. Some reactions can be reduced or prevented by modified (filtered, washed, or irradiated) blood components. When an adverse reaction is suspected, the transfusion should be stopped and reported to the blood bank for investigation. Transfusion reactions may result from immune and nonimmune mechanisms. Immune-mediated reactions are often due to preformed donor or recipient antibody; however, cellular elements may also cause adverse effects. Nonimmune causes of reactions are due to the chemical and physical properties of the stored blood component and its additives.


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InternalMed_Harrison. Transfusion-transmitted viral infections are increasingly rare due to improved screening and testing. As the risk of viral infection is reduced, the relative risk of other reactions increases, such as hemolytic transfusion reactions and sepsis from bacterially contaminated components. Pretransfusion quality assurance improvements further increase the safety of transfusion therapy. Infections, like any adverse transfusion reaction, must be brought to the attention of the blood bank for appropriate studies (Table 138e-3). IMMUNE-MEDIATED REACTIONS Acute Hemolytic Transfusion Reactions Immune-mediated hemolysis occurs when the recipient has preformed antibodies that lyse donor erythrocytes. The ABO isoagglutinins are responsible for the majority of these reactions. However, alloantibodies directed against other RBC antigens, i.e., Rh, Kell, and Duffy, are responsible for more fatal hemolytic transfusion reactions.


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InternalMed_Harrison. Acute hemolytic reactions may present with hypotension, tachypnea, tachycardia, fever, chills, hemoglobinemia, hemoglobinuria, chest and/or flank pain, and discomfort at the infusion site. Monitoring Frequency, Episodes: Unit aInfectious agents rarely associated with transfusion, theoretically possible, or of unknown risk include West Nile virus, hepatitis A virus, parvovirus B19, Babesia microti and Babesia duncani (babesiosis), Borrelia burgdorferi (Lyme disease), Anaplasma phagocytophilum (human granulocytic ehrlichiosis), Trypanosoma cruzi (Chagas’ disease), Treponema pallidum, and human herpesvirus-8. Abbreviations: FNHTR, febrile nonhemolytic transfusion reaction; HTLV, human T lymphotropic virus; RBC, red blood cell; TRALI, transfusion-related acute lung injury.


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InternalMed_Harrison. Abbreviations: FNHTR, febrile nonhemolytic transfusion reaction; HTLV, human T lymphotropic virus; RBC, red blood cell; TRALI, transfusion-related acute lung injury. the patient’s vital signs before and during the transfusion is important to identify reactions promptly. When acute hemolysis is suspected, the transfusion must be stopped immediately, intravenous access maintained, and the reaction reported to the blood bank. A correctly labeled posttransfusion blood sample and any untransfused blood should be sent to the blood bank for analysis. The laboratory evaluation for hemolysis includes the measurement of serum haptoglobin, lactate dehydrogenase (LDH), and indirect bilirubin levels.


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InternalMed_Harrison. The immune complexes that result in RBC lysis can cause renal dysfunction and failure. Diuresis should be induced with intravenous fluids and furosemide or mannitol. Tissue factor released from the lysed erythrocytes may initiate DIC. Coagulation studies including prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and platelet count should be monitored in patients with hemolytic reactions.


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InternalMed_Harrison. Errors at the patient’s bedside, such as mislabeling the sample or transfusing the wrong patient, are responsible for the majority of these reactions. The blood bank investigation of these reactions includes examination of the preand posttransfusion samples for hemolysis and repeat typing of the patient samples; direct antiglobulin test (DAT), sometimes called the direct Coombs test, of the posttransfusion sample; repeating the cross-matching of the blood component; and checking all clerical records for errors. DAT detects the presence of antibody or complement bound to RBCs in vivo (Fig. 138e-1). Delayed Hemolytic and Serologic Transfusion Reactions Delayed hemolytic transfusion reactions (DHTRs) are not completely preventable.


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InternalMed_Harrison. Delayed Hemolytic and Serologic Transfusion Reactions Delayed hemolytic transfusion reactions (DHTRs) are not completely preventable. These reactions occur in patients previously sensitized to RBC alloantigens who have a negative alloantibody screen due to low antibody levels. When the patient is transfused with antigen-positive blood, an anamnestic response results in the early production of alloantibody that binds donor RBCs. The alloantibody is detectable 1–2 weeks following the transfusion, and the posttransfusion DAT may become positive due to circulating donor RBCs coated with antibody or complement. The transfused, alloantibody-coated erythrocytes are cleared by the reticuloendothelial system. These reactions are detected most commonly in the blood bank when a subsequent patient sample reveals a positive alloantibody screen or a new alloantibody in a recently transfused recipient.


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InternalMed_Harrison. No specific therapy is usually required, although additional RBC transfusions may be necessary. Delayed serologic transfusion reactions are similar to DHTR, because the DAT is positive and alloantibody is detected; however, RBC clearance is not increased.


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InternalMed_Harrison. Febrile Nonhemolytic Transfusion Reaction The most frequent reaction associated with the transfusion of cellular blood components is a febrile nonhemolytic transfusion reaction (FNHTR). These reactions are characterized by chills and rigors and a ≥1°C rise in temperature. FNHTR is diagnosed when other causes of fever in the transfused patient are ruled out. Antibodies directed against donor leukocyte and HLA antigens may mediate these reactions; thus, multiply transfused patients and multiparous women are felt to be at increased risk. Although anti-HLA antibodies may be demonstrated in the recipient’s serum, investigation is not routinely done because of the mild nature test result Positive test result Indirect Coombs test/ indirect antiglobulin test (Coombs reagent) the reb blood cell surface anti-RBC antibodies Blood sample from a patient with immune mediated haemolytic anaemia: antibodies are shown attached to antigens on the RBC surface. Recipient’s serum is obtained, containing


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InternalMed_Harrison. anti-RBC antibodies Blood sample from a patient with immune mediated haemolytic anaemia: antibodies are shown attached to antigens on the RBC surface. Recipient’s serum is obtained, containing anitbodies (Ig’s). Donor’s blood sample is added to the tube with serum. Recipient’s Ig’s that target the donor’s red blood cells form antibody-antigen complexes. Anti-human Ig’s (Coombs antibodies) are added to the solution. Agglutination of red blood cells occurs, because human Ig’s are attached to red blood cells. The patient’s washed RBCs are incubated with antihuman antibodies (Coombs reagent). RBCs agglutinate: antihuman antibodies form links between RBCs by binding to the human antibodies on the RBCs. FIGURE 138E-1 Direct and indirect Coombs test. The direct Coombs (antiglobulin) test detects the presence of antibodies (or complement) on the surface of erythrocytes. The indirect Coombs (antiglobulin) test detects antibodies in the serum that may bind to donor erythrocytes. RBC, red blood


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InternalMed_Harrison. the presence of antibodies (or complement) on the surface of erythrocytes. The indirect Coombs (antiglobulin) test detects antibodies in the serum that may bind to donor erythrocytes. RBC, red blood cell. (Adapted from http://upload.wikimedia.org/wikipedia/commons/1/1c/coombs_test_schematic.png.) of most FNHTR. The use of leukocyte-reduced blood products may prevent or delay sensitization to leukocyte antigens and thereby reduce the incidence of these febrile episodes. Cytokines released from cells within stored blood components may mediate FNHTR; thus, leukoreduction before storage may prevent these reactions.


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InternalMed_Harrison. Allergic Reactions Urticarial reactions are related to plasma proteins found in transfused components. Mild reactions may be treated symptomatically by temporarily stopping the transfusion and administering antihistamines (diphenhydramine, 50 mg orally or intramuscularly). The transfusion may be completed after the signs and/or symptoms resolve. Patients with a history of allergic transfusion reaction should be premedicated with an antihistamine. Cellular components can be washed to remove residual plasma for the extremely sensitized patient.


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InternalMed_Harrison. Anaphylactic Reaction This severe reaction presents after transfusion of only a few milliliters of the blood component. Symptoms and signs include difficulty breathing, coughing, nausea and vomiting, hypotension, bronchospasm, loss of consciousness, respiratory arrest, and shock. Treatment includes stopping the transfusion, maintaining vascular access, and administering epinephrine (0.5–1 mL of 1:1000 dilution subcutaneously). Glucocorticoids may be required in severe cases. Patients who are IgA-deficient, <1% of the population, may be sensitized to this Ig class and are at risk for anaphylactic reactions associated with plasma transfusion. Individuals with severe IgA deficiency should therefore receive only IgA-deficient plasma and washed cellular blood components. Patients who have anaphylactic or repeated allergic reactions to blood components should be tested for IgA deficiency.


