aplastic Anemia

Hematopoetic stem cells in the bone marrow are continuously being stimulated to produce differentiated granulocytes, erythrocytes, and platelets. An adequate pool of these cells is required to deliver oxygen to tissues (erythrocytes), prevent infection (granulocytes), and maintain blood clotting ability (platelets), as well as maintaining hematopoesis. The high production rates and relatively short life spans, which range from to ! " days, of the differentiated end cells are #ey in producing rapidly serious clinical consequences following compromised bone marrow function. Aplastic anemia, first described by $aul %hrlich in !&&&, is characteri'ed by the development of peripheral blood pancytopenia and a hypocellular bone marrow. The normal hematopoetic tissue is replaced to a greater or lesser extent by fatty marrow. The absent or decreased bone marrow function results in inadequate production of granulocytes, erythrocytes, and platelets. Table ! is a brea#down of the pathogenesis, etiology, and characteristics of the varied forms of aplastic anemia.
PATHOGENESIS (nevitable ETIOLOGY )ytotoxic drugs (rradiation CHARACTERISTICS *ose+dependent $redictable ,nset and recovery dependent on the dose and nature of the etiologic agent (diosyncratic *rugs -iruses (diopathic (nherited 0anconi1s anemia *ys#eratosis congenita ,thers (nfection2(mmune (nfectious mononucleosis .are .are /npredictable in onset $rolonged course (nherited disorders with delayed but progressive aplasia

Associated with autoimmune )irculating hematopoesis inhibitors disease may be detected (ndustrial 3en'ene and other petrochemicals $esticides, insecticides *ose+dependent $roliferative pancytopenia with rare aplasia

4alignant

Acute lymphoblastic leu#emia

4ainly but not exclusively in children

Acute myeloblastic leu#emia 5pontaneous or steroid+induced remission followed by later appearance of leu#emia 4yelodysplastic aplasia

Table 1 The disease can be congenital or acquired, with the latter constituting the ma6ority of cases. Typically, the condition arises in an individual who was previously healthy with no evidence of malignant disease, or exposure to cytotoxic drugs or radiation. Although 7" to 8"9 of cases are idiopathic, drugs, chemicals, toxins, radiation, and infection may cause aplastic anemia. ,ther rare causes of acquired aplastic anemia include pregnancy and thymoma. (t is possible that several inhibitory mechanisms operate at the same time to prevent hematopoesis, and that in any individual different mechanisms may be more or less important. $athology can vary from mild to fatal, and can affect any or all of the marrow+derived cell lines. 5evere aplasia is defined by a leu#ocyte count less than ".7 : !"; 2<, platelet and reticulocyte counts less than " : !"; 2<, and a hypocellular bone marrow. $atients diagnosed with severe disease have a grave prognosis with median survival of under = months, and &"9 mortality within ! to years. *ata suggest an incidence of to 7 cases per million per year in the /nited 5tates, which translates into approximately 7"" to 7"" cases annually. 4en and women are affected non+preferentially. A biphasic distribution has been proposed where incidence rises in patients under ", and pea#s again in those over =".

ETIOLOGY OF ACQUIRED APLASTIC ANE IA

Drugs As a well+#nown cause of aplastic anemia, drugs may produce predictable marrow failure, such as a myelosuppression following cancer chemotherapy. (n Aplastic anemia, drug+induced bone marrow failure is usually an undesirable side effect that may or may not be reversible. .eversible effects are usually dose+dependent and may disappear following withdrawal of the drug. )hloramphenicol, thyroid medications, phenytoin, and chlorproma'ine are all examples that may produce such reversible failure. *rug+induced toxicity that is not dose+dependent, and develops unpredictably wee#s or months post+ treatment is unaffected by withdrawal of the drug and may reflect a genetic predisposition. Although the mechanism for such drug+induced damage is yet elusive, some drugs and their metabolites appear to be directly toxic to hematopoetic stem cells. ,thers are implicated in immune mechanisms such as antibody+mediated suppression of marrow function. Chemicals and Toxins (n !;&&, approximately ,""" cases of aplastic anemia were diagnosed. According to the Aplastic Anemia 0oundation in 3altimore, the rate of incidence has risen to about 7,""" cases annually as of !;;8. (t remains ambiguous as to why exposure to certain chemicals may produce symptoms in some people and not others. The Aplastic Anemia 0oundation has identified a list of suspect chemicals that include some medicines, insecticides, household cleaners, mothballs, dry+cleaning liquids, glues, hair

