Anemia

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Anemia is a condition of the blood characterized by too few red blood cells to support normal physiology.[1] Anemia (AmE) or anaemia (BrE), from the Greek (Ἀναιμία) meaning "without blood", refers to a quantitative or qualitative deficiency of red blood cells (RBCs) and/or hemoglobin. It is clinically manifested as pallor. Homeostasis dictates that red cell production and destruction are usually balanced in an organism. Anemias are caused by either excess red cell destruction, or underproduction of red cells, because of reduced intake, or ineffective absorption through the GI tract, of essential nutrients like iron. Reduction in the red blood cell content of blood can have a wide range of clinical consequences, from no noticeable symptoms for gradual-onset anemia, to cardiovascular collapse and death from rapid, profound reductions, such as seen in bleeding.

The classification of anemia is commonly based on the etiology, or on the microscopic morphology of the red blood cells. Sometimes the morphology can give clues as to the etiology of anemia, as in the microcytic anemia of iron deficiency.

Hemoglobin is the pigmented protein in blood that carries oxygen; reductions in blood hemoglobin concentrations in anemia can lead to decreased oxygen delivery to tissues.

The measurement of anemia has changed with available technology. The spun hematocrit was one of the earliest indicators of anemia. Later, the development of the flow cytometry, first deployed as the Coulter Counter, automated the measurement of red blood cell size, and colorimetric assays facilitated the measurement of hemoglobin.

While it is common to use one of the basic red blood cell parameters, usually hematocrit, as a preliminary indicator of anemia, even before going to more advanced tests, the hematocrit alone should not be used for a firm diagnosis. The hematocrit measures the percentage of blood cells with respect to total blood, so a low hematocrit may indicate inappropriate fluid balance rather than true anemia. Dehydration can artificially raise the hematocrit, but if the body responds with a surge of fluid replacement, it can be low. Confirmation of anemia is best done with the erythrocyte indices, which consider ratios among the three core measurements. Small red blood cells (i.e., low mean corpuscular volume — MCV) may indicate the bone marrow is rushing to resupply cells; the MCV will go low even before the reticulocyte or nucleated red cell count. This is termed microcytic anemia. Also to be examined is the mean corpuscular hemoglobin concentration (MCHC), which, if low, suggests not enough hemoglobin is being produced for the erythrocytes. A low MCHC is a microchromic anemia, which may coexist with microcytic anemia.

Classification

Production vs. destruction or loss

The "kinetic" approach to anemia yields what many argue is the most clinically relevant classification of anemia. This classification depends on evaluation of several hematological parameters, particularly the blood reticulocyte (one precursor of mature RBCs) count; the reticulocyte count is not a part of the basic complete blood count. [[Nucleated red cell]s, which may be reported in the CBC, precede reticulocytes in the maturation of red blood cells. This then yields the classification of defects by decreased RBC production versus increased RBC destruction and/or loss. Clinical signs of loss or destruction include abnormal peripheral blood smear with signs of hemolysis; elevated LDH suggesting cell destruction; or clinical signs of bleeding, such as guiaic-positive stool, radiographic findings, or frank bleeding.

Red blood cell size

In the morphological approach, anemia is classified by the size of red blood cells; this is either done automatically or on microscopic examination of a peripheral blood smear. The size is reflected in the mean corpuscular volume (MCV). If the cells are smaller than normal (under 80 fl), the anemia is said to be microcytic; if they are normal size (80-100 fl), normocytic; and if they are larger than normal (over 100 fl), the anemia is classified as macrocytic. This scheme quickly exposes some of the most common causes of anemia; for instance, a microcytic anemia is often the result of iron deficiency. In clinical workup, the MCV will be one of the most reliable pieces of information available; so even among clinicians who consider the "kinetic" approach more useful pragmatically, morphology will remain an important element of classification and diagnosis.

Other characteristics visible on the peripheral smear may provide valuable clues about a more specific diagnosis; for example, abnormal white blood cells may point to a cause in the bone marrow.

Microcytic anemia

  • Iron deficiency anemia is the most common type of anemia overall and it has many causes. RBCs on often appear hypochromic (paler than usual) and microcytic (smaller than usual) when viewed with a microscope.

