ANEMIAS AND OTHER RED CELL DISORDERS - PART 6 pps

10 PEDIATRIC BONE MARROW FAILURE SYNDROMESDIAMOND-BLACKFAN ANEMIA, ERYTHROGENESIS pro-of the disorders present in the neonatal period or early in childhood.. CHAPTER 10 PEDIATRIC BONE MA

S E C T I O N

IV

Stem Cell Dysfunction

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10 PEDIATRIC BONE MARROW FAILURE SYNDROMES

(DIAMOND-BLACKFAN ANEMIA, ERYTHROGENESIS

pro-of the disorders present in the neonatal period or early in childhood Improveddiagnostic tools along with recognition of the variability inherent in these condi-tions now reveal mild manifestations or forme fruste in adolescents or even youngadults The uneven clinical texture of these conditions is a continuing challenge toclinicians

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䊏 FANCONI’S ANEMIA (CONGENITAL APLASTIC ANEMIA)

In 1927, Professor Guido Fanconi of Zurich, Switzerland, described several families inwhich there were children with striking congenital anomalies including absent radii,abnormal thumbs, short stature, and hyperpigmentation Children with no obviouscongenital anomalies have also been described These children develop hematologicalabnormalities at a mean age of about 7 years; initially thrombocytopenia followedprogressively by neutropenia and anemia

FA is a heterogeneous conglomeration of disorders derived from a collection ofimpendent mutations involving genes on several chromosomes.1Cell fusion studiesdone in vitro show that cellular components from two unrelated patients with FA cancombine to eliminate the Fanconi phenotype In other words, cells from the two FA

patients complement each other and correct the defect Of the 11 currently known

complementation groups, gene identification data exist for 8.2Three genes, FANCA,

FANCC, and FANCG, account for 90% of FA cases Interestingly, FANCD1 is identical

to the breast cancer susceptibility gene BRCA2.

The molecular details of the cellular action of the FA complementation groupproteins are unclear A number of the proteins appear to be components of a molecularcomplex that fosters chromosomal stability.3,4Absence of the FA proteins impairs the

function of the complex Deranged regulation of apoptosis in FA cells and aberranttelomere shortening could be consequences of deranged chromosome stability factors

In the fully developed syndrome, the patients have pancytopenia and the bone row is hypocellular The red cells are macrocytic with increased Hb F content that canprecede marrow failure The usual diagnostic test for FA involves culturing peripheralblood lymphocytes in the presence of a DNA cross-linking agent such as diepoxybu-tane (DEB) In FA, the chromosomal metaphases show DNA repair abnormalitiesevidenced by a high proportion of chromatid breaks, gaps, and rearrangements andendoreduplications

mar-Androgen therapy improves the anemia in about two-thirds of patients, but mostbecome resistant to the treatment over time Complications of synthetic androgentherapy include masculinization, severe acne, and hepatic damage (hepatic peliosisand liver tumors) Supportive treatment with red cell and platelet transfusions then isoften required Total bone marrow failure with consequent death within a few years

of its onset is the fate of most patients

Longer survival of some patients with FA has unveiled a high cumulative incidence

of myelodysplasia and leukemia, in the range of 10% over 25 years.5Long-survivingpatients are also 50 times more likely than normal to develop solid tumors involvingparticularly the esophagus and oropharynx.6The prognosis is dismal in such cases.Stem cell transplantation is the only cure for FA.7However, because the cells ofthese patients cannot repair DNA damage, conditioning procedure with immunosup-pressive agents and radiation must be modified with reduced intensity Cures havebeen obtained using HLA-compatible stem cells from siblings, and most recentlywith cord blood stem cells

CHAPTER 10 PEDIATRIC BONE MARROW FAILURE SYNDROMES 187

䊏 CONGENITAL HYPOPLASTIC ANEMIA (DIAMOND-BLACKFAN ANEMIA, ERYTHROGENESIS IMPERFECTA)

In 1938, Drs Louis K Diamond and Kernneth Blackfan described four children withsevere, aregenerative, macrocytic anemia that developed in the first year of life Theanemia was so severe that regular RBC transfusions were necessary to sustain life.The other formed elements of the blood were normal, so it was classified as a “purered cell anemia.” In the subsequent years more than 500 cases have been formallyreported, but a current national registry includes more than 1000 cases.8

The disease appears in 2–7 per million live births Diamond-Blackfan anemia(DBA) affects most ethnic groups, but Caucasian children predominate among thereported cases Although repeat cases have been noted in a some families, suggest-ing a genetic cause, the preponderance of cases is sporadic.9 Although the cause

of DBA has not been established in most cases, about 25% of patients studied todate have mutations involving RPS19, a ubiquitously expressed ribosomal proteinrequired for efficient translation in all cells The mutations in DBA disrupt its normallocalization in the nucleolus.10In vitro experiments that disrupt production of RPS19

in hematopoietic precursor cells produce a phenotype very similar to that seen inDBA.11