dyes, paint removers, varnishes and other petrochemical products. 3en'ene and insecticides are most commonly implicated in the pathogenesis of aplastic anemia. Their effect is dose+related and therefore potentially reversible. <ength and amount of exposure to such potential mutagens may also affect presentation of symptoms. >enetic studies from 4idwest farmers indicated that the rate of chromosomal mutation in the farmer1s blood rose sharply in the spring as compared to the fall. $resumably, pesticide and herbicide use were highest in the spring, as compared to the fall and winter when chemical use was absent or minimal. 0urther epidemiological studies may elucidate the role of such chemicals and toxins in causing aplastic anemia. Radiation 4uch evidence exists that radiation has dose+related suppressive effects on marrow function. (ndividuals with prolonged exposure to radiation, such as patients receiving chemotherapy , radiologist, and those exposed to nuclear weapons or nuclear reactors are appear to be at greatest ris# for developing aplastic anemia. 4arrow function usually recovers following withdrawal of the agent. Infection Association of viral infection with aplastic anemia is well documented. $arvovirus 3!; has been shown to cause aplastic crises. *engue viruses often cause transient marrow suppression. Human immunodeficiency virus can produce neutropenia or pancytopenia with hypocellular marrow. EpsteinBarr virus (%3-), which causes infectious mononucleosis, is present in the bone marrow of some aplastic patients. Although the pathogenesis is unclear, %3- is thought to induce suppression of hematopoesis via T cell mediated mechanisms. (mmunologic induction of abnormal T suppressor+T helper cell ratios, abnormal T cell activation and T suppressor proliferation, and enhanced lympho#ine production are possible contributors. 4ost cases with a clear viral+association are in hepatitis patients, usually adolescent boys within = months of infection. Aplastic anemia has been reported to occur either during the acute or recovery phase of hepatitis infection. Although types A and 3 may also be involved, type C hepatitis (H)-) is considered to be the main culprit in hepatitis+associated aplastic anemia. The severity of the viral infection does not appear to correlate with the subsequent development of aplastic anemia. (nterestingly, unli#e %3-, H)- is absent in both marrow and serum. Anti+H)- antibodies are also absent despite progression towards a chronic phase of viral infection. These data suggest that another non+A, non+3, non+) agent may produce both the hepatitis and subsequent aplasia. /nfortunately, the prognosis for such patients is particularly grim, with median survival less than = months and ;"9 mortality at ! year. Pregnancy $regnancy+associated aplastic anemia is extremely rare since marrow cellularity and erythropoesis normally increase during pregnancy. The origin is attributed to the presence of an inhibitor or an absence of a stimulator of hematopoesis. A placenta+crossing inhibitor has been implicated in thrombocytopenia in infants born to mothers diagnosed in pregnancy. 5ince some of these mothers were transfusion recipients, anti+platelet or anti+erythrocyte alloantibodies may be responsible for the infant cytopenia, which generally undergoes spontaneous recovery a few wee#s after birth. $atients with pregnancy+associated aplastic anemia are generally treated with supportive therapy, including platelet and erythrocyte transfusions before delivery. A third of the cases recover following termination of the pregnancy, either following therapeutic abortion or delivery. 5ince symptoms may return upon subsequent pregnancies, the condition itself may induce pathogenesis. Although implicated in some species, estrogens appear not be responsible for the marrow failure in humans. Thymoma

Although the association between thymoma and pure red cell aplasia has been well documented, aplastic anemia is a rare complication. .ecovery following thymectomy has been reported in some cases.

