Anemia

What every physician needs to know about anemia:

Anemia (defined as a reduction in the number of circulating red blood cells below normal limits for age and gender) is among the most common abnormalities encountered in medicine. Anemia is recognized as a low hematocrit, hemoglobin, or red blood cell count value. Hematocrit is the most commonly used metric.

There are literally hundreds of possible causes of anemia: acute or chronic blood loss, reactions to drugs, autoimmunity, suppression of the bone marrow by systemic or intrinsic hematopoietic stem cell disease processes, external factors such as burns, drowning, ionizing radiation, malnutrition, etc.

Many forms of anemia are due to intrinsic defects in bone marrow function, or the structure or function of erythroid progenitors or erythrocytes. However, in the majority of patients with anemia, the underlying cause will be systemic disease processes, toxic exposures, medications, infectious agents, or physical factors (e.g., heat, fresh water drowning) that adversely affect the erythron.

By far the most common cause of anemia is bleeding. A thorough bleeding evaluation should accompany every anemia work-up even if other factors contributing to or causing the anemia co-exist. Bleeding frequently uncovers other subclinical abnormalities that predispose to anemia.

While there are many sophisticated tests that can be done to assist a work-up for anemia, most cases will be diagnosed on the basis of a thorough history (particularly for bleeding or systemic diseases, nutritional inadequacies, medications), physical examination, and simple laboratory evaluations that include a complete blood count with differential, a reticulocyte count, and an expert review of the peripheral blood smear. This invariably guides the proper choice of further tests that will narrow down the possible causes for anemia, and elucidates the appropriate approach to therapy.

The most practically useful among many possible diagnostic approaches is to consider first whether the anemia is due to blood loss, underproduction of red cells, or to excessive red cell destruction recognizing that in some cases more than one process can contribute.

There are four steps in an anemia work-up, and these are listed below:

Step one: ask if the patient is losing blood.

Anemias due to acute or chronic blood loss are by far the most common, and commonly overlooked, forms of anemia. Menometrorrhagia, gastrointestinal (GI) bleeding, and blood losses incurred during pregnancy and delivery are the most common. Bleeding is the most common cause of iron deficiency, but acute bleeding or brisk chronic bleeding can cause anemia before iron deficiency develops, especially if bone marrow compensation is compromised (e.g., renal failure). The possibility of bleeding as the primary, or a contributing, cause should be a prominent suspicion in every anemia work-up.

Step two: ask if underproduction of red cells, excessive destruction of red cells (hemolysis), or both, are occurring.

Underproduction anemias are characterized by a low or normal reticulocyte count, or reticulocyte count that is inadequately elevated for the severity of the anemia. These anemias can be due to:

(1) primary failure of the bone marrow to produce red cell progenitors and/or complete their differentiation into circulating erythrocytes (e.g., aplastic anemia, myelodysplasia, Diamond-Blackfan anemia, paroxysmal nocturnal hemoglobinuria, true red cell aplasia secondary to Parvovirus infections, certain drugs, etc.), or

(2) impairment of bone marrow function by toxins, autoimmunity, or imbalance in cytokines (anemia of chronic inflammation), cytotoxic chemotherapy, ionizing radiation, severe malnutrition, folate or vitamin B12 deficiency, or infiltration (solid tumor metastases, hematologic malignancies, granulomas, or fibrosis). Bone marrow examination in these patients usually reveals reduced numbers of erythroid progenitors and, sometimes, infiltration of lymphocytes, tumor cells, eosinophils, granulomas, or fibrous tissue. Renal failure is a common cause of underproduction anemia due to loss of renal erythropoietin, the peptide hormone that stimulates erythropoiesis.

Anemias due to excessive red cell destruction are called hemolytic anemias. These occur when something reduces red cell survival in the circulation significantly below the normal 100-120 days. They are characterized, classically, by an increased reticulocyte count and peripheral evidence of excessive products of red cell destruction, such as an elevated serum lactate acid dehydrogenase (LDH), indirect bilirubin, hepatosplenomegaly and a low haptoglobin (reflecting clearance of haptoglobin/plasma hemoglobin complexes). When red cell destruction occurs at high rates within the circulation, hemoglobin will also appear in the urine.