Anemia (or pallor) is noteworthy at or shortly after birth, and instances of found intrauterine anemia causing hydrops fetalis have been described Two-thirds ofchildren are diagnosed by 6 months and virtually all are identified before 1 year ofage At the time of diagnosis, hemoglobin levels can be as low as 2.0 g/dL The redcells are macrocytic with a higher than normal Hb F content The reticulocyte count

pro-is very low (<0.1%) The remainder of the peripheral blood count is usually

nor-mal, although moderate neutropenia occurs in some patients Erythrocyte adenosinedeaminase (ADA) levels are two to three times greater than normal in most patients(Table 10-1).12Plasma and urinary levels of erythropoietin are elevated over baseline.The bone marrow is normally cellular with normal complements of neutrophilprecursors, megakaryocytes, and lymphocytes However, erythroid precursors of ev-ery maturational stage are markedly reduced or absent, producing myeloid/erythroidratios ranging from 10/1 to 200/1 Bone marrow cultures produce very few BFU-E

or CFU-E

About 25% of patients have physical abnormalities, including short stature andfacial, cardiac, and renal abnormalities A small subset of patients have tri- rather thanbiphalangeal thumbs (Asse syndrome) The incidence of cancer in DBA is higher thannormal but lower than that seen in FA

About two-thirds of children respond to corticosteroid therapy, maintaining mal or near normal hemoglobin levels without transfusions.13 Corticosteroids such

nor-as oral prednisone in a dose of 2–4 mg/kg/day is the initial treatment with responseheralded by a reticulocytosis in 1–2 weeks followed by a rise in hemoglobin to normallevels At that time a gradual reduction in prednisone dose is possible, sometimes to

as little as 0.5–1.0 mg/day Some patients respond to alternate day steroids, which

T A B L E 10 - 1 KEY DIAGNOSTIC POINTS IN PEDIATRIC BONE

MARROW FAILURE

DBA versus TEC • Anemia • Normochromic red cells in

TEC; macrocytic red cells inDBA

• Normal neutrophiland platelet counts

• Pancytopenia • Physical examination looking

for subtle features of FA

• Chromosome instability test

DBA, Diamond-Blackfan anemia; TEC, transient erythroblastic anemia of childhood; ADA, adenosine deaminase; FA, Fanconi’s anemia.

produce fewer side effects Response failures sometimes occur with usual doses ofsteroids, but patient rescue occurs at times with higher doses Patients who initiallyrespond to steroids can become refractory to the treatment Spontaneous remissionshave also been described

Children who do not respond to steroids or who need toxic doses of the drugsrequire regular red cell transfusions Transfusional hemosiderosis requiring chelationtherapy complicates this intervention Children with DBA develop transfusional ironoverload more slowly than do those with hemolytic anemias, probably because ironabsorption is not increased Hematopoietic stem cell transplantation can cure DBAand should be considered for transfusion-dependent children, particularly when theyhave an HLA-compatible sibling potential donor.14

Pure red cell anemia does occur in older children and adults (see Chapter 2) Thecondition sometimes is associated with a thymic tumor Drugs such as chlorampheni-col also occasionally induce pure red cell anemia

䊏 TRANSIENT ERYTHROBLASTIC ANEMIA

OF CHILDHOOD

Transient erythroblastic anemia of childhood (TEC) is a self limited, aregenerativeanemia that occurs in otherwise healthy children (Table 10-2).15 The mean age atonset is about 2 years Pallor and symptoms of anemia are the usual presentingmanifestations TEC seems to be an autoimmune disease as indicated by the presence

of circulating immunoglobulins in the patient that inhibit the growth of BFU-E andCFU-E in tissue culture The basis of this aberrant antibody production is unknown,but it is not related to parvovirus B19 (see below)

The anemia, which may be severe, develops slowly since there is no concomitanthemolytic process Patients often are remarkably asymptomatic given the severity

CHAPTER 10 PEDIATRIC BONE MARROW FAILURE SYNDROMES 189

Long-term management

of Fanconi’s anemia

Androgens improve the pancytopenia in most cases

Androgen efficacy declines over time whileandrogen-associated complications increase Stem celltransplantation should be considered when anHLA-matched sibling exists

Transient erythroblasticanemia of childhoodversus parvovirus B19infection

TEC occurs in normal children and is self-limited, usuallyrequiring no intervention Children with mild previouslyundiagnosed hemolytic anemias sometimes present due toparvovirus B19 infection The picture can be very similar tothat of TEC These children can however develop

life-threatening anemia Serum IgM titers againstparvovirus B19 clarify the diagnosis Transfusion supportmay be needed until recovery

DBA, Diamond-Blackfan anemia; TEC, transient erythroblastic anemia of childhood.

of the anemia The reticulocyte count is very low (<0.1%) In contrast to DBA,

TEC patients are older, have normocytic rather than macrocytic red cells, and theerythrocyte levels of ADA and Hb F are normal The rest of the peripheral bloodelements are usually normal, but some patients have thrombocytosis The bone marrow

is normally cellular and initially shows few red cell precursors

Spontaneous recovery occurs within 1–2 months In the recovery period there is

a brisk reticulocytosis that may be misinterpreted as indicating a hemolytic process.The reticulocytosis ends when the hemoglobin level returns to normal Recurrencesare unusual

