Desk Reference for hematology - part 2 pps

ANTHRACYCLINES 73 infiltration of the joints by lymphocytes and plasma cells, with local bone erosion at the attachments of intervertebral and other ligaments. Other hematological disorders include: Anemia of chronic disorders Elevated erythrocyte sedimentation rate Leukemia, particularly if radiotherapy has been administered for treatment to the lumbosacral region in the past; local bone marrow hypoplasia will remain, with extensive chromosomal changes to cells as a consequence of which the risk of leukemia is ten times greater than that of the normal population Routine treatment has been nonsteroidal anti-inflammatory drugs (NSAIDS) and phys- iotherapy. Anti-tumor necrosis factor -α blocking agents infliximab, adalimumab and etanercept are under trial. 58 ANKYRIN A protein constituent of red blood cell membranes (Band 2.1) that links spectrin to Band 3 protein. Rare deficiency results in heat-sensitive fragmentation hemolytic anemia. ANTENATAL SCREENING See Hemolytic disease of the newborn; Transfusion-transmitted infections. ANTHRACYCLINES See also Cytotoxic agents. (Cytotoxic antibiotics) A group of drugs used for cytotoxic therapy that are natural prod- ucts of the soil bacterium Streptomyces spp. and probably inhibit DNA replication by intercalation. They are cell-cycle-phase nonspecific agents that are given intravenously, usually in pulses. They are metabolized in the liver and excreted in bile, so that patients with poor liver function should receive reduced doses. The anthracyclines most often used in the treatment of acute myeloid leukemia (AML) are daunorubicin, doxorubicin (Adri- amycin), idarubicin, and bleomycin. They are also used as part of cytotoxic regimes in the treatment of myelomatosis and non-Hodgkin lymphoma, especially diffuse large B-cell lymphoma treated with R-CHOP and Hodgkin lymphoma with ABVD. Many anthracy- clines act as radiomimetics and so should be avoided when radiotherapy is also used. Cardiotoxicity is a major cumulative dose-limiting toxicity, occurring clinically above doses of approximately 450 mg/m 2 . However, at much lower doses, microscopic cardiac muscle changes are seen. Lower doses should be used where patients have received radiotherapy to the mediastinum, which potentiates cardiotoxicity. Other adverse drug reactions include gastrointestinal tract upsets, especially mucositis. Alopecia is common. Bleomycin causes skin pigmentation and subcutaneous sclerotic plaques, but little bone marrow hypoplasia. Progressive pulmonary fibrosis becomes a problem if the cumulative dose exceeds 300,000 units. Mitoxantrone, related to daunorubicin, kills cells by interca- lating with DNA and is myelosuppressive. It is given intravenously for 2 to 5 days, alone or in combination with cytarabine or vincristine. It produces remission rates in relapsed or resistant AML and in acute lymphoblastic leukemia (ALL) of up to 60%. In de novo childhood AML, remission rates of approximately 80% have been obtained when included in multidrug schedules. It has similar cardiotoxic potential to daunorubicin. 3393_book.fm Page 73 Thursday, October 25, 2007 5:17 PM 74 ANTIBODY ANTIBODY A soluble immunoglobulin secreted by plasma cells, present in serum and secretions, that specifically react with antigens and thus play a crucial effector role in the immuno- logical elimination of these antigens. Antibody is the component of the immune response that mediates humoral immunity. Major effector mechanisms include neutralization, op- sonization, activation of complement, and antibody-mediated cellular cytotoxicity. De- pending upon their origin or function, a variety of antibody types are described: Natural antibody: immunoglobulins secreted by B-cells, which express CD5; examples are anti-A and anti-B of the ABO (H) blood groups Isoantibody: having the same genotype Alloantibody: isoantibody raised to allotype determinants Autoantibody: produced when failure of self-tolerance does not occur by apoptosis Monoclonal antibody: single-type immunoglobulins that react with a single epitope of its target antigen Heterophil antibody: IgM that reacts with a similar organ, i.e., red blood cells of a different species Anti-idiotypic antibody concerned with the idiotypic area of an antigen ANTICOAGULANT THERAPY See Aspirin; Coumarins; Dipyridamole; Heparin; Warfarin. ANTI-D IMMUNOGLOBULIN See Hemolytic disease of