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InternalMed_Harrison. Graft-Versus-Host Disease Graft-versus-host disease (GVHD) is a frequent complication of allogeneic stem cell transplantation, in which lymphocytes from the donor attack and cannot be eliminated by an immunodeficient host. Transfusion-related GVHD is mediated by donor T lymphocytes that recognize host HLA antigens as foreign and mount an immune response, which is manifested clinically by the development of fever, a characteristic cutaneous eruption, diarrhea, and liver function abnormalities. GVHD can also occur when blood components that contain viable T lymphocytes are transfused to immunodeficient recipients or to immunocompetent recipients who share HLA antigens with the donor (e.g., a family donor). In addition to the aforementioned clinical features of GVHD, transfusion-associated GVHD (TA-GVHD) is characterized by marrow aplasia and pancytopenia. TA-GVHD is highly resistant to treatment with immunosuppressive therapies, including glucocorticoids, cyclosporine, antithymocyte


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InternalMed_Harrison. GVHD (TA-GVHD) is characterized by marrow aplasia and pancytopenia. TA-GVHD is highly resistant to treatment with immunosuppressive therapies, including glucocorticoids, cyclosporine, antithymocyte globulin, and ablative therapy followed by allogeneic bone marrow transplantation. Clinical manifestations appear at 8–10 days, and death occurs at 3–4 weeks after transfusion.


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InternalMed_Harrison. TA-GVHD can be prevented by irradiation of cellular components (minimum of 2500 cGy) before transfusion to patients at risk. Patients at risk for TA-GVHD include fetuses receiving intrauterine transfusions, selected immunocompetent (e.g., lymphoma patients) or immunocompromised recipients, recipients of donor units known to be from a blood relative, and recipients who have undergone marrow transplantation. Directed donations by family members should be discouraged (they are not less likely to transmit infection); lacking other options, the blood products from family members should always be irradiated.


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InternalMed_Harrison. Transfusion-Related Acute Lung Injury Transfusion-related acute lung injury (TRALI) is the most common cause of transfusion related fatalities. The recipient develops symptoms of hypoxia (Pao2/FIo2 <300 mmHg) and signs of noncardiogenic pulmonary edema, including bilateral interstitial infiltrates on chest x-ray, either during or within 6 h of transfusion. Treatment is supportive, and patients usually recover without sequelae. TRALI usually results from the transfusion of donor plasma that contains high-titer anti-HLA class II antibodies that bind recipient leukocytes. The leukocytes aggregate in the pulmonary vasculature and release mediators that increase capillary permeability. Testing the donor’s plasma for anti-HLA antibodies can support this diagnosis. The implicated donors are frequently multiparous women. The transfusion of plasma from male and nulliparous women donors reduces the risk of TRALI. Recipient factors that are associated 138e-5 with increased risk of TRALI include


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InternalMed_Harrison. multiparous women. The transfusion of plasma from male and nulliparous women donors reduces the risk of TRALI. Recipient factors that are associated 138e-5 with increased risk of TRALI include smoking, chronic alcohol use, shock, liver surgery (transplantation), mechanical ventilation with >30 cmH2O pressure support and positive fluid balance.


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InternalMed_Harrison. Posttransfusion Purpura This reaction presents as thrombocytopenia 7–10 days after platelet transfusion and occurs predominantly in women. Platelet-specific antibodies are found in the recipient’s serum, and the most frequently recognized antigen is HPA-1a found on the platelet glycoprotein IIIa receptor. The delayed thrombocytopenia is due to the production of antibodies that react to both donor and recipient platelets. Additional platelet transfusions can worsen the thrombocytopenia and should be avoided. Treatment with intravenous immunoglobulin may neutralize the effector antibodies, or plasmapheresis can be used to remove the antibodies.


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InternalMed_Harrison. Alloimmunization A recipient may become alloimmunized to a number of antigens on cellular blood elements and plasma proteins. Alloantibodies to RBC antigens are detected during pretransfusion testing, and their presence may delay finding antigen-negative crossmatch-compatible products for transfusion. Women of childbearing age who are sensitized to certain RBC antigens (i.e., D, c, E, Kell, or Duffy) are at risk for bearing a fetus with hemolytic disease of the newborn. Matching for D antigen is the only pretransfusion selection test to prevent RBC alloimmunization.


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InternalMed_Harrison. Alloimmunization to antigens on leukocytes and platelets can result in refractoriness to platelet transfusions. Once alloimmunization has developed, HLA-compatible platelets from donors who share similar antigens with the recipient may be difficult to find. Hence, prudent transfusion practice is directed at preventing sensitization through the use of leukocyte-reduced cellular components, as well as limiting antigenic exposure by the judicious use of transfusions and use of SDAPs. NONIMMUNOLOGIC REACTIONS Fluid Overload Blood components are excellent volume expanders, and transfusion may quickly lead to transfusion-associated circulatory overload (TACO). Dyspnea with PaO2 <90% on room air, bilateral infiltrates on chest x-ray, and systolic hypertension are found with TACO. Brain natriuretic peptide (BNP) is often elevated (>1.5) compared with pretransfusion levels. Monitoring the rate and volume of the transfusion and using a diuretic can minimize this problem.


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InternalMed_Harrison. Hypothermia Refrigerated (4°C) or frozen (−18°C or below) blood components can result in hypothermia when rapidly infused. Cardiac dysrhythmias can result from exposing the sinoatrial node to cold fluid. Use of an in-line warmer will prevent this complication. Electrolyte Toxicity RBC leakage during storage increases the concentration of potassium in the unit. Neonates and patients in renal failure are at risk for hyperkalemia. Preventive measures, such as using fresh or washed RBCs, are warranted for neonatal transfusions because this complication can be fatal.


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InternalMed_Harrison. Citrate, commonly used to anticoagulate blood components, chelates calcium and thereby inhibits the coagulation cascade. Hypocalcemia, manifested by circumoral numbness and/or tingling sensation of the fingers and toes, may result from multiple rapid transfusions. Because citrate is quickly metabolized to bicarbonate, calcium infusion is seldom required in this setting. If calcium or any other intravenous infusion is necessary, it must be given through a separate line. Iron Overload Each unit of RBCs contains 200–250 mg of iron. Symptoms and signs of iron overload affecting endocrine, hepatic, and cardiac function are common after 100 units of RBCs have been transfused (total-body iron load of 20 g). Preventing this complication by using alternative therapies (e.g., erythropoietin) and judicious transfusion is preferable and cost effective. Chelating agents, such as deferoxamine and deferasirox, are available, but the response is often suboptimal.


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InternalMed_Harrison. Hypotensive Reactions Transient hypotension may be noted among transfused patients who take angiotensin-converting enzyme (ACE) inhibitors. Because blood products contain bradykinin that is normally degraded by ACE, patients on ACE inhibitors may have increased bradykinin levels that cause hypotension in the recipient. The blood pressure typically returns to normal without intervention. Immunomodulation Transfusion of allogeneic blood is immunosuppressive. Multiply transfused renal transplant recipients are less likely to reject the graft, and transfusion may result in poorer outcomes in cancer patients and increase the risk of infections. Transfusion-related immunomodulation is thought to be mediated by transfused leukocytes. Leukocyte-depleted cellular products may cause less immunosuppression, although controlled data are unlikely to be obtained as the blood supply becomes universally leukocyte depleted.


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InternalMed_Harrison. The blood supply is initially screened by selecting healthy donors without high-risk lifestyles, medical conditions, or exposure to transmissible pathogens, such as intravenous drug use or visiting malaria endemic areas. Multiple tests performed on donated blood to detect the presence of infectious agents using nucleic acid amplification testing (NAAT) or evidence of prior infections by testing for antibodies to pathogens and sterility of platelet products further reduce the risk of transfusion-acquired infections. Viral Infections • Hepatitis C virus (HCv) Blood donations are tested for antibodies to HCV and HCV RNA. The risk of acquiring HCV through transfusion is now calculated to be approximately 1 in 2,000,000 units. Infection with HCV may be asymptomatic or lead to chronic active hepatitis, cirrhosis, and liver failure.


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InternalMed_Harrison. Human immunodefiCienCy virus type 1 (Hiv-1) Donated blood is tested for antibodies to HIV-1, HIV-1 p24 antigen, and HIV RNA using NAAT. Approximately a dozen seronegative donors have been shown to harbor HIV RNA. The risk of HIV-1 infection per transfusion episode is 1 in 2,000,000. Antibodies to HIV-2 are also measured in donated blood. No cases of HIV-2 infection have been reported in the United States since 1992. Hepatitis B virus (HBv) Donated blood is screened for HBV using assays for hepatitis B surface antigen (HbsAg). NAAT testing is not practical because of slow viral replication and lower levels of viremia. The risk of transfusion-associated HBV infection is several times greater than for HCV. Vaccination of individuals who require longterm transfusion therapy can prevent this complication.