䊏 RED CELL APLASIA ASSOCIATED WITH PARVOVIRUS B19 INFECTION

Parvovirus B19 infection often produces exaggerated anemia and reticulocytopenia(aplastic crises) in children with various kinds of hemolytic anemias Since parvovirusinfections in childhood with consequent erythema infectiosum (Fifth disease) arethe norm, this complication is usually but not exclusively a pediatric problem No

parvovirus vaccine suitable for human use currently exists, although one is availablefor veterinary purposes.

The parvovirus directly infects the CFU-E and inhibits proliferation A virtualcessation of red cell production ensues lasting for 1–2 weeks until host production ofIgM antibodies clear the organism In a normal child, with an erythrocyte life span

of 120 days, 10 days of red cell aplasia lowers the hemoglobin level insignificantly.However, in children with hemolytic anemia, such as sickle cell disease, where redcell survival can be as short as 10–20 days, 1–2 weeks of erythroid inactivity producesprofound anemia During aplastic crises the anemia worsens and bilirubin levels de-crease Profound reticulocytopenia (<0.1%) develops Bone marrow aspiration shows

a marked decrease in erythroid precursors Giant pronormoblasts are characteristic ofthis disease, and electron microscopy can demonstrate a plethora of viral particles intheir cytoplasm

The anemia can be sufficiently profound as to require red cell transfusions Onlysmall transfusions (5–7 mL/kg of RBC) are necessary, however, since prompt, spon-taneous recovery is routine Treatment with intravenous immunoglobulin may hastenrecovery During the recovery period, the child can still have severe anemia in associ-ation with a prodigious reticulocytosis Children initially seen during early recoverysometimes receive an erroneous diagnosis of “hemolytic crisis.”

Parvovirus infection produces lasting immunity in the immunologically intact dividuals, meaning that recurrent aplastic crises do not occur However, immunocom-promised individuals who cannot mount an antibody response (e.g., HIV infection)can develop a chronic aregenerative anemia due to persistent viral infection Periodicinfusions of intravenous gamma globulin may be indicated A mother with a primaryparvovirus infection during pregnancy can transmit the virus to the fetus Gestationalinfection can produce severe anemia with a mortality rate of about 10% with theoccasional development of hydrops fetalis

in-䊏 PEARSON SYNDROME

This rare syndrome is characterized by a refractory, aregenerative, macrocytic mia that is accompanied by exocrine pancreatic dysfunction and metabolic acidosis.16The anemia is present in early life and is often transfusion dependent Striking mor-phological abnormalities are present in the bone marrow There is intensive vac-uolization of myeloid and erythroid precursors and the presence of “ringed sider-oblasts” (erythroid precursors with iron laden mitochondria in the cytoplasm) (seeChapter 12) Patients develop, and often die, of the consequence of mitochondrial dys-function including metabolic acidosis and deranged metabolism involving oxidativephosphorylation

ane-The syndrome is caused by extensive deletions of mitochondrial DNA.17,18

The inheritance of this condition is maternal, because mitochondria are presentonly in the ovum19 but no familial cases have been described Most of these chil-dren die in infancy, but a few have survived with improvement of the anemia but

of the skin, and leukoplakia Three quarters of cases are inherited as an X-linkeddisorder, and these boys have an abnormal gene at chromosome Xq28 that encodesthe protein dyskerin About 50% of patients develop marrow failure and pancytopenia

at an average age of 15 years at onset Various therapies aimed at the hematologicabnormalities have been used with varying degrees of effectiveness including G-CSF,androgens, and stem cell transplantation Acute myelogenous leukemia and othermalignancies have been reported in adult life The average survival is about 30 years,most patients dying as a result of complications of pancytopenia or malignancy

References

1 Alter B 1993 Fanconi’s anemia: Current concepts Am J Pediatr Hematol Oncol 14:170

2 Tischkowitz M, Dokal I 2004 Fanconi anaemia and leukaemia—clinical and molecularaspects Br J Haematol 126:176–191

3 Taniguchi T, Tischkowitz M, Ameziane N, et al 2003 Disruption of the Fanconi anemia—BRCA pathway in cisplatin-sensitive ovarian tumors Nat Med 9:568–574

4 Hussain S, Witt E, Huber PA, Medhurst AL, Ashworth A Mathew CG 2003 Direct action of the Fanconi anaemia protein FANCG with BRCA2/FANCD1 Hum Mol Genet12:2503–2510

inter-5 Alter BP, Caruso JP, Drachtman RA, Uchida T, Velagaleti GV, Elghetany MT 2000 Fanconianemia Myelodysplasia as a predictor of outcome Cancer Genet Cytogenet 117:125–131

