Hemolytic Anemia

Author: Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA Copyright 1994-2010 by Medscape Updated: Apr 27, 2009

Introduction
Background
Hemolysis is the premature destruction of erythrocytes, and it leads to hemolytic anemia when bone marrow activity cannot compensate for the erythrocyte loss. Clinical presentation depends on whether the onset of hemolysis is gradual or abrupt and on the severity of erythrocyte destruction. A patient with mild hemolysis may be asymptomatic. In more serious cases, the anemia can be life threatening, and patients can present with angina and cardiopulmonary decompensation. The clinical presentation also reflects the underlying cause for hemolysis. For example, sickle cell anemia is associated with a painful occlusive crisis (see Image 4 or below).

Peripheral blood smear with sickled cells at 1000X magnification. Image courtesy of Ulrich Woermann, MD.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.

Pathophysiology
Hemolysis is the final event triggered by a large number of hereditary and acquired disorders. The etiology of premature erythrocyte destruction is diverse and can be due

to conditions such as intrinsic membrane defects, abnormal hemoglobins, erythrocyte enzymatic defects, immune destruction of erythrocytes, mechanical injury, and hypersplenism. Hemolysis is associated with a release of hemoglobin and lactic acid dehydrogenase (LDH). An increase in indirect bilirubin and urobilinogen is derived from released hemoglobin A patient with mild hemolysis may have normal hemoglobin levels if increased production matches the rate of erythrocyte destruction. Alternatively, patients with mild hemolysis may experience marked anemia if their bone marrow erythrocyte production is transiently shut off by viral (parvovirus B19) or other infections, resulting in uncompensated destruction of erythrocytes (aplastic hemolytic crisis, in which a decrease in the erythrocytes occurs in a patient with ongoing hemolysis). Skull and skeletal deformities can occur with a marked increase in hematopoiesis, expansion of bone in infancy, and early childhood disorders such as sickle cell anemia or thalassemia.

Polychromasia.

Spherocytes. One arrow points to a spherocyte; the other, to a normal RBC with a central pallor.

Frequency
International Hemolytic anemia represents approximately 5% of all anemias.

Mortality/Morbidity
The overall incidence of death is low in cases of hemolytic anemia. However, older patients and patients with cardiovascular impairment are at an increased risk. Morbidity is dependent on the etiology of the hemolysis and the underlying disorder such as sickle cell anemia or malaria.

Tachycardia and dyspnea symptoms occur when the onset of hemolysis is abrupt and the anemia is severe. Angina and heart failure symptoms can occur in patients with underlying cardiovascular disease and severe uncompensated hemolysis. Hemosiderosis, leg ulcers, folate deficiency, and gallstones can also occur.

Race
Most of the disorders that lead to hemolysis are not specific to any race.

Sickle cell disorders are found primarily in Africans, African Americans, some Arabic peoples, and Aborigines in southern India. Several variants of glucose-6-phosphate dehydrogenase (G6PD) deficiency exist. The A variant is generally found in West Africans and African Americans. Approximately 10% of African Americans carry at least 1 copy of the gene for this variant. The Mediterranean variant occurs in individuals of Mediterranean descent and in some Asians.

Sex

Most cases of hemolytic anemia are not sex specific. Autoimmune hemolytic anemia (AIHA) is slightly more likely to occur in females than in males. G6PD deficiency is an X-linked recessive disorder. Males are usually affected, and females are carriers.

Age

Hemolytic anemia can occur in persons of any age. Hereditary disorders are usually evident early in life. Autoimmune hemolytic anemia is more likely to occur in middle-aged and older individuals.

Clinical
History
Symptoms of hemolytic anemia are diverse and are due to the anemia, the extent of compensation, previous treatment, and the underlying disorder.

