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InternalMed_Harrison. abnormalities of redox metabolism glucose 6-phosphate dehydrogenase (g6pd) deficiency G6PD is a housekeeping enzyme critical in the redox metabolism of all aerobic cells (Fig. 129-1). In red cells, its role is even more critical, because it is the only source of NADPH, which directly and via glutathione (GSH) defends these cells against oxidative stress (Fig. 129-5). G6PD deficiency is a prime example of an HA due to interaction between FIGURE 129-5 Diagram of redox metabolism in the red cell. 6PG, 6-phosphogluconate; G6P, glucose 6-phosphate; G6PD, glucose 6-phosphate dehydrogenase; GSH, reduced glutathione; GSSG, oxidized glutathione; Hb, hemoglobin; MetHb, methemoglobin; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate.


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InternalMed_Harrison. an intracorpuscular cause and an extracorpuscular cause, because in the majority of cases hemolysis is triggered by an exogenous agent. Although a decrease in G6PD activity is present in most tissues of G6PD-deficient subjects, in other cells, the decrease is much less marked than in red cells, and it does not seem to impact on clinical expression. The G6PD gene is X-linked, and this has important implications.


InternalMed_Harrison

InternalMed_Harrison. First, because males have only one G6PD gene (i.e., they are hemizy gous for this gene), they must be either normal or G6PD deficient. By contrast, females, who have two G6PD genes, can be either normal or deficient (homozygous) or intermediate (heterozygous). As a result of the phenomenon of X chromosome inactivation, heterozygous females are genetic mosaics, with a highly variable ratio of G6PDnormal to G6PD-deficient cells and an equally variable degree of clinical expression; some heterozygotes can be just as affected as hemizygous males. The enzymatically active form of G6PD is either a dimer or a tetramer of a single protein subunit of 514 amino acids. G6PDdeficient subjects have been found invariably to have mutations in the coding region of the G6PD gene (Fig. 129-5). Almost all of the approximately 180 different mutations known are single missense point mutations, entailing single amino acid replacements in the G6PD protein. In most cases, these mutations cause G6PD


InternalMed_Harrison

InternalMed_Harrison. all of the approximately 180 different mutations known are single missense point mutations, entailing single amino acid replacements in the G6PD protein. In most cases, these mutations cause G6PD deficiency by decreasing the in vivo stability of the protein; thus, the physiologic decrease in G6PD activity that takes place with red cell aging is greatly accelerated. In some cases, an amino acid replacement can also affect the catalytic function of the enzyme.


InternalMed_Harrison

InternalMed_Harrison. Among these mutations, those underlying chronic nonspherocytic hemolytic anemia (CNSHA; see below) are a discrete subset. This much more severe clinical phenotype can be ascribed in some cases to adverse qualitative changes (for instance, a decreased affinity for the substrate, glucose 6-phosphate) or simply to the fact that the enzyme deficit is more extreme, because of a more severe instability of the enzyme. For instance, a cluster of mutations map at or near the dimer interface, and clearly they compromise severely the formation of the dimer.


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InternalMed_Harrison. epidemiology G6PD deficiency is widely distributed in tropical and subtropical parts of the world (Africa, Southern Europe, the Middle East, Southeast Asia, and Oceania) (Fig. 129-6) and wherever people from those areas have migrated. A conservative estimate is that at least 400 million people have a G6PD deficiency gene. In several of these areas, the frequency of a G6PD deficiency gene may be as high as 20% or more. It would be quite extraordinary for a trait that causes significant pathology to spread widely and reach high frequencies in many populations without conferring some biologic advantage. Indeed, G6PD is one of the best-characterized examples of genetic polymorphisms in the human species. Clinical field studies and in vitro experiments strongly support the view that G6PD deficiency 655 has been selected by Plasmodium falciparum malaria, by virtue of the fact that it confers a relative resistance against this highly lethal infection. Different G6PD variants underlie G6PD


InternalMed_Harrison

InternalMed_Harrison. 655 has been selected by Plasmodium falciparum malaria, by virtue of the fact that it confers a relative resistance against this highly lethal infection. Different G6PD variants underlie G6PD deficiency in different parts of the world. Some of the more widespread variants are G6PD Mediterranean on the shores of that sea, in the Middle East, and in India; G6PD A– in Africa and in Southern Europe; G6PD Vianchan and G6PD Mahidol in Southeast Asia; G6PD Canton in China; and G6PD Union worldwide. The heterogeneity of polymorphic G6PD variants is proof of their independent origin, and it supports the notion that they have been selected by a common environmental agent, in keeping with the concept of convergent evolution (Fig. 129-6).


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InternalMed_Harrison. clinical manifestations The vast majority of people with G6PD deficiency remain clinically asymptomatic throughout their lifetime; however, all of them have an increased risk of developing neonatal jaundice (NNJ) and a risk of developing acute HA (AHA) when challenged by a number of oxidative agents. NNJ related to G6PD deficiency is very rarely present at birth; the peak incidence of clinical onset is between day 2 and day 3, and in most cases, the anemia is not severe. However, NNJ can be very severe in some G6PD-deficient babies, especially in association with prematurity, infection, and/or environmental factors (such as naphthalene-camphor balls, which are used in babies’ bedding and clothing), and the risk of severe NNJ is also increased by the coexistence of a monoallelic or biallelic mutation in the uridyl transferase gene (UGT1A1; the same mutations are associated with Gilbert’s syndrome). If inadequately managed, NNJ associated with G6PD deficiency can produce kernicterus and


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InternalMed_Harrison. mutation in the uridyl transferase gene (UGT1A1; the same mutations are associated with Gilbert’s syndrome). If inadequately managed, NNJ associated with G6PD deficiency can produce kernicterus and permanent neurologic damage.


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InternalMed_Harrison. AHA can develop as a result of three types of triggers: (1) fava beans, (2) infections, and (3) drugs (Table 129-5). Typically, a hemolytic attack starts with malaise, weakness, and abdominal or lumbar pain. After an interval of several hours to 2–3 days, the patient develops jaundice and often dark urine. The onset can be extremely abrupt, especially with favism in children. The anemia is moderate to extremely severe, usually normocytic and normochromic, and due partly to intravascular hemolysis; hence, it is associated with hemoglobinemia, hemoglobinuria, high LDH, and low or absent plasma haptoglobin. The blood film shows anisocytosis, polychromasia, and spherocytes typical of hemolytic anemias. The most typical feature of G6PD deficiency is the presence of bizarre poikilocytes, with red cells that appear to have unevenly distributed hemoglobin (“hemighosts”) and red cells that appear to have had parts of them bitten away (“bite cells” or “blister cells”) (Fig. 129-7). A classical


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InternalMed_Harrison. cells that appear to have unevenly distributed hemoglobin (“hemighosts”) and red cells that appear to have had parts of them bitten away (“bite cells” or “blister cells”) (Fig. 129-7). A classical test, now rarely carried out, is supravital staining with methyl violet, which, if done promptly, reveals the presence of Heinz bodies (consisting of precipitates of denatured hemoglobin and hemichromes), which are regarded as a signature of oxidative damage to red cells (they are also seen with unstable hemoglobins). LDH is high, and so is the unconjugated


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InternalMed_Harrison. CHAPTEr129 Hemolytic Anemias and Anemia Due to Acute Blood Loss FIGURE 129-6 Epidemiology of glucose 6-phosphate dehydrogenase (G6PD) deficiency throughout the world. The different shadings indicate increasingly high levels of prevalence, up to about 20%; the different colored symbols indicate individual genetic variants of G6PD, each one having a different mutation. (From L Luzzatto et al, in C Scriver et al [eds]: The Metabolic & Molecular Bases of Inherited Disease, 8th ed. New York, McGraw-Hill, 2001.) bilirubin, indicating that there is also extravascular hemolysis. The most serious threat from AHA in adults is the development of acute renal failure (this is exceedingly rare in children). Once the threat of acute anemia is over and in the absence of comorbidity, full recovery from AHA associated with G6PD deficiency is the rule.


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InternalMed_Harrison. Although it was primaquine (PQ) that led to the discovery of G6PD deficiency, this drug has not been very prominent subsequently, because it is not necessary for the treatment of life-threatening P. falciparum malaria. Today there is a revival of interest in PQ because it is the only effective agent for eliminating the gametocytes of P. falciparum (thus preventing further transmission) and eliminating the hypnozoites of Plasmodium vivax (thus preventing endogenous relapse). In countries aiming to eliminate malaria, there may be a call for mass administration of PQ; this ought to be associated with G6PD testing. At the other end of the historic spectrum, the latest addition to the list of potentially hemolytic drugs (Table 129-5) is rasburicase; again G6PD testing ought to be made mandatory before giving this drug because fatal cases have been reported in newborns with kidney injury and in adults with tumor lysis syndrome.


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InternalMed_Harrison. FIGURE 129-7 Peripheral blood smear from a glucose 6-phosphate dehydrogenase (G6PD)-deficient boy experiencing hemolysis. Note the red cells that are misshapen and called “bite” cells. (From MA Lichtman et al: Lichtman's Atlas of Hematology: http://www .accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc. All rights reserved.)


InternalMed_Harrison

InternalMed_Harrison. A very small minority of subjects with G6PD deficiency have chronic nonspherocytic hemolytic anemia (CNSHA) of variable severity. The patient is nearly always a male, usually with a history of NNJ, who may present with anemia, unexplained jaundice, or gallstones later in life. The spleen may be enlarged. The severity of anemia ranges in different patients from borderline to transfusion dependent. The anemia is usually normomacrocytic, with reticulocytosis. Bilirubin and LDH are increased. Although hemolysis is, by definition, chronic in these patients, they are also vulnerable to acute oxidative damage, and therefore the same agents that can cause AHA in people with the ordinary type of G6PD deficiency will cause severe exacerbations in people with CNSHA associated with G6PD deficiency. In some cases of CNSHA, the deficiency of G6PD is so severe in granulocytes that it becomes rate-limiting for their oxidative burst, with consequent increased susceptibility to some bacterial


InternalMed_Harrison

InternalMed_Harrison. In some cases of CNSHA, the deficiency of G6PD is so severe in granulocytes that it becomes rate-limiting for their oxidative burst, with consequent increased susceptibility to some bacterial infections.


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InternalMed_Harrison. laboratory diagnosis The suspicion of G6PD deficiency can be confirmed by semiquantitative methods often referred to as screening tests, which are suitable for population studies and can correctly classify male subjects, in the steady state, as G6PD normal or G6PD deficient. However, in clinical practice, a diagnostic test is usually needed when the patient has had a hemolytic attack; this implies that the oldest, most G6PD-deficient red cells have been selectively destroyed, and young red cells, having higher G6PD activity, are being released into the circulation. Under these conditions, only a quantitative test can give a definitive result. In males, this test will identify normal hemizygotes and G6PD-deficient hemizygotes; among females, some heterozygotes will be missed, but those who are at most risk of hemolysis will be identified. Of course, G6PD deficiency also can be diagnosed by DNA testing.