Microcytic anemia is primarily a result of hemoglobin synthesis failure/insufficiency, which could be caused by several etiologies:

  • Heme synthesis defect
  • Globin synthesis defect
    • alpha-, and beta-thalassemia
    • HbE syndrome
    • HbC syndrome
    • and various other unstable hemoglobin diseases
  • Sideroblastic defect
    • Hereditary Sideroblastic anemia
    • Acquired Sideroblastic anemia including lead toxicity
    • Reversible Sideroblastic anemia

A mnemonic commonly used to remember causes of microcytic anemia is TAILS: T - Thalassemia, A - Anemia of chronic disease, I - Iron deficiency anemia, L - Lead toxicity associated anemia, S - Sideroblastic anemia.

Normocytic anemia

Normocytic anaemia is when the overall Hb levels are decreased, but the red blood cell size (MCV) remains normal. Causes include:

Macrocytic anemia

Macrocytic anemia can be further divided into "megaloblastic anemia" or "non-megaloblastic macrocytic anemia". The cause of megaloblastic anemia is primarily a failure of DNA synthesis with preserved RNA synthesis, which result in restricted cell division of the progenitor cells. The megaloblastic anemias often present with neutrophil hypersegmentation (6-10 lobes). The non-megaloblastic macrocytic anemias have different etiologies (i.e. there is unimpaired DNA synthesis,) which occur, for example in alcoholism.

The treatment for vitamin B12-deficient macrocytic and pernicious anemias was first devised by William Murphy who bled dogs to make them anemic and then fed them various substances to see what (if anything) would make them healthy again. He discovered that ingesting large amounts of liver seemed to cure the disease. George Minot and George Whipple then set about to chemically isolate the curative substance and ultimately were able to isolate the vitamin B12 from the liver. For this, all three shared the 1934 Nobel Prize in Medicine. Symptoms of vitamin B12 deficiency include having a smooth, red tongue. Minot, in one of the dramas of medicine, was one of the first patients saved by insulin therapy, for which the 1923 Nobel Prize in Medicine was awarded.

Dimorphic anemia

Here there are two types of anemia simultaneously, e.g., macrocytic hypochromic, due to hookworm infestation leading to deficiency of both iron and vitamin B12 or folic acid [1] or following a blood transfusion. One hint that this kind of anemia may exist is a wide RBC distribution width (RDW), which suggests a wider-than-normal range of sizes of red blood cells.

Underproduction anemias

Vitamin and mineral deficiency

Iron deficiency anemia

  • Iron deficiency anemia is commonly caused by insufficient dietary intake or absorption of iron. Iron is an essential part of hemoglobin, and low iron levels result in decreased incorporation of hemoglobin into red blood cells. In the United States, 20% of all women of childbearing age have iron deficiency anemia, compared with only 2% of adult men. The principal cause of iron deficiency anemia in premenopausal women is blood lost during menses. Studies have shown that iron deficiency without anemia causes poor school performance and lower IQ in teenage girls. Iron deficiency is the most prevalent deficiency state on a worldwide basis. Iron deficiency affects women from different cultures and ethnicities. Iron found in animal meats are more easily absorbed by the body than iron found in non-meat sources; this is because of preferential absorption of heme iron in the hemoglobin and myoglobin found in meat. In countries where animal meats are only occasionally available in the diet, iron deficiency anemia is six to eight times more prevalent than in North America and Europe. Iron deficiency is sometimes the cause of abnormal fissuring of the angular (corner) sections of the lips (angular cheilitis).
  • Iron deficiency anemia can also due to bleeding lesions of the gastrointestinal tract. Fecal occult blood testing, upper endoscopy and lower endoscopy are often performed to identify bleeding lesions. Iron deficiency in the elderly should indicate the possibility of an occult gastrointestinal tract malignancy.

B vitamin deficiencies

Other nutrient deficiencies

Myelodysplastic syndrome

Myelodysplastic syndrome is a loosely-defined condition of ineffectual hematopoeisis by the bone marrow. The hallmark characteristics of myelodysplastic syndrome are:

  • Cytogenetic abnormalities of bone marrow stem cells
  • Morphological changes in marrow stem cells, in all three hematopoeitic cell lines
  • Progressive cytopenias, usually starting in one cell line, then progressing to two or three
  • Potential to transform to acute leukemia

Aplastic anemia

Aplastic anemia is clinical syndrome characterized by a hypoplastic bone marrow in the setting of pancytopenia. The pathogenesis of aplastic anemia is damage to the pluripotent stem cell reserves of the bone marrow.