the newborn. ANTIFIBRINOLYTIC AGENTS See Fibrinolysis. ANTIGEN The molecular structure to which a specific immune response develops. It should be noted that the terms “antigen” and “immunogen” are not synonymous. The term “immunogen” is used to indicate a substance capable of eliciting by itself an immune response. Not all antigens are immunogens: the classic examples are those small molecules described as haptens, which by themselves do not induce an immune response but when complexed with a larger molecule (usually protein, described as a carrier) can induce antibodies. Natural antigens are most commonly proteins, although antibody (but not cell-mediated responses) may develop against other macromolecules, notably carbohydrates and nucleic acids. The nature of antigens can only be discussed in the context of the nature of the components of the immune system that specifically recognize them. These are the T-cell antigen receptors (see Antigen presentation) and immunoglobulin (see B-lymphocytes). Immunoglobulin may be either present in the B-cell membrane, where it is functioning as the B-cell receptor for antigen (B-CR), or as soluble antibody. 3393_book.fm Page 74 Thursday, October 25, 2007 5:17 PM ANTIGEN PRESENTATION 75 Antigen Structure In essence, the T-cell receptor (TCR) and immunoglobulins interacting with macromolec- ular antigens do not recognize the entire structure but, instead, recognize smaller parts described as epitopes. (“Determinant” is an older term meaning essentially the same thing.) T-cell epitopes, by the nature of the process of antigen presentation, are short linear fragments of protein antigens (obviously, nonprotein antigens cannot form T-cell epitopes), and in the context of a given human leukocyte antigen (HLA) there may be few (one or two) or no epitopes in a given protein. On the other hand, the epitopes with which immunoglobulins react are surface struc- tures of the intact antigen. These may be linear peptides (say, a loop of sequence on the surface of the protein), but in practice, they are more often an array of amino acid residues on the protein surface, derived from different regions of the protein sequence. Because the antigen-combining site of the immunoglobulin reacts in a lock-and-key fashion with its epitope, the conformation of the epitope is crucial, and thus many antibodies will react only with the native protein. For this same reason, these epitopes are referred to as conformational epitopes. There are multiple, overlapping immunoglobulin-reactive epitopes on the surface of a protein, but some may be immunodominant, eliciting a greater response than others. A protein antigen therefore possesses two sets of epitopes, one for immunoglobulin and one for the TCR, which are functionally and physically quite distinct. The nature of immunoglobulin epitopes explains why antibody responses to nonprotein antigens may develop, provided the “antigen” is present on the surface of a protein (e.g., hapten, carbohydrate moiety of a glycoprotein). The nonprotein antigen separate from its protein carrier is not immunogenic because there are no helper T-cell epitopes — which must be peptide in nature — for the B-cell to present to its helper T-cell (see B-lymphocytes). ANTIGEN PRESENTATION The means by which a protein antigen activates T-lymphocyte responses by being “pro- cessed” within a cell and thereafter “presented” to a T-cell in the context of class I or II histocompatibility antigens of the major histocompatibility complex (MHC). The details of antigen processing and presentation differ, depending on whether presentation is by class I antigens to CD8-positive T-cells or by class II antigens to CD4-positive cells (see Human leukocyte antigens). Class I/CD8 Presentation Proteins synthesized within the cell (“endogenous”) are degraded, probably by protea- somes (large multimeric proteases), some of whose components are encoded by genes (LMP 1 and 2) in the MHC to peptides, which are nonselectively transported into the endoplasmic reticulum by a class of peptide transporters also encoded in the MHC (TAP 1 and 2). Here the peptides encounter newly synthesized class I antigens, which bind peptides of eight or nine amino acids in length and transport them via the Golgi apparatus to the cell surface. Binding is to a cleft between the a1 and a2 domains, where the polymorphic residues are concentrated. Although a particular