Hemolytic Anemia
Practice Essentials
Hemolysis is the premature destruction of erythrocytes. A hemolytic anemia will develop if bone marrow activity cannot compensate for the erythrocyte loss. The clinical severity of the anemia depends on whether the onset of hemolysis is gradual or abrupt as well as the extent of erythrocyte destruction. Mild hemolysis can be asymptomatic while the anemia in severe hemolysis can be life threatening and lead to angina and cardiopulmonary decompensation.
The clinical presentation also reflects the underlying cause for hemolysis. For example, sickle cell anemia (see the image below) is associated with painful vaso-occlusive crises. (See Presentation.)
Peripheral blood smear with sickled cells at 1000X magnification. Image courtesy of Ulrich Woermann, MD.
Hemolytic anemia has multiple causes, and the clinical presentation can differ depending on the etiology. An array of laboratory tests are available for detecting hemolysis, and specialized tests may be indicated to diagnose the cause of hemolysis, There are differences in the management of various types of hemolytic anemias.
Pathophysiology
Hemolysis can be due to hereditary and acquired disorders. [1, 2] 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 can occur intravascularly or extravascularly. Autoimmune hemolytic anemia and hereditary spherocytosis are examples of extravascular hemolysis because the red blood cells are destroyed in the spleen and other reticuloendothelial tissues. [3] Intravascular hemolysis occurs in hemolytic anemia due to the following:
Prosthetic cardiac valves
Transfusion of ABO incompatible blood
COVID-19 [4, 5]
Hemolysis may also be intramedullary, when fragile red blood cell (RBC) precursors are destroyed in the bone marrow prior to release into the circulation. Intramedullary hemolysis occurs in pernicious anemia and thalassemia major. Skull and other skeletal deformities can occur in childhood due to a marked increase in hematopoiesis and resultant bone marrow expansion in disorders such as thalassemia.
Hemolysis is associated with a release of RBC lactate dehydrogenase (LDH). Hemoglobin released from damaged RBCs leads to an increase in indirect bilirubin and urobilinogen levels.
A patient with mild hemolysis may have normal hemoglobin levels if increased RBC production matches the rate of RBC destruction. However, patients with mild hemolysis may develop marked anemia if their bone marrow erythrocyte production is transiently shut off by viral (parvovirus B19) or other infections. This scenario would be an aplastic crisis since the bone marrow can no longer compensate for ongoing hemolysis.
Etiology
A wide range of causes of hemolytic anemia have been documented. [7, 8, 9, 10, 11, 12, 13, 14, 15, 1, 16] Only the more commonly encountered hemolytic disorders are discussed in this article.
Hereditary disorders may cause hemolysis as a result of erythrocyte membrane abnormalities, enzymatic defects, and hemoglobin abnormalities. Hereditary disorders include the following:
Acquired causes of hemolysis include the following:
Immune disorders
intravenous immunoglobulin G (IVIG) [17]
Toxic chemicals and drugs [8, 18]
Antiviral agents (eg, ribavirin [19] )
Physical damage
Infections [20, 21]
Post-valve replacement [22]
Contrast medium iomeprol [23]
Autoimmune hemolytic anemia (AIHA) can be due to warm or cold autoantibody types and, rarely, mixed types. [16, 24, 25, 26] Most warm autoantibodies belong to the immunoglobulin IgG class. These antibodies can be detected by a direct Coombs test, which also is known as a direct antiglobulin test (DAT). AIHA may occur after allogeneic hematopoietic stem cell transplantation. The 3-year cumulative incidence in this population has been reported at 4.44%. [27]
AIHA is rare in children and has a range of causes. Autoimmune hemolysis can be primary or secondary to conditions such as infections (viral, bacterial, and atypical), systemic lupus erythematosus (SLE), autoimmune hepatitis (AIH), and H1N1 influenza. H1N1 influenza–associated AIHA in children may respond to treatment with oseltamivir and intravenous immunoglobulin. [9]
Fetal splenomegaly and associated hepatomegaly could be due to hemolysis, but infections are the most likely cause. Congestive heart failure and metabolic disorders should be considered. Rarely, leukemia, lymphoma, and histiocytosis are associated with splenomegaly. [28]
Microangiopathic hemolytic anemia, which results in the production of fragmented erythrocytes (schistocytes), may be caused by any of the following [29, 30] :
Defective prosthetic cardiac valves
Disseminated intravascular coagulation (DIC)
Hemolytic uremic syndrome (HUS)
Thrombotic thrombocytopenic purpura (TTP)
In paroxysmal nocturnal hemoglobinuria, hemolysis is due to intravascular complement-mediated destruction of erythrocytes.