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InternalMed_Harrison. The AHA of G6PD deficiency is largely preventable by avoiding exposure to triggering factors of previously screened subjects. Of course, the practicability and cost-effectiveness of screening depend on the prevalence of G6PD deficiency in each individual community. Favism is entirely preventable in G6PD-deficient subjects by not eating fava beans. Drug-induced hemolysis can be prevented by testing for G6PD deficiency before prescribing; in most cases, one can use alternative drugs. When AHA develops and once its cause is recognized, in most cases, no specific treatment is needed. However, if the anemia is severe, it may be a medical emergency, especially in children, requiring immediate action, including blood transfusion. This has been the case with an antimalarial drug combination containing dapsone (called Lapdap, introduced in 2003) that has caused severe acute hemolytic episodes in children with malaria in several African countries; after a few years, the drug was taken off the


InternalMed_Harrison

InternalMed_Harrison. dapsone (called Lapdap, introduced in 2003) that has caused severe acute hemolytic episodes in children with malaria in several African countries; after a few years, the drug was taken off the market. If there is acute renal failure, hemodialysis may be necessary, but if there is no previous kidney disease, recovery is the rule. The management of NNJ associated with G6PD deficiency is no different from that of NNJ due to other causes.


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InternalMed_Harrison. In cases with CNSHA, if the anemia is not severe, regular folic acid supplements and regular hematologic surveillance will suffice. It will be important to avoid exposure to potentially hemolytic drugs, and blood transfusion may be indicated when exacerbations occur, mostly in concomitance with intercurrent infection. In rare patients, regular blood transfusions may be required, in which case appropriate iron chelation should be instituted. Unlike in HS, there is no evidence of selective red cell destruction in the spleen; however, in practice, splenectomy has proven beneficial in severe cases.


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InternalMed_Harrison. other abnormalities of the redox system As mentioned above, GSH is a key player in the defense against oxidative stress. Inherited defects of GSH metabolism are exceedingly rare, but each one can give rise to chronic HA (Table 129-4). A rare, peculiar, usually self-limited severe HA of the first month of life, called infantile poikilocytosis, may be associated with deficiency of glutathione peroxidase (GSHPX) due not to an inherited abnormality, but to transient nutritional deficiency of selenium, an element essential for the activity of GSHPX.


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InternalMed_Harrison. pyrimidine 5′-nucleotidase (p5n) deficiency P5N is a key enzyme in the catabolism of nucleotides arising from the degradation of nucleic acids that takes place in the final stages of erythroid cell maturation. How exactly its deficiency causes HA is not well understood, but a highly distinctive feature of this condition is a morphologic abnormality of the red cells known as basophilic stippling. The condition is rare, but it probably ranks third in frequency among red cell enzyme defects (after G6PD deficiency and PK deficiency). The anemia is lifelong, of variable severity, and may benefit from splenectomy.


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InternalMed_Harrison. Familial (Atypical) Hemolytic-Uremic Syndrome The term familial (atypical) hemolytic-uremic syndrome is used to designate a group of rare disorders, mostly affecting children, characterized by microangiopathic HA with presence of fragmented erythrocytes in the peripheral blood smear, thrombocytopenia (usually mild), and acute renal failure. (The word atypical is part of the phrase for historical reasons; it was hemolytic-uremic syndrome [HUS] caused by infection with Escherichia coli producing the Shiga toxin that was regarded as typical). The genetic basis of atypical HUS (aHUS) has been elucidated. Studies of 657 >100 families have revealed that those family members who developed HUS had mutations in any one of several genes encoding complement regulatory proteins: complement factor H (CFH), CD46 or membrane cofactor protein (MCP), complement factor I (CFI), complement component C3, complement factor B (CFB), and thrombomodulin. Thus, whereas all other inherited HAs are due to


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InternalMed_Harrison. H (CFH), CD46 or membrane cofactor protein (MCP), complement factor I (CFI), complement component C3, complement factor B (CFB), and thrombomodulin. Thus, whereas all other inherited HAs are due to intrinsic red cell abnormalities, this group is unique in that hemolysis results from an inherited defect external to red cells (Table 129-1). Because the regulation of the complement cascade has considerable redundancy, in the steady state, any of the above abnormalities can be tolerated. However, when an intercurrent infection or some other trigger activates complement through the alternative pathway, the deficiency of one of the complement regulators becomes critical. Endothelial cells get damaged, especially in the kidney; at the same time, and partly as a result of this, there will be brisk hemolysis (thus, the more common Shiga toxin–related HUS [Chap. 149] can be regarded as a phenocopy of aHUS). aHUS is a severe disease, with up to 15% mortality in the acute phase and up to 50% of


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InternalMed_Harrison. hemolysis (thus, the more common Shiga toxin–related HUS [Chap. 149] can be regarded as a phenocopy of aHUS). aHUS is a severe disease, with up to 15% mortality in the acute phase and up to 50% of cases progressing to end-stage renal disease. Not infrequently, aHUS undergoes spontaneous remission; but because its basis is an inherited abnormality, it is not surprising that, given renewed exposure to a trigger, the syndrome will tend to recur; when it does, the prognosis is always serious. The standard treatment has been plasma exchange, which will supply the deficient complement regulator. The anti-C5 complement inhibitor eculizumab (see below) was found to greatly ameliorate the microangiopathic picture, with improvement in platelet counts and in renal function, thus abrogating the need for plasma exchange. It remains to be seen for how long eculizumab treatment will have to be continued in individual patients and whether it will influence the controversial issue of kidney (and


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InternalMed_Harrison. need for plasma exchange. It remains to be seen for how long eculizumab treatment will have to be continued in individual patients and whether it will influence the controversial issue of kidney (and liver) transplantation.


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InternalMed_Harrison. ACQUIRED HEMOLYTIC ANEMIA Mechanical Destruction of Red Cells Although red cells are characterized by the remarkable deformability that enables them to squeeze through capillaries narrower than themselves for thousands of times in their lifetime, there are at least two situations in which they succumb to shear, if not to wear and tear; the result is intravascular hemolysis, resulting in hemoglobinuria (Table 129-6). One situation is acute and self-inflicted, march hemoglobinuria. Why sometimes a marathon runner may develop this complication, whereas on another occasion, this does not happen, we do not know (perhaps her or his footwear needs attention). A similar syndrome may develop after prolonged barefoot ritual dancing or intense playing of bongo drums. The other situation is chronic and iatrogenic (it has been called microangiopathic hemolytic anemia). It takes place in patients with prosthetic heart valves, especially when paraprosthetic regurgitation is present. If the hemolysis


InternalMed_Harrison

InternalMed_Harrison. iatrogenic (it has been called microangiopathic hemolytic anemia). It takes place in patients with prosthetic heart valves, especially when paraprosthetic regurgitation is present. If the hemolysis consequent on mechanical trauma to the red cells is mild, and if the supply of iron is adequate, the loss may be largely compensated; if more


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InternalMed_Harrison. Hemolytic Anemias and Anemia Due to Acute Blood Loss Paroxysmal nocturnal hemo-Chronic with acute Complement (C)-mediated destruc-Flow cytometry to display a Exacerbations due to C activation globinuria (PNH) exacerbations tion of CD59(−) red cells CD59(−) red cell population through any pathway 658 than mild anemia develops, reintervention to correct regurgitation may be required.


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InternalMed_Harrison. Infection By far the most frequent infectious cause of HA, in endemic areas, is malaria (Chap. 248). In other parts of the world, the most frequent direct cause is probably Shiga toxin–producing E. coli O157:H7, now recognized as the main etiologic agent of HUS, which is more common in children than in adults (Chap. 149). Life-threatening intravascular hemolysis, due to a toxin with lecithinase activity, occurs with Clostridium perfringens sepsis, particularly following open wounds, septic abortion, or as a disastrous accident due to a contaminated blood unit. Rarely, and if at all in children, HA is seen with sepsis or endocarditis from a variety of organisms. In addition, bacterial and viral infections can cause HA by indirect mechanisms (see above section on G6PD deficiency and Table 129-6).


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InternalMed_Harrison. Immune Hemolytic Anemias These can arise through at least two distinct mechanisms. (1) There is a true autoantibody directed against a red cell antigen, i.e., a molecule present on the surface of red cells. (2) When an antibody directed against a certain molecule (e.g., a drug) reacts with that molecule, red cells may get caught in the reaction, whereby they are damaged or destroyed. Because the antibodies involved differ in optimum reactivity temperatures, they are classified in the time-honored categories of “cold” and “warm” (Table 129-7). Autoantibody-mediated HAs may be seen in isolation (when they are called idiopathic) or as part of a systemic autoimmune disorder such as systemic lupus erythematosus. Here we discuss the most distinctive clinical pictures.


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InternalMed_Harrison. autoimmune Hemolytic anemia (aiHa) Once a red cell is coated by an autoantibody (see [1] above), it will be destroyed by one or more mechanisms. In most cases, the Fc portion of the antibody will be recognized by the Fc receptor of macrophages, and this will trigger erythrophagocytosis. Thus, destruction of red cells will take place wherever macrophages are abundant, i.e., in the spleen, liver, or bone marrow; this is called extravascular hemolysis (Fig. 129-8). Because of the special anatomy of the spleen, this organ is particularly efficient in Type of Antibody Drug-dependent: antibody destroys red cells only when drug present (e.g., rarely penicillin) Drug-independent: antibody can destroy red cells even when drug no longer present (e.g., methyldopa)


InternalMed_Harrison

InternalMed_Harrison. Drug-dependent: antibody destroys red cells only when drug present (e.g., rarely penicillin) Drug-independent: antibody can destroy red cells even when drug no longer present (e.g., methyldopa) Abbreviations: AIHA, autoimmune hemolytic anemia; CAD, cold agglutinin disease; CLL, chronic lymphocytic leukemia; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; HSCT, hematopoietic stem cell transplantation; IBD, inflammatory bowel disease; SLE, systemic lupus erythematosus. trapping antibody-coated red cells, and often this is the predominant site of red cell destruction. In some cases, the nature of the antibody is such (usually an IgM antibody) that the antigen-antibody complex on the surface of red cells is able to activate complement (C); as a result, a large amount of membrane attack complex will form, and the red cells may be destroyed directly; this is known as intravascular hemolysis.