histocompatibility antigen can bind a wide range of peptides, binding is not promiscuous and there are common features displayed by binding peptides. Usually one or two “anchor” residues are conserved at particular sites in a series of peptides binding to a particular class I antigen, or at least varying in a conservative manner. These anchor residues have been shown to interact with specific 3393_book.fm Page 75 Thursday, October 25, 2007 5:17 PM 76 ANTIGEN PRESENTATION amino acid residues in the peptide-binding cleft. In general, only one or two peptides from a given protein will interact with a given class I antigen, hence the restricted range of T-cell epitopes. Class II/CD4 Presentation Proteins taken up from outside the cell (“exogenous”) are degraded to peptides in an endosomal compartment. Class II proteins, complexed with the invariant protein (CD74), travel to some ill-defined endosomal compartment where the invariant protein is degraded and the exogenously derived peptide binds. The role of the invariant protein is to prevent binding of endogenous peptides to class II antigens while within the endoplasmic retic- ulum; however, there is unequivocal evidence that, in some circumstances, endogenous proteins are processed via the class II pathway. There is some evidence that “professional” antigen-presenting cells have a specialized compartment for interaction between class II antigens and their peptides. The class II/peptide complex is then transported to the cell surface. The nature of peptide binding is broadly similar to that for class I antigens, with the peptide-binding cleft of class II antigens having a similar structure to the class I cleft. Slightly larger peptides bind to class II antigens. Antigen-Presenting Cells (APCs) Probably all cells expressing class I antigens can present endogenous antigens to CD8 T-cells, and all cells expressing class II antigens can present to CD4 T-cells. However, the efficiency with which they do so varies widely. In the case of presentation to CD4 cells, some APCs, particularly dendritic reticulum cells (various sorts), B-cells, and histiocytes (macrophages), are so much more efficient than others that they are described as profes- sional APCs. The reasons for this include possession of specific antigen receptors (B-cells) or of extremely efficient phagocytic (e.g., macrophages) and specialized cellular compart- ments for processing antigen. In the case of dendritic reticulum cells, which in some assays are the most potent APCs, the reason for this efficacy is not clear, as the cells are not phagocytic and do not have antigen receptors as such, but do have receptors for antibodies and com- plement and thus can bind opsonized antigens. However, this does not explain how dendritic reticulum cells function in primary responses, which is probably their main role. Production of cytokines by APCs, particularly macrophages, is also important in their function. Role of Cytokines in Controlling Presentation Antigen presentation is, to some extent, an inducible function of cells, in that cytokines (interferon tumor necrosis factor, IFN-γ; tumor necrosis factor, TNF-α; and interleukin, IL- 4, in particular) can upregulate expression of many of the components of the antigen-pro- cessing and -presentation machinery, including proteasome subunits, transporters in antigen presentation (TAP), and histocompatibility antigens. There is experimental evidence that this increases the efficiency of presentation to T-cells. Contrariwise, IFN-α and -β and transform- ing growth factor (TGF)-β downregulate class II histocompatibility antigens in at least some cell types. The importance of these cytokine effects is probably to extend the range of cells able to present antigen to T-cells and the efficacy of antigen presentation during infection. Histocompatibility Antigen Restriction A consequence of the dual recognition of peptide and histocompatibility antigen by the T-cell is that the histocompatibility antigen has to be correct. During ontogeny, T-cells 3393_book.fm Page 76 Thursday, October 25, 2007 5:17 PM ANTIMETABOLITES 77 “learn” to recognize self-histocompatibility antigens and so respond only to APCs that bear the same histocompatibility antigens, whether from the same or a different but matched individual. Restriction was first described in the context of the killing of virus- infected cells by cytotoxic T-lymphocytes. It