Many intrinsic inherited red cell defects result in a shortened red cell life span, including sickle cell anemia, thalassemia, red cell membrane disorders (spherocytosis, elliptocytosis, and pyropoikilocytosis), and many red cell enzyme defects. These are usually characterized by typical alterations in red cell morphology.

Hemolysis can also result from extrinsic forces in the circulation and in the body. Notable among these are auto-antibodies (immune hemolytic anemia), mechanical shear forces due to fibrin deposits or vessel turbulence (thrombotic thrombocytopenic purpura [TTP], malignant hypertension, and hemolytic-uremic syndrome [HUS]), artificial heart valves, turbulent flow through arterial venous malformations, etc. These are called microangiopathic anemias. Red cells can be destroyed by thermal or osmotic stresses (fresh water drowning, burns). Certain infectious agents or their toxins can provoke hemolysis, such as malaria, babesiosis, Clostridium perfringens toxin, etc.

Suppression of the bone marrow can co-exist with factors shortening red cell survival in many situations (for example, a cancer patient on a myelosuppressive chemotherapeutic agent might develop immune hemolytic anemia or TTP, or renal failure developing in a patient with sickle cell anemia). In these situations, signs of compensatory red cell over production may not be apparent in the form of a high reticulocyte, depriving the diagnostician of a vital clue. Evidence of excessive red cell destruction (LDH, indirect bilirubin, abnormal red cell forms on the peripheral smear, etc.) will need to sought.

Deciding whether underproduction or excessive destruction is the predominant cause of an anemia is almost always possible by evaluating the simple tests outlined above in the context of a good history and physical that focuses on the underlying diseases and factors highlighted above.

Step three: assess red cell size and size distribution.

The third step in working up an anemia is to assess red cell size (i.e., volume – the mean corpuscular volume [MCV], normal range ca. 80-100 femtoliters) and size distribution (the red blood cell distribution width [RDW], a measure of circulating red cell size variability, attempts to quantitate the older descriptor for size heterogeneity:”anisocytosis”)

An abnormal MCV can be very helpful in narrowing the likely source of anemia. Conversely, a normal MCV cannot be taken to rule out those sources typically associated with microcytosis (MCV, 80) or macrocytosis (MCV>100).

Microcytic anemias (MCV < 80) are invariably due to defects in hemoglobin production. This occurs because of iron deficiency (by far the most common), thalassemia, sideroblastic anemias, or, uncommonly, the anemia of chronic inflammation. Thalassemia trait usually presents with profound microcytosis and mild to moderate anemia (MCV, 70, Hct, 30), in iron deficiency the MCV rarely falls below 80 until the anemia is significant (Hct, 30%).

Macrocytic anemias (MCV >100) are due to megaloblastic anemias, most commonly Vitamin B12 or toxicities from drugs disrupting their metabolism. Folate deficiency is a much less common cause of macrocytic anemia in the United States since the introduction of folate supplementation in foods. “Benign macrocytosis” is associated with liver disease and/or alcoholism but is not by itself usually accompanied by anemia. Mild macrocytosis or the presence of macrocytic red cells is sometimes encountered in myelodysplastic syndromes and hypothyroidism. Significant reticulocytosis can elevate the MCV because the MCV of a typical reticulocyte is about 140 fl.

Most anemias present with normocytic red cells. The most important points about normocytic anemias, before thinking of the myriad other causes, is to remember that iron deficiency anemia, becomes microcytic only at an advanced stage. Early and moderate iron deficiency usually presents with normocytic red cell indices. Moderately severe or advanced iron deficiency anemia may reveal itself through the appearance of microcytic red cells or target cells (a characteristic of cells with inadequate hemoglobin) on a peripheral smear before accumulating in high enough numbers to lower the MCV. The RDW value will be high in these cases. In thalassemia trait (the presentation of severe thalassemia – profound microcytosis, hemolysis and severe anemia is usually obvious in childhood), red cells are uniformly and profoundly microcytic, so both the RDW and the MCV are low. This is one of the more useful applications of the RDW.