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InternalMed_Harrison. clinical features AIHA is a serious condition; without appropriate treatment, it may have a mortality of approximately 10%. The onset is often abrupt and can be dramatic. The hemoglobin level can drop, within days, to as low as 4 g/dL; the massive red cell removal will produce jaundice; and sometimes the spleen is enlarged. When this triad is present, the suspicion of AIHA must be high. When hemolysis is (in part) intravascular, the telltale sign will be hemoglobinuria, which the patient may report or about which we must enquire or test for. The diagnostic test for AIHA is the direct antiglobulin test developed in 1945 by R. R. A. Coombs and known since by this name. The beauty of this test is that it detects directly the pathogenetic mediator of the disease, i.e., the presence of antibody on the red cells themselves. When the test is positive, it clinches the diagnosis; when it is negative, the diagnosis is unlikely. However, the sensitivity of the Coombs test varies depending on the


InternalMed_Harrison

InternalMed_Harrison. on the red cells themselves. When the test is positive, it clinches the diagnosis; when it is negative, the diagnosis is unlikely. However, the sensitivity of the Coombs test varies depending on the technique that is used, and in doubtful cases, a repeat in a specialized lab is advisable; the term Coombs-negative AIHA is a last resort. In some cases, the autoantibody has a defined identity; it may be specific for an antigen belonging to the Rhesus system (it is often anti-e). In many cases, it is regarded as “nonspecific” because it reacts with virtually all types of red cells.


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InternalMed_Harrison. When AIHA develops in a person who is already known to have, for instance, systemic lupus or chronic lymphocytic leukemia (Table 129-7), we call it a complication; conversely, when AIHA presents on its own, it may be a pointer to an underlying condition that we ought to seek out. In both cases, what brings about AIHA remains, as in other autoimmune disorders, obscure. In some cases, AIHA can be associated, on first presentation or subsequently, with autoimmune thrombocytopenia (Evans’ syndrome).


InternalMed_Harrison

InternalMed_Harrison. Severe acute AIHA can be a medical emergency. The immediate treatment almost invariably includes transfusion of red cells. This may pose a special problem because, if the antibody involved is nonspecific, all of the blood units cross-matched will be incompatible. In these cases, it is often correct, paradoxically, to transfuse incompatible blood, with the rationale being that the transfused red cells will be destroyed no less but no more than the patient’s own red cells, but in the meantime, the patient stays alive. A situation like this requires close liaison and understanding between the clinical unit treating the patient and the blood transfusion/serology lab. Whenever the anemia is not immediately life-threatening, blood transfusion should be withheld (because compatibility problems may increase with each unit of blood transfused), and medical treatment started immediately with prednisone (1 mg/kg per day), which will produce a remission promptly in at least one-half of patients.


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InternalMed_Harrison. increase with each unit of blood transfused), and medical treatment started immediately with prednisone (1 mg/kg per day), which will produce a remission promptly in at least one-half of patients. Rituximab (anti-CD20) was regarded as second-line treatment, but it is increasingly likely that a relatively low dose (100 mg/wk × 4) of rituximab together with prednisone will become a first-line standard. It is especially encouraging that this approach seems to reduce the rate of relapse, a common occurrence in AIHA. For patients who do relapse or are refractory to medical treatment, one may have to consider splenectomy, which, although it does not cure the disease, can produce significant benefit by removing a major site of hemolysis, thus improving the anemia and/or reducing the need for other therapies (e.g., the dose of prednisone). Since the introduction of rituximab, azathioprine, cyclophosphamide, cyclosporine, and intravenous immunoglobulin have become secondor third-line agents.


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InternalMed_Harrison. therapies (e.g., the dose of prednisone). Since the introduction of rituximab, azathioprine, cyclophosphamide, cyclosporine, and intravenous immunoglobulin have become secondor third-line agents. In very rare severe refractory cases, either autologous or allogeneic hematopoietic stem cell transplantation may have to be considered.


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InternalMed_Harrison. Destroyed red cell with formation of membrane and membrane free hemoglobin Reticuloendothelial attack complex system


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InternalMed_Harrison. FIGURE 129-8 Mechanism of antibody-mediated immune destruction of red blood cells (RBCs). ADCC, antibody-dependent cell-mediated cytotoxicity. (From N Young et al: Clinical Hematology. Philadelphia, Elsevier, 2006; with permission.) paroxysmal cold Hemoglobinuria (pcH) PCH is a rather rare form of AIHA occurring mostly in children, usually triggered by a viral infection, usually self-limited, and characterized by the involvement of the so-called Donath-Landsteiner antibody. In vitro, this antibody has unique serologic features; it has anti-P specificity and binds to red cells only at a low temperature (optimally at 4°C), but when the temperature is shifted to 37°C, lysis of red cells takes place in the presence of complement. Consequently, in vivo there is intravascular hemolysis, resulting in hemoglobinuria. Clinically the differential diagnosis must include other causes of hemoglobinuria (Table 129-6), but the presence of the Donath-Landsteiner antibody will prove PCH. Active


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InternalMed_Harrison. in hemoglobinuria. Clinically the differential diagnosis must include other causes of hemoglobinuria (Table 129-6), but the presence of the Donath-Landsteiner antibody will prove PCH. Active supportive treatment, including blood transfusion, is needed to control the anemia; subsequently, recovery is the rule.


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InternalMed_Harrison. cold agglutinin disease (cad) This designation is used for a form of chronic AIHA that usually affects the elderly and has special clinical and pathologic features. First, the term cold refers to the fact that the autoantibody involved reacts with red cells poorly or not at all at 37°C, whereas it reacts strongly at lower temperatures. As a result, hemolysis is more prominent the more the body is exposed to the cold. The antibody is usually IgM; usually it has an anti-I specificity (the I antigen is present on the red cells of almost everybody), and it may have a very high titer (1:100,000 or more has been observed). Second, the antibody is produced by an expanded clone of B lymphocytes, and sometimes its concentration in the plasma is high enough to show up as a spike in plasma protein electrophoresis, i.e., as a monoclonal gammopathy. Third, because the antibody is IgM, CAD is related to Waldenström’s macroglobulinemia (WM) (Chap. 136), although in most cases, the other clinical


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InternalMed_Harrison. electrophoresis, i.e., as a monoclonal gammopathy. Third, because the antibody is IgM, CAD is related to Waldenström’s macroglobulinemia (WM) (Chap. 136), although in most cases, the other clinical features of this disease are not present. Thus, CAD must be regarded as a form of WM (i.e., as a low-grade mature B cell lymphoma) that manifests at an earlier stage precisely because the unique biologic properties of the IgM that it produces give the clinical picture of chronic HA.


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InternalMed_Harrison. In mild forms of CAD, avoidance of exposure to cold may be all that is needed to enable the patient to have a reasonably comfortable quality of life; but in more severe forms, the management of CAD is not easy. Blood transfusion is not very effective because donor red cells are I positive and will be rapidly removed. Immunosuppressive/cytotoxic treatment with azathioprine or cyclophosphamide can reduce the antibody titer, but clinical efficacy is limited, and in view of the chronic nature of the disease, the side effects may prove unacceptable. Unlike in AIHA, prednisone and splenectomy are ineffective. Plasma exchange will remove antibody and is, therefore, in theory, a rational approach, but it is laborious and must be carried out at frequent intervals if it is to be beneficial. The management of CAD has changed significantly with the advent of rituximab; although its impact on CAD is not as great as on AIHA, up to 60% of patients respond, and remissions may be more durable with a


InternalMed_Harrison

InternalMed_Harrison. of CAD has changed significantly with the advent of rituximab; although its impact on CAD is not as great as on AIHA, up to 60% of patients respond, and remissions may be more durable with a rituximab-fludarabine combination. Given the long clinical course of CAD, it remains to be seen with what schedule or periodicity these agents will need to be administered.


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InternalMed_Harrison. Toxic Agents and Drugs A number of chemicals with oxidative potential, whether medicinal or not, can cause hemolysis even in people who are not G6PD deficient (see above). Examples are hyperbaric oxygen (or 100% oxygen), nitrates, chlorates, methylene blue, dapsone, cisplatin, and numerous aromatic (cyclic) compounds. Other chemicals may be hemolytic through nonoxidative, largely unknown mechanisms; examples include arsine, stibine, copper, and lead. The HA caused by lead poisoning is characterized by basophilic stippling; it is in fact a phenocopy of that seen in P5N deficiency (see above), suggesting it is mediated at least in part by lead inhibiting this enzyme.


InternalMed_Harrison

InternalMed_Harrison. In these cases, hemolysis appears to be mediated by a direct chemical action on red cells. But drugs can cause hemolysis through at least two other mechanisms. (1) A drug can behave as a hapten and induce antibody production; in rare subjects, this happens, for instance, with penicillin. Upon a subsequent exposure, red cells are caught, as innocent bystanders, in the reaction between penicillin and antipenicillin antibodies. Hemolysis will subside as soon as penicillin administration is stopped. (2) A drug can trigger, perhaps through mimicry, the production of an antibody against a red cell antigen. The best known example is methyldopa, an antihypertensive agent no longer in use, which in a small fraction of patients stimulated the production of the


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InternalMed_Harrison. Hemolytic Anemias and Anemia Due to Acute Blood Loss 660 Rhesus antibody anti-e. In patients who have this antigen, the anti-e is a true autoantibody, which then causes an autoimmune HA (see below). Usually this will gradually subside once methyldopa is discontinued. Severe intravascular hemolysis can be caused by the venom of certain snakes (cobras and vipers), and HA can also follow spider bites. Paroxysmal Nocturnal Hemoglobinuria (PNH) PNH is an acquired chronic HA characterized by persistent intravascular hemolysis subject to recurrent exacerbations. In addition to hemolysis, there is often pancytopenia and a distinct tendency to venous thrombosis. This triad makes PNH a truly unique clinical condition; however, when not all of these three features are manifest on presentation, the diagnosis is often delayed, although it can always be made by appropriate laboratory investigations (see below).


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InternalMed_Harrison. PNH has about the same frequency in men and women and is encountered in all populations throughout the world, but it is a rare disease; its prevalence is estimated to be approximately 5 per million (it may be somewhat less rare in Southeast Asia and in the Far East). There is no evidence of inherited susceptibility. PNH has never been reported as a congenital disease, but it can present in small children or as late as in the seventies, although most patients are young adults.


