Background Anemia is strictly defined as a decrease in red blood cell (RBC) mass.

The function of the RBC is to deliver oxygen from the lungs to the tissues and carbon dioxide from the tissues to the lungs. This is accomplished by using hemoglobin (Hb), a tetramer protein composed of heme and globin. Anemia impairs the ability of the RBCs to transport oxygen and carbon dioxide. (See Etiology.)[1] Anemia, like a fever, is a symptom of disease that requires investigation to determine the underlying etiology. Often, practicing physicians overlook mild anemia. This is similar to failing to seek the etiology of a fever. The purpose of this article is to provide a method of determining the etiology of an anemia. (See the image below.) (See Etiology, History, Physical Examination, and Workup.) Methods for measuring RBC mass are time consuming and expensive and usually require transfusion of radiolabeled erythrocytes. Thus, in practice, anemia is usually discovered and quantified by measurement of the RBC count, Hb concentration, and hematocrit (Hct). These values should be interpreted cautiously, because they are concentrations affected by changes in plasma volume. For example, dehydration elevates these values, and increased plasma volume in pregnancy can diminish them without affecting the RBC mass. (See Workup.) RBCs contain fluid Hb encased in a lipid membrane supported by a cytoskeleton. Abnormalities of the membrane, the chemical composition of the Hb, or certain glycolytic enzymes can reduce the life span of RBCs to cause anemia. (See Etiology.) Complications The most serious complications of severe anemia arise from tissue hypoxia. Shock, hypotension, or coronary and pulmonary insufficiency can occur. This is more common in older individuals with underlying pulmonary and cardiovascular disease. (See Pathophysiology.) Erythrocyte life cycle Erythroid precursors develop in bone marrow at rates usually determined by the requirement for sufficient circulating Hb to oxygenate tissues adequately. Erythroid precursors differentiate sequentially from stem cells to progenitor cells to erythroblasts to normoblasts in a process requiring growth factors and cytokines. This process of differentiation requires several days. Normally, erythroid precursors are released into circulation as reticulocytes. Reticulocytes remain in the circulation for approximately 1 day before reticulin is excised by reticuloendothelial cells with the delivery of the mature erythrocyte into circulation. The mature erythrocyte remains in circulation for about 120 days before being engulfed and destroyed by phagocytic cells of the reticuloendothelial system. Erythrocytes are highly deformable and increase their diameter from 7 m to 13 m when they traverse capillaries with a 3-m diameter. They possess a negative charge on their surface, which may serve to discourage phagocytosis. Because erythrocytes have no nucleus, they lack a Krebs cycle and rely on glycolysis via the Embden-Meyerhof and pentose pathways for energy. Many enzymes required by the aerobic and anaerobic glycolytic pathways decrease within the cell as it ages. In addition, the aging cell has a decrease in potassium concentration and an increase in sodium concentration. These factors contribute to the demise of the erythrocyte at the end of its 120-day lifespan. Patient education Inform patients of the etiology of their anemia, the significance of their medical condition, and the therapeutic options available for treatment. Because no effective specific treatment of the underlying disease exists, educate patients requiring periodic transfusions about the symptoms that herald the need for transfusion. Likewise, they should be aware of the potential complications of transfusion. Pathophysiology The physiologic response to anemia varies according to acuity and the type of insult. Gradual onset may allow

