Which term means a blood disorder characterized by an absence of all formed blood elements?

Aplastic and Hypoplastic Anemia

Aplastic anemia is characterized by pancytopenia and hypoproliferative reticulocyte count in the presence of a hypocellular bone marrow. If it is left untreated, patients usually die from infection or bleeding. Although many drugs (indomethacin, carbamazepine, chloramphenicol, chloroquine, methimazole), environmental toxins (benzene), viruses, and ionizing radiation have been reported to be causally associated with acquired aplastic anemia, the current understanding of the disease mechanism is that of an immune-mediated attack on hematopoietic stem cells.

Holly described eight patients with hypoplastic anemia detected during pregnancy that remitted spontaneously after delivery.91 The bone marrow was described as hypocellular with an increase in megakaryocytes. There are now many case reports and series of pregnancy-associated aplastic anemia, although they present a spectrum of clinical and bone marrow findings that makes it difficult to substantiate the existence of an aplastic anemia specifically related to pregnancy.92–96 Many papers used the criteria delineated by Snyder and coworkers97 as evidence that the disease was pregnancy related: identification of the disease after the onset of pregnancy; no other etiology of aplastic anemia; decrease in all blood cell counts and in Hb level; and hypoplastic bone marrow. However, recovery from the aplastic anemia was not universally documented after delivery, which raises the question of whether it is truly pregnancy related.93,94

Patients with aplastic anemia seek medical attention because of symptoms related to profound anemia, bleeding, or infection. Although fatality rates used to be extremely high, with the current standard of treatment with bone marrow transplantation from an HLA-identical related donor, overall survival of nearly 90% can be achieved in nonpregnant women.98,99 For those without an HLA-identical related donor, immunosuppressive therapy (antithymocyte globulin and cyclosporine) is the treatment of choice. Results of unrelated donor transplantations in these patients, however, have improved from 30% to 70%.100 Bone marrow transplantation is not an option for pregnant women. Alternatives include stem cell stimulation therapy and other supportive therapy.98,99 Survivors have had successful pregnancies after bone marrow transplantation.101,102 The largest series examined pregnancy outcomes in 146 pregnancies occurring after treatment for aplastic anemia in 41 women.102 The outcomes for women treated with total-body irradiation and bone marrow transplantation were compared with those for women treated with high-dosage chemotherapy and bone marrow transplantation. These data demonstrated no increase in the incidence of congenital anomalies in infants. However, total-body irradiation was associated with an increased risk for spontaneous abortion. Twenty-five percent of the pregnancies ended with a preterm birth or delivery of a low-birth-weight infant.102 Another paper described pregnancy outcomes of 36 women with aplastic anemia who had been treated with immunosuppression before their pregnancy.103 Only 11 of these women had complete remission before they became pregnant, and 19% of the total group had a relapse of their aplastic anemia during pregnancy that required transfusion. Two women died, one of whom also had PNH, and two women had eclampsia. The majority of the pregnancies resulted in live births, with a 14% prematurity rate. Several patients were treated with cyclosporine or corticosteroids during their pregnancy.103

Aplastic Anemia

Definition

Aplastic anemia (AA) is a hematologic disorder characterized by pancytopenia on peripheral blood smear and a markedly hypocellular or acellular marrow (see Figure 1). The diagnosis of AA requires the presence of two of three specific criteria in the peripheral blood, as described by the International Agranulocytosis and Aplastic Anemia Study Group. They include hemoglobin <10 g dl− 1 or hematocrit <30%, platelet count <50 × 109 l− 1, and leukocytes <3.5 × 109 l− 1 or granulocytes <1.5 × 109 l− 1. The reticulocyte count should be <30 × 109 l− 1 if one of the two criteria includes hemoglobin <10 g dl− 1. The diagnosis also requires absence or diminution of all hematopoietic cell lines in a hypocellular marrow or decreased granulopoiesis and megakaryopoiesis in normocellular marrow with erythroid hyperplasia, along with the absence of fibrosis or neoplastic infiltration.

Figure 1. Aplastic anemia. H&amp;E. 400 ×.

Adapted from Bennett, J.M., Orazi, A., 2009. Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach. Haematologica 94, 264–268, with permission.