InternalMed_Harrison

InternalMed_Harrison. clinical features The patient may seek medical attention because, one morning, she or he passed blood instead of urine (Fig. 129-9). This distressing or frightening event may be regarded as the classical presentation; however, more frequently, this symptom is not noticed or is suppressed. Indeed, the patient often presents simply as a problem in the differential diagnosis of anemia, whether symptomatic or discovered incidentally. Sometimes, the anemia is associated from the outset with neutropenia, thrombocytopenia, or both, thus signaling an element of bone marrow failure (see below). Some patients may present with recurrent attacks of severe abdominal pain defying a specific diagnosis and eventually found to be related to thrombosis. When thrombosis affects the hepatic veins, it may produce acute hepatomegaly and ascites, i.e., a full-fledged Budd-Chiari syndrome, which, in the absence of liver disease, ought to raise the suspicion of PNH.


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InternalMed_Harrison. The natural history of PNH can extend over decades. Without treatment, the median survival is estimated to be about 8–10 years; in the past, the most common cause of death has been venous thrombosis, followed by infection secondary to severe neutropenia and hemorrhage secondary to severe thrombocytopenia. Rarely (estimated 1–2% of all cases), PNH may terminate in acute myeloid leukemia. On the other hand, full spontaneous recovery from PNH has been documented, albeit rarely.


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InternalMed_Harrison. laboratory investigations and diagnosis The most consistent blood finding is anemia, which may range from mild to moderate to very severe. The anemia is usually normomacrocytic, with unremarkable red cell morphology. If the MCV is high, it is usually largely accounted for by reticulocytosis, which may be quite marked (up to 20%, or up to 400,000/μL). The anemia may become microcytic if the patient is allowed to become iron deficient as a result of chronic urinary blood loss through hemoglobinuria. Unconjugated bilirubin is mildly or moderately elevated; LDH is typically markedly elevated (values in the thousands are common); and haptoglobin is usually undetectable. All of these findings make the diagnosis of hemolytic anemia compelling. Hemoglobinuria may be overt in a random urine sample; if it is not, it may be helpful to obtain serial urine samples, because hemoglobinuria can vary dramatically from day to day and even from hour to hour. The bone marrow is usually cellular, with


InternalMed_Harrison

InternalMed_Harrison. if it is not, it may be helpful to obtain serial urine samples, because hemoglobinuria can vary dramatically from day to day and even from hour to hour. The bone marrow is usually cellular, with marked to massive erythroid hyperplasia, often with mild to moderate dyserythropoietic features (not to be confused with myelodysplastic syndrome). At some stage of the disease, the marrow may become hypocellular or even frankly aplastic (see below).


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InternalMed_Harrison. FIGURE 129-9 Consecutive urine samples from a patient with par-oxysmal nocturnal hemoglobinuria (PNH). The variation in the severity of hemoglobinuria within hours is probably unique to this condition. The definitive diagnosis of PNH must be based on the demonstration that a substantial proportion of the patient’s red cells have an increased susceptibility to complement (C), due to the deficiency on their surface of proteins (particularly CD59 and CD55) that normally protect the red cells from activated C. The sucrose hemolysis test is unreliable; in contrast, the acidified serum (Ham) test is highly reliable but is carried out only in a few labs. The gold standard today is flow cytometry, which can be carried out on granulocytes as well as on red cells. A bimodal distribution of cells, with a discrete population that is CD59 and CD55 negative, is diagnostic of PNH. In PNH patients, this population is at least 5% of the total red cells and at least 20% of the total granulocytes.


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InternalMed_Harrison. patHopHysiology Hemolysis in PNH is mainly intravascular and is due to an intrinsic abnormality of the red cell, which makes it exquisitely sensitive to activated C, whether it is activated through the alternative pathway or through an antigen-antibody reaction. The former mechanism is mainly responsible for chronic hemolysis in PNH; the latter explains why the hemolysis can be dramatically exacerbated in the course of a viral or bacterial infection. Hypersusceptibility to C is due to deficiency of several protective membrane proteins (Fig. 129-10), of which CD59 is the most important, because it hinders the insertion into the membrane of C9 polymers. The molecular basis for the deficiency of these proteins has been pinpointed not to a defect in any of the respective genes, but rather to the shortage of a unique glycolipid molecule, GPI (Fig. 129-2), which, through a peptide bond, anchors these proteins to the surface membrane of cells. The shortage of GPI is due in turn to a mutation


InternalMed_Harrison

InternalMed_Harrison. shortage of a unique glycolipid molecule, GPI (Fig. 129-2), which, through a peptide bond, anchors these proteins to the surface membrane of cells. The shortage of GPI is due in turn to a mutation in an X-linked gene, called PIG-A, required for an early step in GPI biosynthesis. In virtually each patient, the PIGA mutation is different. This is not surprising, because these mutations are not inherited; rather, each one takes place de novo in a hemopoietic stem cell (i.e., they are somatic mutations). As a result, the patient’s marrow is a mosaic of mutant and nonmutant cells, and the peripheral blood always contains both PNH cells and normal (non-PNH) cells. Thrombosis is one of the most immediately life-threatening complications of PNH and yet one of the least understood in its pathogenesis. It could be that deficiency of CD59 on the PNH platelet causes inappropriate platelet activation; however, other mechanisms are possible.


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InternalMed_Harrison. bone marrow failure (bmf) and relationsHip between pnH and aplastic anemia (aa) It is not unusual that patients with firmly established PNH have a previous history of well-documented AA; indeed, BMF preceding overt PNH is probably the rule rather than the exception. On the other hand, sometimes a patient with PNH becomes less hemolytic and more pancytopenic and ultimately has the clinical picture of AA. Because AA is probably an organ-specific autoimmune disease, in which T cells cause damage to hematopoietic stem cells, the same may be true of PNH, with the specific proviso that the damage spares PNH stem cells. PIG-A mutations can be demonstrated in normal people, and there is evidence from mouse models that PNH stem cells do not expand when the rest of the bone marrow is normal. Thus, we can visualize PNH as always having two components: failure of normal hematopoiesis and massive expansion of a PNH clone. Findings supporting this notion include skewing of the T cell repertoire and


InternalMed_Harrison

InternalMed_Harrison. can visualize PNH as always having two components: failure of normal hematopoiesis and massive expansion of a PNH clone. Findings supporting this notion include skewing of the T cell repertoire and the demonstration of GPI-reactive T cells in patients with PNH.


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InternalMed_Harrison. A Normal, steady state A normal (CD55+, CD59+) red cell can withstand the hazard of complement activation. Intact normal (CD55+/CD59+) B PNH, steady state RBCs CHAPTEr 129 An abnormal (CD55–, CD59–) red cell (PNH cell) will be lysed sooner or later by activated complement (intravascular hemolysis). Hemolytic Anemias and Anemia Due to Acute Blood Loss C PNH, on eculizumab C3 C3 C3 opsonization RES macrophages (liver, spleen) Amplification loop C5 convertase Eculizumab + Lectin pathway Alternative pathway Classical pathway C3 C5b C6 C7 C8 C9 C5C3b C3b EcuC5C5C5C555 C3convertase C3convertase C3convertase MAC With C5 blocked, a PNH red cell will be protected from undergoing intravascular hemolysis, but once opsonized by C3 it will become prey to macrophages.


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InternalMed_Harrison. FIGURE 129-10 The complement cascade and the fate of red cells. A. Normal red cells are protected from complement activation and subsequent hemolysis by CD55 and CD59. These two proteins, being GPI-linked, are missing from the surface of PNH red cells as a result of a somatic mutation of the X-linked PIG-A gene that encodes a protein required for an early step of the GPI molecule biosynthesis. B. In the steady state, PNH erythrocytes suffer from spontaneous (tick-over) complement activation, with consequent intravascular hemolysis through formation of the membrane attack complex (MAC); when extra complement is activated through the classical pathway, an exacerbation of hemolysis will result. C. On eculizumab, PNH erythrocytes are protected from hemolysis from the inhibition of C5 cleavage; however, upstream complement activation may lead to C3 opsonization and possible extravascular hemolysis. GPI, glycosylphosphatidylinositol; PNH, paroxysmal nocturnal hemoglobinuria. (From L


InternalMed_Harrison

InternalMed_Harrison. however, upstream complement activation may lead to C3 opsonization and possible extravascular hemolysis. GPI, glycosylphosphatidylinositol; PNH, paroxysmal nocturnal hemoglobinuria. (From L Luzzatto et al: Haematologica 95:523, 2010.) which, for some patients, means quite frequently. Folic acid supplements (at least 3 mg/d) are mandatory; the serum iron should be checked periodically, and iron supplements should be administered as appropriate. Long-term glucocorticoids are not indi-


InternalMed_Harrison

InternalMed_Harrison. Unlike other acquired hemolytic anemias, PNH may be a lifelong condition, and most patients receive supportive treatment only, including transfusion of filtered red cells1 whenever necessary, 1Now that filters with excellent retention of white cells are routinely used, the traditional cated because there is no evidence that they have any effect on chronic hemolysis; in fact, they are contraindicated because their side effects are considerable and potentially dangerous. A major advance in the management of PNH has been the development of a humanized monoclonal antibody, eculizumab, which binds to washing of red cells, aiming to avoid white cell reactions triggering hemolysis, is no the complement component C5 near the site that, when cleaved, longer necessary and is wasteful. will trigger the distal part of the complement cascade leading to 662 the formation of membrane attack complex (MAC). In an international, placebo-controlled, randomized trial of 87 patients (so far the only


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InternalMed_Harrison. the distal part of the complement cascade leading to 662 the formation of membrane attack complex (MAC). In an international, placebo-controlled, randomized trial of 87 patients (so far the only controlled therapeutic trial in PNH) who had been selected on grounds of having severe hemolysis making them transfusion-dependent, eculizumab proved effective and was licensed in 2007. Eculizumab, by abrogating complement-dependent intravascular hemolysis, significantly improves the quality of life of PNH patients. One would expect that the need for blood transfusion would also be abrogated; indeed, this is the case in about one-half of patients, in many of whom there is also a rise in hemoglobin levels. In the remaining patients, however, the anemia remains sufficiently severe to require blood transfusion. One reason for this is that, once the distal complement pathway is blocked, red cells no longer destroyed by the MAC become opsonized by complement (C3) fragments and undergo extravascular


InternalMed_Harrison

InternalMed_Harrison. One reason for this is that, once the distal complement pathway is blocked, red cells no longer destroyed by the MAC become opsonized by complement (C3) fragments and undergo extravascular hemolysis (Fig. 129-10). The extent to which this happens depends in part on a genetic polymorphism of the complement receptor CR1. Based on its half-life, eculizumab must be administered intravenously every 14 days. The only form of treatment that currently can provide a definitive cure for PNH is allogeneic BMT. When an HLA-identical sibling is available, BMT should be offered to any young patient with severe PNH; the availability of eculizumab has decreased significantly the proportion of patients receiving BMT. For patients with the PNH-AA syndrome, immunosuppressive treatment with antithymocyte globulin and cyclosporine A may be indicated, especially in order to relieve severe thrombocytopenia and/or neutropenia in patients in whom these were the main problem(s); of course, this treatment will


InternalMed_Harrison

InternalMed_Harrison. and cyclosporine A may be indicated, especially in order to relieve severe thrombocytopenia and/or neutropenia in patients in whom these were the main problem(s); of course, this treatment will have little or no effect on hemolysis. Any patient who has had venous thrombosis or who has a genetically determined thrombophilic state in addition to PNH complications that do not resolve otherwise, ment with tissue plasminogen activator may be indicated.