for compensatory mechanisms to take place. With anemia due to acute blood loss, a reduction in oxygencarrying capacity occurs along with a decrease in intravascular volume, with resultant hypoxia and hypovolemia. Hypovolemia leads to hypotension, which is detected by stretch receptors in the carotid bulb, aortic arch, heart, and lungs. These receptors transmit impulses along afferent fibers of the vagus and glossopharyngeal nerves to the medulla oblongata, cerebral cortex, and pituitary gland. In the medulla, sympathetic outflow is enhanced, while parasympathetic activity is diminished. Increased sympathetic outflow leads to norepinephrine release from sympathetic nerve endings and discharge of epinephrine and norepinephrine from the adrenal medulla. Sympathetic connection to the hypothalamic nuclei increases antidiuretic hormone (ADH) secretion from the pituitary gland.[2] ADH increases free water reabsorption in the distal collecting tubules. In response to decreased renal perfusion, juxtaglomerular cells in the afferent arterioles release renin into the renal circulation, leading to increased angiotensin I, which is converted by angiotensin-converting enzyme (ACE) to angiotensin II. Angiotensin II has a potent pressor effect on arteriolar smooth muscle. Angiotensin II also stimulates the zona glomerulosa of the adrenal cortex to produce aldosterone. Aldosterone increases sodium reabsorption from the proximal tubules of the kidney, thus increasing intravascular volume. The primary effect of the sympathetic nervous system is to maintain perfusion to the tissues by increasing systemic vascular resistance (SVR). The augmented venous tone increases the preload and, hence, the end-diastolic volume, which increases stroke volume. Therefore, stroke volume, heart rate, and SVR all are maximized by the sympathetic nervous system. Oxygen delivery is enhanced by the increased blood flow. In states of hypovolemic hypoxia, the increased venous tone due to sympathetic discharge is thought to dominate the vasodilator effects of hypoxia. Counterregulatory hormones (eg, glucagon, epinephrine, cortisol) are thought to shift intracellular water to the intravascular space, perhaps because of the resultant hyperglycemia. This contribution to the intravascular volume has not been clearly elucidated. Prognosis Usually, the prognosis depends on the underlying cause of the anemia. However, the severity of the anemia, its etiology, and the rapidity with which it develops can each play a significant role in the prognosis. Similarly, the age of the patient and the existence of other comorbid conditions influence outcome. Bleeding from esophageal varices Approximately 30% of patients with cirrhosis die from variceal bleeding. Patients with Child class C liver disease have a 50% mortality rate. The rate of rebleeding in medically treated patients is in excess of 70%.[7] Aortic rupture The prognosis for traumatic rupture is very poor, with approximately an 80% prehospital mortality rate. If untreated, the majority of patients die within 2 weeks. Nontraumatic aneurysmal rupture also has a poor prognosis and is essentially fatal if untreated. Immediate surgical repair still carries a high mortality rate, often greater than 80%. Sickle cell anemia Patients who are homozygous (Hgb SS) have the worst prognosis, because they tend to have more frequent crises. Patients who are heterozygous (Hgb AS) have sickle cell traits, and they have crises only under extreme conditions. Thalassemias Patients who are homozygous for beta thalassemia (Cooley anemia) have a worse prognosis than do patients with any of the other thalassemias. Death among people with beta thalassemia usually occurs when they are younger than age 30 years. Patients who are heterozygous for beta thalassemia have mild microcytic anemia that is not clinically significant.

Aplastic anemia Chances of survival are poorer for patients with idiosyncratic aplasia caused by chloramphenicol and viral hepatitis and better when paroxysmal nocturnal hemoglobinuria or anti-insecticides are the probable etiology. The prognosis for idiopathic aplasia lies between these 2 extremes, with an untreated mortality rate of approximately 60-70% within 2 years after diagnosis. The 2-year fatality rate for severe aplastic anemia is 70% without bone marrow transplantation or a response to immunosuppressive therapy. Hyperplasia Among patients with a hyperplastic bone marrow and decreased production of RBCs, one group has an excellent prognosis, and the other is unresponsive, refractory to therapy, and has a relatively poor prognosis. The former includes patients with disorders of relative bone marrow failure due to nutritional deficiency in whom proper treatment with vitamin B-12, folic acid, or iron leads to a correction of anemia once the appropriate etiology is established. Drugs acting as an antifolic antagonist or inhibitor of DNA synthesis can produce similar effects. The second group includes patients with an idiopathic hyperplasia that may respond partially to pyridoxine therapy in pharmacologic doses but more frequently does not. These patients have ringed sideroblasts in the bone marrow, indicating an inappropriate use of iron in the mitochondria for heme synthesis. Certain patients with marrow hyperplasia (see the image below) may have refractory anemia for years, but some of the group eventually develop acute myelogenous leukemia. Bone marrow aspirate showing erythroid hyperplasia and many binucleated erythroid precursors. Other conditions In ectopic pregnancy, the prognosis with prompt management is excellent, with a mortality rate of about 1-2%. In patients with hemophilia, about 15% of them eventually develop inhibitors to factor VIII and may die from bleeding complications. Patients with idiopathic thrombocytic purpura (ITP) usually respond to immunosuppression or splenectomy and have an excellent prognosis. Approximately 80-90% of patients who have TTP and undergo plasmapheresis recover completely. Hemolytic-uremic syndrome carries a significant morbidity and mortality if untreated. As many as 40% of those affected die, and as many as 80% develop renal insufficiency.