Epidemiology
Hemolytic anemia represents approximately 5% of all anemias. Acute AIHA is relatively rare, with an incidence of one to three cases per 100,000 population per year. [31]
A review of the Nationwide Inpatient Sample database found that the prevalence of nonimmune hemolytic anemia was 0.17% in all hospitalized patients with alcoholic liver disease. The presence of anemia among inpatients with alcoholic liver disease was associated with a significantly worse prognosis, including longer average length of stay (8.8 vs. 6.0 d1), increased hospital charges ($38,961 vs. $25,244), and higher mortality (9.0% vs. 5.6%). [32]
Hemolytic anemias are not specific to any race. However, sickle cell disorders are found primarily in Africans, African Americans, some Arabic populations, and Aborigines in southern India.
Several variants of G6PD deficiency exist. The A(-) variant is 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.
Most cases of hemolytic anemia are not sex specific. However, AIHA is slightly more likely to occur in females than in males. G6PD deficiency is an X-linked recessive disorder and therefore primarily males are affected while females are more commonly carriers.
Although hemolytic anemia can occur in persons of any age, hereditary disorders are usually evident early in life. AIHA is more likely to occur in middle-aged and older individuals.
Prognosis
The prognosis for patients with hemolytic anemia depends on the underlying cause.
Overall, mortality rates are low in hemolytic anemias. However, the risk is greater in older patients and patients with cardiovascular impairment.
Morbidity depends on the etiology of the hemolysis and the underlying disorder, such as sickle cell anemia or malaria.
Patient Education
Patients should be able to identify symptoms and signs of the recurrence of hemolysis. They should seek prompt medical attention if symptoms reoccur.
Patients with G6PD deficiency should know which medications to avoid.
Clinical Presentation
History
Signs and symptoms of hemolytic anemia are diverse and are due to anemia, the extent of compensation, previous treatment, and the underlying disorder. Patients with minimal or long-standing hemolytic anemia may be asymptomatic, and hemolysis is often found incidentally during routine laboratory testing. Clinical manifestations may include the following:
Dark urine may occur in patients with intravascular hemolysis, due to hemoglobinuria; chronic intravascular hemolysis may result in iron deficiency.
Tachycardia, dyspnea, angina, and weakness occur in patients with severe anemia, as cardiac function is sensitive to anoxia.
Persistent hemolysis may result in the development of bilirubin gallstones; these patients may present with abdominal pain.
Bronze skin color and diabetes occur in hematosiderosis; iron overload may occur in patients who have received multiple transfusions or those who have been administered iron therapy erroneously.
In addition to hemolysis, patients with thrombotic thrombocytopenic purpura (TTP) may experience fever, neurologic signs, kidney failure, and thrombocytopenia.
Leg ulcers may develop in patients with sickle cell anemia, thalassemia major, and other hemolytic disorders, as a result of decreased red blood cell (RBC) deformability, endothelial changes, and chronic hypoxia.
Venous thromboembolism occurs in 15% to 33% of adults with warm autoimmune hemolytic anemia, especially in the first few weeks after onset. [33] Children with hereditary spherocytosis (HS) are also at increased risk for thrombosis. Hypercoagulability is especially marked in children with HS who are experiencing a hemolytic crisis. [34]
Patients may report recent use of medications that can cause immune hemolysis. These include penicillin, quinine, quinidine, and L-dopa. Dimethyl fumarate, which used in the treatment of relapsing forms of multiple sclerosis, has recently been shown to cause a hemolytic anemia. [35]
In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemolysis can be triggered by oxidant drugs and stress from infections. Fava beans can induce hemolysis in susceptible individuals with the Mediterranean variant of G6PD deficiency.