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InternalMed_Harrison. otHer Hepatitis viruses Hepatitis A virus is rarely transmitted by transfusion; infection is typically asymptomatic and does not lead to chronic disease. Other transfusion-transmitted viruses—TT virus, SEN virus, and GB virus C—do not cause chronic hepatitis or other disease states. Routine testing does not appear to be warranted. West nile virus (Wnv) Transfusion-transmitted WNV infections were documented in 2002. This RNA virus can be detected using NAAT; routine screening began in 2003. WNV infections range in severity from asymptomatic to fatal, with the older population at greater risk.


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InternalMed_Harrison. Cytomegalovirus This ubiquitous virus infects ≥50% of the general population and is transmitted by the infected “passenger” WBCs found in transfused PRBCs or platelet components. Cellular components that are leukocyte-reduced have a decreased risk of transmitting CMV, regardless of the serologic status of the donor. Groups at risk for CMV infections include immunosuppressed patients, CMV-seronegative transplant recipients, and neonates; these patients should receive leukocyte-depleted components or CMV seronegative products. Human t lympHotropiC virus (Htlv) type 1 Assays to detect HTLV-1 and -2 are used to screen all donated blood. HTLV-1 is associated with adult T cell leukemia/lymphoma and tropical spastic paraparesis in a small percentage of infected persons (Chap. 225e). The risk of HTLV-1 infection via transfusion is 1 in 641,000 transfusion episodes. HTLV-2 is not clearly associated with any disease.


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InternalMed_Harrison. parvovirus B19 Blood components and pooled plasma products can transmit this virus, the etiologic agent of erythema infectiosum, or fifth disease, in children. Parvovirus B19 shows tropism for erythroid precursors and inhibits both erythrocyte production and maturation. Pure red cell aplasia, presenting either as acute aplastic crisis or chronic anemia with shortened RBC survival, may occur in individuals with an underlying hematologic disease, such as sickle cell disease or thalassemia (Chap. 130). The fetus of a seronegative woman is at risk for developing hydrops from this virus. Bacterial Contamination The relative risk of transfusion-transmitted bacterial infection has increased as the absolute risk of viral infections has dramatically decreased.


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InternalMed_Harrison. Most bacteria do not grow well at cold temperatures; thus, PRBCs and FFP are not common sources of bacterial contamination. However, some gram-negative bacteria can grow at 1–6°C. Yersinia, Pseudomonas, Serratia, Acinetobacter, and Escherichia species have all been implicated in infections related to PRBC transfusion. Platelet concentrates, which are stored at room temperature, are more likely to contain skin contaminants such as gram-positive organisms, including coagulase-negative staphylococci. It is estimated that 1 in 1000–2000 platelet components is contaminated with bacteria. The risk of death due to transfusion-associated sepsis has been calculated at 1 in 17,000 for single-unit platelets derived from whole blood donation and 1 in 61,000 for apheresis product. Since 2004, blood banks have instituted methods to detect contaminated platelet components.


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InternalMed_Harrison. Recipients of transfusion contaminated with bacteria may develop fever and chills, which can progress to septic shock and DIC. These reactions may occur abruptly, within minutes of initiating the transfusion, or after several hours. The onset of symptoms and signs is often sudden and fulminant, which distinguishes bacterial contamination from an FNHTR. The reactions, particularly those related to gram-negative contaminants, are the result of infused endotoxins formed within the contaminated stored component. When these reactions are suspected, the transfusion must be stopped immediately. Therapy is directed at reversing any signs of shock, and broad-spectrum antibiotics should be given. The blood bank should be notified to identify any clerical or serologic error. The blood component bag should be sent for culture and Gram stain.


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InternalMed_Harrison. Other Infectious Agents Various parasites, including those causing malaria, babesiosis, and Chagas’ disease, can be transmitted by blood transfusion. Geographic migration and travel of donors shift the incidence of these rare infections. Other agents implicated in transfusion transmission include dengue, chikungunya virus, variant Creutzfeldt-Jakob disease, A. phagocytophilum, and yellow fever vaccine virus, and the list will grow. Tests for some pathogens are available, such as T. cruzi, but not universally required, whereas others are being developed (B. microti). These infections should be considered in the transfused patient in the appropriate clinical setting.


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InternalMed_Harrison. Alternatives to allogeneic blood transfusions that avoid homologous donor exposures with attendant immunologic and infectious risks remain attractive. Autologous blood is the best option when transfusion is anticipated. However, the cost-benefit ratio of autologous transfusion remains high. No transfusion is a zero-risk event; clerical errors and bacterial contamination remain potential complications even with autologous transfusions. Additional methods of autologous transfusion in the surgical patient include preoperative hemodilution, recovery of shed blood from sterile surgical sites, and postoperative drainage collection. Directed or designated donation from friends and family of the potential recipient has not been safer than volunteer donor component transfusions. Such directed donations may in fact place the recipient at higher risk for complications such as GVHD and alloimmunization.


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InternalMed_Harrison. Granulocyte and granulocyte-macrophage colony-stimulating factors are clinically useful to hasten leukocyte recovery in patients with leukopenia related to high-dose chemotherapy. Erythropoietin stimulates erythrocyte production in patients with anemia of chronic renal failure and other conditions, thus avoiding or reducing the need for transfusion. This hormone can also stimulate erythropoiesis in the autologous donor to enable additional donation.


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InternalMed_Harrison. hematopoietic Cell transplantation Frederick R. Appelbaum Bone marrow transplantation was the original term used to describe the collection and transplantation of hematopoietic stem cells, but with 139e the demonstration that peripheral blood and umbilical cord blood are also useful sources of stem cells, hematopoietic cell transplantation has become the preferred generic term for this process. The procedure is usually carried out for one of two purposes: (1) to replace an abnormal but nonmalignant lymphohematopoietic system with one from a normal donor or (2) to treat malignancy by allowing the administration of higher doses of myelosuppressive therapy than would otherwise be possible. The use of hematopoietic cell transplantation has been increasing, both because of its efficacy in selected diseases and because of increasing availability of donors. The Center for International Blood and Marrow Transplant Research (http://www.cibmtr.org) estimates that about 65,000 transplants are


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InternalMed_Harrison. diseases and because of increasing availability of donors. The Center for International Blood and Marrow Transplant Research (http://www.cibmtr.org) estimates that about 65,000 transplants are performed each year.


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InternalMed_Harrison. Several features of the hematopoietic stem cell make transplantation clinically feasible, including its remarkable regenerative capacity, its ability to home to the marrow space following intravenous injection, and the ability of the stem cell to be cryopreserved (Chap. 89e). Transplantation of a single stem cell can replace the entire lymphohematopoietic system of an adult mouse. In humans, transplantation of a small percentage of a donor’s bone marrow volume regularly results in complete and sustained replacement of the recipient’s entire lymphohematopoietic system, including all red cells, granulocytes, B and T lymphocytes, and platelets, as well as cells comprising the fixed macrophage population, including Kupffer cells of the liver, pulmonary alveolar macrophages, osteoclasts, Langerhans cells of the skin, and brain microglial cells. The ability of the hematopoietic stem cell to home to the marrow following intravenous injection is mediated, in part, by an interaction between


InternalMed_Harrison

InternalMed_Harrison. cells of the skin, and brain microglial cells. The ability of the hematopoietic stem cell to home to the marrow following intravenous injection is mediated, in part, by an interaction between CXCL12, also known as stromal cell–derived factor 1, produced by marrow stromal cells and the alpha-chemokine receptor CXCR4 found on stem cells. Homing is also influenced by the interaction of cell-surface molecules, termed selectins, including Eand L-selectin, on bone marrow endothelial cells with ligands, termed integrins, such as VLA-4, on early hematopoietic cells. Human hematopoietic stem cells can survive freezing and thawing with little, if any, damage, making it possible to remove and store a portion of the patient’s own bone marrow for later reinfusion following treatment of the patient with high-dose myelotoxic therapy.


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InternalMed_Harrison. Hematopoietic cell transplantation can be described according to the relationship between the patient and the donor and by the anatomic source of stem cells. In ~1% of cases, patients have identical twins who can serve as donors. With the use of syngeneic donors, there is no risk of graft-versus-host disease (GVHD), which often complicates allogeneic transplantation, and unlike the use of autologous marrow, there is no risk that the stem cells are contaminated with tumor cells.


InternalMed_Harrison

InternalMed_Harrison. Allogeneic transplantation involves a donor and a recipient who are not genetically identical. Following allogeneic transplantation, immune cells transplanted with the stem cells or developing from them can react against the patient, causing GVHD. Alternatively, if the immunosuppressive preparative regimen used to treat the patient before transplant is inadequate, immunocompetent cells of the patient can cause graft rejection. The risks of these complications are greatly influenced by the degree of matching between donor and recipient for antigens encoded by genes of the major histocompatibility complex.