Patients with minimal or long-standing hemolytic anemia can be asymptomatic, so hemolysis is often found incidentally during routine laboratory testing. In intravascular hemolysis, iron deficiency due to chronic hemoglobinuria can exacerbate anemia and weakness. Tachycardia, dyspnea, angina, and weakness occur in patients with severe anemia. Cardiac function is sensitive to anoxia. Angina and evidence of cardiac decompensation occurs if anemia is severe or if the onset is rapid. Gallstones may cause abdominal pain. Bilirubin stones can develop in patients with persistent hemolysis. Bronze skin color and diabetes result from hemochromatosis due to multiple transfusions or erroneously administered iron therapy. Hemoglobinuria produces dark urine. It can occur in patients with intravascular hemolysis and has similar results to a transfusion of ABOincompatible blood. Patients with thrombotic thrombocytopenic purpura (TTP) may experience fever, neurologic signs, renal failure, petechiae, and hemolysis because of the widespread occlusion of small vessels. Leg ulcers may develop in patients with sickle cell anemia and other hemolytic disorders as a result of decreased red blood cell deformity and endothelial changes. Penicillin, quinine, quinidine, L-dopa, and other agents may cause immune hemolysis (see Medical Care). Oxidant drugs (see Diet) and stress from infections can trigger hemolysis in patients with G6PD deficiency. Fava beans can induce hemolysis in susceptible individuals with the Mediterranean variant of G6PD deficiency. A patient who needs a transfusion but does not show evidence of blood loss or bone marrow suppression may have hemolytic anemia.

Physical
The physical examination in an individual with hemolytic anemia can reveal signs of anemia, erythrocyte destruction, complications of hemolysis, and evidence of an underlying disease.

General pallor and pale conjunctivae and fingernails indicate anemia but are not specific for hemolytic anemias. Tachycardia, tachypnea, and hypotension due to anoxia and decreased vascular volume usually occur in severe anemias but are not specific for hemolytic anemias. Jaundice may occur because of a modest increase in indirect bilirubin in hemolysis. The rise is not specific for hemolytic disorders and may occur in

liver disease, biliary obstruction, and hereditary liver disorders. Bilirubin levels are rarely greater than 4 mg/dL in hemolysis unless complicated by hepatic disease or cholelithiasis. Splenomegaly o Splenomegaly occurs in hereditary spherocytosis and other hemolytic anemias, but it is not present in other hemolytic disorders such as G6PD deficiency. o The presence of splenomegaly suggests underlying disorders such as chronic lymphocytic leukemia (CLL), some lymphomas, and systemic lupus erythematosus (SLE). Leg ulcers Right upper abdominal quadrant tenderness may indicate gallbladder disease. Bleeding and petechiae indicate thrombocytopenia due to Evans syndrome or thrombotic thrombocytopenic purpura if neurologic signs are also present. Butterfly malar rash and arthritis suggest SLE. Lymphadenopathy with splenomegaly may indicate an underlying chronic CLL.

Causes
More than 200 causes for hemolysis exist. Only the main categories and some examples of hemolytic disorders are considered in this article.

Hereditary disorders include erythrocyte membrane and enzymatic defects and hemoglobin abnormalities. Some hereditary disorders include the following: o G6PD deficiency o Hereditary spherocytosis o Sickle cell anemia Acquired hemolytic conditions can be due to immune disorders, toxic chemicals and drugs, antiviral agents (eg, ribavirin1 ) physical damage, and infections. They can include the following: o Autoimmune hemolytic anemia (AIHA) may result from warm or cold autoantibody types; rarely, mixed types occur.2,3,4 Most warm autoantibodies are immunoglobulin (Ig) G and can be detected with the direct Coombs test, which is also known as the direct antiglobulin test (DAT). o AIHA may occur after allogeneic hematopoietic stem cell transplantation. The 3-year cumulative incidence in this population has been reported at 4.44%.5 o Microangiopathic anemia is found in patients with disseminated intravascular coagulation (DIC) or hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura.6 Fragmented erythrocytes (schistocytes) also occur with defective prosthetic cardiac valves. Autoimmune hemolytic anemia and hereditary spherocytosis are classified as examples of extravascular hemolysis because the red blood cells are destroyed in the spleen and other reticuloendothelial organs. Intravascular hemolysis occurs in hemolytic anemia due to prosthetic cardiac valves, G6PD deficiency, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, and paroxysmal nocturnal hemoglobinuria (PNH).

