Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 4)

Infections Hepatitis is the most common preceding infection, and posthepatitis marrow failure accounts for about 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, non-G) and possibly due to a novel, as yet undiscovered, virus. 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, and Epstein-Barr virus has been found in the...
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Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 4) Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 4) Infections Hepatitis is the most common preceding infection, and posthepatitismarrow failure accounts for about 5% of etiologies in most series. Patients areusually young men who have recovered from a bout of liver inflammation 1 to 2months earlier; the subsequent pancytopenia is very severe. The hepatitis isseronegative (non-A, non-B, non-C, non-G) and possibly due to a novel, as yetundiscovered, virus. Fulminant liver failure in childhood also follows seronegativehepatitis, and marrow failure occurs at a high rate in these patients. Aplasticanemia can rarely follow infectious mononucleosis, and Epstein-Barr virus hasbeen found in the marrow of a few patients, some without a suggestive precedinghistory. Parvovirus B19, the cause of transient aplastic crisis in hemolytic anemiasand of some PRCAs (see below), does not usually cause generalized bone marrowfailure. Mild blood count depression is frequent in the course of many viral andbacterial infections but resolves with the infection. Immunologic Diseases Aplasia is a major consequence and the inevitable cause of death intransfusion-associated graft-versus-host disease (GVDH), which can occur afterinfusion of unirradiated blood products to an immunodeficient recipient. Aplasticanemia is strongly associated with the rare collagen vascular syndrome calledeosinophilic fasciitis, which is characterized by painful induration of subcutaneoustissues (Chap. 316). Pancytopenia with marrow hypoplasia can also occur insystemic lupus erythematosus. Pregnancy Aplastic anemia very rarely may occur and recur during pregnancy andresolve with delivery or with spontaneous or induced abortion. Paroxysmal Nocturnal Hemoglobinuria An acquired mutation in the PIG-A gene in a hematopoietic stem cell isrequired for the development of PNH, but PIG-A mutations probably occurcommonly in normal individuals. If the PIG-A mutant stem cell proliferates, theresult is a clone of progeny deficient in glycosylphosphatidylinositol-linked cellsurface membrane proteins (Chap. 101). Such PNH cells are now accuratelyenumerated using fluorescence-activated flow cytometry of CD55 or CD59expression on granulocytes rather than Ham or sucrose lysis tests on red cells.Small clones of deficient cells can be detected in about half of patients withaplastic anemia at the time of presentation [and PNH cells are also seen in MDS(see below)]; frank hemolysis and thrombotic episodes occur in patients with largePNH clones (>50%). Functional studies of bone marrow from PNH patients, eventhose with mainly hemolytic manifestations, show evidence of defectivehematopoiesis. Patients with an initial clinical diagnosis of PNH, especiallyyounger individuals, may later develop frank marrow aplasia and pancytopenia;patients with an initial diagnosis of aplastic anemia may suffer from hemolyticPNH years after recovery of blood counts. One popular but unproven explanationfor the aplastic anemia/PNH syndrome is selection of the deficient clones becausethey are favored for proliferation in the peculiar environment of immune-mediatedmarrow destruction. Constitutional Disorders Fanconis anemia, an autosomal recessive disorder, manifests as congenitaldevelopmental anomalies, progressive pancytopenia, and an increased risk ofmalignancy. Chromosomes in Fanconis anemia are peculiarly susceptible to DNAcross-linking agents, the basis for a diagnostic assay. Patients with Fanconisanemia typically have short stature, café au lait spots, and anomalies involving thethumb, radius, and genitourinary tract. At least 12 different genetic defects (all butone with an identified gene) have been defined; the most common, type AFanconis anemia, is due to a mutation in FANCA. Most of the Fanconis anemiagene products form a protein complex that activates FANCD2 bymonoubiquitination to play a role in the cellular response to DNA damage andespecially interstrand cross-linking, a response that includes BRCA1, ATM, andNBS1. Dyskeratosis congenita is characterized by mucous membrane leukoplasia,dystrophic nails, reticular hyperpigmentation, and the development of aplasticanemia during childhood. The X-linked variety is due to mutations in the DKC1(dyskerin) gene; the more unusual autosomal dominant type is due to mutation inhTERC, which encodes an RNA template, and hTERT, which encodes the catalyticreverse transcriptase, telomerase; these gene products cooperate in a repaircomplex to maintain telomere length. In Shwachma ...