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InternalMed_Harrison. The human leukocyte antigen (HLA) molecules are responsible for binding antigenic proteins and presenting them to T cells. The antigens presented by HLA molecules may derive from exogenous sources (e.g., during active infections) or may be endogenous proteins. 139e-1 If individuals are not HLA-matched, T cells from one individual will react strongly to the mismatched HLA, or “major antigens,” of the second. Even if the individuals are HLA-matched, the T cells of the donor may react to differing endogenous or “minor antigens” presented by the HLA of the recipient. Reactions to minor antigens tend to be less vigorous. The genes of major relevance to transplantation include HLA-A, -B, -C, and -D; they are closely linked and therefore tend to be inherited as haplotypes, with only rare crossovers between them. Thus, the odds that any one full sibling will match a patient are one in four, and the probability that the patient has an HLA-identical sibling is 1 − (0.75)n, where n equals the


InternalMed_Harrison

InternalMed_Harrison. between them. Thus, the odds that any one full sibling will match a patient are one in four, and the probability that the patient has an HLA-identical sibling is 1 − (0.75)n, where n equals the number of siblings.


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InternalMed_Harrison. With current techniques, the risk of graft rejection is 1–3%, and the risk of severe, life-threatening acute GVHD is ~15% following transplantation between HLA-identical siblings. The incidence of graft rejection and GVHD increases progressively with the use of family member donors mismatched for one, two, or three antigens. Although survival following a one-antigen mismatched transplant is not markedly altered, survival following twoor three-antigen mismatched transplants is significantly reduced. Since the formation of the National Marrow Donor Program and other registries, it has become possible to identify HLA-matched unrelated donors for many patients. The genes encoding HLA antigens are highly polymorphic, and thus the odds of any two unrelated individuals being HLA identical are extremely low, somewhat less than 1 in 10,000. However, by identifying and typing >20 million volunteer donors, HLA-matched donors can now be found for ~60% of patients for whom a search is initiated,


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InternalMed_Harrison. low, somewhat less than 1 in 10,000. However, by identifying and typing >20 million volunteer donors, HLA-matched donors can now be found for ~60% of patients for whom a search is initiated, with higher rates among whites and lower rates among minorities and patients of mixed race. It takes, on average, 3–4 months to complete a search and schedule and initiate an unrelated donor transplant. With improvements in HLA typing and supportive care measures, survival following matched unrelated donor transplantation is essentially the same as that seen with HLA-matched siblings.


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InternalMed_Harrison. Autologous transplantation involves the removal and storage of the patient’s own stem cells with subsequent reinfusion after the patient receives high-dose myeloablative therapy. Unlike allogeneic transplantation, there is no risk of GVHD or graft rejection with autologous transplantation. On the other hand, autologous transplantation lacks a graft-versus-tumor (GVT) effect, and the autologous stem cell product can be contaminated with tumor cells, which could lead to relapse. A variety of techniques have been developed to “purge” autologous products of tumor cells. Some use antibodies directed at tumor-associated antigens plus complement, antibodies linked to toxins, or antibodies conjugated to immunomagnetic beads. Another technique is positive selection of stem cells using antibodies to CD34, with subsequent column adherence or flow techniques to select normal stem cells while leaving tumor cells behind. All of these approaches can reduce the number of tumor cells from 1000to


InternalMed_Harrison

InternalMed_Harrison. to CD34, with subsequent column adherence or flow techniques to select normal stem cells while leaving tumor cells behind. All of these approaches can reduce the number of tumor cells from 1000to 10,000-fold and are clinically feasible; however, no prospective randomized trials have yet shown that any of these approaches results in a decrease in relapse rates or improvements in disease-free or overall survival.


InternalMed_Harrison

InternalMed_Harrison. Bone marrow aspirated from the posterior and anterior iliac crests initially was the source of hematopoietic stem cells for transplantation. Typically, anywhere from 1.5 to 5 × 108 nucleated marrow cells per kilogram are collected for allogeneic transplantation. Several studies have found improved survival in the settings of both matched sibling and unrelated transplantation by transplanting higher numbers of bone marrow cells.


InternalMed_Harrison

InternalMed_Harrison. Hematopoietic stem cells circulate in the peripheral blood but in very low concentrations. Following the administration of certain hematopoietic growth factors, including granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), and during recovery from intensive chemotherapy, the concentration of hematopoietic progenitor cells in blood, as measured either by colony-forming units or expression of the CD34 antigen, increases markedly. This has made it possible to harvest adequate numbers of stem cells from the peripheral blood for transplantation. Donors are typically treated with 4 or 5 days of hematopoietic growth factor, following which stem cells are collected in one or two 4-h pheresis sessions. In the autologous setting, transplantation of >2.5 × 106 CD34 cells per kilogram, a number that can be collected in most circumstances, leads to rapid and sustained engraftment in virtually all cases. In the 10–20% of patients who fail to


InternalMed_Harrison

InternalMed_Harrison. of >2.5 × 106 CD34 cells per kilogram, a number that can be collected in most circumstances, leads to rapid and sustained engraftment in virtually all cases. In the 10–20% of patients who fail to mobilize sufficient CD34+ cells with growth factor alone, the addition of plerixafor, an antagonist of CXCR4, may be useful. Compared to the use of autologous marrow, use of peripheral blood stem cells results in more rapid hematopoietic recovery, with granulocytes recovering to 500/μL by day 12 and platelets recovering to 20,000/μL by day 14. Although this more rapid recovery diminishes the morbidity rate of transplantation, no studies show improved survival.


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InternalMed_Harrison. Hesitation in studying the use of peripheral blood stem cells for allogeneic transplantation occurred because peripheral blood stem cell products contain as much as 1 log more T cells than are contained in the typical marrow harvest; in animal models, the incidence of GVHD is related to the number of T cells transplanted. Nonetheless, clinical trials have shown that the use of growth factor–mobilized peripheral blood stem cells from HLA-matched family members leads to faster engraftment without an increase in acute GVHD. Chronic GVHD may be increased with peripheral blood stem cells, but in trials conducted so far, this has been more than balanced by reductions in relapse rates and nonrelapse mortality rates, with the use of peripheral blood stem cells resulting in improved overall survival. However, in the setting of matched unrelated donor transplantation, use of peripheral blood results in more chronic GVHD without a compensatory survival advantage, favoring the use of bone marrow


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InternalMed_Harrison. However, in the setting of matched unrelated donor transplantation, use of peripheral blood results in more chronic GVHD without a compensatory survival advantage, favoring the use of bone marrow in this setting.


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InternalMed_Harrison. Umbilical cord blood contains a high concentration of hematopoietic progenitor cells, allowing for its use as a source of stem cells for transplantation. Cord blood transplantation from family members has been explored in the setting where the immediate need for transplantation precludes waiting the 9 or so months generally required for the baby to mature to the point of donating marrow. Use of cord blood results in slower engraftment and peripheral count recovery than seen with marrow but a lower incidence of GVHD, perhaps reflecting the low number of T cells in cord blood. Multiple cord blood banks have been developed to harvest and store cord blood for possible transplantation to unrelated patients from material that would otherwise be discarded. Currently more than 500,000 units are cryopreserved and available for use. The advantages of unrelated cord blood are rapid availability and decreased immune reactivity allowing for the use of partially matched units, which is of


InternalMed_Harrison

InternalMed_Harrison. are cryopreserved and available for use. The advantages of unrelated cord blood are rapid availability and decreased immune reactivity allowing for the use of partially matched units, which is of particular importance for those without matched unrelated donors. The risks of graft failure and transplant-related mortality are related to the dose of cord blood cells per kilogram, which previously limited the application of single cord blood transplantation to pediatric and smaller adult patients. Subsequent trials have found that the use of double cord transplants diminishes the risk of graft failure and early mortality even though only one of the donors ultimately engrafts. Survival rates are now similar with unrelated donor and cord blood transplantation.


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InternalMed_Harrison. The treatment regimen administered to patients immediately preceding transplantation is designed to eradicate the patient’s underlying disease and, in the setting of allogeneic transplantation, immunosuppress the patient adequately to prevent rejection of the transplanted marrow. The appropriate regimen therefore depends on the disease setting and source of marrow. For example, when transplantation is performed to treat severe combined immunodeficiency and the donor is a histocompatible sibling, no treatment is needed because no host cells require eradication and the patient is already too immunoincompetent to reject the transplanted marrow. For aplastic anemia, there is no large population of cells to eradicate, and high-dose cyclophosphamide plus antithymocyte globulin are sufficient to immunosuppress the patient adequately to accept the marrow graft. In the setting of thalassemia and sickle cell anemia, high-dose busulfan is frequently added to cyclophosphamide in order to


InternalMed_Harrison

InternalMed_Harrison. to immunosuppress the patient adequately to accept the marrow graft. In the setting of thalassemia and sickle cell anemia, high-dose busulfan is frequently added to cyclophosphamide in order to eradicate hyperplastic host hematopoiesis. A variety of different regimens have been developed to treat malignant diseases. Most of these regimens include agents that have high activity against the tumor in question at conventional doses and have myelosuppression as their predominant dose-limiting toxicity. Therefore, these regimens commonly include busulfan, cyclophosphamide, melphalan, thiotepa, carmustine, etoposide, and total-body irradiation in various combinations.