The RDW will also rise in dimorphic anemias, e.g., the co-existence of a folate/B-12 deficiency with iron deficiency that can have a misleadingly normal MCV, iron deficiency developing in a renal failure patient, etc.

Most hemolytic anemias, acute blood loss anemia, and anemias due to bone marrow hypoplasia are normocytic. As noted above, patients with high reticulocyte counts may exhibit macrocytosis – from this mechanism can be suspected by noting “polychromasia” – bluish or purple large red cells – on the peripheral smear. This population includes younger red cells and reticulocytes. The appearance of many of these or nucleated erythroblasts in the peripheral smear are good indicators of either a hemolytic process or a “myelophthisic” process whereby tumor cells, granulomas, or fibrosis are “forcing” early progenitor elements out of the marrow and into the peripheral blood.

Step four: review the peripheral blood smear.

The fourth step in the anemia work up is to review the peripheral blood smear. In hemolytic anemias, spherocytes are often a good indicator of hereditary spherocytosis or immune mediated hemolysis, while schistocytes or helmet cells indicate a microangiopathic process (e.g., TTP or HUS). Target cells coupled with macrocytosis suggests liver disease, normocytic target cells raise the suspicion of hemoglobin C or SC disease, while microcytosis with target cells indicate iron deficiency or thalassemia trait.

Elliptocytes or bizarre misshapen cells indicate inherited membrane disorders like elliptocytosis, pyropoikilocytosis, ovalocytosis, tomatocytosis, xerocytosis. Burr cells accompany renal failure and spur cells accompany severe liver disease. Tear drops accompanied by circulating erythroblasts, large platelet fragments and/or early white cell progenitors (e.g., myelocytes) constitute a “leukoerythroblastic picture” indicative of a myeloproliferative process (eg, myelofibrosis), or infiltrating disease processes such as granulomas, fibrosis, or tumor metastases. Sickled cells and oak leaf cells point to sickle cell anemia.

Valuable clues can be gotten from remembering to look for white cell or platelet changes as well. For example, thrombocytosis could indicate bleeding, iron deficiency, or myeloid metaplasia/myelofibrosis in its earlier stages. Thrombocytopenia with schistocytes indicates possible TTP or HUS, or disseminated intravascular coagulation (DIC).

Toxic granulations in polymorphonuclear leukocyte (PMN’s) could indicate sepsis as a possible cause of the anemia of chronic inflammation, or DIC. Hypersegmented PMN’s suggest megaloblastic anemia while hyposegmented PMN’s suggest myelodysplasia. Lymphocytosis can indicate chronic lymphocytic leukemia (CLL) with attendant marrow suppression and/or immune hemolysis.

A thorough and physical examination, review of the blood count and peripheral smear for the aforementioned changes, and assessment of iron folate and vitamin B12 stores via standard tests should lead to a correct diagnosis of anemia in the vast majority of patients if the aforementioned four step approach is taken.

What features of the presentation will guide me toward possible causes and next treatment steps:

See above for the major clues and approaches to work-up for anemia. To reiterate:

Anemia with low reticulocyte count, normal LDH, bilirubin, and haptoglobin – hypoproduction anemia, intrinsic bone marrow defects (e.g., myelodysplasia), suppression of bone marrow due to drugs, autoimmunity, etc.

Anemia with high reticulocyte count, increased LDH, bilirubinemia, splenomegaly, and/or low haptoglobin – hemolytic anemia such as autoimmune hemolytic anemia, TTP or hemolytic uremic syndrome, drug induced hemolysis, red cell defects such as sickle cell anemia, enteropathies , thalassemia, etc.

Microcytic anemia – invariably defects of hemoglobin production, iron deficiency, sideroblastic anemias, thalassemias.

Normocytic anemias – hemolysis or intrinsic red cell defects, bone marrow suppression by drugs, radiation, etc.

Macrocytic anemias – large red cells associated with folate or vitamin B12 deficiency, myelodysplasia, liver disease.

Always consider bleeding as a source or aggravating factor underlying the anemia. Remember that iron deficiency, especially if mild, or slowly developing, presents first with a normocytic anemia even though iron deficiency is by far the most common cause also of hypochromic microcytic anemia. The latter occurs only in severe and advanced stages of the process. Iron deficiency almost always involves bleeding even if nutritional insufficiency of iron is a contributing factor, except, perhaps, in newborns (milk-fed babies).