InternalMed_Harrison

InternalMed_Harrison. The latter type of anemia is covered in Chap. 126 cerned with the former type, i.e., posthemorrhagic anemia lows acute blood loss. This can be external ric hemorrhage) or internal tract, rupture of the spleen, rupture of an ectopic pregnancy, subarachnoid hemorrhage). In any of these cases, after the sudden loss of a large amount of blood, there are three clinical/pathophysiologic stages. (1) At first, the dominant feature is hypovolemia, which poses a threat particularly to organs that normally have a high blood supply, like the brain and the kidneys; therefore, loss of consciousness and acute renal failure are major threats. It is important to note that at this stage an ordinary blood count will not show anemia, because the hemoglobin concentration is not affected. (2) Next, as an emergency response, baroreceptors and stretch receptors will cause release of vasopressin and other peptides, and the body will shift fluid from the extravascular to the intravascular compartment,


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InternalMed_Harrison. an emergency response, baroreceptors and stretch receptors will cause release of vasopressin and other peptides, and the body will shift fluid from the extravascular to the intravascular compartment, producing hemodilution; thus, the hypovolemia gradually converts to anemia. The degree of anemia will reflect the amount of blood lost. If after 3 days the hemoglobin is, for example, 7 g/dL, it means that about half of the entire blood has been lost. (3) Provided bleeding does not continue, the bone marrow response will gradually ameliorate the anemia.


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InternalMed_Harrison. The diagnosis of acute posthemorrhagic anemia (APHA) is usually straightforward, although sometimes internal bleeding episodes (e.g., after a traumatic injury), even when large, may not be immediately obvious. Whenever an abrupt fall in hemoglobin has taken place, whatever history is given by the patient, APHA should be suspected. Supplementary history may have to be obtained by asking the appropriate questions, and appropriate investigations (e.g., a sonogram or an endoscopy) may have to be carried out. With respect to treatment, a two-pronged approach is imperative.


InternalMed_Harrison

InternalMed_Harrison. With respect to treatment, a two-pronged approach is imperative. (1) In many cases, the blood lost needs to be replaced promptly. Unlike with many chronic anemias, when finding and correcting the cause of the anemia is the first priority and blood transfusion may not be even necessary because the body is adapted to the anemia, with acute blood loss the reverse is true; because the body is not adapted to the anemia, blood transfusion takes priority. (1) While the emergency is being confronted, it is imperative to stop the hemorrhage and to eliminate its source.


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InternalMed_Harrison. A special type of APHA is blood loss during and immediately after surgery, which can be substantial (e.g., up to 2 L in the case of a radical prostatectomy). Of course with elective surgical procedures, the patient’s own stored blood may be available (through preoperative autologous blood donation), and in any case, blood loss ought to have been carefully monitored/measured. The fact that this blood loss is iatrogenic dictates that ever more effort should be invested in optimizing its management.


InternalMed_Harrison

InternalMed_Harrison. A Holy Grail of emergency medicine for a long time has been the idea of a blood substitute that would be universally available, suitable for all recipients, easy to store and to transport, safe, and as effective as blood itself. Two main paths have been pursued: (1) fluorocarbon synthetic chemicals that bind oxygen reversibly, and (2) artificially modified hemoglobins, known as hemoglobin-based oxygen carriers (HBOCs). Although there are numerous anecdotal reports of the use of both approaches in humans, and although HBOCs have reached the stage of phase 2–3 clinical trials, no “blood substitute” has yet become standard treatment. Neal S. Young


InternalMed_Harrison

InternalMed_Harrison. Neal S. Young The hypoproliferative anemias are normochromic, normocytic, or macrocytic and are characterized by a low reticulocyte count. Hypoproliferative anemia is also a prominent feature of hematologic diseases that are described as bone marrow failure states; these include aplastic anemia, myelodysplastic syndrome (MDS), pure red cell aplasia (PRCA), and myelophthisis. Anemia in these disorders is often not a solitary or even the major hematologic finding. More frequent in bone marrow failure is pancytopenia: anemia, leukopenia, and thrombocytopenia. Low blood counts in the marrow failure diseases result from deficient hematopoiesis, as distinguished from blood count depression due to peripheral destruction of red cells (hemolytic anemias), platelets (idiopathic thrombocytopenic purpura [ITP] or due to splenomegaly), and granulocytes (as in the immune leukopenias). Marrow damage and dysfunction also may be secondary to infection, inflammation, or cancer.


InternalMed_Harrison

InternalMed_Harrison. Hematopoietic failure syndromes are classified by dominant morphologic features of the bone marrow (Table 130-1). Although practical distinction among these syndromes usually is clear, some processes are so closely related that the diagnosis may be complex. Patients may seem to suffer from two or three related diseases simultaneously, or one diagnosis may appear to evolve into another. Many of these syndromes share an immune-mediated mechanism of marrow destruction and some element of genomic instability resulting in a higher rate of malignant transformation. It is important that the internist and general practitioner recognize the marrow failure syndromes, as their prognosis may be poor if the Pancytopenia with Hypocellular Bone Marrow Acquired aplastic anemia Constitutional aplastic anemia (Fanconi anemia, dyskeratosis congenita) Some myelodysplasia Rare aleukemic leukemia Some acute lymphoid leukemia Some lymphomas of bone marrow Pancytopenia with Cellular Bone Marrow


InternalMed_Harrison

InternalMed_Harrison. Pancytopenia with Cellular Bone Marrow Primary bone marrow diseases Secondary to systemic diseases Myelodysplasia Systemic lupus erythematosus Paroxysmal nocturnal Hypersplenism B12, folate deficiency Myelofibrosis Overwhelming infection Some aleukemic leukemia Alcohol Myelophthisis Brucellosis Bone marrow lymphoma Sarcoidosis Hairy cell leukemia Tuberculosis Q fever Legionnaires’ disease Anorexia nervosa, starvation patient is untreated; effective therapies are often available but sufficiently complicated in their choice and delivery so as to warrant the care of a hematologist or oncologist.


InternalMed_Harrison

InternalMed_Harrison. Aplastic anemia is pancytopenia with bone marrow hypocellularity. Acquired aplastic anemia is distinguished from iatrogenic aplasia, marrow hypocellularity after intensive cytotoxic chemotherapy for cancer. Aplastic anemia can also be constitutional: the genetic diseases Fanconi anemia and dyskeratosis congenita, although frequently associated with typical physical anomalies and the development of pancytopenia early in life, can also present as marrow failure in normal-appearing adults. Acquired aplastic anemia is often stereotypical in its manifestations, with the abrupt onset of low blood counts in a previously well young adult; seronegative hepatitis or a course of an incriminated medical drug may precede the onset. The diagnosis in these instances is uncomplicated. Sometimes blood count depression is moderate or incomplete, resulting in anemia, leukopenia, and thrombocytopenia in some combination. Aplastic anemia is related to both paroxysmal nocturnal hemoglobinuria (PNH; Chap.


InternalMed_Harrison

InternalMed_Harrison. depression is moderate or incomplete, resulting in anemia, leukopenia, and thrombocytopenia in some combination. Aplastic anemia is related to both paroxysmal nocturnal hemoglobinuria (PNH; Chap. 129) and to MDS, and in some cases, a clear distinction among these disorders may not be possible.


InternalMed_Harrison

InternalMed_Harrison. The incidence of acquired aplastic anemia in Europe and Israel is two cases per million persons annually. In Thailand and China, rates of five to seven per million have been established. In general, men and women are affected with equal frequency, but the age distribution is biphasic, with the major peak in the teens and twenties and a second rise in older adults. The origins of aplastic anemia have been inferred from several recurring clinical associations (Table 130-2); unfortunately, these relationships are not reliable in an individual patient and may not be etiologic. In addition, although most cases of aplastic anemia are idiopathic, little other than history separates these cases from those with a presumed etiology such as a drug exposure. Epstein-Barr virus (infectious Preleukemia (monosomy 7, etc.) mononucleosis) Hepatitis (non-A, non-B, non-C Nonhematologic syndrome (Down, hepatitis) Dubowitz, Seckel) Parvovirus B19 (transient aplastic crisis, PRCA) HIV-1 (AIDS)


InternalMed_Harrison

InternalMed_Harrison. Parvovirus B19 (transient aplastic crisis, PRCA) HIV-1 (AIDS) Abbreviation: PRCA, pure red cell aplasia. Radiation Marrow aplasia is a major acute sequela of radiation. Radiation damages DNA; tissues dependent on active mitosis are particularly susceptible. Nuclear accidents involve not only power plant workers but also employees of hospitals, laboratories, and industry (food sterilization, metal radiography, etc.), as well as innocents exposed to stolen, misplaced, or misused sources. Whereas the radiation dose can be approximated from the rate and degree of decline in blood counts, dosimetry by reconstruction of the exposure can help to estimate the patient’s prognosis and also to protect medical personnel from contact with radioactive tissue and excreta. MDS and leukemia, but probably not aplastic anemia, are late effects of radiation.