InternalMed_Harrison

InternalMed_Harrison. Although high-dose treatment regimens have typically been used in transplantation, the understanding that much of the antitumor effect of transplantation derives from an immunologically mediated GVT response has led investigators to ask if reduced-intensity conditioning regimens might be effective and more tolerable. Evidence for a GVT effect comes from studies showing that posttransplant relapse rates are lowest in patients who develop acute and chronic GVHD, higher in those without GVHD, and higher still in recipients of T cell–depleted allogeneic or syngeneic marrow. The demonstration that complete remissions can be obtained in many patients who have relapsed after transplant by simply administering viable lymphocytes from the original donor further strengthens the argument for a potent GVT effect. Accordingly, a variety of reduced-intensity regimens have been studied, ranging from the very minimum required to achieve engraftment (e.g., fludarabine plus 200 cGy total-body


InternalMed_Harrison

InternalMed_Harrison. a potent GVT effect. Accordingly, a variety of reduced-intensity regimens have been studied, ranging from the very minimum required to achieve engraftment (e.g., fludarabine plus 200 cGy total-body irradiation) to regimens of more immediate intensity (e.g., fludarabine plus melphalan). Studies to date document that engraftment can be readily achieved with less toxicity than seen with conventional transplantation. Furthermore, the severity of acute GVHD appears to be somewhat decreased. Complete sustained responses have been documented in many patients, particularly those with more indolent hematologic malignancies. In general, relapse rates are higher following reduced-intensity conditioning, but transplant-related mortality is lower, favoring the use of reduced-intensity conditioning in older patients and those with significant comorbidities. High-dose regimens are favored in younger, fitter patients.


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InternalMed_Harrison. Marrow is usually collected from the donor’s posterior and sometimes anterior iliac crests, with the donor under general or spinal anesthesia. Typically, 10–15 mL/kg of marrow is aspirated, placed in heparinized media, and filtered through 0.3and 0.2-mm screens to remove fat and bony spicules. The collected marrow may undergo further processing depending on the clinical situation, such as the removal of red cells to prevent hemolysis in ABO-incompatible transplants, the removal of donor T cells to prevent GVHD, or attempts to remove possible contaminating tumor cells in autologous transplantation. Marrow donation is safe, with only very rare complications reported.


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InternalMed_Harrison. Peripheral blood stem cells are collected by leukapheresis after the donor has been treated with hematopoietic growth factors or, in the setting of autologous transplantation, sometimes after treatment with a combination of chemotherapy and growth factors. Stem cells for transplantation are infused through a large-bore central venous catheter. Such infusions are usually well tolerated, although occasionally patients develop fever, cough, or shortness of breath. These symptoms typically resolve with slowing of the infusion. When the stem cell product has been cryopreserved using dimethyl sulfoxide, patients more often experience short-lived nausea or vomiting due to the odor and taste of the cryoprotectant.


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InternalMed_Harrison. Peripheral blood counts usually reach their nadir several days to a week after transplant as a consequence of the preparative regimen; then cells produced by the transplanted stem cells begin to appear in the peripheral blood. The rate of recovery depends on the source of stem cells, the use of posttransplant growth factors, and the form of GVHD prophylaxis used. If marrow is the source of stem cells, recovery to 100 granulocytes/μL occurs on average by day 16 and to 500/μL by day 22. Use of G-CSF–mobilized peripheral blood stem cells speeds the rate of recovery by ~1 week when compared to marrow, whereas engraftment following cord blood transplantation is typically delayed by ~1 week compared to marrow. Use of a myeloid growth factor (G-CSF or GM-CSF) after transplant can accelerate recovery by 3–5 days, whereas use of methotrexate to prevent GVHD delays engraftment by a similar


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InternalMed_Harrison. FIGURE 139e-1 Major syndromes complicating marrow transplantation. CMV, cytomegalovirus; GVHD, graft-versus-host disease; HSV, herpes simplex virus; SOS, sinusoidal obstructive syndrome (formerly venoocclusive disease); VZV, varicella-zoster virus. The size of the shaded area roughly reflects the period of risk of the complication. period. Following allogeneic transplantation, engraftment can be documented using fluorescence in situ hybridization of sex chromosomes if donor and recipient are sex-mismatched or by analysis of a variable number of tandem repeats or short tandem repeat polymorphisms after DNA amplification.


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InternalMed_Harrison. COMPLICATIONS FOLLOWING HEMATOPOIETIC CELL TRANSPLANT Early Direct Chemoradiotoxicities The transplant preparative regimen may cause a spectrum of acute toxicities that vary according to intensity of the regimen and the specific agents used, but frequently results in nausea, vomiting, and mild skin erythema (Fig. 139e-1). Regimens that include high-dose cyclophosphamide can result in hemorrhagic cystitis, which can usually be prevented by bladder irrigation or with the sulfhydryl compound mercaptoethanesulfonate (MESNA); rarely, acute hemorrhagic carditis is seen. Most high-dose preparative regimens will result in oral mucositis, which typically develops 5–7 days after transplant and often requires narcotic analgesia. Use of a patient-controlled analgesic pump provides the greatest patient satisfaction and results in a lower cumulative dose of narcotic. Keratinocyte growth factor (palifermin) can shorten the duration of mucositis by several days following autologous transplantation.


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InternalMed_Harrison. satisfaction and results in a lower cumulative dose of narcotic. Keratinocyte growth factor (palifermin) can shorten the duration of mucositis by several days following autologous transplantation. Patients begin losing their hair 5–6 days after transplant and by 1 week are usually profoundly pancytopenic.


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InternalMed_Harrison. Depending on the intensity of the conditioning regimen, 3–10% of patients will develop sinusoidal obstruction syndrome (SOS) of the liver (formerly called venoocclusive disease), a syndrome that results from direct cytotoxic injury to hepatic-venular and sinusoidal endothelium, with subsequent deposition of fibrin and the development of a local hypercoagulable state. This chain of events leads to the clinical symptoms of tender hepatomegaly, ascites, jaundice, and fluid retention. These symptoms can develop any time during the first month after transplant, with the peak incidence at day 16. Predisposing factors include prior exposure to intensive chemotherapy, pretransplant hepatitis of any cause, and use of more intense conditioning regimens. The mortality rate of sinusoidal obstruction syndrome is ~30%, with progressive hepatic failure culminating in a terminal hepatorenal syndrome. Both thrombolytic and antithrombotic agents, such as tissue plasminogen activator, heparin, and


InternalMed_Harrison

InternalMed_Harrison. syndrome is ~30%, with progressive hepatic failure culminating in a terminal hepatorenal syndrome. Both thrombolytic and antithrombotic agents, such as tissue plasminogen activator, heparin, and prostaglandin E, have been studied as therapy, but none has proven of consistent major benefit in controlled trials, and all have significant toxicity. Studies with defibrotide, a polydeoxyribonucleotide, seem encouraging.


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InternalMed_Harrison. Although most pneumonias developing early after transplant are caused by infectious agents, in ~5% of patients a diffuse interstitial pneumonia will develop that is thought to be the result of direct toxicity of high-dose preparative regimens. Bronchoalveolar lavage 139e-3 usually shows alveolar hemorrhage, and biopsies are typically characterized by diffuse alveolar damage, although some cases may have a more clearly interstitial pattern. High-dose glucocorticoids or antitumor necrosis factor therapies are sometimes used as treatment, although randomized trials testing their utility have not been reported.


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InternalMed_Harrison. Late Direct Chemoradiotoxicities Late complications of the preparative regimen include decreased growth velocity in children and delayed development of secondary sex characteristics. These complications can be partly ameliorated with the use of appropriate growth and sex hormone replacement. Most men become azoospermic, and most postpubertal women will develop ovarian failure, which should be treated. However, pregnancy is possible after transplantation, and patients should be counseled accordingly. Thyroid dysfunction, usually well compensated, is sometimes seen. Cataracts develop in 10–20% of patients and are most common in patients treated with total-body irradiation and those who receive glucocorticoid therapy after transplant for treatment of GVHD. Aseptic necrosis of the femoral head is seen in 10% of patients and is particularly frequent in those receiving chronic glucocorticoid therapy. Both acute and late chemoradiotoxicities (except those due to glucocorticoids and other


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InternalMed_Harrison. head is seen in 10% of patients and is particularly frequent in those receiving chronic glucocorticoid therapy. Both acute and late chemoradiotoxicities (except those due to glucocorticoids and other agents used to treat GVHD) are considerably less frequent in recipients of reduced-intensity compared to high-dose preparative regimens.