6 Alter BP, Greene MH, Velazquez I, Rosenberg PS 2003 Cancer in Fanconi anemia Blood101:2072

7 Socie G, Devergie A, Girinski T, et al 1998 Transplantation for Fanconi’s anaemia:Longterm follow-up of fifty patients transplanted from a sibling donor after low-dosecyclophosphamide and thoraco-abdominal irradiation for conditioning Br J Haematol103:249–255

8 Vlachos A, Klein GW, Lipton JM 2001 The Diamond Blackfan Anemia registry: Toolfor investigating the epidemiology and biology of Diamond Blackfan anemia J PediatrHematol Oncol 23:377–382

9 Orfali KA, Ohene-Abuakwa Y, Ball SE 2004 Diamond Blackfan anaemia in the UK:Clinical and genetic heterogeneity Br J Haematol 125:243–252

10 Da Costa L, Tchernia G, Gascard P, et al 2003 Nucleolar localization of RPS19 protein

in normal cells and mislocalization due to mutations in the nucleolar localization signals

in 2 Diamond-Blackfan anemia patients: Potential insights into pathophysiology Blood101(12):5039–5045

11 Flygare J, Kiefer T, Miyake K, et al 2005 Deficiency of ribosomal protein S19 inCD34+ cells generated by siRNA blocks erythroid development and mimics defects seen

in Diamond-Blackfan anemia Blood 105:4627–4634

12 Glader BE, Backer K 1986 Elevated erythrocyte adenosine deaminase levels in congenitalhypoplastic anemia N Eng J Med 309:486

13 Willig TN, Niemeyer CM, Leblanc T, et al 1999 Identification of new prognosis factorsfrom the clinical and epidemiologic analysis of a registry of 229 Diamond-Blackfan ane-mia patients DBA group of Societe d’Hematologie et d’Immunologie Pediatrique (SHIP),Gesellshaft fur Padiatrische Onkologie und Hamatologie (GPOH), and the European So-ciety for Pediatric Hematology and Immunology (ESPHI) Pediatr Res 46:553–561

14 Vlachos A, Lipton JM Hematopoietic stem cell transplant for inherited bone marrow failuresyndromes In: Mehta P, ed Pediatric Stem Cell Transplantation Sudbury, MA: Jones andBartlett; 2004:281–311

15 Wang NC, Mentzer WC 1976 Differentiation of transient erythroblastopenia of childhoodfrom congenital hypoplastic anemia J Pediatr 88:784

16 Pearson HA, Lobel JS, Kocoshis SA, et al 1979 A new syndrome of refractory sideroblasticanemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction JPediatr 95:976–984

17 Cormier V, Rotig A, Quartino AR, et al 1990 Widespread multi-tissue deletions of themitochondrial genome in the Pearson marrow-pancreas syndrome J Pediatr 117:599–602

18 Rotig A, Cormier V, Koll F, et al 1991 Site specific deletions of the mitochondrial genome

in the Pearson Marrow Pancreas Syndrome Genomics 10:502–504

19 Lightowlers RN, Chinnery PF, Turnbull DM, Howell N 1997 Mammalian mitochondrialgenetics: Heredity, heteroplasmy and disease Trends Genet 13:450–455

20 Drachtman RA, Alter BP 1995 Dyskeratosis congenital Dermatol Clin 13: 33

11 ACQUIRED BONE MARROW FAILURE SYNDROMES

CLINICAL PRESENTATION 194 ETIOLOGY 196 TREATMENT OF APLASTIC ANEMIA 199

Normal bone marrow function is vital both to health and survival The organ isremarkable in its ability to compensate for defects that impair the operation or function

of any of the major cell lineages Bone marrow failure produces not only anemia,but also varying degrees of thrombocytopenia and neutropenia The clinical impactthat arises from the loss of neutrophil and platelet cell lineages often determinesthe patient’s ultimate fate with respect to bone marrow failure Anemia often is animportant but decidedly secondary factor in these events

Table 11-1 classifies the primary causes of acquired bone marrow failure The orders have both similarities and differences Placing a patient’s condition specificallyinto one category or another at times is problematic due to the significant overlap inclinical features that characterize the several groups Myelodysplasia has singularlyimportant clinical characteristics that set it apart from the other three conditions inthe list Not only are chromosomal disturbances more common with myelodysplasia,the disorder has a risk of conversion into acute leukemia that substantially exceedsthat associated with any of the other conditions in Table 11-1 In fact, myelodysplasiawas once termed “preleukemia,” a testament to its leukemic potential The disorder

dis-is covered separately from the other conditions in Table 11-1

䊏 APLASTIC ANEMIA

Aplastic anemia is a rare disorder whose incidence approximates two per million inWestern countries Paul Ehrlich introduced the concept of aplastic anemia in 1888when he described a pregnant woman who died of bone marrow failure In 1904,

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T A B L E 11 - 1 ACQUIRED BONE MARROW FAILURE SYNDROMES

Aplastic anemiaPure red cell aplasiaParoxysmal nocturnal hemoglobinuriaMyelodysplasia