Diagnosis

The evaluation of pancytopenic patients first requires examination of the peripheral blood smear (Chapter 148). If there are morphologic or clinical signs of vitamin B12 or folic acid deficiency (e.g., hypersegmented neutrophils and oval macrocytes), those disorders should be formally ruled out because a bone marrow aspiration and biopsy might not be required in those conditions. Others require a bone marrow aspiration and biopsy. Obtaining both types of samples is important. The biopsy best assesses overall bone marrow cellularity and provides the most sensitive evidence for some infiltrative processes. The aspirated sample can be examined microscopically for the presence of abnormal cells but also provides cells for cytogenetic analyses (which can provide evidence supporting hypoplastic myelodysplasia and acute leukemia). Gene mutations associated with inherited marrow failure syndromes and somatic mutations associated with a high risk of clonal evolution of marrow failure syndromes to myelodysplasia (MDS) and acute myeloid leukemia (AML) are now emerging. Acquired aplastic anemia patients in whom certain somatic mutations (e.g.,ASXL1 andDNMT3A) are detected are reportedly more likely to evolve to myelodysplasia than either those without mutations or mutations ofBCOR,BCORL1, orPIGA. Mutations ofASXL1, DNMT3A, andTET2 are interesting candidates for risk assessment in aplastic anemia patients but the issue is not settled (seeE-Table 156-2) because mutations of these genes are not sufficient to cause MDS or AML.8 It is clear, however, that targeted gene sequencing for both inherited and somatic mutations will be increasingly utilized in the initial evaluation of all patients with unexplained cytopenias or aplastic anemia.8b

E-TABLE 156-2. SOMATIC MUTATIONS REPORTEDLY PREDICTIVE OF CLONAL EVOLUTION TO A MYELOID NEOPLASM∗

AUTOIMMUNE FEATURES AND PATHOGENIC MECHANISMS

Aplastic anemia was originally thought to result from a quantitative deficiency of hematopoietic stem cells precipitated by a direct toxic effect on stem cells. However, attempts to treat aplastic anemia by simple transfusion of bone marrow from an identical twin failed to reconstitute hematopoieisis in most patients. Retransplant of many of these patients following a high-dose cyclophosphamide preparative regimen was successful, suggesting that the pathophysiology of aplastic anemia was more intricate (Champlin et al., 1984; Hintererger et al., 1997).

In the late 1960s, Mathé et al. (1970) were among the first to postulate an immune basis for aplastic anemia. They performed BMT in patients with aplastic anemia using partially mismatched donors after administering antilymphocyte globulin as an immunosuppressive conditioning regimen. Although the patients failed to engraft, the investigators witnessed autologous recovery of hematopoiesis in some patients. This suggested that functional hematopoietic stem cells existed in aplastic anemia patients and that the immune system was somehow suppressing their growth and the differentiation of hematopoietic stem cells. The response to immunosuppressive therapy was the first clear evidence that aplastic anemia was truly an autoimmune disease. Additionally, there appears to be an underlying genetic predisposition to acquired aplastic anemia, as evidenced by the over-representation of the HLA-DR2 subtypes (Nimer et al., 1994).

The first laboratory experiments suggesting an autoimmune pathophysiology were co-culture experiments showing that T lymphocytes from aplastic patients inhibited hematopoietic colony formation in vitro (Nissen et al., 1980; Hoffman et al., 1997). Since then, it has been shown that the immune destruction of hematopoietic stem cells in aplastic anemia is mediated by cytotoxic T cells, and involves inhibitory type 1 helper T-cell (Th2) cytokines and the Fas-dependent cell death pathway. The cytotoxic T cells are usually more conspicuous in the bone marrow than in the peripheral blood (Zoumbos et al., 1985; Maciejewski et al., 1994; Melenhorst et al., 1997b) and overproduce interferon (IFN)-γ and tumor necrosis factor (TNF) (Nakao et al., 1992; Nistico and Young, 1994). TNF and IFN-γ are direct inhibitors of hematopoiesis and appear to upregulate Fas expression on CD34+ cells (Maciejewski et al., 1995). Immortalized CD4+ and CD8+ T-cell clones from some aplastic anemia patients have been shown to secret Th2 cytokines and are capable of killing autologous CD34 cells (Nakao et al., 1997; Zeng et al., 2001). Recently, evidence for a humoral autoimmune response in aplastic anemia has also been reported; 7 of 18 aplastic anemia patients were found to have autoantibodies against kinectin, a 1300 amino acid molecule expressed on human hematopoietic cells, as well as liver, ovary, testis, and brain cells (Hirano et al., 2003).

Studies examining T-cell diversity using complementarity-determining region (CDR3) spectratyping have further implicated the immune system in aplastic anemia. Several groups have found limited heterogeneity of the T cell receptor β chain (Vβ) in aplastic anemia, suggesting that there is oligoclonal or even monoclonal expansion of T-cells in response to a specific antigen (Manz et al., 1997; Melenhorst et al., 1997a; Zeng et al., 1999; 2001). Thus, it is likely that, regardless of the inciting event in aplastic anemia, damage to hematopoietic progenitors initiates an immune process that inhibits hematopoiesis.