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InternalMed_Harrison. Graft Failure Although complete and sustained engraftment is usually seen after transplant, occasionally marrow function either does not return or, after a brief period of engraftment, is lost. Graft failure after autologous transplantation can be the result of inadequate numbers of stem cells being transplanted, damage during ex vivo treatment or storage, or exposure of the patient to myelotoxic agents after transplant. Infections with cytomegalovirus (CMV) or human herpesvirus type 6 have also been associated with loss of marrow function. Graft failure after allogeneic transplantation can also be due to immunologic rejection of the graft by immunocompetent host cells. Immunologically based graft rejection is more common following use of less immunosuppressive preparative regimens, in recipients of T cell–depleted stem cell products, and in patients receiving grafts from HLA-mismatched donors or cord blood.


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InternalMed_Harrison. Treatment of graft failure usually involves removing all potentially myelotoxic agents from the patient’s regimen and attempting a short trial of a myeloid growth factor. Persistence of lymphocytes of host origin in allogeneic transplant recipients with graft failure indicates immunologic rejection. Reinfusion of donor stem cells in such patients is usually unsuccessful unless preceded by a second immunosuppressive preparative regimen. Standard high-dose preparative regimens are generally tolerated poorly if administered within 100 days of a first transplant because of cumulative toxicities. However, use of regimens combining, for example, fludarabine plus low-dose total-body irradiation, or cyclophosphamide plus antithymocyte globulin, has been effective in some cases.


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InternalMed_Harrison. Graft-Versus-Host Disease GVHD is the result of allogeneic T cells that are transferred with the donor’s stem cell inoculum reacting with antigenic targets on host cells. Acute GVHD usually occurs within the first 3 months after transplant with a peak onset around 4 weeks and is characterized by an erythematous maculopapular rash; by persistent anorexia or diarrhea, or both; and by liver disease with increased serum levels of bilirubin, alanine and aspartate aminotransferase, and alkaline phosphatase. Because many conditions can mimic acute GVHD, the diagnosis usually requires skin, liver, or endoscopic biopsy for confirmation. In all these organs, endothelial damage and lymphocytic infiltrates are seen. In skin, the epidermis and hair follicles are damaged; in liver, the small bile ducts show segmental disruption; and in intestines, destruction of the crypts and mucosal ulceration may be noted. A commonly used rating system for acute GVHD is shown in Table 139e-1. Grade I acute GVHD


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InternalMed_Harrison. show segmental disruption; and in intestines, destruction of the crypts and mucosal ulceration may be noted. A commonly used rating system for acute GVHD is shown in Table 139e-1. Grade I acute GVHD is of little clinical significance, does not affect the likelihood of survival, and does not require treatment. In contrast, grades II to IV GVHD are associated with significant symptoms and a poorer probability of survival, and they require aggressive therapy.


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InternalMed_Harrison. infection. Early after transplantation, patients are profoundly neutropenic, and because the risk of Liver—Bilirubin, bacterial infection is so great, most centers initiate falls to <500/μL. Fluconazole prophylaxis at a dose of 200–400 mg/d reduces the risk of can-Diarrhea >1500 mL/d didal infections. Patients seropositive for herpes Ileus simplex should receive acyclovir prophylaxis. One approach to infection prophylaxis is shown in Gut Stage Table 139e-2. Despite these prophylactic measures, The incidence of acute GVHD is higher in recipients of stem cells from mismatched or unrelated donors, in older patients, and in patients unable to receive full doses of drugs used to prevent the disease.


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InternalMed_Harrison. One general approach to the prevention of GVHD is the administration of immunosuppressive drugs early after transplant. Combinations of methotrexate and either cyclosporine or tacrolimus are among the most effective and widely used regimens. Prednisone, anti–T cell antibodies, mycophenolate mofetil, sirolimus, and other immunosuppressive agents have also been or are being studied in various combinations. A second general approach to GVHD prevention is removal of T cells from the stem cell inoculum. While effective in preventing GVHD, T cell depletion has been associated with an increased incidence of graft failure, infectious complications, and tumor recurrence after transplant; as yet, it is unsettled whether T cell depletion improves cure rates in any specific setting.


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InternalMed_Harrison. Despite prophylaxis, significant acute GVHD will develop in ~30% of recipients of stem cells from matched siblings and in as many as 60% of those receiving stem cells from unrelated donors. The disease is usually treated with glucocorticoids, additional immunosuppressants, or monoclonal antibodies targeted against T cells or T cell subsets.


InternalMed_Harrison

InternalMed_Harrison. Chronic GVHD occurs most commonly between 3 months and 2 years after allogeneic transplant, developing in 20–50% of recipients. The disease is more common in older patients, in recipients of mismatched or unrelated stem cells, and in those with a preceding episode of acute GVHD. The disease resembles an autoimmune disorder with malar rash, sicca syndrome, arthritis, obliterative bronchiolitis, and bile duct degeneration and cholestasis. Single-agent prednisone or cyclosporine is standard treatment at present, although trials of other agents are under way. Mortality rates from chronic GVHD average around 15%, but range from 5–50% depending on severity. In most patients, chronic GVHD resolves, but it may require 1–3 years of immunosuppressive treatment before these agents can be withdrawn without the disease recurring. Because patients with chronic GVHD are susceptible to significant infection, they should receive prophylactic trimethoprim-sulfamethoxazole, and all suspected infections


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InternalMed_Harrison. the disease recurring. Because patients with chronic GVHD are susceptible to significant infection, they should receive prophylactic trimethoprim-sulfamethoxazole, and all suspected infections should be investigated and treated aggressively.


InternalMed_Harrison

InternalMed_Harrison. Although onset before or after 3 months after transplant is often used to discriminate between acute and chronic GVHD, occasional patients will develop signs and symptoms of acute GVHD after 3 months (late-onset acute GVHD), whereas others will exhibit signs and symptoms of both acute and chronic GVHD (overlap syndrome). There are as yet no data to suggest that these patients should be treated differently than those with classic acute or chronic GVHD. From 3–5% of patients will develop an autoimmune disorder following allogeneic HCT, most commonly autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura. Unrelated donor source and chronic GVHD are risk factors, but autoimmune disorders have been reported in patients with no obvious GVHD. Treatment is with prednisone, cyclosporine, or rituximab.


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InternalMed_Harrison. most patients will develop fever and signs of infection after transplant. The management of patients who become febrile despite bacterial and fungal prophylaxis is a difficult challenge and is guided by individual aspects of the patient and by the institution’s experience. The general problem of infection in the immunocompromised host is discussed in Chap. 169.


InternalMed_Harrison

InternalMed_Harrison. Once patients engraft, the incidence of bacterial infection diminishes; however, patients, particularly allogeneic transplant recipients, remain at significant risk of infection. During the period from engraftment until about 3 months after transplant, the most common causes of infection are gram-positive bacteria, fungi (particularly Aspergillus), and viruses including CMV. CMV infection, which in the past was frequently seen and often fatal, can be prevented in seronegative patients transplanted from seronegative donors by the use of either seronegative blood products or products from which the white blood cells have been removed. In seropositive patients or patients transplanted from seropositive donors, the use of ganciclovir, either as prophylaxis beginning at the time of engraftment or initiated when CMV first reactivates as evidenced by development of antigenemia or viremia, can significantly reduce the risk of CMV disease. Foscarnet is effective for some patients who develop


InternalMed_Harrison

InternalMed_Harrison. or initiated when CMV first reactivates as evidenced by development of antigenemia or viremia, can significantly reduce the risk of CMV disease. Foscarnet is effective for some patients who develop CMV antigenemia or infection despite the use of ganciclovir or who cannot tolerate the drug.


InternalMed_Harrison

InternalMed_Harrison. Pneumocystis jiroveci pneumonia, once seen in 5–10% of patients, can be prevented by treating patients with oral trimethoprimsulfamethoxazole for 1 week before transplant and resuming the treatment once patients have engrafted. The risk of infection diminishes considerably beyond 3 months after transplant unless chronic GVHD develops, requiring continuous immunosuppression. Most transplant centers recommend continuing trimethoprim-sulfamethoxazole prophylaxis while patients are receiving any immunosuppressive drugs and also recommend careful monitoring for late CMV reactivation. In addition, many centers recommend prophylaxis against varicella-zoster, using acyclovir for 1 year after transplant. Patients should be revaccinated against tetanus, diphtheria, Haemophilus influenzae, polio, and pneumococcal pneumonia starting at 12 months after transplant and against measles, mumps, and rubella (MMR), varicella-zoster virus, and possibly pertussis at 24 months.