CONGENITAL FOR S OF APLASTIC ANE IA

Fanconis anemia 0anconi1s anemia, frequently associated with dysplasia of the radius and other bones, is an autosomal recessive disorder that is slowly progressive throughout childhood. Although idiopathic, an increased frequency of chromosome brea#s has led to the hypothesis that the condition results from faulty *?A repair mechanisms. *evelopment of leu#emia is a substantial ris#. )lic# here for more information on clinical trials for 0anconi@s anemia. Rare Constitutional Forms ,ne third of patients with Shwachman Diamond Syndrome (a condition characteri'ed by pancreatic insufficiency, malabsorption, and decreased numbers of granulocytes) develop aplastic anemia. Dyskeratosis congenita, another rare :+lin#ed dermatologic syndrome, produces aplastic anemia in approximately half the cases. (n addition, some cases of amegakaryocytic thrombocytopenia have been reported to progress to aplastic anemia. The evidence for genetic predisposition is wea#. )ases of blood dyscrasia in twins have been reported, but the nature of their condition appears to be atypical of idiosyncratic acquired aplastic anemia. Association with H<A type and drug metabolism constitutes another possible genetic predisposition, but interpretation is difficult without adequate #nowledge of the pathogenesis of aplastic anemia.

PATHOPHYSIOLOGY
Defects In or Absence of Stem Cells Animal models provide evidence that loss of marrow function results from defects in or absence of stem cells. 3oggs and 3oggs suggested that marrow failure might result from an inappropriate balance between stem cell replication and differentiation following observations in irradiated mice. *epletion of hematopoetic stem cells via irradiation in mice produces compensatory increases in stem cell replication and a decrease in stem cell differentiation. ,ther studies in mice with drug+induced AlatentA marrow failure indicate a large deficit in stem cells, while having normal blood counts and marrow cellularity. 5ome aplastic anemia cases in humans show data consistent with a quantitative abnormality in stem cells (see 0igure !). In vitro studies of bone marrow cells from patients indicate a decrease in hematopoetic progenitor cells. .estoration of normal hematopoesis following bone marrow transplantation from a genetically identical twin or human leu#ocyte antigen (H<A)+identical sibling in most cases provides further support for this hypothesis. $roviding adequate numbers of normal stem cells is the presumed cause for this recovery. )lic# on the image to have a closer loo# . . .

Fi!"#e 1 A bone marrow biopsy of a patient with aplastic anemia (source) ,ne way to determine if the intrinsic abnormality in hematopoetic stem cells is the pathogenesis of aplastic anemia is to study the effects of bone marrow transplantation in twins. (f absence of or defects in stem cells are important, then infusion of genetically identical marrow cells from the healthy twin should restore normal marrow function. (n one study patients failed to recover when transplantation was not preceded by immunosuppression. Bhen given a second transplant, preceded by immunosuppression, all patients recovered normal marrow function, suggesting an immune mechanism operative in these cases. (n vitro analysis, however, failed to detect antibody+ or cell+mediated suppression of hematopoesis. (n other studies one half of the cases responded to the transplant as if they had a stem cell defect while others recovered normal function only when the transplant was preceded by immunosuppression. 5uch data indicate that the presence of mechanisms other than stem cell defect that may suppress hematopoesis. Microen ironment Defects The 5!25!d mouse is a model of microenvironment defects causing marrow failure. 3one marrow cells from 5!25!d mice can restore hematopoesis in lethally irradiated mice, but infusion of normal marrow cells into these mice does not correct their anemia. The results that a microenvironmental defect, and not stem cell function may be operative in 5!25!d mice. A similar abnormality was noted in one patient with congenital hypoplastic anemia, but further investigation is warranted. Abnormal hormonal regulation does not appear to be a frequent contributor to aplastic anemia pathogenesis because levels of erythropoetin and other granulopoesis stimulants are normal in most cases. Immune Su!!ression of "emato!oesis Antibodies to normal myeloid progenitor cells have been found in approximately 79 of aplastic anemia patients, as well as multiply transfused patients without marrow failure. (mmune mechanisms of bone marrow failure that include transfusion related antibodies may only rarely cause aplastic anemia. ,ther studies have suggested that when abnormal, cellular interactions (which are necessary for regulation of normal hematopoesis) may be important in pathogenesis. T lymphocytes have been reported to promote growth of human erythroid stem cells. Animal models of congenital anemia indicate immune defects involving regulatory T cells may be partly responsible for development of the disease. T lymphocytes from some patients have been shown to inhibit growth of bone marrow cells from normal donors. Callenberg and cowor#ers have shown that a defective stimulating capacity of leu#ocytes, caused by an increased number of suppressor T cells, may contribute to aplastic anemia in some constitutional forms. 3efore transplantation the patient1s mononuclear leu#ocytes displayed defective stimulating capacity and hyporesponsiveness in mixed allogenic leu#ocyte culture. After removal of the T cells, the stimulating capacity of leu#ocytes was completely restored in culture. 5tudies suggest that the generation of suppressor T cells may be a consequence of previous blood transfusions, but the inconsistency of this result between patients ma#es interpretation difficult. .egulation of hematopoesis by T lymphocytes may be both stimulatory and suppressive. *ecreased helper+inducer T cells, increased suppressor+cytotoxic T cells, or the state of activation of T cells are sometimes associated with hematopoesis inhibition, and may produce pathogenesis of aplastic anemia. <ympho#ine abnormalities, such as increased interferon ((0?+ ) by peripheral blood mononuclear