An intriguing association exists with hepatitis and is seen in about 1% of newly diagnosed cases. Virtually all cases of the hepatitis–aplastic anemia syndrome are seronegative for known hepatitis viruses (non-A through -G hepatitis). The disease predominantly affects young males, with a precipitous onset of severe pancytopenia occurring within 2–3 months after the onset of hepatitis (Brown et al., 1997; Hagler et al., 1975). Moreover, aplastic anemia has been reported to occur in up to 30% of patients following orthotopic liver transplantation for seronegative hepatitis (Tzakis et al., 1988; Cattral et al., 1994). The aplastic anemia in the hepatitis/aplastic anemia syndrome is autoimmune since most cases respond to immunosuppressive therapy; however, it remains unclear whether the hepatitis results from an undiscovered virus or whether this too is autoimmune.

Aplastic Anemia

Aplastic anemia (AA) is an acquired immune-mediated dis­order of variable severity with predisposing genetic and environmental factors that trigger disease.157 Acquired AA is multifactorial in etiology but is most commonly idiopathic. Patients present with symptoms of anemia or hemorrhage and are found to have pancytopenia and hypocellular bone marrows. Severe AA is characterized by a markedly hypocellular bone marrow (<25% of normal for age or 25% to 50% of normal with <30% hematopoietic cells) accompanied by two of the following: granulocytes <0.5 × 109/L; platelets <20 × 109/L; or corrected reticulocyte count <1% (Fig. 11-46).158 Very serious disease is particularly ominous and further defined by granulocytes <0.2 × 109/L; infection is the major cause of death among these patients.159 The mechanistic focus is increasingly on an immune-mediated process that diminishes the self-renewal and repopulation capacity of normal hematopoietic stem cells.157 T-cell–targeted apoptosis of CD34+ stem cells, and aberrant T-cell activation likely play a role through cytokine-mediated suppression and triggering of immune response pathways. Up to one third of patients have shortened telomeres.160 Severe AA requires immunosuppressive therapy or hematopoietic cell transplantation to stop the immune-mediated destruction. Small PNH clones in 50% to 60% of AA patients are associated with better responsiveness to immunosuppressive therapy in some studies. An erythrocyte PNH clone size of 3% to 5% and a granulocyte PNH clone size of 20% to 25% best predict development of clinical PNH in these patients.161 Bone marrow evaluation for dysplasia, increased CD34+ cells, or progressive karyotypic abnormalities helps to identify progression to hypocellular MDS.

Approximately 25% of children and up to 10% of adults with AA have inherited bone marrow failure syndromes. Pancytopenia is the usual presentation for patients with Fanconi anemia or dyskeratosis congenita. The other congenital syndromes more commonly present with anemia (Diamond-Blackfan anemia), neutropenia (SCN, Kostmann syndrome, SDS), or thrombocytopenia (thrombocytopenia with absent radii, congenital amegakaryocytic thrombocytopenia), and they tend to remain single-lineage disorders (seeTables 11-7, 11-9, and 11-11). In addition to Fanconi anemia and dyskeratosis congenita, patients with SDS and congenital amegakaryocytic thrombocytopenia develop secondary AA, and all patients have an increased risk for progression to MDS or acute myeloid leukemia.

Classification

Aplastic anemia is a hematopoietic blood disorder that results in pancytopenia. Pancytopenia is classified as reduction in number of erythrocytes, all lines of white blood cells, and platelets Young (1997). The disorder may be further classified by its severity: moderate, severe, and very severe.

Moderate aplastic anemia includes the following: Marrow cellularity <30%, absence of severe pancytopenia, and depression of at least two of three blood elements below normal.

Criteria for severe aplastic anemia include bone marrow cellularity of <25% or 25–50% with <30% residual hematopoietic cells with two of three of the following 1) neutrophils <0.5 x 109/l 2), platelets <20 x 109/l, 3) reticulocytes <20 x 109/l.

Criteria for very severe aplastic anemia include the same as above with exception of neutrophils < 0.2 x 109/l Marsh (2006).

