AUTOIMMUNE HEMOLYTIC ANEMIA

Autoimmune hemolytic anemia (AIHA) is characterized by development of antibodies against own RBCs, either due to inappropriate immune response to a normal RBC antigen or alteration of RBC antigens by some disease/ drugs, to render them 'foreign' or antigenic.

Types: Depending on the immunological abnormality, AHA may be classified as:

• AIHA with warm antibodies (usually IgG class), which are active between 35-40°C (common in children and usually idiopathic in origin)

• AIHA with cold antibodies (usually IgM class), which are most active lt;37°C (rare in children and usually secondary to some disease)

• Drug-induced immune hemolytic anemia.

Etiology: Common causes of AIHA are:

• Primary or idiopathic

• Secondary

- Infections: EBV, mycoplasma, other viruses

- Lymphoproliferative disorders and neoplasms

- Connective tissue disorders, e.g. SLE

• Drugs: Penicillin, quinine, methyldopa

Clinical manifestations may be of two types:

• Acute transient hemolytic anemia (70-80%), with sudden hemoglobinuria, rapidly progressive pallor, jaundice and splenomegaly. This presentation is common at 2-12 years of age, characterized by absence of underlying disease in most cases, spontaneous recovery in 3-6 months and good response to steroids.

• Chronic hemolytic anemia, persisting for many years is common in infants or adolescents. These cases usually have underlying systemic disease and do not respond well to steroids.

Diagnosis depends on: (a) exclusion of other causes for acquired hemolytic anemia, (b) strongly positive direct Coomb test suggestive of the presence of antibodies on RBC surface, and (c) frequently positive indirect Coomb test suggestive of the presence of free antibodies in serum.

Management: While no treatment is needed in mild cases, moderate/severe AIHA is treated with:

• Blood transfusions (cross-matching may be difficult in these cases).

• Long-term steroids (PO Prednisolone 1-2 mg#8725; kg/d q6hr for 4-8 weeks or till normalization of hemoglobin, followed by low-dose alternate day maintenance therapy for 3-6 months.

• IV immunoglobulins (1 gm/kg/day x 2 days) and plasmapheresis in steroid non-responsive cases.

• Immunosuppressive therapy with cyclophosphamide, cyclosporine must be considered in steroid-refractory or dependent cases. Rituximab (anti-CD20) monoclonal antibodies have shown a response rate of 80% in AIHA with cold agglutinins, not responding to steroids.

Splenectomy leads to sustained remission in gt; 50% cases, though should be avoided in children.

Other newer therapies include Bortezomib (inhibitor of 26S proteasome) and Eculizumab (mono­clonal anti-C5 antibody licensed for paroxysmal nocturnal hemoglobinuria).

• Cases with cold AIHA are unlikely to respond to steroids but usually have a self-limiting course and must be managed with supportive care till recovery, including repeated transfusions.

19.6 APLASTIC ANEMIA

Aplastic anemia (AA) is a sign of bone marrow dysfunc­tion, characterized by pancytopenia or bicytopenia due to marked reduction in hematopoietic stem cells or progenitor cells of multiple cell-lines. However, isolated pure red cell anemia of bone-marrow origin is not uncommon, which should not be grouped as aplastic anemia (discussed later).

Etiology: Aplastic anemia may be constitutional or acquired (Table 19.14).

• Constitutional AA denotes intrinsic deficiency of stem-cells, seen in many chromosomal/genetic disorders. Commonest cause of constitutional AA is Fanconi anemia-usually an autosomal recessive disorders (FANC genes), frequently associated with physical stigmata, e.g. short stature, hyperpigmented skin, multiple cafe-au-lait spots and bony defects, e.g. hypoplastic thumb.

• Acquired AA is either due to: (a) destruction of stem cells or colony forming units by direct or immunological marrow injury following infections, drugs, toxins, etc., or (b) deficiency of growth factors, e.g.

Acquired AA is more common than constitutional AA and responds poorly to marrow stimulant therapy.

Clinical presentation: Constitutional AA usually pre­sents at ~5-10 years of age, while acquired AA can

TABLE 19.14: Causes of aplastic anemia

Congenital: (constitutional)

• Fanconi anemia

• Shwachman-Diamond syndrome

• Dyskeratosis congenital

Acquired:

• Drugs: Chloramphenicol, cytotoxic agents, NSAIDs

• Viruses: Parvovirus B19, EBV, HIV, CMV

• Toxins: DDT, benzene, heavy metals

• Indltrative lesions: Leukemia, metastasis

• Others: Thymoma, radiation, PNH

• Idiopathic

PNH: Paroxysmal noctural hemoglobinuria

present at any age depending on the cause, with common clinical features of:

• Severe pallor due to erythropenia,

• Bleeding tendencies due to thrombocytopenia,

• Recurrent infections due to leucopenia.

Hepatosplenomegaly is typically absent or minimal. Dysmorphic features, discussed earlier, are common in Fanconi anemia, while features of causative marrow insult may be present in acquired AA.

Diagnosis rests on hematological picture suggestive of depression of all (pancytopenia) or at least two cell lines (bicytopenia), i.e.

• Severe anemia with low reticulocyte count (RPI lt;1%),

• Leukopenia with absolute neutrophil count lt;500/ mm3

• Thrombocytopenia (lt;20,000/mm3)

Bone marrow examination is essential to confirm the diagnosis (hypocellular bone marrow) and exclude other causes of pancytopenia, e.g. leukemia.