Look for abnormalities in the platelets and white count as well as in red cells. Low white cells and platelet counts along with anemia usually indicate bone marrow failure, bone marrow suppression, or displacement of a bone marrow by fibrosis, metastatic tumor, hematologic malignancies, granulomas or fibrosis.

Hepatosplenomegaly can indicate the presence of hemolysis, or of infiltrative processes such as lymphoma or a myelophthisic process (myelofibrosis) as a source of anemia. Lymphadenopathy can indicate chronic infection or a primary hematologic malignancy (lymphoma, chronic lymphocytic leukemia, etc.) that could be the cause of anemia by bone marrow suppression or immune hemolytic anemia secondary to lymphoproliferative disease.

Physical examination findings indicative of malnutrition, infection (e.g., tuberculosis, viral disease, etc.), and signs of major chronic illnesses such as collagen vascular diseases, cancer or a diabetes, can all point to systemic causes of a bone marrow suppression as the cause of anemia.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

A complete blood count with differential, review of red cell indices and RDW, and a reticulocyte count should be part of every anemia work-up. As indicated above, the red cell indices, especially the MCV, can narrow the diagnostic work-up, especially if there is marked microcytosis or macrocytosis.

A reticulocyte count is a very useful marker of adequate or inadequate production of red cells in response to the patient’s supply of red cells. The reticulocyte index (reticulocyte count x Hct/45) is a measure of whether or not the marrow is responding appropriately to the degree of anemia. A high reticulocyte index usually indicates a primary hemolytic anemia process. A low reticulocyte index usually, but not always, indicates a hypoproliferative anemia. However, a low reticulocyte index by itself does not rule out a hemolytic process as the primary or at least partial cause of the anemia. Thus, a hemolytic process in a patient with inadequate iron folate or B12 stores, parvovirus BA19 infection (the cause of so-called aplastic or hypoplastic crises), or due to cytotoxic drugs, will prevent inadequate bone marrow response to erythropoietin driven stimulation of red cell production.

Standard laboratory tests aiding in the diagnosis of anemia include the bilirubin, which is elevated, particularly indirect bilirubin in hemolytic processes, as is the LDH. As noted earlier, the haptoglobin is low in hemolytic anemia.

A serum ferritin level is the best marker for iron deficiency, but can be misleading in the presence of acute or chronic inflammation. Ferritin is an acute phase reactant and can be artificially elevated in the presence of inflammatory stimuli. However, a ferritin less than 30 is almost always indicative of low iron stores, while ferritins over 100 are rarely seen if iron deficiency is truly present.

The serum iron and total iron binding capacities (TIBC, a fairly good surrogate for serum transferrin) can provide useful ancillary information about iron deficiency or the anemia of chronic inflammation. Typically, patients with iron deficiency have a low serum iron and a high TIBC with a consequent low Fe/TIPC ratio of less than 15 %. Patients with anemia of chronic inflammation can often have a low serum iron but a correspondingly low total iron binding capacity. This differentiates and can sometimes help to distinguish between iron deficiency anemia and chronic inflammation. The use of soluble transferrin receptor assays in everyday practice is still under evaluation. The free erythrocyte protoporphyrin level is greatly elevated in lead poisoning and is very useful for childhood screening; it is less useful in most anemia work-ups.

What conditions can underlie anemia:

As noted above, almost any abnormality can disrupt the normal homeostasis of red cell production and destruction leading to anemia. Red cell production and destruction are a barometer of myriad functioning or malfunctioning systems in the body. That said, a few useful guidelines can emerge from the work-up outlined above.

Anemias due to hypoproduction of red cells are most often caused by:

1.) suppression by inflammation, malignancy, infection, anemia of chronic inflammation

2.) cytotoxic drugs or external agents: chemotherapy, certain antibiotics (bactrim), ionizing radiation

3.) immune suppression of marrow function (some forms of aplastic anemia) large granular lymphocyte leukemia

4.) intrinsic bone marrow failure syndrome (some forms of aplastic anemia and red cell hypoplasia, Diamond-Blackfan syndrome, transient erythroblastopenia of childhood, etc.)