was noted that killing only occurred if the T-cell and the target cell possessed identical class I histocompatibility antigens. A similar phenomenon occurs in the activation of helper T-cells. The phenomenon is important in that it helps to distinguish cellular immunological mechanisms mediated by T-cells; if the phenomenon is not restricted, then the likelihood is that T-cells are not involved. ANTIGLOBULIN (COOMBS) TEST See Direct antiglobulin (Coombs) test; Indirect antiglobulin (Coombs) test. ANTIHEMOPHILIC GLOBULIN See Factor VIII. ANTI-IDIOTYPIC ANTIBODY Naturally occurring and experimentally induced autoantibodies that react with an anti- gen-binding site or idiotype of an antibody, which is thus functioning as an epitope. A theory, associated with Neils Jerne, held that networks of antibody idiotypes and anti- idiotypes regulated the immune response; this is now disregarded. ANTIMETABOLITES See also Cytotoxic agents. A group of drugs used for cytotoxic therapy that are analogs of normal compounds needed for cell division and function. They damage cells by interacting or competing with enzyme systems. Methotrexate Acts by competing for the folic acid-binding sites of dihydrofolate reductase, thus inhib- iting the synthesis of tetrahydrofolate and resulting in decreased nucleotide synthesis with consequential reduced deoxyribonucleic acid (DNA) synthesis, leading to cell death. Methotrexate is used orally, parenterally, and intrathecally, chiefly in the treatment of primary and secondary non-Hodgkin lymphoma affecting the central nervous system (CNS) and in the prophylaxis of acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma associated with risk factors. Adverse reactions include skin rashes, gastrointestinal tract complications (especially mucositis), liver cell damage, immunosup- pression, and rarely pneumonitis. Lymphoproliferative disorders — diffuse large B-cell lymphoma, Hodgkin lymphoma, polymorphic posttransplant lymphoproliferative disor- der — have been reported, often related to Epstein-Barr virus (EBV) infection. They may regress with cessation of methotrexate therapy. The cytotoxicity of methotrexate is revers- ible using folinic acid, which converts intracellularly to reduced folate. Folinic acid should be used as “rescue” after high-dose methotrexate treatments, such as those used to treat primary non-Hodgkin lymphoma affecting the CNS, ALL, and acute myeloid leukemia (AML). It should be avoided if there is renal or hepatic impairment and also if pleural effusion or ascites are present. Response is particularly susceptible to genetic polymorphisms. 3393_book.fm Page 77 Thursday, October 25, 2007 5:17 PM 78 ANTINEUTROPHILIC CYTOPLASMIC ANTIBODIES Cytosine Arabinoside (Cytarabine) A pyrimidine analog with an arabinosyl sugar moiety, active during S phase of the cell cycle, killing cells by incorporation into DNA. Because of its short half-life of about 2 h, it is either used by continuous intravenous or subcutaneous infusion, or by frequent intravenous bolus injection. The drug inefficiently crosses the blood-brain barrier, so that high-dose systemic treatments lead to CNS levels capable of killing leukemia cells. More conventionally, it is used intrathecally as an alternative or complementary drug to meth- otrexate in the prophylaxis of the CNS in ALL. Systemically, standard dosage for AML treatments is 100 to 200 mg/m 2 daily for 5 to 10 days, repeated at intervals usually with an anthracycline. High-dose cytosine, 1 to 3 g/m 2 twice daily for 2 to 6 days, is useful in the treatment of relapsed and resistant AML. It may also be incorporated into regimes of treatment for relapsed non-Hodgkin lymphoma (diffuse large B-cell lymphoma). A com- monly used related agent is Fludarabine, used in the treatment of chronic lymphatic leukemia after failure of an initial alkylating agent. Another, Clofarabine, is under inves- tigation for relapsed/refractory ALL. Fludarabine A cytarabine derivative with similar activity to vincristine and vinblastine (see Vinca alkaloids). It is dephosphorylated in vivo and rephosphorylated intracellularly to form 2- arafluoro adenosine triphosphate (ATP), which inhibits DNA by blocking DNA poly- merase and ribonucleotide reductase. It is used as a second-line agent to treat chronic lymphatic leukemia (CLL)/low-grade non-Hodgkin lymphoma at dosages of 25 to 30 μg/m 2 IV daily in courses lasting 5 days. Although it is associated with severe bone marrow hypoplasia and immunode- ficiency with subsequent viral and other infections, but rarely with CNS toxicity or metabolic acidosis, it is increasingly used in combination therapy to treat CLL resistant to chlorambucil. 