Collagen Vascular Diseases

AA is a component of the collagen vascular syndrome called eosinophilic fasciitis. This severe, scleroderma-like disease is characterized by fibrosis of subcutaneous and fascial tissue, localized skin induration, eosinophilia, hypergammaglobulinemia, and an elevated erythrocyte sedimentation rate. The rheumatologic symptoms of fasciitis respond to corticosteroids, but the associated AA has a very poor prognosis. A few patients have survived after BM transplantation or immunosuppressive therapy. More rarely, AA has complicated systemic lupus erythematosus and rheumatoid arthritis, but in many cases, the role of concomitant drug therapy is confounding. Rarely, AA can accompany Sjögren syndrome, multiple sclerosis, and immune thyroid disease. AA occasionally occurs in individuals with hypogammaglobulinemia or congenital immunodeficiency syndrome, thymoma, or thymic hyperplasia.

2 Bone Marrow Failure

AA is a group of inherited and acquired hematologic disorders characterized by the quantitative and qualitative impairment of HSCs in the bone marrow, resulting in a hypoplastic marrow and low peripheral blood cell counts (pancytopenia).18 In AA, HSCs are not capable of producing the daily demand for red cells, leukocytes, and platelets. In acquired AA, an immune-mediated destruction of hematopoietic stem and progenitor cells is the major mechanism of disease and it affects both children and adults. Clinical manifestations are due to low blood cell counts: anemia, infection, and mucocutaneous bleeding. Inherited forms of AA usually manifest in the first decade of life and a variety of gene defects compromising HSC function are etiologic. In inherited AA, in addition to hematologic manifestations, physical anomalies also may be observed, such as growth retardation, organ impairment, skin lesions, endocrine insufficiency, and a proclivity for cancer development. FA is the most common type of constitutional AA in which lesions in genes involved in DNA repair (FA pathway) cause marrow failure. DC is the second most common type of inherited AA in which abnormal telomere repair is etiologic. SDS is another type of constitutional AA in which marrow failure associates with exocrine pancreatic deficiency.

Abnormal telomere maintenance plays a role in disease development in both acquired and inherited forms of AA. DC is a more severe phenotype with higher penetrance and the prototype for telomere diseases.

Aplastic Anemia (Pancytopenia)

Aplastic anemia results from a severe decrease in bone marrow production of blood cells, resulting in pancytopenia. In general, the neutrophil count is less than 1500/mm3, the platelet count less than 50,000/mm3, and the hemoglobin concentration less than 10 g/dL. The mortality rate is 46%.12 The International Agranulocytosis and Aplastic Anemia Study reported that 27% of their cases of aplastic anemia were likely drug-related.12 Penicillamine, gold, and carbamazepine were most commonly implicated (Table 63.2). A French group compared drug use in patients with aplastic anemia to hospitalized patients and neighborhood control groups.17 The use of gold, d-penicillamine, or colchicine was associated with higher risk of aplastic anemia. The Swedish Blood Dyscrasia study also found that 25% of their cases of aplastic anemia were probably drug associated.16 TMP-SMX had a reported risk of 13 cases/106 patient-years. However, concomitant viral disease might have played a role in the development of aplasia in some patients. The risk of aplastic anemia from TMP-SMX was much lower in other studies (1.4 cases/106 users per 5-month period12 (see ‘Sulfonamides’ section). Other drugs used in dermatology and associated with risk of aplastic anemia include nonsteroidal anti-inflammatory drugs (NSAID), dapsone, β-lactam antibiotics, and chloroquine.23

The larger studies cited addressing drug causation of aplastic anemia are from decades ago. Interestingly, the most recent review of aplastic anemia mentions drugs, only as causation of chemotherapy related and usually reversible pancytopenia. In addition, they emphasized increasing evidence for mutations leading to genetic predisposition to aplastic anemia and the induction of probable immune mechanisms of cytopenia, triggered by chemical, viruses, drugs, or antigens.29–30

Aplastic Anemia (AA); PRCA (ASFA Category III [Recommendation Grade 2C] for AA; ASFA Category II [Recommendation Grade 2C] for PRCA)

AA is defined as marked pancytopenia with hypocellular bone marrow and PRCA is characterized by normochromic normocytic anemia, reticulopenia, with almost complete absence of marrow erythroblasts. Most cases of AA and PRCA are acquired, however unusual inherited forms exist. For both AA and PRCA, underlying etiologies, such as medications, malignancies or infections, should be sought and treated. TPE has been successful in the treatment of AA in patients with autoimmune diseases. TPE may be considered in patients with severe AA who do not have a HPC transplant option and have failed to respond to conventional immunosuppressive therapy. TPE may also improve PRCA developing after major ABO-mismatched HPC transplant or in the setting of erythropoietin therapy with anti-erythropoietin antibodies. TPE should be performed daily or every other day until recovery of hematopoiesis, which can take at least 2–3 weeks.