InternalMed_Harrison

InternalMed_Harrison. Chemicals Benzene is a notorious cause of bone marrow failure: epidemiologic, clinical, and laboratory data link benzene to aplastic anemia, acute leukemia, and blood and marrow abnormalities. For leukemia, incidence is correlated with cumulative exposure, but susceptibility must also be important, because only a minority of even heavily exposed workers develop myelotoxicity. The employment history is important, especially in industries where benzene is used for a secondary purpose, usually as a solvent. Benzene-related blood diseases have declined with regulation of industrial exposure. Although benzene is no longer generally available as a household solvent, exposure to its metabolites occurs in the normal diet and in the environment. The association between marrow failure and other chemicals is much less well substantiated. Agents that regularly produce marrow depression as major toxicity in com monly used doses or normal exposures:


InternalMed_Harrison

InternalMed_Harrison. Agents that regularly produce marrow depression as major toxicity in com monly used doses or normal exposures: Cytotoxic drugs used in cancer chemotherapy: alkylating agents, antime tabolites, antimitotics, some antibiotics Agents that frequently but not inevitably produce marrow aplasia: Agents associated with aplastic anemia but with a relatively low probability: Antiprotozoals: quinacrine and chloroquine, mepacrine Nonsteroidal anti-inflammatory drugs (including phenylbutazone, indomethacin, ibuprofen, sulindac, aspirin) Anticonvulsants (hydantoins, carbamazepine, phenacemide, felbamate) Heavy metals (gold, arsenic, bismuth, mercury) Sulfonamides: some antibiotics, antithyroid drugs (methimazole, methyl- thiouracil, propylthiouracil), antidiabetes drugs (tolbutamide, chlorprop amide), carbonic anhydrase inhibitors (acetazolamide and methazolamide) Antihistamines (cimetidine, chlorpheniramine) Agents whose association with aplastic anemia is more tenuous:


InternalMed_Harrison

InternalMed_Harrison. Antihistamines (cimetidine, chlorpheniramine) Agents whose association with aplastic anemia is more tenuous: Other antibiotics (streptomycin, tetracycline, methicillin, mebendazole, trimethoprim/sulfamethoxazole, flucytosine) Sedatives and tranquilizers (chlorpromazine, prochlorperazine, piperaceta zine, chlordiazepoxide, meprobamate, methyprylon) Carbimazole Note: Terms set in italics show the most consistent association with aplastic anemia.


InternalMed_Harrison

InternalMed_Harrison. Drugs (Table 130-3) Many chemotherapeutic drugs have marrow suppression as a major toxicity; effects are dose dependent and will occur in all recipients. In contrast, idiosyncratic reactions to a large and diverse group of drugs may lead to aplastic anemia without a clear dose-response relationship. These associations rest largely on accumulated case reports until a large international study in Europe in the 1980s quantitated drug relationships, especially for nonsteroidal analgesics, sulfonamides, thyrostatic drugs, some psychotropics, penicillamine, allopurinol, and gold. Association does not equal causation: a drug may have been used to treat the first symptoms of bone marrow failure (antibiotics for fever or the preceding viral illness) or provoked the first symptom of a preexisting disease (petechiae by nonsteroidal anti-inflammatory agents administered to the thrombocytopenic patient). In the context of total drug use, idiosyncratic reactions, although individually devastating,


InternalMed_Harrison

InternalMed_Harrison. (petechiae by nonsteroidal anti-inflammatory agents administered to the thrombocytopenic patient). In the context of total drug use, idiosyncratic reactions, although individually devastating, are rare events. Risk estimates are usually lower when determined in population-based studies. Furthermore, the low absolute risk is also made more obvious: even a 10or 20-fold increase in risk translates, in a rare disease, to just a handful of drug-induced aplastic anemia cases among hundreds of thousands of exposed persons.


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InternalMed_Harrison. Infections Hepatitis is the most common preceding infection, and posthepatitis marrow failure accounts for approximately 5% of etiologies in most series. Patients are usually young men who have recovered from a bout of liver inflammation 1 to 2 months earlier; the subsequent pancytopenia is very severe. The hepatitis is seronegative (non-A, non-B, non-C) and possibly due to an as yet undiscovered infectious agent. Fulminant liver failure in childhood also follows seronegative hepatitis, and marrow failure occurs at a high rate in these patients. Aplastic anemia can rarely follow infectious mononucleosis. Parvovirus B19, the cause of transient aplastic crisis in hemolytic anemias and of some PRCAs (see below), does not usually cause generalized bone marrow failure. Mild blood count depression is frequent in the course of many viral and bacterial infections but resolves with the infection.


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InternalMed_Harrison. Immunologic Diseases Aplasia is a major consequence and the inevitable cause of death in transfusion-associated graft-versus-host disease (GVHD) that can occur after infusion of nonirradiated blood products to an immunodeficient recipient. Aplastic anemia is strongly associated with the rare collagen vascular syndrome eosinophilic fasciitis that is characterized by painful induration of subcutaneous tissues (Chap. 382). Thymoma and hypoimmunoglobulinemia are occasional associations with aplastic anemia. Pancytopenia with marrow hypoplasia can also occur in systemic lupus erythematosus (SLE). Pregnancy Aplastic anemia very rarely may occur and recur during pregnancy and resolve with delivery or with spontaneous or induced abortion.


InternalMed_Harrison

InternalMed_Harrison. Paroxysmal Nocturnal Hemoglobinuria An acquired mutation in the PIG-A gene in a hematopoietic stem cell is required for the development of PNH, but PIG-A mutations probably occur commonly in normal individuals. If the PIG-A mutant stem cell proliferates, the result is a clone of progeny deficient in glycosylphosphatidylinositol-linked cell surface membrane proteins (Chap. 129). Small clones of deficient cells can be detected by sensitive flow cytometry tests in one-half or more of patients with aplastic anemia at the time of presentation. Functional studies of bone marrow from PNH patients, even those with mainly hemolytic manifestations, show evidence of defective hematopoiesis. Patients with an initial clinical diagnosis of PNH, especially younger individuals, may later develop frank marrow aplasia and pancytopenia; patients with an initial diagnosis of aplastic anemia may suffer from hemolytic PNH years after recovery of blood counts.


InternalMed_Harrison

InternalMed_Harrison. Constitutional Disorders Fanconi anemia, an autosomal recessive disorder, manifests as congenital developmental anomalies, progressive pancytopenia, and an increased risk of malignancy. Chromosomes in Fanconi anemia are peculiarly susceptible to DNA cross-linking agents, the basis for a diagnostic assay. Patients with Fanconi anemia typically have short stature, café au lait spots, and anomalies involving the thumb, radius, and genitourinary tract. At least 16 different genetic defects (all but one with an identified gene) have been defined; the most common, type A Fanconi anemia, is due to a mutation in FANCA. Most of the Fanconi anemia gene products form a protein complex that activates FANCD2 by monoubiquitination to play a role in the cellular response to DNA damage and especially interstrand cross-linking.


InternalMed_Harrison

InternalMed_Harrison. Dyskeratosis congenita is characterized by the triad of mucous membrane leukoplasia, dystrophic nails, reticular hyperpigmentation, and with the development of aplastic anemia in childhood. Dyskeratosis is due to mutations in genes of the telomere repair complex, which acts to maintain telomere length in replicating cells: the X-linked variety is due to mutations in the DKC1 (dyskerin) gene; the more unusual autosomal dominant type is due to mutation in TERC, which encodes an RNA template, and TERT, which encodes the catalytic reverse transcriptase, telomerase. Mutations in TNF2, a component of the shelterin complex, proteins that bind the telomere DNA, also occur. In Shwachman-Diamond syndrome, presentation is early in life with neutropenia with pancreatic insufficiency and malabsorption; most patients have compound heterozygous mutations in SBDS that may affect both ribosomal biogenesis (as in Diamond-Blackfan anemia; see below) and marrow stroma function.


InternalMed_Harrison

InternalMed_Harrison. While these constitutional syndromes can on occasion present in adults, genetic mutations are also risk factors for bone marrow failure. In the recently recognized telomeropathies, mutations in TERT and TERC have subtle effects on hematopoietic function. Typical presentations include not only severe but also moderate aplastic anemia, which can be chronic and not progressive, and isolated macrocytic anemia or thrombocytopenia. Physical anomalies are usually not found in the patient, although early hair gray ing is a clue to the diagnosis. A careful family history may disclose pulmonary fibrosis and hepatic cirrhosis. Specific involvement of the bone marrow, liver, and lung is highly variable, as is penetrance of clinical phenotype, both within families and among kindreds. Variable penetrance means that TERT and TERC mutations represent risk factors for marrow failure, as family members with the same mutations may have normal or only slight hematologic abnormalities but more subtle


InternalMed_Harrison

InternalMed_Harrison. means that TERT and TERC mutations represent risk factors for marrow failure, as family members with the same mutations may have normal or only slight hematologic abnormalities but more subtle evidence of (compensated) hematopoietic insufficiency.


InternalMed_Harrison

InternalMed_Harrison. Bone marrow failure results from severe damage to the hematopoietic cell compartment. In aplastic anemia, replacement of the bone marrow by fat is apparent in the morphology of the biopsy specimen (Fig. 130-1) and magnetic resonance imaging (MRI) of the spine. Cells bearing the CD34 antigen, a marker of early hematopoietic cells, are greatly diminished, and in functional studies, committed and primitive progenitor cells are virtually absent; in vitro assays BD have suggested that the stem cell pool FIGURE 130-1 Normal and aplastic bone marrow. A. Normal bone marrow biopsy. B. Normal is reduced to ≤1% of normal in severe bone marrow aspirate smear. The marrow is normally 30–70% cellular, and there is a heterogeneous disease at the time of presentation. mix of myeloid, erythroid, and lymphoid cells. C. Aplastic anemia biopsy. D. Marrow smear in aplas-


InternalMed_Harrison

InternalMed_Harrison. An intrinsic stem cell defect exists tic anemia. The marrow shows replacement of hematopoietic tissue by fat and only residual stromal for the constitutional aplastic anemias: and lymphoid cells. cells from patients with Fanconi anemia exhibit chromosome damage and death on exposure to certain chemical agents. Telomeres are short in some patients with aplastic anemia, due to heterozygous mutations in genes of the telomere repair complex. Telomeres may also shorten physiologically in acquired marrow failure due to replicative demands on a limited stem cell pool.


InternalMed_Harrison

InternalMed_Harrison. Drug Injury Extrinsic damage to the marrow follows massive physical or chemical insults such as high doses of radiation and toxic chemicals. For the more common idiosyncratic reaction to modest doses of medical drugs, altered drug metabolism has been invoked as a likely mechanism. The metabolic pathways of many drugs and chemicals, especially if they are polar and have limited water solubility, involve enzymatic degradation to highly reactive electrophilic compounds; these intermediates are toxic because of their propensity to bind to cellular macromolecules. For example, derivative hydroquinones and quinolones are responsible for benzene-induced tissue injury. Excessive generation of toxic intermediates or failure to detoxify the intermediates may be genetically determined and apparent only on specific drug challenge; the complexity and specificity of the pathways imply multiple susceptibility loci and would provide an explanation for the rarity of idiosyncratic drug reactions.