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InternalMed_Harrison. 400 mg PO qd to day 75 posttransplant 800 mg PO bid to day 30 800 mg PO bid to day 365 5 mg/kg IV bid for 7 days, then 5 (mg/kg)/d 5 days/week to day 100 Infection Posttransplant patients, particularly recipients of alloge neic transplantation, require unique approaches to the problem of TREATMENT OF SPECIFIC DISEASES USING HEMATOPOIETIC CELL be expected if patients are transplanted before they develop hepa-139e-5 TRANSPLANTATION tomegaly or portal fibrosis and if they have been given adequate iron chelation therapy. Among such patients, the probabilities of 5-year survival and disease-free survival are 95 and 90%, respectively. Although prolonged survival can be achieved with aggressive


InternalMed_Harrison

InternalMed_Harrison. By replacing abnormal stem cells with cells from a normal donor, hematopoietic cell transplantation can cure patients of a variety of immunodeficiency disorders including severe combined immunodeficiency, Wiskott-Aldrich syndrome, and Chédiak-Higashi syndrome. The widest experience has been with severe combined immunodeficiency disease, where cure rates of 90% can be expected with HLA-identical donors and success rates of 50–70% have been reported using haplotype-mismatched parents as donors (Table 139e-3).


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InternalMed_Harrison. Transplantation from matched siblings after a preparative regimen of high-dose cyclophosphamide and antithymocyte globulin can cure up to 90% of patients age <40 years with severe aplastic anemia. Results in older patients and in recipients of mismatched family member or unrelated marrow are less favorable; therefore, a trial of immunosuppressive therapy is generally recommended for such patients before considering transplantation. Transplantation is effective in all forms of aplastic anemia including, for example, the syndromes associated with paroxysmal nocturnal hemoglobinuria and Fanconi’s anemia. Patients with Fanconi’s anemia are abnormally sensitive to the toxic effects of alkylating agents, and so less intensive preparative regimens must be used in their treatment (Chap. 130). Marrow transplantation from an HLA-identical sibling following a preparative regimen of busulfan and cyclophosphamide can cure 80–90% of patients with thalassemia major. The best outcomes can


InternalMed_Harrison

InternalMed_Harrison. Marrow transplantation from an HLA-identical sibling following a preparative regimen of busulfan and cyclophosphamide can cure 80–90% of patients with thalassemia major. The best outcomes can Disease Allogeneic, % Autologous, % aThese estimates are generally based on data reported by the International Bone Marrow Transplant Registry. The analysis has not been reviewed by their Advisory Committee. Abbreviations: ID, insufficient data; N/A, not applicable.


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InternalMed_Harrison. Abbreviations: ID, insufficient data; N/A, not applicable. chelation therapy, transplantation is the only curative treatment for thalassemia. Transplantation is being studied as a curative approach to patients with sickle cell anemia. Two-year survival and disease-free survival rates of 90 and 80%, respectively, have been reported following matched sibling or cord blood transplantation. Decisions about patient selection and the timing of transplantation remain difficult, but transplantation represents a reasonable option for younger patients who suffer repeated crises or other significant complications and who have not responded to other interventions (Chap. 127).


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InternalMed_Harrison. Theoretically, hematopoietic cell transplantation should be able to cure any disease that results from an inborn error of the lymphohematopoietic system. Transplantation has been used successfully to treat congenital disorders of white blood cells such as Kostmann’s syndrome, chronic granulomatous disease, and leukocyte adhesion deficiency. Congenital anemias such as Blackfan-Diamond anemia can also be cured with transplantation. Infantile malignant osteopetrosis is due to an inability of the osteoclast to resorb bone, and because osteoclasts derive from the marrow, transplantation can cure this rare inherited disorder.


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InternalMed_Harrison. Hematopoietic cell transplantation has been used as treatment for a number of storage diseases caused by enzymatic deficiencies, such as Gaucher’s disease, Hurler’s syndrome, Hunter’s syndrome, and infantile metachromatic leukodystrophy. Transplantation for these diseases has not been uniformly successful, but treatment early in the course of these diseases, before irreversible damage to extramedullary organs has occurred, increases the chance for success. Transplantation is being explored as a treatment for severe acquired autoimmune disorders. These trials are based on studies demonstrating that transplantation can reverse autoimmune disorders in animal models and on the observation that occasional patients with coexisting autoimmune disorders and hematologic malignancies have been cured of both with transplantation.


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InternalMed_Harrison. Allogeneic hematopoietic cell transplantation cures 15–20% of patients who do not achieve complete response from induction chemotherapy for acute myeloid leukemia (AML) and is the only form of therapy that can cure such patients. Cure rates of 30–35% are seen when patients are transplanted in second remission or in first relapse. The best results with allogeneic transplantation are achieved when applied during first remission, with disease-free survival rates averaging 55–60%. Meta-analyses of studies comparing matched related donor transplantation to chemotherapy for adult AML patients age <60 years show a survival advantage with transplantation. This advantage is greatest for those with unfavorable-risk AML and is lost in those with favorable-risk disease. The role of autologous transplantation in the treatment of AML is less well defined. The rates of disease recurrence with autologous transplantation are higher than those seen after allogeneic transplantation, and cure rates are


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InternalMed_Harrison. in the treatment of AML is less well defined. The rates of disease recurrence with autologous transplantation are higher than those seen after allogeneic transplantation, and cure rates are somewhat less.


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InternalMed_Harrison. Similar to patients with AML, adults with acute lymphocytic leukemia who do not achieve a complete response to induction chemotherapy can be cured in 15–20% of cases with immediate transplantation. Cure rates improve to 30–50% in second remission, and therefore transplantation can be recommended for adults who have persistent disease after induction chemotherapy or who have subsequently relapsed. Transplantation in first remission results in cure rates about 55%. Transplantation appears to offer a clear advantage over chemotherapy for patients with high-risk disease, such as those with Philadelphia chromosome–positive disease. Debate continues about whether adults with standard-risk disease should be transplanted in first remission or whether transplantation should be reserved until relapse. Autologous transplantation is associated with a higher relapse rate but a somewhat lower risk of nonrelapse mortality when compared to allogeneic transplantation. There is no obvious role of


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InternalMed_Harrison. relapse. Autologous transplantation is associated with a higher relapse rate but a somewhat lower risk of nonrelapse mortality when compared to allogeneic transplantation. There is no obvious role of autologous transplantation for acute lymphocytic leukemia in first remission, and for second-remission patients, most experts recommend use of allogeneic stem cells if an appropriate donor is available.


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InternalMed_Harrison. Allogeneic hematopoietic cell transplantation is the only therapy shown to cure a substantial portion of patients with chronic myeloid leukemia (CML). Five-year disease-free survival rates are 15–20% for patients transplanted for blast crisis, 25–50% for accelerated-phase patients, and 60–70% for chronic-phase patients, with cure rates as high as 80% at selected centers. However, with the availability of imatinib mesylate and other highly active tyrosine kinase inhibitors (TKIs), transplantation is generally reserved for those who fail to achieve a complete cytogenetic response with a TKI, relapse after an initial response, or are intolerant of the drugs (Chap. 133).


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InternalMed_Harrison. Allogeneic transplantation using a high-dose preparative regimen has rarely been used for chronic lymphocytic leukemia (CLL), in large part because of the chronic nature of the disease and because of the age profile of patients. In those cases where it was studied, complete remissions were achieved in the majority of patients, with disease-free survival rates of ~50% at 3 years, despite the advanced stage of the disease at the time of transplant. The marked antitumor effects have resulted in the increased use and study of allogeneic transplantation using reduced-intensity conditioning for the treatment of CLL.


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InternalMed_Harrison. Between 20 and 65% of patients with myelodysplasia appear to be cured with allogeneic transplantation. Results are better among younger patients and those with less advanced disease. However, patients with early-stage myelodysplasia can live for extended periods without intervention, and so transplantation is generally reserved for patients with an International Prognostic Scoring System (IPSS) score of Int-2 or for selected patients with an IPSS score of Int-1 who have other poor prognostic features (Chap. 130).


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InternalMed_Harrison. Patients with disseminated intermediateor high-grade non-Hodgkin’s lymphoma who have not been cured by first-line chemotherapy and are transplanted in first relapse or second remission can still be cured in 40–50% of cases. This represents a clear advantage over results obtained with conventional-dose salvage chemotherapy. It is unsettled whether patients with high-risk disease benefit from transplantation in first remission. Most experts favor the use of autologous rather than allogeneic transplantation for patients with intermediateor high-grade non-Hodgkin’s lymphoma, because fewer complications occur with this approach and survival appears equivalent. For patients with recurrent disseminated indolent nonHodgkin’s lymphoma, autologous transplantation results in high response rates and improved progression-free survival compared to salvage chemotherapy. However, late relapses are seen after transplantation. The role of autologous transplantation in the initial treatment of patients


InternalMed_Harrison

InternalMed_Harrison. improved progression-free survival compared to salvage chemotherapy. However, late relapses are seen after transplantation. The role of autologous transplantation in the initial treatment of patients is debated. It may be indicated in the small subset of patients presenting with high-risk prognostic factors but is not clearly more effective in those in lower risk groups. Reduced-intensity conditioning regimens followed by allogeneic transplantation result in high response rates in patients with indolent lymphomas, but the exact role of this approach remains to be defined.