Anatole Chauffard coined the term “aplastic anemia” to describe this devastatinghematological syndrome Case reports and autopsy findings in the early part of thetwentieth century slowly filled in key clinical aspects of the illness and establishedaplastic anemia as the paradigm of bone marrow failure A striking bimodal agedistribution characterizes aplastic anemia, with the largest group of patients beingadolescents or young adults A second cohort of patients present in later adulthood,typically in the sixth or seventh decades of life

Aplastic anemia has no ethnic or racial predilection However, the disorder is morefrequent in the developing world Estimates vary, but the incidence in developingcountries appears to exceed those in the West by between two- and fourfold Thediscrepancy likely represents the impact of environmental factors that predispose tobone marrow aplasia

CLINICAL PRESENTATION

The clinical presentation of aplastic anemia depends on where the patient stands inthe evolution of the disorder Fatigue, shortness of breath and ringing in the ears, man-ifestations of severe anemia, most commonly prompt the initial physician visit Olderpatients sometimes have chest pains, reflecting impaired cardiac oxygen delivery in

a setting of cardiac blood flow limited in part by atherosclerosis Nearly everyonereports a recent tendency toward easy bruising that reflects the thrombocytopeniaassociated with bone marrow aplasia Interestingly, complaints related to neutropeniaare uncommon at presentation

Striking pallor dominates the initial clinical impression The manifestation ismost obvious in people with relatively low levels of intrinsic skin pigmentation.Pale mucous membranes and nail beds are the key finding in people with darkerskin Jaundice typically is absent from the otherwise pasty complexion Ecchymosesalong the waistline represent bruising from clothing, including the impact of belts andsupportive garments Ecchymoses and petechiae are nearly universal on the dependentbody surfaces including the pretibial surfaces, ankles, and wrists

Direct ophthalmoscopy commonly shows pale retinae often with small areas ofhemorrhage Gingival oozing is a frequent manifestation Although some patients

CHAPTER 11 ACQUIRED BONE MARROW FAILURE SYNDROMES 195

spontaneously give a history of bleeding with tooth brushing, others provide thishistory only upon direct questioning Poor dental hygiene and associated gingivitisincreases the prominence of this finding

Prominent manifestations on cardiac examination include tachycardia and systolicmurmurs Both findings directly reflect the enhanced cardiac activity that develops

in part as compensation for the severe anemia Bounding pulses are routine Carotidbruits occur frequently in older patients

Less common manifestations at presentation include folliculitis and other skininfections Stool guaiac examination commonly is positive, but frank blood in thestool is uncommon Women often report heavier than normal menses over the weeks

or months preceding presentation Metrorrhagia is a distinctly less common plaint Lymphadenopathy is uncommon at presentation and prominent lymph nodeenlargement raises the specter of other conditions, such as lymphoma

com-Pancytopenia is the hallmark of aplastic anemia Uneven depression ofhemoglobin value, platelet count, and neutrophil count often exists at presentation,particularly in the early stages in the evolution of the disorder Aplastic anemia alsovaries tremendously in severity Some people have moderate depression of all threecell lines and require little or no treatment Other less fortunate people need immedi-ate and sometimes heroic intervention in response to a condition of life-threateningseverity The prognosis for severe aplastic anemia is more tenebrous than that ofmilder disease

The diagnosis of aplastic anemia applies to patients who show two of the followingthree criteria: (1) hemoglobin<10 g/dL, (2) platelets <50,000/μL, (3) neutrophils

<1500/μL.1 Bone marrow examination shows a marked reduction in the number

of hematopoietic elements, with fat cells filling the vacuum Although some of theresidual hematopoietic precursors can appear aberrant, striking dysplastic featuresare not characteristic of aplastic anemia Myelodysplasia is the major diagnosticconsideration in patients who have marked dysplasia of the hematopoietic elements

In such diagnostic dilemmas, chromosome analysis is very useful since karyotypeanomalies are hallmarks of myelodysplasia but are infrequent with aplastic anemia.The bone marrow examination is an important step in ruling out disorders that sec-ondarily produce peripheral blood pancytopenia and thus impersonate aplastic anemia(Table 11-2) Leukemia in which malignant cells are confined to the bone marrowproduces a pancytopenia that fully mimics aplastic anemia The occasional blastcell can evade detection on peripheral blood examination This so-called “aleukemicleukemia” is much more of an issue in childhood acute lymphocytic leukemia than isthe case with acute myelogenous leukemia

Less commonly, marrow replacement by lymphoma cells or myeloma cells duces a peripheral blood picture consistent with aplastic anemia Extensive bone mar-row fibrosis associated with a myeloproliferative disorder, most prominently myelofi-brosis with myeloid metaplasia, at times produces a bland pancytopenia Schistocytesand other features on peripheral blood examination that point to distorted bone marrowarchitecture due to fibrosis are sometimes subtle Miliary tuberculosis with extensivebone marrow involvement at times presents a peripheral blood picture that is indis-tinguishable from aplastic anemia

pro-T A B L E 11 - 2 CONDITIONS THAT MIMIC APLASTIC ANEMIA DUE TO

MARROW REPLACEMENT

Leukemia confined to the bone marrow

LymphomaMultiple myelomaMyelofibrosisTuberculosis of the bone marrowMetastatic neuroblastoma in children