cells, are often present. (0?+ has an inhibitory effect on hematopoesis. Tumor ?ecrosis 0actor+ (T?0+ ), secreted by activated monocytes and macrophages, and by lymphocytes, has been shown to have similar inhibitory effects. 5hinohara et al have observed increased T?0+ production by peripheral blood mononuclear cells in aplastic anemia patients. (n addition, the elevated activities of T?0+ and platelet count were inversely correlated, suggesting a role for T?0+ in the suppression of hematopoesis. Imm"ne F"ncti$n (nterestingly, although most patients have profound abnormalities in hematopoesis, immune function is generally normal. The disparity may be related to the long life span of lymphocytes, which range from months to years, as compared to that of erythrocytes, platelets, and granulocytes. Therefore, abnormalities in marrow function are manifest in circulating hematopoetic cells long before they are noted in circulating lymphocytes. 4inor abnormalities have been noted in some patients, including increased T+ or 3+ lymphocytes, decreased s#in test reactivity, and decreased immunoglobulins. $atient heterogeneity and effects of treatment, however, often complicate critical analyses of such observations. (n a study of ;D patients with severe aplastic anemia !E cases were hepatitis+associated aplasia and the rest idiopathic. >ale, 4itsuyasu, and Fale reported that the !E hepatitis+associated patients had the most notable immune abnormalities. Tests revealed reduced levels of T and 3 cells and monocytes, functional abnormalities in immunoglobulin, decreased alloantigen and mitogen responsiveness in mixed lymphocyte culture and mitogen induced proliferation to phytohemagglutinin and concanavilin A, and impaired s#in test reactivity. 5imilar results have not been reported in hepatitis patients without aplastic anemia, and whether aplastic anemia is the cause or the result of these abnormalities remains to be determined. There is evidence that patients with a history of transfusions exhibit alloimmunity to lymphocytes from H<A+identical donors. Barren and cowor#ers noted that some patients exhibited autoimmune (rarely seen in normal individuals) as well as alloimmune phenomena in patients with no history of transfusion. This indicates an alteration in immunity in these aplastic anemia patients that is only rarely seen in normal individuals. 0urther, the autologous and allogeneic reactivities appear to share a common pathway for cytotoxicity in most instances. Bhile transfusion+induced sensiti'ation to non+ H<A antigens may be responsible for some of the allogeneic reactivity, the alloimmunity noted in patients with no history of transfusion indicates another mechanism at wor#. Barren et al have suggested two possible explanations which argue that pathogenesis of aplastic anemia may be mediated by immunologic mechanisms in some instances. ,ne explanation is that the auto+ and alloimmune phenomena may be secondary to an intrinsic stem cell defect producing the loss of a suppressor or regulator cell for cytotoxic cells. Another is that these phenomena may be a result of a primary event in aplastic anemia, such as the disappearance of suppressor cells, or infection+induced autocytotoxicity.