Patterns of aplastic anemia include:

  • Hereditary
  • Drug-induced
  • Radiation
  • Infections
  • Idiopathic

Extramedullary hematopoeisis

Anemia of chronic disease

Four mechanisms contribute to anemia in the context of inflammatory disease:

  • Immune system cytokines shorten RBC lifespan by 10-20 days (citation).
  • Poor iron reutilization from macrophage recirculation in the bone marrow
  • Ineffectual hematopoeisis response to erythropoietin, or inadequate erythropoietin production
  • Direct Cytokine inhibiton of erythropoeisis

Several categories of chronic diseases can contribute to anemia.

Chronic renal insufficiency

The production of red blood cells in the bone marrow depends on stimulation of erythroid stem cells by the growth factor, erythropoietin. Erythropoietin is principally manufactured in the kidneys, and the liver to a lesser extent.

About half of patients with chronic kidney disease and an estimated glomerular filtration rate of 25-30 ml/min have a hematrocrit below 36%.[2]

Erythropoietin deficiency in renal disease leads to an anemia that is correctable with recombinant pharmacological erythropoietin. A pair of articles in the New England Journal of Medicine in November, 2006 drew attention to the concept that excessive correction of anemia in renal failure patients did not improve cardiovascular function[3], and could in fact be deleterious. Patients treated to a higher target hemoglobin showed an improved quality of life, but had excess mortality, compared with patients treated to a lower target hemoglobin.[4]

Chronic inflammatory disease

The anemia of chronic disease or anemia of chronic inflammatory disease consist of anemias caused by poor iron reutilization by the reticuloendothelial system and inappropriate cytokine production in the inflammatory state. Some commonly-cited causes of the anemia of chronic disease:

Heart disease

Congestive heart failure is a cited etiology of anemia.

Myeloma and other malignancies

The anemia of malignancy is multifactorial, and can stem directly from bleeding, bone marrow compartment replacement by malignant cells, hemolytic anemia, immunoglobulin deposition, chemotherapy, or immune-mediated pure red-cell aplasia

Hereditary anemia syndromes

Hemoglobinopathies

Hemoglobinopathies include sickle cell anemia, thalassemias, and other hemoglobinopathies

Non-hemoglobinopathies

Other causes of hereditary anemia include Fanconi anemia

Substance-induced anemias

Excess red cell destruction anemias

These anemias are characterized by increased reticulocytes.[7] The percentage of red blood cells that are reticulocytes are normally less than 3% (usually 1.0% to 1.5%).[7] Alternative indices are:

Absolute reticulocyte count, normal is 50,000 and 150,000 reticulocytes/mL:[7]

The absolute reticulocyte count can be corrected for the increased time of circulation of reticulocytes in the peripheral blood during anemia. The normal reticulocyte maturation time in the peripheral blood is 1 day, but extends to 2 days at a hematocrit 25 percent:[7]

Reticulocyte index:[7]

In autoimmune hemolytic anemia, reticulocytes can be 9% of red blood cells and 75% of patients will double their reticulocyte production index.[7]

Hemolytic anemias

For more information, see: Hemolytic anemia.


Splenic sequestration

Mechanical destruction

Bleeding

Signs and symptoms

The physical examination has some ability to detect anemia. In one study:[8]

  • The most sensitive findings are pallor for conjunctivae, face, or palms.
    • 80% of patients with a hematocrit below 30% will have pallor at one of these sites.
    • 65% of patients with a hematocrit below 40% will have pallor at one of these sites.
  • The most specific finding is loss of redness in the palmar creases
    • All patients with a hematocrit above 40% will have normal palmar creases.
    • 98% of patients with a hematocrit above 30% will have normal palmar creases.

Conjunctival pallor is helpful.[9]

Learning the examination may be improved by learning standardized colors.[10]

Treatment of anemia

Treatment is directed as the specific cause of anemia. In addition, blood transfusion or erythropoiesis-stimulating agents may be used.

Blood transfusions

Clinical practice guidelines address thresholds for blood transfusions:[11]

Among patients receiving coronary artery bypass grafting, there may be no meaningful difference between transfusing to maintain a hemoglobin levels > 8 g/dL versus a hemoglobin levels > 9 g/dL.[12] However, hemoglobin levels < 8 g/dL may increase complications.[13]

Among patients in critical care units, there may not be a meaningful difference in outcomes between transfusing blood to maintain a hemoglobin > 7.0 g/dl versus a hemoglobin > 10.0 g/dl except among patients with acute coronary syndrome.[14]

Erythropoiesis-stimulating agents

Using erythropoiesis-stimulating agents in patients with cancer may increase embolism and thrombosis and mortality.[15]