Differential Diagnoses
Disseminated Intravascular Coagulation Systemic Lupus Erythematosus Thrombotic Thrombocytopenic Purpura

Other Problems to Be Considered

Other causes for anemia Other causes for fatigue, tachycardia, and dyspnea

Workup
Laboratory Studies

Complete blood cell (CBC) count o The test documents anemia, leukocyte counts, and differential counts. o Platelet counts help to exclude an underlying infection or hematologic malignancy. The platelet count is within the reference range in most hemolytic anemias. o Thrombocytopenia can occur in SLE, CLL, and microangiopathic hemolytic anemia (defective prosthetic cardiac valves, TTP, HUS, and DIC). Thrombocytopenia associated with a positive direct Coombs test result is known as Evans syndrome.7

Peripheral smear and morphologic examination o Identifies polychromasia, indicating RBC immaturity reticulocytosis (see Image 1 or below)

Polychromasia. o

Demonstrates spherocytes, suggesting congenital spherocytosis or autoimmune hemolytic anemia (AIHA, see Image 2 or below)

Spherocytes. One arrow points to a spherocyte; the other, to a normal RBC with a central pallor. o

Can identify schistocytes (fragmented red blood cells, suggesting TTP, HUS, or mechanical damage (see Image 3 or below)

Schistocytes (thrombotic thrombocytopenic purpura). o

Can help diagnose a concomitant underlying hematologic malignancy associated with hemolysis (eg, CLL)

Red blood cell indices o These studies are performed when a CBC count is requested. o A low mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) are consistent with a microcytic hypochromic anemia, which may occur in chronic intravascular hemolysis (eg, PNH).

A high MCV is consistent with a macrocytic anemia. Macrocytosis is usually due to megaloblastic anemias but can occur in liver disease. A high number of reticulocytes also may cause a high MCH. A high MCH and mean corpuscular hemoglobin concentration (MCHC) suggest spherocytosis.

Increased red blood cell distribution width (RDW) study o This study is usually performed when a CBC count is requested. o An increased RDW is a measure of anisocytosis, which is likely in hemolytic anemia.

Reticulocyte count o An increased reticulocyte count is a criterion for hemolysis but is not specific for hemolysis. o An increase may be caused by blood loss or a bone marrow response to iron, vitamin B-12, or folate deficiencies. o The reticulocyte count may be normal or low in patients with bone marrow suppression despite ongoing severe hemolysis.

LDH
o

Serum LDH elevation is a criterion for hemolysis. LDH is not specific because it is ubiquitous and can be released from the neoplastic cells of the liver or other damaged organs. Although an increase in LDH isozyme 1 and 2 is more specific for red blood cell destruction, these enzymes are also increased in patients with myocardial infarction.

Serum haptoglobin o A low serum haptoglobin level is a criterion for moderate to severe hemolysis. o A decrease in serum haptoglobin is more likely in intravascular hemolysis than in extravascular hemolysis, but it is an acute phase reactant. o The presence of concomitant infection, other reactive states, or chronic hemolysis may mask the diagnosis by raising haptoglobin levels.

Indirect bilirubin

o o

Unconjugated bilirubin is a criterion for hemolysis, but it is not specific because an elevated bilirubin also may indicate Gilbert disease. With hemolysis, the level of indirect bilirubin usually is less than 4 mg/dL. Higher levels of indirect bilirubin indicate compromised hepatic function or cholelithiasis and hemolysis.

Changes in the LDH and serum haptoglobin levels are the most sensitive general tests because the indirect bilirubin is not always increased.