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InternalMed_Harrison. The role of transplantation in Hodgkin’s disease is similar to that in intermediateand high-grade non-Hodgkin’s lymphoma. With transplantation, 5-year disease-free survival is 20–30% in patients who never achieve a first remission with standard chemotherapy and up to 70% for those transplanted in second remission. Transplantation has no defined role in first remission in Hodgkin’s disease. Patients with myeloma who have progressed on first-line therapy can sometimes benefit from allogeneic or autologous transplantation. Prospective randomized studies demonstrate that the inclusion of autologous transplantation as part of the initial therapy of patients results in improved disease-free survival and overall survival. Further benefit is seen with the use of lenalidomide maintenance therapy following transplantation. The use of autologous transplantation followed by nonmyeloablative allogeneic transplantation has yielded mixed results.


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InternalMed_Harrison. Randomized trials evaluating autologous transplantation as treatment for primary or metastatic breast cancer have failed to show a consistent survival advantage with this approach, and therefore, there is no established role for transplantation in this disease. Patients with testicular cancer in whom first-line platinum-containing chemotherapy has failed can still be cured in ~50% of cases if treated with high-dose chemotherapy with autologous stem cell support, an outcome better than that seen with low-dose salvage chemotherapy. The use of high-dose chemotherapy with autologous stem cell support is being studied for several other solid tumors, including neuroblastoma and pediatric sarcomas. As in most other settings, the best results have been obtained in patients with limited amounts of disease and where the remaining tumor remains sensitive to conventional-dose chemotherapy. Few randomized trials of transplantation in these diseases have been completed.


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InternalMed_Harrison. Partial and complete responses have been reported following nonmyeloablative allogeneic transplantation for some solid tumors, most notably renal cell cancers. The GVT effect, well documented in the treatment of hematologic malignancies, may apply to selected solid tumors under certain circumstances.


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InternalMed_Harrison. Patients who relapse following autologous transplantation sometimes respond to further chemotherapy and may be candidates for possible allogeneic transplantation, particularly if the remission following the initial autologous transplant was long. Several options are available for patients who relapse following allogeneic transplantation. Of particular interest are the response rates seen with infusion of unirradiated donor lymphocytes. Complete responses in as many as 75% of patients with chronic myeloid leukemia, 40% in myelodysplasia, 25% in AML, and 15% in myeloma have been reported. Major complications of donor lymphocyte infusions include transient myelosuppression and the development of GVHD. These complications depend on the number of donor lymphocytes given and the schedule of infusions, with less GVHD seen with lower dose, fractionated schedules.


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InternalMed_Harrison. Disorders of Platelets and Vessel wall Barbara A. Konkle Hemostasis is a dynamic process in which the platelet and the blood vessel wall play key roles. Platelets become activated upon adhesion to 140 sEC TION 3 Disorders of Platelets and Vessel Wall von Willebrand factor (VWF) and collagen in the exposed subendothelium after injury. Platelet activation is also mediated through shear forces imposed by blood flow itself, particularly in areas where the vessel wall is diseased, and is also affected by the inflammatory state of the endothelium. The activated platelet surface provides the major physiologic site for coagulation factor activation, which results in further platelet activation and fibrin formation. Genetic and acquired influences on the platelet and vessel wall, as well as on the coagulation and fibrinolytic systems, determine whether normal hemostasis or bleeding or clotting symptoms will result.


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InternalMed_Harrison. Platelets are released from the megakaryocyte, likely under the influence of flow in the capillary sinuses. The normal blood platelet count is 150,000–450,000/μL. The major regulator of platelet production is the hormone thrombopoietin (TPO), which is synthesized in the liver. Synthesis is increased with inflammation and specifically by interleukin 6. TPO binds to its receptor on platelets and megakaryocytes, by which it is removed from the circulation. Thus a reduction in platelet and megakaryocyte mass increases the level of TPO, which then stimulates platelet production. Platelets circulate with an average life span of 7–10 days. Approximately one-third of the platelets reside in the spleen, and this number increases in proportion to splenic size, although the platelet count rarely decreases to <40,000/μL as the spleen enlarges. Platelets are physiologically very active, but are anucleate, and thus have limited capacity to synthesize new proteins.


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InternalMed_Harrison. Normal vascular endothelium contributes to preventing thrombosis by inhibiting platelet function (Chap. 78). When vascular endothelium is injured, these inhibitory effects are overcome, and platelets adhere to the exposed intimal surface primarily through VWF, a large multimeric protein present in both plasma and in the extracellular matrix of the subendothelial vessel wall. Platelet adhesion results in the generation of intracellular signals that lead to activation of the platelet glycoprotein (Gp) IIb/IIIa (αIIbβ3) receptor and resultant platelet aggregation.


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InternalMed_Harrison. Activated platelets undergo release of their granule contents, which include nucleotides, adhesive proteins, growth factors, and procoagulants that serve to promote platelet aggregation and blood clot formation and influence the environment of the forming clot. During platelet aggregation, additional platelets are recruited to the site of injury, leading to the formation of an occlusive platelet thrombus. The platelet plug is stabilized by the fibrin mesh that develops simultaneously as the product of the coagulation cascade. Endothelial cells line the surface of the entire circulatory tree, totaling 1–6 × 1013 cells, enough to cover a surface area equivalent to about six tennis courts. The endothelium is physiologically active, controlling vascular permeability, flow of biologically active molecules and nutrients, blood cell interactions with the vessel wall, the inflammatory response, and angiogenesis.


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InternalMed_Harrison. The endothelium normally presents an antithrombotic surface (Chap. 78) but rapidly becomes prothrombotic when stimulated, which promotes coagulation, inhibits fibrinolysis, and activates platelets. In many cases, endothelium-derived vasodilators are also platelet inhibitors (e.g., nitric oxide) and, conversely, endothelium-derived vasoconstrictors (e.g., endothelin) can also be platelet activators. The net effect of vasodilation and inhibition of platelet function is to promote blood fluidity, whereas the net effect of vasoconstriction and platelet activation is to promote thrombosis. Thus, blood fluidity and hemostasis are regulated by the balance of antithrombotic/prothrombotic and vasodilatory/vasoconstrictor properties of endothelial cells.


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InternalMed_Harrison. Thrombocytopenia results from one or more of three processes: (1) decreased bone marrow production; (2) sequestration, usually in an enlarged spleen; and/or (3) increased platelet destruction. Disorders of production may be either inherited or acquired. In evaluating a patient with thrombocytopenia, a key step is to review the peripheral blood smear and to first rule out “pseudothrombocytopenia,” particularly in a patient without an apparent cause for the thrombocytopenia. Pseudothrombocytopenia (Fig. 140-1B) is an in vitro artifact resulting from platelet agglutination via antibodies (usually IgG, but also IgM and IgA) when the calcium content is decreased by blood collection in ethylenediamine tetraacetic (EDTA) (the anticoagulant present in tubes [purple top] used to collect blood for complete blood counts [CBCs]). If a low platelet count is obtained in EDTA-anticoagulated blood, a blood smear should be evaluated and a platelet count determined in blood collected into sodium


InternalMed_Harrison

InternalMed_Harrison. for complete blood counts [CBCs]). If a low platelet count is obtained in EDTA-anticoagulated blood, a blood smear should be evaluated and a platelet count determined in blood collected into sodium citrate (blue top tube) or heparin (green top tube), or a smear of freshly obtained unanticoagulated blood, such as from a finger stick, can be examined.


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InternalMed_Harrison. FIGURE 140-1 Photomicrographs of peripheral blood smears. A. Normal peripheral blood. B. Platelet clumping in pseudothrombocytopenia. C. Abnormal large platelet in autosomal dominant macrothrombocytopenia. D. Schistocytes and decreased platelets in microangiopathic hemolytic anemia. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. The history and physical examination, results of the CBC, and review of the peripheral blood smear are all critical components in the initial evaluation of thrombocytopenic patients (Fig. 140-2). The overall health of the patient and whether he or she is receiving drug treatment will influence the differential diagnosis. A healthy young adult with thrombocytopenia will have a much more limited differential diagnosis than an ill hospitalized patient who is receiving multiple medications. Except in unusual inherited disorders, decreased platelet production usually results from bone marrow disorders that also affect red blood cell (RBC) and/or white blood cell (WBC) production. Because myelodysplasia can present with isolated thrombocytopenia, the bone marrow should be examined in patients presenting with isolated thrombocytopenia who are older than 60 years of age. While inherited thrombocytopenia is rare, any prior platelet counts should be retrieved and a family history regarding


InternalMed_Harrison

InternalMed_Harrison. presenting with isolated thrombocytopenia who are older than 60 years of age. While inherited thrombocytopenia is rare, any prior platelet counts should be retrieved and a family history regarding thrombocytopenia obtained. A careful history of drug ingestion should be obtained, including nonprescription and herbal remedies, because drugs are the most common cause of thrombocytopenia.