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InternalMed_Harrison. Immune-Mediated Injury The recovery of marrow function in some patients prepared for bone marrow transplantation with antilymphocyte globulin first suggested that aplastic anemia might be immune mediated. Consistent with this hypothesis was the frequent failure of simple bone marrow transplantation from a syngeneic twin, without conditioning cytotoxic chemotherapy, which also argued both against simple stem cell absence as the cause and for the presence of a host factor producing marrow failure. Laboratory data support an important role for the immune system in aplastic anemia. Blood and bone marrow cells of patients can suppress normal hematopoietic progenitor cell growth, and removal of T cells from aplastic anemia bone marrow improves colony formation in vitro. Increased numbers of activated cytotoxic T cell clones are observed in aplastic anemia patients and usually decline with successful immunosuppressive therapy; type 1 cytokines are implicated; and interferon γ (IFN-γ) induces


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InternalMed_Harrison. cytotoxic T cell clones are observed in aplastic anemia patients and usually decline with successful immunosuppressive therapy; type 1 cytokines are implicated; and interferon γ (IFN-γ) induces Fas expression on CD34 cells, leading to apoptotic cell death. The early immune system events in aplastic anemia are not well understood, but an oligoclonal, T cell response implies antigenic stimulus. The rarity of aplastic anemia despite common exposures (medicines, seronegative hepatitis) suggests that genetically determined features of the immune response can convert a normal physiologic response into a sustained abnormal autoimmune process, including polymorphisms in histocompatibility antigens, cytokine genes, and genes that regulate T cell polarization and effector function.


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InternalMed_Harrison. CLINICAL FEATURES History Aplastic anemia can appear abruptly or insidiously. Bleeding is the most common early symptom; a complaint of days to weeks of easy bruising, oozing from the gums, nose bleeds, heavy menstrual flow, and sometimes petechiae will have been noticed. With thrombocytopenia, massive hemorrhage is unusual, but small amounts of bleeding in the central nervous system can result in catastrophic intra-cranial or retinal hemorrhage. Symptoms of anemia are also frequent, including lassitude, weakness, shortness of breath, and a pounding sensation in the ears. Infection is an unusual first symptom in aplastic anemia (unlike in agranulocytosis, where pharyngitis, anorectal infection, or frank sepsis occurs early). A striking feature of aplastic anemia is the restriction of symptoms to the hematologic system, and patients often feel and look remarkably well despite drastically reduced blood counts. Systemic complaints and weight loss should point to other etiologies of


InternalMed_Harrison

InternalMed_Harrison. symptoms to the hematologic system, and patients often feel and look remarkably well despite drastically reduced blood counts. Systemic complaints and weight loss should point to other etiologies of pancytopenia. Prior drug use, chemical exposure, and preceding viral illnesses must often be elicited with repeated questioning. A family history of hematologic diseases or blood abnormalities, of pulmonary or liver fibrosis, or of early hair graying points to a telomeropathy.


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InternalMed_Harrison. 666 Physical Examination Petechiae and ecchymoses are typical, and retinal hemorrhages may be present. Pelvic and rectal examinations can often be deferred but, when performed, should be undertaken with great gentleness to avoid trauma; these will often show bleeding from the cervical os and blood in the stool. Pallor of the skin and mucous membranes is common except in the most acute cases or those already transfused. Infection on presentation is unusual but may occur if the patient has been symptomatic for a few weeks. Lymphadenopathy and splenomegaly are highly atypical of aplastic anemia. Café au lait spots and short stature suggest Fanconi anemia; peculiar nails and leukoplakia suggest dyskeratosis congenita; early graying (and use of hair dyes to mask it!) suggests a telomerase defect.


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InternalMed_Harrison. LABORATORY STUDIES Blood The smear shows large erythrocytes and a paucity of platelets and granulocytes. Mean corpuscular volume (MCV) is commonly increased. Reticulocytes are absent or few, and lymphocyte numbers may be normal or reduced. The presence of immature myeloid forms suggests leukemia or MDS; nucleated red blood cells (RBCs) suggest marrow fibrosis or tumor invasion; abnormal platelets suggest either peripheral destruction or MDS.


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InternalMed_Harrison. Bone Marrow The bone marrow is usually readily aspirated but dilute on smear, and the fatty biopsy specimen may be grossly pale on withdrawal; a “dry tap” instead suggests fibrosis or myelophthisis. In severe aplasia, the smear of the aspirated specimen shows only red cells, residual lymphocytes, and stromal cells; the biopsy (which should be >1 cm in length) is superior for determination of cellularity and shows mainly fat under the microscope, with hematopoietic cells occupying <25% of the marrow space; in the most serious cases, the biopsy is virtually all fat. The correlation between marrow cellularity and disease severity is imperfect, in part because marrow cellularity declines physiologically with aging. Additionally, some patients with moderate disease by blood counts will have empty iliac crest biopsies, whereas “hot spots” of hematopoiesis may be seen in severe cases. If an iliac crest specimen is inadequate, cells may also be obtained by aspiration from the sternum.


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InternalMed_Harrison. have empty iliac crest biopsies, whereas “hot spots” of hematopoiesis may be seen in severe cases. If an iliac crest specimen is inadequate, cells may also be obtained by aspiration from the sternum. Residual hematopoietic cells should have normal morphology, except for mildly megaloblastic erythropoiesis; megakaryocytes are invariably greatly reduced and usually absent. Granulomas may indicate an infectious etiology of the marrow failure.


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InternalMed_Harrison. Ancillary Studies Chromosome breakage studies of peripheral blood using diepoxybutane or mitomycin C should be performed on children and younger adults to exclude Fanconi anemia. Very short telomere length (available commercially) strongly suggests the presence of a telomerase or shelterin mutation, which can be pursued by family studies and nucleotide sequencing. Chromosome studies of bone marrow cells are often revealing in MDS and should be negative in typical aplastic anemia. Flow cytometry offers a sensitive diagnostic test for PNH. Serologic studies may show evidence of viral infection, such as Epstein-Barr virus and HIV. Posthepatitis aplastic anemia is seronegative. The spleen size should be determined by computed tomography (CT) scanning or ultrasound if the physical examination of the abdomen is unsatisfactory. Occasionally MRI may be helpful to assess the fat content of vertebrae in order to distinguish aplasia from MDS.


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InternalMed_Harrison. The diagnosis of aplastic anemia is usually straightforward, based on the combination of pancytopenia with a fatty bone marrow. Aplastic anemia is a disease of the young and should be a leading diagnosis in the pancytopenic adolescent or young adult. When pancytopenia is secondary, the primary diagnosis is usually obvious from either history or physical examination: the massive spleen of alcoholic cirrhosis, the history of metastatic cancer or SLE, or miliary tuberculosis on chest radiograph (Table 130-1).


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InternalMed_Harrison. Diagnostic problems can occur with atypical presentations and among related hematologic diseases. Although pancytopenia is most common, some patients with bone marrow hypocellularity have depression of only one or two of three blood lines, with later progression to pancytopenia. The bone marrow in constitutional aplastic anemia is morphologically indistinguishable from the aspirate in acquired disease. The diagnosis can be suggested by family history, abnormal blood counts since childhood, or the presence of associated physical anomalies. Aplastic anemia may be difficult to distinguish from the hypocellular variety of MDS: MDS is favored by finding morphologic abnormalities, particularly of megakaryocytes and myeloid precursor cells, and typical cytogenetic abnormalities (see below).


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InternalMed_Harrison. The natural history of severe aplastic anemia is rapid deterioration and death. Historically, provision first of RBC and later of platelet transfusions and effective antibiotics were of some benefit, but few patients show spontaneous recovery. The major prognostic determinant is the blood count. Severe disease has been defined by the presence of two of three parameters: absolute neutrophil count <500/μL, platelet count <20,000/μL, and corrected reticulocyte count <1% (or absolute reticulocyte count <60,000/μL). In the era of effective immunosuppressive therapies, absolute numbers of reticulocytes (>25,000/μL) and lymphocytes (>1000/μL) may be better predictors of response to treatment and long-term outcome.


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InternalMed_Harrison. Severe acquired aplastic anemia can be cured by replacement of the absent hematopoietic cells (and the immune system) by stem cell transplant, or it can be ameliorated by suppression of the immune system to allow recovery of the patient’s residual bone marrow function. Glucocorticoids are not of value as primary therapy. Suspect exposures to drugs or chemicals should be discontinued; however, spontaneous recovery of severe blood count depression is rare, and a waiting period before beginning treatment may not be advisable unless the blood counts are only modestly depressed.


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InternalMed_Harrison. This is the best therapy for the younger patient with a fully histocompatible sibling donor (Chap. 139e). Human leukocyte antigen (HLA) typing should be ordered as soon as the diagnosis of aplastic anemia is established in a child or younger adult. In transplant candidates, transfusion of blood from family members should be avoided so as to prevent sensitization to histocompatibility antigens, but limited numbers of blood products probably do not greatly affect outcome. For allogeneic transplant from fully matched siblings, long-term survival rates for children are approximately 90%. Transplant morbidity and mortality are increased among adults, due to the higher risk of chronic GVHD and serious infections.


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InternalMed_Harrison. Most patients do not have a suitable sibling donor. Occasionally, a full phenotypic match can be found within the family and serve as well. Far more available are other alternative donors, either unrelated but histocompatible volunteers or closely but not perfectly matched family members. High-resolution matching at HLA and more effective conditioning regimens and GVHD prophylaxis have led to improved survival rates in patients who proceed to alternative donor transplant, in some series approximating results with conventional sibling donors. Patients will be at risk for late complications, especially a higher rate of cancer, if radiation is used as a component of conditioning.


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InternalMed_Harrison. The standard regimen of antithymocyte globulin (ATG) in combination with cyclosporine induces hematologic recovery (independence from transfusion and a leukocyte count adequate to prevent infection) in 60–70% of patients. Children do especially well, whereas older adult patients often suffer complications due to the presence of comorbidities. An early robust hematologic response correlates with long-term survival. Improvement in granulocyte number is generally apparent within 2 months of treatment. Most recovered patients continue to have some degree of blood count depression, the MCV remains elevated, and bone marrow cellularity returns toward normal very slowly if at all. Relapse (recurrent pancytopenia) is frequent, often occurring as cyclosporine is discontinued; most, but not all, patients respond to reinstitution of immunosuppression, but some responders become dependent on continued cyclosporine administration. Development of MDS, with typical marrow morphologic or cytogenetic


InternalMed_Harrison

InternalMed_Harrison. respond to reinstitution of immunosuppression, but some responders become dependent on continued cyclosporine administration. Development of MDS, with typical marrow morphologic or cytogenetic abnormalities, occurs in approximately 15% of treated patients, usually but not invariably associated with a return of pancytopenia, and some patients develop leukemia. A laboratory diagnosis of PNH can generally be made at the time of presentation of aplastic anemia by flow cytometry; recovered patients may have frank hemolysis if the PNH clone expands. Bone marrow examinations should be performed if there is an unfavorable change in blood counts.