Specific studies directed by history, physical examination, peripheral smear, and other laboratory findings o The DAT result is usually positive in autoimmune hemolytic anemia, but it may be occasionally negative in this disorder. DAT-negative autoimmune hemolytic anemias have been reviewed.8 From 5% to 10% of all autoimmune hemolytic anemias are DAT negative. The polybrene test can detect DAT-negative autoimmune hemolytic anemia.8 In addition, the immunoradiometric assay (IRMA) for red blood cell bound IgG can be used to diagnose AIHA in patients whose autoantibody levels are too low to be detected by conventional DAT.9 o The urine free hemoglobin test reveals hemoglobinuria, which occurs with intravascular hemolysis when the amount of free hemoglobin exceeds the available haptoglobin. Urine may be dark due to hemoglobinuria, but myoglobinuria, porphyria, and other conditions can also cause dark urine. o Urine hemosiderin may suggest intravascular hemolysis. Hemosiderin is detected in spun urinary sediment as an iron stain in sloughed renal epithelial cells. o Red blood cell survival (chromium-51 [51 Cr] survival) is rarely used, but it can definitively demonstrate a shortened red blood cell survival (hemolysis). This test is ordered when the clinical history and laboratory studies cannot establish a diagnosis of hemolysis. o Cold agglutinin titer: A high titer of anti-I antibody may be found in mycoplasmal infections and a high titer of anti-i antibody may be found in hemolysis associated with infectious mononucleosis. An antiP cold agglutinin may be seen in paroxysmal cold hemoglobinuria. o A G6PD screen can usually detect deficiency of this enzyme, but results are normal if the reticulocyte count is elevated (reticulocytes contain a considerable amount of G6PD). A Heinz body preparation also detects G6PD deficiency (see Image 5 or below).

Supra vital stain in hemoglobin H disease that reveals Heinz bodies (golf ball appearance).

Screen for sickle cell syndrome: This is done by demonstrating sickling under reduced conditions (sickle cell preparations) and testing for hemoglobin solubility (see Image 4 or below). Hemoglobin electrophoresis confirms the presence of abnormal hemoglobin.

Peripheral blood smear with sickled cells at 1000X magnification. Image courtesy of Ulrich Woermann, MD.

Other tests depend on the possibility of sickle cell anemia, hereditary spherocytosis, SLE, a hematologic malignancy, and types of hemolytic anemias that are more rare.

Imaging Studies

Use ultrasonography to estimate the spleen size. The physical examination occasionally does not detect significant splenomegaly.

Chest radiography is used to evaluate cardiopulmonary status.

Other Tests

Electrocardiography (ECG) and other studies are used to evaluate cardiopulmonary status.

Treatment
Medical Care
More than 200 types of hemolytic anemia exist, and each type requires specific treatment. Therefore, only the aspects of medical care relevant to most cases of hemolytic anemia are discussed here.

Transfusion therapy o Avoid transfusions unless absolutely necessary, but they may be essential for patients with angina or severely compromised cardiopulmonary status. o Administer packed red blood cells slowly to avoid cardiac stress. o In autoimmune hemolytic anemia (AIHA), type matching and crossmatching may be difficult. Use the least incompatible blood if transfusions are indicated. The risk of acute hemolysis of transfused blood is high, but the degree of the hemolysis is dependent on the rate of infusion. Slowly transfuse by administering half units of packed red blood cells to prevent rapid destruction of transfused blood. o Iron overload from repeated transfusions for chronic anemia (eg, thalassemia or sickle cell disorder) can be treated with chelation therapy. A recent systematic review compared the oral iron chelator deferasirox with the oral chelator deferiprone and the traditional parenteral agent, deferoxamine.10 Discontinuing medications o Discontinue penicillin and other agents that can cause immune hemolysis and oxidant medication such as sulfa drugs (see Diet). o Medications that can cause immune hemolysis include the following (see References for more complete lists): Penicillin Cephalothin Ampicillin Methicillin Quinine Quinidine Administer folic acid, because active hemolysis may consume folate and cause megaloblastosis. Corticosteroids are indicated in autoimmune hemolytic anemia. Intravenous immunoglobulin G (IVIG) has been used for patients with AIHA, but only a few patients have had treatment responses, and the response has been transient. Iron therapy

o o

This is indicated for patients with severe intravascular hemolysis in which persistent hemoglobinuria has caused substantial iron loss. Before iron is administered, document the iron deficiency by serum iron studies and, possibly, by assessing iron stores in bone marrow aspirates. Because iron stores increase in hemolysis, iron administration is generally contraindicated in hemolytic disorders, particularly those that require chronic transfusion support.