6-Mercaptopurine A purine analog that is active in its ribonucleotide form against leukemic cells. It is used mainly in the maintenance of remissions in ALL, often with methotrexate. It is metabolized by xanthine oxidase to thiouric acid. As allopurinol inhibits xanthine oxidase, this drug will block this metabolic pathway, increasing the level of 6-mercaptopurine, which should be reduced to about one-third dosage in patients taking allopurinol. Azathioprine is metabolized to mercaptopurine, so if it is given simultaneously, the dose of both drugs should be reduced. 6-Tioguanine (Thioguanine) A purine analog with a similar action, in its ribonucleotide form, to 6-mercaptopurine. It is mainly used for AML induction regimens with cytosine arabinoside, with which it is synergistic in vitro, although clinically results are similar with and without its addition to these regimens. ANTINEUTROPHILIC CYTOPLASMIC ANTIBODIES (ANCA) Autoantibodies that act against bactericidal permeability increasing (BPI) pro- tein. They occur in two forms: 3393_book.fm Page 78 Thursday, October 25, 2007 5:17 PM ANTIPHOSPHOLIPID-ANTIBODY SYNDROME 79 Cytoplasmic (c-ANCA), directed against proteinase 3 — Wegener’s granulomatosis Perinuclear (p-ANCA), directed against myeloperoxidase — Wegener’s granuloma- tosis and, in microscopic polyangiitis, a form of polyarteritis nodosa They have also been reported in patients with systemic vasculitis and multisystem Behçet’s disease. ANTINUCLEAR FACTOR (ANF, ANA) Antibodies that react with nucleic acids, nuclear proteins, and cell-surface antigens (Sm antigens) to form circulating immune complexes. They arise in the plasma of patients with systemic lupus erythematosus (SLE), Sjögren’s syndrome, rheumatoid arthritis, chronic hepatitis, thyroiditis, myasthenia gravis, gastric disorders leading to intrinsic-factor deficiency, ulcerative colitis, and pure red cell aplasia. ANF can be demonstrated by: Immunofluorescence using a section of tissue (e.g., rat liver) to which has been added fluorescein-labeled antihuman gammaglobulin Radioimmunoassay in which isotope-labeled antigen is added to the test serum and the mixture treated with 50% saturated ammonium sulfate to precipitate the immunoglobulin; the precipitate will contain radioatoms only if an antibody- antigen reaction has occurred, the amount of which is measured as the concen- tration of ANF present Latex particles coated with nuclear material, which are aggregated by ANF L-E cell test when caused by SLE 59 ANTIPHOSPHOLIPID-ANTIBODY SYNDROME (APS; Hughes syndrome) A disorder in which venous thromboembolic disease or arterial thrombosis or both may occur, the serologic markers being antiphospholipid antibodies (aPL). 60,61 This is a heterogeneous group of antibodies that includes anticardiolipin anti- bodies (aCL), the lupus anticoagulant (LA), and antithrombotic antibodies. The aPL antibodies are directed against different phospholipid/protein complexes; LA antibodies recognize the prothrombin-phospholipid complex and in this way inhibit the phospho- lipid-dependent coagulation reactions. In contrast, aCL antibodies are directed against b2- glycoprotein I (b2GPI) bound to an anionic lipid surface. This increases the risk of pre- disposition to atherosclerosis. The aCL antibodies arising secondary to infections, e.g., tuberculosis, Klebsiella spp., do not have the b2GPI requirement. The measurement of anti- b2GPI antibodies identifies patients with aCL antibodies that are not associated with infection and appear to be more closely associated with a history of thromboembolic complications than aCL antibodies. It is possible that thrombosis is induced by the binding of aCL antibodies to Annexin A5 (placental anticoagulant protein). 