Physical Examination
The physical examination in an individual with hemolytic anemia can reveal signs of anemia, 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 can 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 and biliary obstruction. Bilirubin levels are rarely greater than 3 mg/dL in hemolysis, unless complicated by liver disease or cholelithiasis.
Splenomegaly occurs in hereditary spherocytosis and other hemolytic anemias, but it is not present in all hemolytic disorders. For example, splenomegaly usually is not present in G6PD deficiency. The presence of splenomegaly could suggest an underlying disorder such as chronic lymphocytic leukemia (CLL), some lymphomas, or systemic lupus erythematosus (SLE). Butterfly malar rash and arthritis also symptoms suggestive of SLE. Lymphadenopathy along with splenomegaly is consistent with CLL.
Splenomegaly sometimes is not evident on physical examination, and ultrasonic imaging or CT scanning may be necessary to define spleen size. When evaluating spleen size, it is important to avoid unnecessary pressure in order to avoid splenic rupture.
Leg ulcers may be present.
Right upper abdominal quadrant tenderness may indicate cholelithiasis (bilirubin gallstones) and gallbladder disease.
Tachycardia and dyspnea may be evident 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.
In patients with chronic hemolytic anemia, increased folate consumption may lead to folate deficiency. Clinical manifestations may include patchy hyperpigmentation, sore tongue, and gastrointestinal symptoms.
Differential Diagnoses
Diagnostic Considerations
Other causes for fatigue, tachycardia, and dyspnea should be considered. Other causes for anemia should be ruled out. A transfusion requirement in the absence of blood loss or bone marrow aplasia would suggest hemolysis.
Go to Anemia, Iron Deficiency Anemia, and Chronic Anemia for complete information on these topics.
Differential Diagnoses
Workup
Approach Considerations
Standard blood studies for the workup of suspected hemolytic anemia include the following:
Complete blood cell count (CBC)
Peripheral blood smear
Serum lactate dehydrogenase (LDH)
Serum haptoglobin
Indirect bilirubin
Hemolysis of collected blood is more likely to occur in standard large vacuum tubes than in small tubes. Thus, it might better to collect blood for these tests in small vacuum tubes, since hemolysis of collected blood can skew the results of these tests. [36]
Changes in the LDH and serum haptoglobin levels are the most sensitive general tests because the indirect bilirubin is not always increased.
Other laboratory studies may be directed by history, physical examination, peripheral smear, and other laboratory findings. Ultrasonography is used to estimate the spleen size, since the physical examination occasionally does not detect significant splenomegaly. Chest radiography, electrocardiography (ECG), and other studies are used to evaluate cardiopulmonary status.
Complete Blood Cell Count
This test can detect an anemia, pancytopenia, and infections. Along with the differential count, a CBC can help diagnose hematologic malignancies and other hematologic disorders. The platelet count usually is normal in most hemolytic anemias.
Thrombocytopenia can occur in systemic lupus erythematosus (SLE), chronic lymphocytic leukemia (CLL), and microangiopathic hemolytic anemias (eg, patients with defective prosthetic cardiac valves, thrombotic thrombocytopenic purpura [TTP], hemolytic uremic syndrome [HUS], and disseminated intravascular coagulation [DIC]). Thrombocytopenia associated with a positive direct Coombs test occurs in the Evans syndrome. [37]
Red blood cell indices
These studies are performed when a CBC is requested. A low mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) are consistent with a microcytic hypochromic anemia due to iron deficiency that may occur in chronic intravascular hemolysis.
A high MCV is consistent with a macrocytic anemia. Folate consumed during chronic hemolysis may lead to megaloblastosis and a high MCV. However, the MCV also may be elevated in patients with high reticulocyte counts since these cells are larger than mature RBCs. A high MCH and mean corpuscular hemoglobin concentration (MCHC) would suggest spherocytosis.
Red blood cell distribution width study
The red blood cell distribution width (RDW) study is usually performed when a CBC is requested. An increased RDW is a measure of anisocytosis that can occur in hemolytic anemias.