Surgical Care

Splenectomy may be the first choice of treatment in some types of hemolytic anemia, such as hereditary spherocytosis. o In other cases, such as in AIHA, splenectomy is recommended when other measures have failed. o Splenectomy is usually not recommended in hemolytic disorders such as cold agglutinin hemolytic anemia. o Immunize against infections with encapsulated organisms, such as Haemophilus influenzae and Streptococcus pneumoniae, as far in advance of the procedure as possible.

Consultations

A hematology consultation helps in selecting appropriate diagnostic approaches and laboratory tests and assists in planning and monitoring therapy. Perform tests to identify hemolysis in an experienced laboratory that is selected by a hematologist. Consult a general surgeon if considering splenectomy.

Diet

Fava beans can cause severe hemolysis in certain populations with the Mediterranean G6PD isoenzyme variant. These patients should avoid eating dishes with fava beans. Medications and chemicals that should be avoided in G6PD deficiency include the following (see References for more complete lists): o Acetanilid o Furazolidone o Isobutyl nitrite o Nalidixic acid o Naphthalene o Niridazole

Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications in patients with hemolytic anemia.

Vitamins
Vitamins are essential for normal DNA synthesis and the formation of a number of coenzymes in many metabolic systems. Folic acid (Folvite) Cofactor for enzymes involved in production of red blood cells. Replenishes depleted folate stores consumed during chronic hemolysis.

Dosing Interactions Contraindications Precautions

Corticosteroids
Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the immune response of the body to diverse stimuli. Glucocorticoids, such as prednisone, are usually the first line of treatment in autoimmune hemolytic anemia (AIHA). Consult a hematologist to individualize therapy and determine whether other forms of therapy are indicated in the treatment of AIHA. Taper glucocorticoids very gradually to avoid a relapse of hemolysis. Prednisone (Deltasone, Orasone, Sterapred) Inhibits phagocytosis of antibody-covered red blood cells. Indicated in some hemolytic disorders such as AIHA

Follow-up
Further Inpatient Care

Monitor the hemoglobin level, reticulocyte count, indirect bilirubin, LDH, and haptoglobin in patients with hemolytic anemia to determine the response to therapy. Monitor urine hemoglobin and hemosiderin to evaluate the response of intravascular hemolysis therapy. Avoid transfusions unless evidence of angina, cardiopulmonary decompensation, or other severe organ impairment due to anemia is present. Continue to administer folic acid. Administer oral iron to patients who have become iron deficient due to intravascular hemolysis. Taper corticosteroids. Treat the underlying cause of the hemolysis.

Further Outpatient Care

Initially, monitor hemoglobin, reticulocyte count, and other parameters of hemolysis closely. After the initial period, monitor these limits as indicated. Treat the underlying disorder. Continue folic acid, because a patient with ongoing hemolysis consumes this vitamin for the accelerated production of erythrocytes. Taper corticosteroids. However, if indicated, patients may have to continue low-dose steroids if no contraindications exist for prolonged corticosteroid therapy.

Deterrence/Prevention

Avoid medications that can induce immune hemolysis in susceptible individuals or oxidant medications that can cause hemolysis in patients with G6PD deficiency.

Prognosis

The prognosis for hemolytic anemia depends upon the underlying cause.

Patient Education

The patient with hemolytic anemia must be able to identify symptoms and signs of hemolysis recurrence and seek prompt medical attention if they occur.

Miscellaneous
Medicolegal Pitfalls

Failure to diagnose hemolytic anemia and treat correctly