Among patient in critical care units, a randomized controlled trial reported "epoetin alfa does not reduce the incidence of red-cell transfusion among critically ill patients, but it may reduce mortality in patients with trauma. Treatment with epoetin alfa is associated with an increase in the incidence of thrombotic events."[16]

References

  1. Anonymous (2015), Anemia (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. Astor BC, Muntner P, Levin A, Eustace JA, Coresh J (June 2002). "Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey (1988-1994)". Arch. Intern. Med. 162 (12): 1401–8. PMID 12076240[e]
  3. Drüeke T, Locatelli F, Clyne N, Eckardt K, Macdougall I, Tsakiris D, Burger H, Scherhag A (2006). "Normalization of hemoglobin level in patients with chronic kidney disease and anemia". N Engl J Med 355 (20): 2071-84. PMID 17108342.
  4. Singh A, Szczech L, Tang K, Barnhart H, Sapp S, Wolfson M, Reddan D (2006). "Correction of anemia with epoetin alfa in chronic kidney disease". N Engl J Med 355 (20): 2085-98. PMID 17108343.
  5. Nanas J, Matsouka C, Karageorgopoulos D, Leonti A, Tsolakis E, Drakos S, Tsagalou E, Maroulidis G, Alexopoulos G, Kanakakis J, Anastasiou-Nana M (2006). "Etiology of anemia in patients with advanced heart failure". J Am Coll Cardiol 48 (12): 2485-9. PMID 17174186.
  6. Szachniewicz J, Petruk-Kowalczyk J, Majda J, Kaczmarek A, Reczuch K, Kalra P, Piepoli M, Anker S, Banasiak W, Ponikowski P (2003). "Anaemia is an independent predictor of poor outcome in patients with chronic heart failure". Int J Cardiol 90 (2-3): 303-8. PMID 12957766.
  7. 7.0 7.1 7.2 7.3 7.4 7.5 Riley RS, Ben-Ezra JM, Goel R, Tidwell A (2001). "Reticulocytes and reticulocyte enumeration". J. Clin. Lab. Anal. 15 (5): 267–94. PMID 11574956[e]
  8. Nardone DA, Roth KM, Mazur DJ, McAfee JH (1990). "Usefulness of physical examination in detecting the presence or absence of anemia". Arch. Intern. Med. 150 (1): 201–4. PMID 2297289[e]
  9. Sheth TN, Choudhry NK, Bowes M, Detsky AS (1997). "The relation of conjunctival pallor to the presence of anemia.". J Gen Intern Med 12 (2): 102-6. PMID 9051559. PMC PMC1497067[e]
  10. Chowdhury ME, Chongsuvivatwong V, Geater AF, Akhter HH, Winn T (2002). "Taking a medical history and using a colour scale during clinical examination of pallor improves detection of anaemia.". Trop Med Int Health 7 (2): 133-9. PMID 11841703[e]
  11. 1. Carson JL, Grossman BJ, Kleinman S, Tinmouth AT, Marques MB, Fung MK, et al. Red Blood Cell Transfusion: A Clinical Practice Guideline From the AABB. Ann Intern Med [Internet]. 2012
  12. Bracey AW, Radovancevic R, Riggs SA, et al (1999). "Lowering the hemoglobin threshold for transfusion in coronary artery bypass procedures: effect on patient outcome". Transfusion 39 (10): 1070–7. PMID 10532600[e]
  13. Carson JL, Noveck H, Berlin JA, Gould SA (2002). "Mortality and morbidity in patients with very low postoperative Hb levels who decline blood transfusion". Transfusion 42 (7): 812–8. PMID 12375651[e]
  14. Hébert PC, Wells G, Blajchman MA, et al (February 1999). "A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group". N. Engl. J. Med. 340 (6): 409–17. PMID 9971864[e]
  15. Bennett, C. L., Silver, S. M., Djulbegovic, B., Samaras, A. T., Blau, C. A., Gleason, K. J., et al. (2008). Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia, JAMA, 299(8), 914-924. http://jama.ama-assn.org/cgi/content/full/299/8/914 DOI:10.1001/jama.299.8.914.
  16. Corwin HL, Gettinger A, Fabian TC, et al (2007). "Efficacy and safety of epoetin alfa in critically ill patients". N. Engl. J. Med. 357 (10): 965–76. DOI:10.1056/NEJMoa071533. PMID 17804841. Research Blogging.