60 Although the antiphospholipid-antibody syndrome often occurs in patients with sys- temic lupus erythematosus (SLE), the majority of patients with the syndrome do not meet the criteria for that disease. The combination of recurrent thromboses and antiphospho- lipid antibodies without features of SLE is called the primary antiphospholipid syndrome. Other features of this syndrome include thrombocytopenia, migraine, central nervous system (CNS) demyelination, livedo reticularis, stenosis of the renal artery, recurrent spontaneous abortions, and infertility. The antiphospholipid antibodies in this syndrome 3393_book.fm Page 79 Thursday, October 25, 2007 5:17 PM 80 A2-ANTIPLASMIN can exist for many years. Thrombosis, the main complication of the syndrome, 62 can affect vessels of all sizes, including cerebral and pulmonary arteries and those of the bone marrow. 63 The risk of thrombosis in symptomatic patients with the antiphospholipid- antibody syndrome is high. Anticoagulant therapy should aim for an international nor- malized ratio (INR) of around 3.0. 64 The associated antithrombotic antibodies are of no clinical significance but can disturb monitoring of anticoagulant therapy. Anticoagulation has been claimed to reduce hypertension and to prevent irreversible renal damage. In pregnancy, therapy with low-molecular-weight heparin, with or without aspirin, has reduced fetal loss, whereas low-dose aspirin alone seems to be relatively ineffective. 65 No improvement has been reported following high-dose immunosuppression. An acute form (catastrophic APS) 66 can be precipitated by surgery, drugs, discontinua- tion of anticoagulant therapy, or infections, probably due to massive vascular endothelial cell activity. Acute renal failure or acute respiratory distress syndrome is the principal complicating disorder. αα αα 2-ANTIPLASMIN See Fibrinolysis — inactivators; Serine protease inhibitors. ANTITHROMBIN III (AT, ATIII) A single-chain glycoprotein of molecular weight 58 kDa that inhibits all of the coagulation serine proteases but in particular activated factor II (thrombin) and activated factor X. The rate of inhibition is accelerated 5,000- to 10,000-fold in the presence of heparin and other sulfated glycosaminoglycans. Heparin is not normally found in the circulation, and, physiologically, antithrombin probably binds to heparin sulfate on the vascular endothelial cells. In such a position, antithrombin is ideally positioned to inactivate free coagulation serine proteases. A deficiency or functional abnormality of antithrombin can result in an increased risk of venous thromboembolic disease. Such deficiencies are classified as either: Type I: a parallel reduction in both functional and immunological antithrombin levels Type II: the presence in the plasma of a dysfunctional protein, which may be present in normal or reduced amounts These can be further subdivided, depending upon whether the mutation affects the heparin-binding domain (IIHBS), the reactive site (IIRS), or has multiple or pleiotropic effects (IIPL). The risks of thrombosis are highest in individuals with type I disease, IIRS, or IIPL and lowest in cases of IIHBS. Type I deficiency is estimated to affect 1:4200 of the general population and type II approximately 1:630. In patients with thromboembolic disease, the incidence of antithrombin deficiency is estimated at between 4 and 6%. Acquired antithrombin deficiency is seen in a variety of clinical disorders, e.g., dissem- inated intravascular coagulation (DIC), severe burns, liver disorders, renal disorders (nephritic syndrome); in association with various drugs ( L-asparaginase); and in patients undergoing cardiopulmonary bypass. The reference ranges for adults are 0.86 to 13.2 U/ml (function) and 0.79 to 1.11 U/ml (antigen). Those for premature infants and for full-term infants over the first 6 months of life are given in Reference Range Tables XVII and XVIII. 3393_book.fm Page 80 Thursday, October 25, 2007 5:17 PM APLASTIC ANEMIAS 81 Antithrombin III concentrates (see Coagulation-factor concentrates) are of benefit in patients with congenital deficiencies of antithrombin, e.g., to cover labor where life-threat- ening thrombosis has occurred or where it may be inappropriate to administer heparin. The evidence that antithrombin supplementation is of value in acquired deficiencies is conflicting. ANTITHROMBOTIC THERAPY Therapeutic agents administered to remove or prevent thrombosis. Their mode of activity covers the whole range of hemostasis: Antiplatelet-function drugs: aspirin, dipyridamole, ticlopidine, abciximab, clopi- dogrel Anticoagulants: • Vitamin K antagonists: coumarins (warfarin) • Direct thrombin inhibitors: argatroban, ximelagatran • Serine protease inhibitors: heparin, heparin cofactor II, hirudin Fibrinolysis stimulants: • Thrombolytic agents: streptokinase, urokinase • Plasminogen activators: alteplase • Fibrinopeptide A cleavage: ancrod The choice of agent depends particularly on the location of the thrombus, its activity, and many other health factors including patient choice. Common treatment usage can be very broadly summarized as: Arterial thrombosis • Recent: fibrinolytic agents followed by aspirin or warfarin • Preventive: aspirin or warfarin Venous thromboembolism • Recent: heparin followed by warfarin • Preventive: aspirin or warfarin APHERESIS See Hemapheresis. APLASTIC ANEMIAS (AAs) Pancytopenia arising as a result of failure of hematopoietic stem cell proliferation and differentiation (see Hematopoiesis). The peripheral-blood examination shows nor- mocytic or macrocytic anemia, neutropenia with variable lymphopenia, and thrombocy- topenia. The bone marrow is hypocellular with normal hematopoietic marrow replaced to a greater or lesser extent by fat cells. Remaining hematopoietic cells are morphologically normal apart from mild macrocytosis and dyserythropoiesis, with increased granulation (“toxic granulation”) in the neutrophils. The features may arise in a number of ways, 3393_book.fm Page 81 Thursday, October 25, 2007 5:17 PM 82 APLASTIC CRISIS which need to be distinguished (see Table 18). In particular, acquired aplastic anemia has a different pathophysiology from bone marrow hypoplasia and pure red cell aplasia. The term is also loosely used to describe the aplastic crisis of parvovirus infection where only the erythron is affected. A summary of causes is given in Table 18. APLASTIC CRISIS An abrupt fall of hemoglobin and red blood cell count due to transient erythroid bone marrow aplasia, which characteristically occurs in patients who already have hemolytic anemia with shortened red cell survival. Originally described in 1942, it was shown in 1981 by Pattison and his colleagues to be due to acute parvovirus B19 infection. Chronic pure red cell aplasia caused by persistent parvovirus infection has been associated with immunodeficiency, especially hypogammaglobulinemia, and acquired immunodeficien- cy syndrome (AIDS). Pathogenesis Parvovirus B19 is usually transmitted by droplet spread, and reticulocytes disappear about 7 to 10 days following inoculation. The B19 virus directly infects, and is cytotoxic to, proliferating erythroid progenitors within the bone marrow, leading to transient erythroid aplasia, which typically lasts 5 to 7 days. In normal, healthy individuals with a red blood cell life span of 120 days, the effect is not clinically significant, but in patients with shortened red blood cell survival — most commonly in those with congenital hemolytic anemia or sickle cell anemia — this interruption results in anemia, which can be very severe and life threatening if the underlying red cell survival is markedly reduced. Aplastic crisis has been described in patients with sickle cell disease, hereditary spherocytosis, congenital dyserythropoietic anemia, hereditary erythroblastic multinuclearity with pos- itive acidified serum test (HEMPAS), paroxysmal nocturnal hemoglobinuria, thalas- semia, and pyruvate kinase deficiency. The transient nature of the illness is due to the rapid development of B19-specific IgM and IgG antibodies. Neutralizing IgM antibodies arise about 10 days postinfection, and erythropoiesis recovers. IgG antibodies follow and produce lifelong immunity to further TABLE 18 Causes of Aplastic Anemia Etiology Classified Disorders Characteristics Idiosyncratic, acquired idiopathic unpredictable drug induced prolonged course viral (hepatitis) probably autoimmune Inevitable cytotoxic agents dose dependent irradiation predictable recovery Genetic Fanconi anemia Dyskeratosis congenita Schwachman-Diamond syndrome Blackfan-Diamond syndrome, erythroid aplasia only amegakaryocytic thrombocytopenia, thrombocytes only Immune, antibody mediated primary acquired AA multiple autoantibodies secondary to SLE Malignant acute leukemia usually ALL precedes emergence of leukemia myelodysplasia hypoplastic myelodysplasia variant 3393_book.fm Page 82 Thursday, October 25, 2007 5:17 PM [...]... day −6; Cytosine, 20 0 mg/m2, days −5 to 2; Cyclophosphamide, 50 mg/kg, days −5 to 2; Thioguanine, 20 0 mg/m2, days −5 to 2 LACE: CCNU®, 20 0 mg/m2, day −7, Etoposide, 1g/m2, day −7; Cytosine, 2 g/m2, days −6 and −5; Cyclophosphamide, 1.8 g/m2, days −4 to 2 Transplant Procedure Pretransplant Harvesting Bone Marrow Transplantation (BMT) The technique is identical to that described for allogeneic SCT... graft-vs.