5.) nutritional deficiencies: iron, folate, vitamin B12, protein calorie malnutrition, alcohol

6.) invasion of bone marrow by malignancy, fibrosis or granulomas

7.) renal failure

Hemolytic anemias are usually caused by:

1.) Autoantibodies due to autoimmune diseases, reaction to drugs or infectious organisms, or as part of a lymphoproliferative disease, especially chronic lymphocytic leukemia

2.) Direct drug toxicities, e.g., antimalarials in G6PD deficiency

3.) Mechanical destruction of red cells due to fibrin deposits (TTP, HUS), mechanical (artificial heart valves, arteriovenous malformations [AVMs]), thermal damage from burns, osmotic damage from fresh water drowning

4.) Intrinsic defects of red cell structure and function – hemoglobinopathies, red cell membrane disorders such as hereditary spherocytosis, enzymopathies such as pyruvate kinase deficiency, etc.

Microcytic anemias are due to defects in hemoglobin production: iron deficiency (only advanced and severe cases), thalassemia, and certain sideroblastic anemias due to defective production of hemoglobin.

Macrocytic anemias are either megaloblastic, due to vitamin deficiency (folate, B12) or myelodysplasia. Non-megaloblastic macrocytosis is usually due to liver disease, hypothyroidism or a high reticulocyte count. Mild macrocytosis is sometimes seen in myelodysplastic syndromes.

Hypoproliferative normocytic anemia – most common cause is early/mild/moderate iron deficiency, or acute or brisk sub-acute bleeding.

When do you need to get more aggressive tests:

If the likely causes of anemia do not emerge from the approach that is described, additional testing might be necessary, notably bone marrow aspiration and biopsy. As a rule, these should be done in consultation with the hematologist, since, based on the patients circumstances, special testing and/or cell/microbial culture of the marrow might be indicated.

If the patient has evidence of hemolysis, thalassemia (microcytosis with evidence of hemolysis), or sickle cell syndrome (painful crises) hemoglobin analysis may be indicated. Traditionally hemoglobin electrophoresis can be ordered but more modern tests employing mass spectrometry or direct globin gene sequencing are supplanting these methods in reference laboratories. Other than a routine hemoglobin analysis from your local laboratory, consultation with a hematologist is indicated.

In patients with hemolysis without obvious microangiopathic changes or characteristic morphologies of intrinsic red cell defects, immune hemolytic anemia should be suspected. When this is suspected, a direct antiglobulin test panel (“Coombs test”) should be ordered. This series of tests attempts to identify autoantibodies coating the red cells and circulating antibodies that are directed against the patient’s red cells. Follow up testing to characterize antibodies or to pursue negative test results that are not consistent with clinical presentation is best done in consultation with a hematologist.

When there is strong clinical, family history, or laboratory support for a diagnosis of an inherited defect, direct DNA analysis for the suspected mutation can be the most efficient approach to confirm or refute the provisional diagnosis.

The follow up evaluation for iron deficiency has been noted earlier. For suspected folate or B-12 deficiency, a red cell folate level and serum B-12 level are useful confirmatory tests. The serum B-12 level is susceptible to artifacts; thus, the serum methylmalonic acid level, which measures accumulation a metabolite in functional B-12 deficiency, is an important adjunctive test.

What imaging studies (if any) will be helpful?

There are no imaging studies that provide specific diagnostic information about the cause of anemia.

However, imaging studies can be very useful to detect the presence of tumors and infections (for example, tuberculosis, hepatosplenomegaly, etc.). Scanning of the bone marrow with magnetic resonance imaging (MRI) or positron emission tomography (PET) scanning sometimes can indicate hyperactivity of the bone marrow, but these tests are not yet diagnostically useful. Pathologic fractures of the bone and alterations of the bony cortex can indicate marrow expansion, in patients with thalassemia, some forms of leukemia and some myeloproliferative syndrome. Computerized tomography scans (CAT) can show the presence of extramedullary masses of hematopoiesis. These are usually readily apparent to most radiologists

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Emergency therapy for anemia is rarely necessary except under the following circumstances:

First, if the anemia is compromising cardiovascular integrity, e.g., the patient is in heart failure, respiratory distress, suffering from coronary ischemia, etc., judicious use of blood transfusions may be indicated, taking very careful precautions to avoid volume overload. Oxygen inhalation therapy is almost always a useful addition in those circumstances.

