Hereditary spherocytosis (HS)

It is a common cause of hemolytic anemia, occurring at a frequency of 1 in 2000 in individuals of Northern European ancestry. Most cases are inherited in an autosomal dominant fashion. In some cases it is inherited as autosomal recessive disease or develops from new mutations. It results from mutations in genes coding for proteins that are part of the RBC membrane and whose normal function is to make RBCs more flexible, membrane transport, maintaining structural integrity and providing attachment to other proteins. As a result, RBCs become more rigid and spherical (spherocytes) rather than biconcave discs. Spherocytes are more prone to hemolysis. Most mutations are in the ANK1 (ankyrin-1) gene, followed by EPB42, SLC4A1, SPTA1 and SPTB.

HS presents with anemia, jaundice and splenomegaly. It may be mild (Hb 11-15 gm/dl), moderate (Hb 8-11 gm/dl) or severe(Hb<8gm/dl). There is increased risk of gallstone formation. Intercurrent Parvovirus B19 infection in HS may cause red cell aplasia (this is a feature seen in most hemolytic anemias). Peripheral smear shows spherocytes. Reticulocytosis is seen. MCV is low and MCHC is high. DAT will be negative. Osmotic fragility test will be positive and shows increased hemolysis in dilute solutions. EMA test or eosin-5-maleimide binding test by flow cytometry is confirmatory. Genetic analysis can be done when needed. Blood transfusions and erythropoietin is needed in severe cases.

IV: Other RBC disorders

1. Aplastic anemia: Pancytopenia as a result of bone marrow failure is called aplastic anemia. Bone marrow is hypocellular in aplastic anemia. It may be idiopathic or secondary to drugs, chemicals, radiation, viruses, anorexia, pregnancy and autoimmune disorders like SLE. Chemotherapeutic agents like methotrexate, daunorubicin, busulfan, anthracyclines, nitrosoureas; drugs like chloramphenicol, chlorpromazine, sulfa drugs, NSAIDS, corticosteroids, gold, antithyroid medications, lithium, antidiabetics like tolbutamide and chlorpropamide; chemicals like benzene derivatives, arsenicals, insecticides like DDT and lindane; infections like Parvovirus B19, HIV, EBV, Hepatitis viruses, dengue virus etc. can cause aplastic anemia.

   In aplastic anemia, hematopoietic stem cells are attacked by effector T cells leading to bone marrow failure. Drugs can cause aplastic anemia by direct cytotoxic effect or idiosyncratic response. Patients with PNH can develop AA and vice versa.

   Clinical features are anemia, hemorrhage and recurrent infections, all resulting from pancytopenia and bone marrow failure. Peripheral smear shows pancytopenia and relative lymphocytosis. Bone marrow aspirate may yield a dry tap. Bone marrow is hypocellular with reduction of all cell lines and increased fat content. Absolute neutrophil count is low, platelet count is low and leukocyte alkaline phosphatase is high. Treatment consists of corticosteroids, removal of offending agent, anti-thymocyte or anti-lymphocyte serum, cyclosporine, blood transfusion, stem cell or bone marrow transplantation, bone marrow stimulants like sargramostim, filgrastim, pegfilgrastim, epoetin alfa and eltrombopag. Antibiotics and antivirals may be required. Some cases may remit once the causal factor is removed as stopping offending drug or radiation; following recovery from viral illness or at the end of pregnancy.

2. Pure red cell aplasia: It is characterized by decrease in the number of erythroid precursors in the bone marrow causing marked anemia. It may be congenital in Diamond Blackfan syndrome or acquired in autoimmune disorders like SLE, collagen vascular disorders, CLL, Parvovirus B19 infections, thymoma, cancers, drugs and toxins. Severe reticulocytopenia with normocytic normochromic anemia is seen. Treatment is by giving corticosteroids and cyclosporine. Many cases are transient.

3. Myelophthisic anemia: It is anemia that develops due to the infiltration of bone marrow with malignancies like leukemia, lymphoma, Gaucher’s disease, myelofibrosis, tuberculosis, metastases from cancers of breast, lung, prostate etc. A leukoerythroblastic reaction is seen characterized by the presence of nucleated RBCs, normoblasts and a “left- shift” in the peripheral smear.

4. Anemia from blood loss: Anemia may result from acute, chronic or acute on chronic blood loss. Acute blood loss anemia is mainly caused by acute GI bleeding like variceal bleeding, retroperitoneal bleeding, postpartum hemorrhage, trauma like fractures or surgery. Chronic blood loss anemia is most often the result of chronic gastrointestinal bleeding. Hb level and hematocrit will drop due to blood loss. Peripheral smear shows normocytic normochromic RBCs.