Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 6)

Immune-Mediated Injury The recovery of marrow function in some patients prepared for bone marrow transplantation with antilymphocyte globulin (ALG) 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...
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Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 6) Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 6) Immune-Mediated Injury The recovery of marrow function in some patients prepared for bonemarrow transplantation with antilymphocyte globulin (ALG) first suggested thataplastic anemia might be immune-mediated. Consistent with this hypothesis wasthe frequent failure of simple bone marrow transplantation from a syngeneic twin,without conditioning cytotoxic chemotherapy, which also argued both againstsimple stem cell absence as the cause and for the presence of a host factorproducing marrow failure. Laboratory data support an important role for the immune system inaplastic anemia. Blood and bone marrow cells of patients can suppress normalhematopoietic progenitor cell growth, and removal of T cells from aplastic anemiabone marrow improves colony formation in vitro. Increased numbers of activated cytotoxic T cells are observed in aplasticanemia patients and usually decline with successful immunosuppressive therapy;cytokine measurements show a T H1 immune response (interferon γ and tumornecrosis factor). Interferon and tumor necrosis factor induce Fas expression on CD34 cells,leading to apoptotic cell death; localization of activated T cells to bone marrowand local production of their soluble factors are probably important in stem celldestruction. Early immune system events in aplastic anemia are not well understood.Analysis of T cell receptor expression suggests an oligoclonal, antigen-drivencytotoxic T cell response. Many different exogenous antigens appear capable ofinitiating a pathologic immune response, but at least some of the T cells mayrecognize true self-antigens. The rarity of aplastic anemia despite common exposures (medicines,hepatitis virus) suggests that genetically determined features of the immuneresponse can convert a normal physiologic response into a sustained abnormalautoimmune process, including polymorphisms in histocompatibility antigens,cytokine genes, and genes that regulate T cell polarization and effector function. Clinical Features History Aplastic anemia can appear with seeming abruptness or have a moreinsidious onset. Bleeding is the most common early symptom; a complaint of daysto weeks of easy bruising, oozing from the gums, nose bleeds, heavy menstrualflow, and sometimes petechiae will have been noticed. With thrombocytopenia, massive hemorrhage is unusual, but smallamounts of bleeding in the central nervous system can result in catastrophicintracranial 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 unusualfirst symptom in aplastic anemia (unlike in agranulocytosis, where pharyngitis,anorectal infection, or frank sepsis occur early). A striking feature of aplastic anemia is the restriction of symptoms to thehematologic system, and patients often feel and look remarkably well despitedrastically reduced blood counts. Systemic complaints and weight loss should point to other etiologies ofpancytopenia. Prior drug use, chemical exposure, and preceding viral illnessesmust often be elicited with repeated questioning. A family history of hematologicdiseases or blood abnormalities may indicate a constitutional etiology of marrowfailure. Physical Examination Petechiae and ecchymoses are typical, and retinal hemorrhages may bepresent. Pelvic and rectal examinations can often be deferred but, when performed,should be undertaken with great gentleness to avoid trauma; these will often showbleeding from the cervical os and blood in the stool. Pallor of the skin and mucousmembranes is common except in the most acute cases or those already transfused.Infection on presentation is unusual but may occur if the patient has beensymptomatic for a few weeks. Lymphadenopathy and splenomegaly are highlyatypical of aplastic anemia. Café au lait spots and short stature suggest Fanconisanemia; peculiar nails and leukoplakia suggest dyskeratosis congenita. Laboratory Studies Blood The smear shows large erythrocytes and a paucity of platelets andgranulocytes. Mean corpuscular volume (MCV) is commonly increased.Reticulocytes are absent or few, and lymphocyte numbers may be normal orreduced. The presence of immature myeloid forms suggests leukemia or MDS;nucleated red blood cells suggest marrow fibrosis or tumor invasion; abnormalplatelets suggest either peripheral destruction or MDS.