Fat comprises up to 90% of the marrow cellularity in some patients with tic anemia The fat cells do not actively replace normal marrow elements, as occurswith the fibroblasts and other stromal elements in patients with myelofibrosis Fatcells merely fill in by default the regions of the marrow left empty by the disap-pearance of the hematopoietic elements The process is general throughout the bonemarrow space as shown by imaging of the vertebra with MRI or other sensitivetechniques

aplas-The severity of aplastic anemia at presentation both affects the prognosis of thecondition and dictates the treatment considerations Severe aplastic anemia as de-fined by the International Aplastic Anemia Study Group requires (1) bone marrowcellularity<25% of normal or 25–50% of normal with <30% residual hematopoi-

etic cells and (2) two of the following three criteria: neutrophils<500/μL, platelets

<20,000/μL, and reticulocytes <1%.2 The prognosis is particularly dire in patients

in whom the neutrophil count falls below 200 cells/μL.

ETIOLOGY

Cases of acquired aplastic anemia most commonly lack a clear cause with as many as60% falling under the “idiopathic” rubric (Table 11-3) Table 11-3 also lists some ofthe conditions known to produce aplastic anemia as a secondary phenomenon Bonemarrow damage from radiation exposure can produce marrow aplasia Radiation ofsufficient intensity to produce aplastic anemia occurs only with medical treatmentfor cancer or in the aftermath of major disasters such as Chernobyl Low-level en-vironmental radiation, such as that associated with radon or other natural sources ofradiation, is not a proven cause of aplastic anemia

Chemicals and drugs figure prominently in the etiology of aplastic anemia Somedrugs produce marrow aplasia as an expected and foreseeable outcome because toxic-ity to proliferating cells is intrinsic to their clinical effect Cancer chemotherapy drugsare the most obvious members of this subgroup Benzene, one of the first industrial

CHAPTER 11 ACQUIRED BONE MARROW FAILURE SYNDROMES 197

ThymomaTransfusion-associated graft-versus-host diseasePregnancy

toxins shown to cause aplastic anemia, also directly injures hematopoietic stem cells.Controls on use and exposure to benzene as well as other organic solvents havevirtually eliminated these agents as sources of aplastic anemia in Western countries.The higher incidence of aplastic anemia in many nations of the developing worldlikely represents unknown or unappreciated exposure to similar agents.3The fact thatpeople of Asian background in the United States do not have the high incidence ofaplastic anemia seen among people in their ancestral countries reinforces the factthat socioeconomic issues in these regions and not genetics dictate the expression ofaplastic anemia.4

Some nonchemotherapy drugs, such as chloramphenicol, have a clear effect relationship with aplastic anemia About half the patients who take high-dosechloramphenicol develop a mild reversible suppression of erythropoiesis that clearswith discontinuation of treatment A conspicuous finding on bone marrow examina-tion is prominent vacuoles, particularly in developing normoblasts Chloramphenicol

cause-and-inhibits mRNA translation by the 70S ribosomes of prokaryotes The drug does notaffect 80S eukaryotic ribosomes Mitochondria, key organelles for both energy pro-duction and heme biosynthesis in erythroid precursor cells, have ribosomes that aresimilar to prokaryotes Chloramphenicol consequently inhibits mitochondrial proteinsynthesis Chloramphenicol-induced vacuole formation in erythroid precursors andthe associated anemia likely reflect this inhibition.5

Distinctly different is the bone marrow aplasia that develops in a small group ofpeople following chloramphenicol exposure In contrast to the mild suppression oferythropoiesis, this idiosyncratic reaction is severe, sustained, affects all cell lines,and does not depend on drug dose.6Data such as the development of aplastic anemia

in identical twins treated with chloramphenicol suggest that a genetic predispositionunderlies this event.7The basis for such a predilection to aplasia with chloramphenicoltreatment remains unknown The rare occurrence of aplastic anemia following theuse of ophthalmic preparations that contain chloramphenicol emphasizes the extremesensitivity of susceptible people.8,9

Establishing a cause-and-effect relationship between a specific drug and aplasticanemia often is a difficult proposition The drugs listed in Table 11-3 only sporadicallycause aplastic anemia The devastating impact of the disorder focuses great attention

on the patient and medications in the patient’s history People commonly are on morethan one medication when the disorder arises, which complicates the task of making

an assignment with respect to cause In contrast to the situation with chloramphenicolwhere idiosyncratic aplastic anemia occurs in relatively close proximity to the start

of drug use, aplastic anemia develops in some patients months or even years afterthey begin using the drugs (see Table 11-3) Most often, therefore, the diagnosis ofdrug-induced aplastic anemia is presumptive