-host disease TABLE 24 Conditioning Protocols for Autologous Stem Cell Transplantation Used in Acute Myeloid Leukemia Total Body Irradiation (TBI)-containing Cyclophosphamide, 60 mg/kg for 2 days plus: TBI ( 12. 0–14.4 Gy over 3 days) TBI (9.50 Gy as a single dose) Non-TBI-containing Bu Cy: Busulfan, 4 mg/kg, days −9 to −6; Cyclophosphamide, 50 mg/kg, days −5 to 2 BACT: BCNU, 20 0 mg/m2, day... on the inability of G6PD-deficient red blood cells to detoxify H2O2 With cyanide as a catalase inhibitor, H2O2 is generated by interaction between ascorbic acid and oxyhemoglobin In cells deficient in G6PD, H2O2 oxidizes hemoglobin to a brown pigment readily detected by the naked eye Normal cells detoxify H2O2 via G6PD-linked reduced glutathione peroxidase The test can be used for the detection of heterozygotes,... Autoagglutination is readily apparent on the peripheral-blood film, but must be distinguished from rouleaux formation of red blood cells AUTOANTIBODIES The antibodies produced when failure of self-tolerance to self-antigens occurs Most selfreactive clones are efficiently eliminated during B- and T-cell ontogeny Some self-antigens 3393_book.fm Page 96 Thursday, October 25 , 20 07 5:17 PM 96 AUTOERYTHROCYTE SENSITIZATION... AUTOERYTHROCYTE SENSITIZATION or epitopes may never be presented, so that while potentially self-reactive lymphocytes occur, they never encounter self-epitopes For other antigens, there may be tolerance of self-reactive T-cells but not B-cells Because specific T-cells are required to help B-cells make high-affinity antibody, autoantibodies are never produced or are of low affinity and are biologically... reduces the risk factors for arterial thrombosis — low-fat diet, moderate exercise, avoidance of smoking — must be recommended For those patients who have raised levels of cholesterol, increasing the levels of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins),84,85 e.g., simvastatin, appreciably reduces the cardiovascular-related morbidity and mortality Long-term administration of... PM 1 02 AUTOLOGOUS STEM CELL TRANSPLANTATION TABLE 23 Advantages and Disadvantages of Autologous and Allogeneic Stem Cell Transplantation Advantages Disadvantages Autologous Applicable to older patients No limitation on donor availability No graft rejection No graft-vs.-host disease No graft-vs.-leukemia effect Possible residual leukemia in graft Allogeneic Infused marrow leukemia free Graft-vs.-leukemia... disease Acromegaly Thyroid disease Drugs Drug-induced hepatic veno-occlusive disease (secondary to stem cell transplantation) Atypical antipsychotics Cox -2 inhibitors Ergotamine Antifibrinolytic agents Corticosteroids 3393_book.fm Page 89 Thursday, October 25 , 20 07 5:17 PM ARTERIAL THROMBOSIS 89 Clinical Features Clinical features suggestive of an inheritable factor for thrombosis include: First thrombosis... of cigarette smoking, moderate regular exercise, dietary prudence to avoid high-calorie or excess saturated fats, and plentiful fruit and vegetables.78 Long-term low-dose aspirin is of benefit for those with known vascular disease Widespread prophylaxis to cover short-term stasis, 3393_book.fm Page 90 Thursday, October 25 , 20 07 5:17 PM 90 ARTERIAL THROMBOSIS such as immobilization during aircraft journeys,... in blood incubated at 37°C for 48 h by measurement in a colorimeter or in a spectrophotometer at 625 nm.89 The reference range in health without added glucose is 0 .2 to 2. 0% and with added glucose 0 to 0.9% While nonspecific, the test does produce some information about the metabolic competence of red blood cells and helps to distinguish membrane defects from enzyme defects, for example in hereditary . standard dosage for AML treatments is 100 to 20 0 mg/m 2 daily for 5 to 10 days, repeated at intervals usually with an anthracycline. High-dose cytosine, 1 to 3 g/m 2 twice daily for 2 to 6 days,. test for glucose-6-phosphate dehydrogenase (G6PD) deficiency. 88 It is based on the inability of G6PD-deficient red blood cells to detoxify H 2 O 2 . With cyanide as a catalase inhibitor, H 2 O 2 . necrosis factor, IFN-γ; tumor necrosis factor, TNF-α; and interleukin, IL- 4, in particular) can upregulate expression of many of the components of the antigen-pro- cessing and -presentation machinery,