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InternalMed_Harrison. Horse ATG is administered as intravenous infusions over 4 days. ATG binds to peripheral blood cells; therefore, platelet and granulocyte numbers may decrease further during active treatment. Serum sickness, a flulike illness with a characteristic cutaneous eruption and arthralgia, often develops approximately 10 days after initiating treatment. Methylprednisolone is administered with ATG to ameliorate the immune consequences of heterologous protein infusion. Excessive or extended glucocorticoid therapy is associated with avascular joint necrosis. Cyclosporine is administered orally at an initial high dose, with subsequent adjustment according to blood levels obtained every 2 weeks; rough levels should be between 150 and 200 ng/mL. The most important side effects are nephrotoxicity, hypertension, seizures, and opportunistic infections, especially Pneumocystis jiroveci (prophylactic treatment with monthly inhaled pentamidine is recommended).


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InternalMed_Harrison. Most patients with aplastic anemia lack a suitable marrow donor, and immunosuppression is the treatment of choice. Overall survival is equivalent with transplantation and immunosuppression. However, successful transplant cures marrow failure, whereas patients who recover adequate blood counts after immunosuppression remain at risk of relapse and malignant evolution. Because of excellent results in children and younger adults, allogeneic transplant should be performed if a suitable sibling donor is available. Increasing age and the severity of neutropenia are the most important factors weighing in the decision between transplant and immunosuppression in adults who have a matched family donor: older patients do better with ATG and cyclosporine, whereas transplant is preferred if granulocytopenia is profound.


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InternalMed_Harrison. Outcomes following both transplant and immunosuppression have improved with time. High doses of cyclophosphamide, without stem cell rescue, have been reported to produce durable hematologic recovery, without relapse or evolution to MDS, but this treatment can produce sustained severe fatal neutropenia, and response is often delayed. The effectiveness of androgens has not been verified in controlled trials, but occasional patients will respond or even demonstrate blood count dependence on continued therapy. Sex hormones upregulate telomerase gene activity in vitro, which is possibly also their mechanism of action in improving marrow function. For patients with moderate disease, especially if a telomere defect is present, or those with severe pancytopenia in whom immunosuppression has failed, a 3to 4-month trial is appropriate.


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InternalMed_Harrison. Hematopoietic growth factors (HGFs) such as erythropoietin and granulocyte colony-stimulating factor (G-CSF) are not definitive therapy for severe aplastic anemia, and even their roles as adjuncts to immunosuppression are not clear. In research protocols, thrombopoietin mimetics have shown surprising activity in patients with refractory aplastic anemia, with patterns of blood count recovery suggesting that they act as stem cell stimulants.


InternalMed_Harrison

InternalMed_Harrison. Meticulous medical attention is required so that the patient may survive to benefit from definitive therapy or, having failed treatment, to maintain a reasonable existence in the face of pancytopenia. First and most important, infection in the presence of severe neutropenia must be aggressively treated by prompt institution 667 of parenteral, broad-spectrum antibiotics, usually ceftazidime or a combination of an aminoglycoside, cephalosporin, and semisynthetic penicillin. Therapy is empirical and must not await results of culture, although specific foci of infection such as oropharyngeal or anorectal abscesses, pneumonia, sinusitis, and typhlitis (necrotizing colitis) should be sought on physical examination and with radiographic studies. When indwelling plastic catheters become contaminated, vancomycin should be added. Persistent or recrudescent fever implies fungal disease: Candida and Aspergillus are common, especially after several courses of antibacterial antibiotics. A major


InternalMed_Harrison

InternalMed_Harrison. vancomycin should be added. Persistent or recrudescent fever implies fungal disease: Candida and Aspergillus are common, especially after several courses of antibacterial antibiotics. A major reason for the improved prognosis in aplastic anemia has been the development of better antifungal drugs and the timely institution of such therapy when infection is suspected. Granulocyte transfusions using G-CSF–mobilized peripheral blood may be effective in the treatment of overwhelming or refractory infections. Hand washing, the single best method of preventing the spread of infection, remains a neglected practice. Nonabsorbed antibiotics for gut decontamination are poorly tolerated and not of proven value. Total reverse isolation does not reduce mortality from infections.


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InternalMed_Harrison. Both platelet and erythrocyte numbers can be maintained by transfusion. Alloimmunization historically limited the usefulness of platelet transfusions and is now minimized by several strategies, including use of single donors to reduce exposure and physical or chemical methods to diminish leukocytes in the product; HLA-matched platelets are often effective in patients refractory to random donor products. Inhibitors of fibrinolysis such as aminocaproic acid have not been shown to relieve mucosal oozing; the use of low-dose glucocorticoids to induce “vascular stability” is unproven and not recommended. Whether platelet transfusions are better used prophylactically or only as needed remains unclear. Any rational regimen of prophylaxis requires transfusions once or twice weekly to maintain the platelet count >10,000/μL (oozing from the gut increases precipitously at counts <5000/μL). Menstruation should be suppressed either by oral estrogens or nasal follicle-stimulating


InternalMed_Harrison

InternalMed_Harrison. to maintain the platelet count >10,000/μL (oozing from the gut increases precipitously at counts <5000/μL). Menstruation should be suppressed either by oral estrogens or nasal follicle-stimulating hormone/luteinizing hormone (FSH/LH) antagonists. Aspirin and other nonsteroidal anti-inflammatory agents inhibit platelet function and must be avoided.


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InternalMed_Harrison. RBCs should be transfused to maintain a normal level of activity, usually at a hemoglobin value of 70 g/L (90 g/L if there is underlying cardiac or pulmonary disease); a regimen of 2 units every 2 weeks will replace normal losses in a patient without a functioning bone marrow. In chronic anemia, the iron chelators, deferoxamine and deferasirox, should be added at approximately the fiftieth transfusion to avoid secondary hemochromatosis.


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InternalMed_Harrison. Other, more restricted forms of marrow failure occur, in which only a single circulating cell type is affected and the marrow shows corresponding absence or decreased numbers of specific precursor cells: aregenerative anemia as in PRCA (see below), thrombocytopenia with amegakaryocytosis (Chap. 140), and neutropenia without marrow myeloid cells in agranulocytosis (Chap. 80). In general, and in contrast to aplastic anemia and MDS, the unaffected lineages appear quantitatively and qualitatively normal. Agranulocytosis, the most frequent of these syndromes, is usually a complication of medical drug use (with agents similar to those related to aplastic anemia), either by a mechanism of direct chemical toxicity or by immune destruction. Agranulocytosis has an incidence similar to aplastic anemia but is especially frequent among older adults and in women. The syndrome should resolve with discontinuation of exposure, but significant mortality is attached to neutropenia in the older and often


InternalMed_Harrison

InternalMed_Harrison. but is especially frequent among older adults and in women. The syndrome should resolve with discontinuation of exposure, but significant mortality is attached to neutropenia in the older and often previously unwell patient. Both pure white cell aplasia (agranulocytosis without incriminating drug exposure) and amegakaryocytic thrombocytopenia are exceedingly rare and, like PRCA, appear to be due to destructive antibodies or lymphocytes and can respond to immunosuppressive therapies. In all of the single-lineage failure syndromes, progression to pancytopenia or leukemia is unusual.


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InternalMed_Harrison. is probably the more common immune mechanism. Cytotoxic lym- Transient erythroblastopenia of childhood killer cell activity inhibitory of erythropoiesis have been demonstrated Transient aplastic crisis of hemolysis (acute B19 parvovirus infection) in particularly well-studied individual cases.


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InternalMed_Harrison. Transient aplastic crisis of hemolysis (acute B19 parvovirus infection) in particularly well-studied individual cases. Fetal red blood cell aplasia Nonimmune hydrops fetalis (in utero B19 parvovirus infection) PERSISTENT PARVOVIRUS B19 INFECTION Hereditary pure red cell aplasia Chronic parvovirus infection is an important, treatable cause of PRCA. Congenital pure red cell aplasia (Diamond-Blackfan anemia) This common virus causes a benign exanthem of childhood (fifth disease) and a polyarthralgia/arthritis syndrome in adults. In patients with production), parvovirus infection can cause a transient aplastic crisis and an abrupt but temporary worsening of the anemia due to failed erythropoiesis. In normal individuals, acute infection is resolved by Paraneoplastic to solid tumors production of neutralizing antibodies to the virus, but in the setting of Connective tissue disorders with immunologic abnormalities congenital, acquired, or iatrogenic immunodeficiency, persistent viral


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InternalMed_Harrison. Systemic lupus erythematosus, juvenile rheumatoid arthritis, rheumatoid infection may occur. The bone marrow shows red cell aplasia and the arthritis presence of giant pronormoblasts (Fig. 130-2), which is the cytopathic Multiple endocrine gland insufficiency sign of B19 parvovirus infection. Viral tropism for human erythroid progenitor cells is due to its use of erythrocyte P antigen as a cellular receptor for entry. Direct cytotoxicity of virus causes anemia if demands Persistent B19 parvovirus, hepatitis, adult T cell leukemia virus, Epstein-Barr on erythrocyte production are high; in normal individuals, the tempo- rary cessation of red cell production is not clinically apparent, and skin and joint symptoms are mediated by immune complex deposition. Especially phenytoin, azathioprine, chloramphenicol, procainamide, isoniazid Antibodies to erythropoietin


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InternalMed_Harrison. Especially phenytoin, azathioprine, chloramphenicol, procainamide, isoniazid Antibodies to erythropoietin History, physical examination, and routine laboratory studies may disclose an underlying disease or a drug exposure. Thymoma should be sought by radiographic procedures. Tumor excision PRCA is characterized by anemia, reticulocytopenia, and absent or rare erythroid precursor cells in the bone marrow. The classification of PRCA is shown in Table 130-4. In adults, PRCA is acquired. An identical syndrome can occur constitutionally: Diamond-Blackfan anemia, or congenital PRCA, is diagnosed at birth or in early childhood and often responds to glucocorticoid treatment; mutations in ribosome protein genes are etiologic. Temporary red cell failure occurs in transient aplastic crisis of hemolytic anemias due to acute parvovirus infection (Chap. 221) and in transient erythroblastopenia of child- hood, which occurs in normal children.


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InternalMed_Harrison. PRCA has important associations with immune system diseases. A small minority of cases occur with a thymoma. More frequently, red cell aplasia can be the major manifestation of large granular lymphocytosis or complicate chronic lymphocytic leukemia. Some patients may be hypogammaglobulinemic. Infrequently (compared to agranulocytosis), PRCA can be due to an idiosyncratic drug reaction. Subcutaneous administration of erythropoietin (EPO) has provoked PRCA mediated by neu-CD tralizing antibodies. FIGURE 130-2 Pathognomonic cells in marrow failure syndromes. A. Giant pronormoblast, the