Viral infections often are implicated in the onset of aplastic anemia In contrast

to a history of drug or chemical exposure, objective markers in hepatitis are clear,allowing precise characterization of the post-hepatitis aplastic anemia syndrome.10

The victims usually are young and the hepatitis almost invariably is seronegative,suggesting that a yet-undefined infectious agent is the culprit (hence, the non-A,non-B, non-C, non-G designation) Laboratory and clinical studies both support animmune component to the pathophysiology of post-hepatitis aplastic anemia Thepositive response to immunosuppressive therapy both of the liver inflammation andmarrow aplasia reinforces the point Case control studies in Southeast Asia alsosupport the strong role of an infectious etiology in aplastic anemia, identifying as riskfactors low socioeconomic status, rice farming, and previous exposure to an entericvirus.11Aplastic anemia arises as a rare sequela of infectious mononucleosis.Immune dysregulation is a central thread in many if not most cases of acquiredaplastic anemia, both idiopathic and secondary The seminal observation came in 1970when Mathe and colleagues documented autologous recovery of hematopoiesis in apatient with aplastic anemia who failed to engraft after marrow transplantation.12Theinvestigators proposed that the immunosuppressive regimen used for conditioningprompted recovery of the patient’s endogenous hematopoietic function Numeroussubsequent studies of immunosuppressive therapy show improved marrow function inapproximately 70% of patients with acquired aplastic anemia.13Although the identity

CHAPTER 11 ACQUIRED BONE MARROW FAILURE SYNDROMES 199

of the inciting antigens that breach immune tolerance with subsequent autoimmunity

is unknown, HLA-DR2 is overrepresented among European and American patientswith aplastic anemia suggesting a role for this haplotype in the process.14

An expanded population of CD8 and HLA-DR+ cytotoxic T lymphocytes, tectable in both the blood and bone marrow of patients with aplastic anemia, probablymediates the suppression of hematopoiesis These cells produce cytokines such as in-terferon gamma and tumor necrosis factor that inhibit growth of progenitor cells invitro These cytokines repress hematopoiesis through effects on mitosis as well asdirect cell killing through Fas-mediated apoptosis The cytokines also induce nitricoxide synthase and nitric oxide production by marrow cells, which contributes toimmune-mediated cytotoxicity and elimination of hematopoietic precursor cells.The occasional association of aplastic anemia with immune-mediated disorderssuch as systemic lupus erythematosis reinforces the association of marrow aplasia withimmune dysregulation Aplastic anemia usually develops years after the onset of theprimary problem, suggesting an evolution of immune disturbances associated withthe underlying disorder that ultimately produce marrow aplasia The rare association

de-of aplastic anemia with pregnancy likely is similar to other instances de-of disorderedimmune function that can arise in pregnancy, of which postpartum deficiency of FactorVIII is a prime example Successful pregnancy requires a reset of maternal immunefunction to accommodate the presence of the fetus (which de facto is a foreign body).The basis of the spectacular though thankfully rare failure in this adjustment to theimmune system is a mystery

TREATMENT OF APLASTIC ANEMIA

A number of factors impinge on treatment decisions for patients with aplastic mia including the severity of the condition, comorbid medical conditions, and theavailability of possible transplant donors The high response rate makes immunosup-pressive therapy the treatment of choice for patients whose disease does not fall intothe severe category The most common immunosuppressive regime involves treat-ment with antiserum against lymphoid cells derived from horse or rabbit sources.Immune suppression regimens commonly also include other drugs that modulate im-mune activity, such as cyclosporine Immunosuppressive therapy also is effective inmany people with severe aplastic anemia who are ineligible for the more aggressivestem cell transplantation regimen

ane-Hematopoietic stem cell transplantation is the approach of choice for patients withsevere aplastic anemia The age window for this treatment has gradually widenedover the years, but has not disappeared Although older people can undergo stemcell transplantation, morbidity and mortality associated with the treatment increaseboth with advancing age and coexisting significant medical conditions People withsignificant cardiac or pulmonary disease are at particular risk of death directly related

to the transplant procedure Graft-versus-host disease is also a greater risk for olderpeople relative to youthful victims of aplastic anemia

The infrequency of aplastic anemia and the complexity of the treatment optionsmean that hematologists who specialize in the management of bone marrow failure

should oversee patient care While this is clearly the case for stem cell transplantation,the same holds for medical management using immunosuppressive drugs.