Management: Hematopoietic stem cell transplantation (HSCT) is the only cure for Fanconi anemia and most of other AA, with success rate of 50-80%. Other principles of management include:

• Supportive care with—(a) avoidance of infections, (b) early diagnosis and treatment of intercurrent illnesses/ infections, and (c) repeated packed RBCs/platelet transfusion to maintain safe hematological profile. Prophylactic platelet transfusion is recommended at platelet count lt;10,000/mm3 while antibiotic and antifungal prophylaxis is recommended at absolute neutrophil count lt; 500 cells/mm3.

• Oral androgen therapy has been widely used to treat Fanconi anemia, in whom HSCT is not possible with initial success rate of ~50%, though relapses are common. Oxymetholone or Nandrolone (PO 2-3 mg/ kg/day) is commonly used for this purpose, given for 3-4 months followed by gradual tapering. Low- dose steroids may be used concomitantly to minimize growth acceleration and virilising side effects of androgens and prevent thrombocytopenic bleeding by promoting vascular stability.

• Immunosuppressive therapy is recommended in acquired AA (not in Fanconi anemia) with transfusion­dependent or severe disease, if HSCT is not possible. It involves a combination of antithymocyte globulin or ATG (IV 20-40 mg/kg/day ? 4-8 days) and cyclosporine (PO 8-15 mg/kg OD), with success rate to induce remission as ~50%. Cyclosporine should be continued for at least 12 months after hematological response, followed by slow tapering to reduce the risk of relapse.

• Gene therapy, though still in evolution phase, has provided fresh hope for these cases.

Prognosis: Spontaneous recovery is rare and long-term prognosis is poor in cases without bone marrow trans­plant. Even after the transplant, prognosis is guarded due to risk of recurrence and secondary cancers.

Other marrow disorders with isolated or predominant erythropenia are as follows:

Congenital pure red cell aplasia (Diamond-Blackfan syndrome) is a rare hereditary (AR/AD) disorder, characterized by an intrinsic defect in erythroid precursor cells with relative insensitivity to erythropoietin.

Clinically these cases present with severe anemia by 2-6 months of age. Associated craniofacial and limb defects (triphalangeal thumb) are present in ~1/3^rd cases.

Diagnosis depends on combination of-(a) macrocytic or normocytic normochromic anemia with immature RBCs in peripheral smear, (b) low reticulocyte count, (c) reduced erythroid precursor cells in bone marrow, and (d) normal leukocyte and platelet counts.

Treatment with long-term corticosteroids is beneficial, but response is not consistent or persistent. High-dose IV immunoglobulins or methylprednisolone may be used to induce the initial response. Most cases require repeated transfusions with chelation therapy. Bone marrow transplant is rarely helpful.

Outcome: Nearly half of these cases survive till adult­hood, with complications, e.g. hypersplenism and hemosiderosis.

Acquired pure red cell anemia is rarer in children than the acquired AA, mostly seen in association with-

(a) viral infections, e.g. EBV or parvovirus B₁₉ infections,

(b) drugs, e.g. phenytoin, sulfonamides, chloramphenicol, etc., and (c) thymoma (due to formation of anti-EPO antibodies).

Most cases respond well to immunosuppressive therapy with steroids or cyclosporin, along with with­drawal of offending drug or treatment of primary cause. Repeated transfusions are necessary till recovery.

Transient erythroblastopenia is relatively more common than congenital or acquired pure red cell anemia, presenting with moderate to severe anemia between 6 months to 3 years. Over 80% cases recover spontaneous in 1-2 months. Exact etiology is not known, but most cases are previously healthy (idiopathic) or have history of minor viral infections.

Anemia in chronic diseases, e.g. infections, inflam­matory disorders, malignancies and chronic renal disease is attributed to multiple factors, e.g. (a) bone marrow dysfunction, (b) low erythropoietin levels, (c) nutritional deficiencies and (d) increased hemolysis.

Hematologically, these cases usually have normocytic normochromic/hypochromic anemia with low reti­culocyte count and hypocellular bone marrow. Low serum iron and total iron binding capacity (d/d high TIBC in iron deficiency) is common.

Congenital dyserythropoietic anemia (CDA) are rare inherited normocytic or macrocytic anemias, characte­rised by multi-nuclearity and abnormal chromatin patterns in RBC precursors suggestive of abnormal bone marrow maturation.

a. CDA type I (15%) presenting any time from infancy onwards with marked erythroid hyperplasia in bone marrow and presence of binuclear erythroblasts (lt;10% cells), inter-nuclear chromatin bridges between erythroblasts and megaloblasts.

b. CDA type II (60%), presenting in second decade with higher percentage of multinuclear erythroblasts (15-30%) and positive HAM test but negative sucrose lysis test (d/d Paroxysmal nocturnal hemoglobinuria).

c. CDA type III (15%), is more common in adults with erythroblastic multinuclearity in 10-40% cells (sometimes Gigantoblasts) and negative HAM test.

Clinically, age and severity of presentation may vary from hydrops fetalis at birth to recurrent/persistent hemolytic anemia in older children or adults with mild icterus and hepatosplenomegaly.

Management varies according to severity. While most cases require occasional transfusions, those with frequent transfusion require chelation therapy and may benefit from splenectomy.

Myelodysplastic syndrome is a pre-leukemic stage with 15-20% risk of evolving into acute myeloid leuke­mia. These cases present at any age with: (a) chronic refractory anemia/pancytopenia, (b) reticulocytopenia despite hypercellular bone marrow, and (c) presence of lt;5% blast cells in bone marrow.

Diagnosis depends on bone marrow studies and treatment is supportive. Prognosis is poor in cases with secondary transformation into leukemia, though bone marrow transplant may be useful.

19.7