Mechanisms Accounting for Unexplained Anemia in the Elderly

Anemia occurs commonly and is associated with adverse outcomes in the elderly. In approximately one third of anemia cases in patients over the age of 65 years, the cause of anemia is not readily apparent (unexplained anemia or UA). Of the various causes of anemia in young adults, overt hemolysis (either acute or chronic) is very uncommon. However, we speculate that older persons tend to develop a low grade hemolytic process which significantly reduces RBC survival, and when this is not adequately countered by increased bone marrow RBC production, anemia (UA) is the consequence. This hypothesis is supported by a few clinical observations. For example, red cells in patients with UA are generally not small and when the peripheral blood smear is examined microscopically, anisocytosis (varying cell size) is observed, as is typical in patients with hemolytic anemia. Similarly, UA is frequently associated with an elevated red cell distribution width (RDW) on electronic measurement. Furthermore, serum erythropoietin levels gradually rise with advancing age (1), and this would be consistent either with a smoldering hemolytic process or a decreased responsiveness to erythropoietin. To address the hypothesis that UA is due, at least in part, to shortened RBC survival, we propose to directly measure red blood cell survival and to correlate this with aspects of red blood cell physiology that may increase susceptibility to the hemolytic process.

• INCLUSION CRITERIA:
• Ambulatory, community dweller
• Age greater than or equal to 70 years or older or between the ages of 18 and 50 years.
• Able to understand English
• Able to complete study questionnaires as determined by the investigator
• Evidence for recent (within 1 year) clinical evaluation for blood loss directed by primary care physician or consultant in subjects referred with microcytic anemia or with referring laboratories indicative of iron deficiency. Furthermore, subjects found to have microcytic anemia will be eligible but will be referred to their primary doctor for evaluation of blood loss.
• Provide informed consent

Exclusion criteria

• Hemoglobin (Hb) less than 9 g/dL during screening
• History of red blood cell transfusion withinthe 3 month period prior to accrual to this study, or evidence for active bleeding as ascertained by medical history (e.g., persistent melena, hematuria or dysfunctional uterine bleeding).
• Patients for whom oral iron supplementation has been prescribed within the past two months. (Patients on a stable dose of oral iron for more than two months may be eligible).
• ALT or AST more than 3 times upper normal limitation of the time of screening
• B12 or folate deficiencies during screening period
• Estimated GFR less than 30 ml/min/1.73m(2)during screening period (by the 4-variable Modification of Diet in Renal Disease [MDRD] equation).
• Receiving hemodialysis or peritoneal dialysis for renal failure, or history of kidney transplant
• Use of exogenous erythropoietin during the past 3 months
• Any major surgery requiring general anesthesia within the past 3 months
• Treatment with chemotherapy or radiotherapy in the past 12 months
• Current diagnosis of active cancer, other than non-melanoma skin cancer and, stable prostate cancer
• History of blood disorders including thalassemia, sickle cell disease or myelodysplasia
• Current severe (NYHA Class III - IV) congestive heart failure or advanced chronic obstructive pulmonary disease
• Positive serum monoclonal protein and immunofixation
• Women who are pregnant or women planning to get pregnant during the duration of the study or those with a positive pregnancy test during screening
• Active infection requiring antibiotic treatment or HIV, Hepatitis B or C
• History of overt chronic inflammation, active Crohn s disease, rheumatoid arthritis, or diabetes(HbA1C greater than 7),
• Known hemolytic anemia
• History of prosthetic heart valve
• History of participation in biotinylation studies or handling biotinylated reagent products.