Physicians who initially see a patient with aplastic anemia must at times decide

on supportive management issues before arrangements for tertiary care are complete

A patient with a hemoglobin value of 5 g/dL and signs of congestive heart failurerequires immediate decisions regarding red cell transfusion and other supportive care

A key point of concern revolves around possible alloimmunization of a patient whomight later prove to be a candidate for stem cell transplantation Limited numbers ofblood transfusions probably do not affect the outcome of stem cell transplantation Afew simple points allow appropriate management of the acute clinical issue withoutjeopardizing the long-term outcome

Patients should receive red cell or platelet transfusions as clinically indicated.The key management point is to avoid family members as blood donors to precludesensitization to the minor histocompatibility antigens of a potential stem cell donor.15

Sensitization to minor histocompatibility antigens increases the risk of graft rejectionfollowing HLA-identical hematopoietic stem cell transplantation Platelet collection

by cytapheresis and leukocyte reduction by ultraviolet light or filtration techniqueslowers the risk alloimmunization from transfusions Prophylactic platelet transfusions

to maintain a platelet count in excess of 10,000 cells/μL reduce the risk of catastrophic

bleeds, such as intracranial hemorrhage

䊏 PURE RED CELL APLASIA

Pure red cell aplasia reflects selective destruction of red cell progenitors tations of severe anemia prompt the patient to seek medical attention With the keyproviso that the neutrophil and platelet counts are normal, the presentation mirrors that

Manifes-of acquired aplastic anemia Symptoms related to severe anemia exist Patients ever lack petechiae, ecchymoses, or other signs of bleeding that factor prominently

how-in the presentation of aplastic anemia

Severe anemia and reticulocytopenia are hallmarks of pure red cell aplasia Absentfrom the peripheral blood are abnormal red cell features such as schistocytes, targetcells, spherocytes, or basophilic stippling The peripheral blood red cells are in factremarkably insipid One clue concerning the basis of the anemia is a modest elevation

of the MCV The mean MCV often is just over 100 fL, a value too high to be ignoredand too low to indicate deficiency of folate or cobalamin

Normal bone marrow cellularity with an overwhelming preponderance of myeloidprecursors can briefly give the impression of a proliferative process involving whitecells A second look however shows the problem to be one of absent erythroid pre-cursors rather than an excess of myeloid progenitors The almost complete absence

of late erythroid precursors is typical Proerythroblasts sometimes exist, depending

on the precise site of the block in erythroid cell maturation Foreign elements such

as fibroblasts and fibrosis are not part of the marrow picture The profound failure

of erythroid progenitors is the basis of the modest MCV elevation Any phenomenonthat severely stresses erythroid production capacity slightly increases the MCV value

CHAPTER 11 ACQUIRED BONE MARROW FAILURE SYNDROMES 201

Most cases of pure red cell aplasia reflect disturbances in immune regulation thatspecifically suppress erythroid precursor maturation The list of disorders associatedwith pure red cell aplasia is manifold, including thymoma, rheumatoid arthritis, sys-temic lupus erythematosis, chronic lymphocytic leukemia, and lymphoma The factthat some of these disorders, such as systemic lupus erythematosis, are very commonwhile pure red cell aplasia is very rare suggests that the etiology reflects an intersectionwith other as yet unknown factors Particularly interesting is the association of purered cell aplasia with large granular lymphocytic leukemia, a disorder that involvesthe cells of natural killer subgroup of lymphocytes

Some patients have serum antibodies that are selectively cytotoxic for marrowerythroid cells or that are directed against erythropoietin.16 In other instances, sup-pression of erythroid precursors is a cell-mediated process involving abnormal Tcells.17,18 The frequent positive response to immunosuppressive therapies, includ-

ing corticosteroids and cyclosporine, in these patients stresses the immunologicalunderpinnings of the anemia.19

Pure red cell aplasia at times develops in the setting of a viral infection, larly infection with human parvovirus B19 This adeno-associated virus causes “FifthDisease,” a normally benign childhood disorder associated with fever, malaise, and

particu-a mild rparticu-ash The virus hparticu-as particu-a tropism for erythroid progenitor cells particu-and impparticu-airs celldivision for a few days during the infection Reticulocyte counts often fall literally tozero Normal people experience, at most, a slight drop in hematocrit since the half-life

of erythrocytes in the circulation is 40–60 days The viral infection resolves in a fewdays with no long-lasting problem

The scenario differs in people who fail to clear the viral infection properly Poorclearance sometimes reflects an underlying immune disorder, but on occasion occurswithout a clear cause.20Persistent infection with parvovirus B19 produces pure redcell aplasia The diagnosis of pure red cell aplasia secondary to parvovirus B19infection is therapeutically important because these patients respond dramatically

to immunoglobulin therapy.21 Commercial immunoglobulin preparations are rich inantibodies directed against parvovirus B19 due to the high exposure rate to the virusamong adults

䊏 PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare condition thatnonetheless provides important insights into the physiology of red cells by highlight-ing the importance of the glycosylphosphatidylinositol (GPI) anchor that attachesmany proteins to the cell membrane The striking nature of its defining characteristic,the passage of dark urine at night, made the condition one of the first clearly de-scribed hematological disorders The hemoglobinuria reflects the massive intravascu-lar hemolysis that afflicts some patients with the condition All patients with PNH havesome degree of hemolysis, even those without the striking pathognomonic episodes.Although this remarkable clinical feature placed the spotlight early on the erythro-cyte, significant and clinically important abnormalities exist as well in platelets and