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= Anemia Owing to Decreased Production of Red Blood Cells = Anemia due to ineffective erythropoiesis may be characterized by macrocytosis associated with a megaloblastic marrow. The bone marrow may be hypercellular, showing evidence of abnormal proliferation and maturation of multiple myeloid cell lines. There are a large number of causes of macrocytic anemia, with the most frequent being disorders resulting in vitamin B12 deficiency or folate deficiency. The diagnostic process begins by establishing the presence of vitamin B12 or folate deficiency and then determining the cause of deficiency. The primary laboratory investigations include a CBC, peripheral blood smear, serum vitamin B12 assay, and red blood cells and serum folate assays.

Megaloblastic anemia and vitamin B12 deficiency
Vitamin B12 (cobalamin) deficiency is a common cause of macrocytic anemia. Megaloblastic or pernicious anemia is an autoimmune disease resulting from autoantibodies directed against intrinsic factor and gastric parietal cells. Vitamin B12 is necessary for the formation of red blood cells.

Oral manifestations
Patients with pernicious anemia may have complaints of a burning sensation in the tongue, lips, buccal mucosa, and other mucosal sites. The tongue may become reddened, with atrophy of papillae. Dysphagia and taste alterations have been reported. The presence of oral signs and symptoms, including glossitis, angular cheilitis, recurrent oral ulcer, oral candidiasis, diffuse erythematous mucositis and pale oral mucosa offer the dentist an opportunity to participate in the diagnosis of this condition. Early diagnosis is important to prevent neurologic signs, which could be irreversible.

Management
Treatment has traditionally been weekly intramuscular injections of 1,000 μg of vitamin B12 for the initial 4 to 6 weeks, followed by 1,000 μg per week indefinitely. Contrary to prevailing medical practice, studies show that supplementation with oral vitamin B12 is a safe and effective treatment for the B12 deficiency state. A recent evidence-based review suggests that 2,000 μg doses of oral vitamin B12 daily and 1,000 μg doses initially daily and thereafter weekly and then monthly may be as effective as intramuscular administration in obtaining short-term hematologic and neurologic responses in vitamin B12 - deficient patients. Even when intrinsic factor is not present to aid in the absorption of vitamin B12 as in pernicious anemia or in other diseases that affect the usual absorption sites in the terminal ileum, oral therapy remains effective.

Aplastic anemia
Aplastic anemia occurs when the bone marrow is unable to produce adequate numbers of red blood cells, white blood cells, and platelets. The hematopoietic stem cells are unable to proliferate, differentiate, or give rise to mature blood cells.

Oral manifestations
The oral findings associated with aplastic anemia include petechiae, ecchymoses, mucosal pallor, ulceration (infection), gingival bleeding, and gingival hyperplasia. The most common oral manifestation of aplastic anemia is hemorrhage, which develops most often in patients with platelet counts less than 25 x109 cells/L. The second and third most common oral manifestations are candidiasis and viral infection, respectively. In a case-control study, patients with aplastic anemia were significantly more likely than controls to present with petechiae, spontaneous gingival bleeding, gingival hyperplasia from prior cyclosporine use, and herpetic lesions.

Management
The course, treatment, and outcome are related to the severity of the quantitative reduction in peripheral blood cell counts, particularly the neutrophil number. Supportive therapy with blood transfusions to correct anemia and thrombocytopenia can be beneficial for many. Immunosuppression with antithymocyte globulins and cyclosporine is effective at restoring blood cell production in the majority of patients, but relapse and especially evolution of clonal hematologic diseases remain problematic. Ultimately, patients with histocompatible sibling donors can be cured by replacement of the hematopoiesis through allogeneic HSCT. The most serious complication of aplastic anemia is the high risk of infection secondary to the absence of neutrophils; overwhelming bacterial sepsis and especially fungal infections are the most frequent causes of death.

Oral health considerations
Neutropenia, caused by the disorder itself and its treatment, leads to an increased susceptibility to infection, and thrombocytopenia leads to bruising and mucosal bleeding. Patients with signs and symptoms of anemia, petechiae, ecchymoses, and gingival bleeding should be referred to a physician for evaluation, diagnosis, and treatment as indicated. Neutropenic fevers must be treated aggressively with parenteral, broad-spectrum antibiotics. Antifungal therapy should be added when patients are persistently febrile because aspergillosis infections can be difficult to diagnose early. Attention to details of oral hygiene and hand washing and avoidance of minor injuries or casual exposure to infectious agents can reduce the risk of serious complications.