Second, if the anemia is due to an urgent underlying condition, such as TTP or HUS, appropriate therapy, e.g., plasma exchange or dialysis, is indicated.

Patients with profound anemia due Vitamin B-12 deficiency are very vulnerable from a cardiovascular perspective. Transfusion should be used very prudently to avoid volume overload and serum potassium levels should be monitored carefully as B-12 deficiency is corrected, because B-12 resupply drives potassium back into the intracellular space and thereby lowers serum potassium which can fall dramatically and dangerously.

In other circumstances, there is usually sufficient time to refine the diagnosis before initiating therapy. Red cell transfusions should not be administered to achieve a particular blood count, except in well defined hematologist-guided circumstances such as hypertransfusion therapy for thalassemia.

What other therapies are helpful for reducing complications?

Whatever the cause of the anemia, addressing the underlying condition is the best way, both short term and long term, to correct the anemia. For example, identifying and addressing the source of chronic bleeding, replacing nutrients that are in inadequate supply such as iron, folate, vitamin B12 or protein/calories, instituting immunosuppressive therapy such as steroids, for autoimmune causes, stopping the offending drug in the case of drug toxicities, etc.

The anemia of chronic inflammation, among the most common anemias encountered in the elderly, will only respond to correction of the underlying condition.

The use of erythropoiesis stimulating agents (ESA) is indicated for the management of chronic renal failure, and infrequently in select other circumstances such as patients with cancer or HIV. The latter uses have recently been shown to have marginal if any beneficial effects on long term survival or quality of life, and to be accompanied by potentially significant adverse events such as hypertension, cardiovascular events, and even stimulation of neoplastic growth in patients with cancer. Therefore, these agents should never be used without careful consultation with knowledgeable oncologists and hematologists.

What should you tell the patient and the family about prognosis?

Except in the case of severe and acute presentations of anemia, the anemia, of and in itself, is infrequently a cause of mortality. However, anemia can significantly impact quality of life and may be a co-morbidity complicating other conditions. Patients need to be educated about the proper uses of transfusion therapy and ESA’s, since patients demand is frequently persistent. The prognosis almost always depends on the underlying condition rather than the anemia itself. These situations are considered in the chapters on the individuals forms of anemia.

“What if” scenarios.

The major pitfalls associated with the work-up of anemia is to order a large array of “shotgun” diagnostic tests without careful consideration of the underlying conditions that could be producing the anemia. The approach outlined above should invariably lead one on the right path to a correct diagnosis.

Transfusing to a particular hematocrit without proper reference to the clinical situation is another common pitfall. Transfusion therapy carries its own array of adverse affects particularly in people whose anemia is due to conditions that cause chronic transfusion dependence. Therefore, blood transfusions should follow from the clinical need for additional oxygen-carrying capacity in the blood, e.g., cardiovascular status, neurologic status, etc.

The most common pitfall that can lead to incorrect or delayed diagnosis of anemia and its contributing underlying causes is failure to pursue the likelihood of bleeding as the sole or contributing factor producing the anemia. Therefore, one should be persistent and exhaustive in pursuing the possibility of bleeding unless there are more obvious other causes of the anemia, such as clear hemolytic parameters, etc.

Pathophysiology

See above – pathophysiology is discussed in context of particular forms of anemia.

What other clinical manifestations may help me to diagnose anemia?

See above. Symptoms of anemia include pallor, easy fatigability, exercise intolerance, cardiovascular compromise. Signs and symptoms are described for individual forms in the chapters describing those forms.

What other additional laboratory studies may be ordered?

See above.

What’s the evidence?

Marks, PW, Hoffman, R, Benz, E, Silberstein, L, Heslop, H, Weitz, J, Anastasi, J. “Approach to Anemia in the Adult and Chilld”. vol. Chapter 32. 2012. pp. 418-426. (A definitive guide to the practical classification and diagnostic evaluation of anemias.)

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