Reticulocyte count
An increased reticulocyte count represents increased RBC production and is a criterion for hemolysis but is not specific for hemolysis. In addition to hemolysis, increased reticulocytes may be a response to blood loss or the treatment of iron, vitamin B12, or folate deficiencies. The reticulocyte count may be normal or low in patients with bone marrow suppression despite ongoing severe hemolysis (aplastic crisis).
Peripheral Blood Smear
Peripheral smear findings can help in the diagnosis of a concomitant underlying hematologic malignancy associated with hemolysis. For example, smears in CLL are characterized by an abundance of small lymphocytes and smudge cells (ruptured CLL cells).
The following are examples of the value of evaluating peripheral blood smears.
Polychromasia indicates RBC immaturity (see the image below).
Polychromasia.
A peripheral smear may demonstrate spherocytes, suggesting congenital spherocytosis or autoimmune hemolytic anemia (AIHA); see the image below.
Spherocytes. One arrow points to a spherocyte; the other, to a normal RBC with central pallor.
The presence of schistocytes (fragmented red blood cells) suggests DIC, TTP, HUS, or mechanical damage (see the image below).
Schistocytes (thrombotic thrombocytopenic purpura).
Lactate Dehydrogenase Study
Serum LDH elevation is a criterion for hemolysis.
LDH elevation is sensitive for hemolysis, but is not specific since LDH is ubiquitous and can be released from neoplastic cells, the liver, or from other damaged organs.
Although an increase in LDH isozymes 1 and 2 is more specific for red blood cell destruction, these enzymes are also increased in patients with myocardial infarction.
Serum Haptoglobin
A low serum haptoglobin level is a criterion for moderate-to-severe hemolysis.
A decrease in serum haptoglobin is more likely in intravascular hemolysis than in extravascular hemolysis.
However, it is an acute phase reactant. Therefore, haptoglobin levels can be normal or elevated despite significant hemolysis in patients with infections and in other reactive states.
Indirect Bilirubin
Unconjugated bilirubin is a criterion for hemolysis, but it is not specific because an elevated indirect bilirubin level also occurs in Gilbert disease.
With hemolysis, the level of indirect bilirubin usually is less than 3 mg/dL. Higher levels of indirect bilirubin indicate compromised liver function or cholelithiasis.
Other Laboratory Studies
The following specific studies may be indicated:
Direct antiglobulin test (DAT)
Plasma free hemoglobin
Urine free hemoglobin test
Urine hemosiderin test
Red blood cell survival test
Cold agglutinin titer
Glucose-6-phosphate dehydrogenase (G6PD) screen
Sickle cell screen
Flow cyometry for paroxysmal nocturnal hemoglobinuria (PNH)
The DAT result is usually positive in autoimmune hemolytic anemia (AIHA), but it may occasionally be negative in this disorder. DAT-negative AIHAs have been reviewed. [38] Approximately 5-10% of all AIHAs are DAT negative. The polybrene test can detect DAT-negative AIHA. [38] 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. [39] DAT-negative AIHA has a better prognosis than DAT-positive AIHA. [40]
A promising new method for diagnosing AIHA measures the binding of red blood cells that have autoimmune IgG on their surface to films containing a monoclonal antibody against human immunoglobulin. This test could potentially be used in place of the direct Coombs test, which is prone to false positives. [41]
MicroRNA analysis has been found to be helpful in the diagnosis of AIHA in patients with chronic lymphocytic leukemia. [42]
In addition to hemoglobinuria, either myoglobinuria or porphyria may result in dark urine. To rule out these possibilities, the urine should be tested for free hemoglobin. Hemoglobinuria occurs when the amount of free hemoglobin released during hemolysis exceeds available haptoglobin.
Urine hemosiderin may suggest severe or intravascular hemolysis. Hemosiderin is detected in iron-stained urinary sediment in sloughed renal epithelial cells. The source of urinary hemosiderin is hemoglobinuria that occurs in severe and intravascular hemolysis. When urinary hemoglobin is reabsorbed by renal tubular cells, it is processed to hemosiderin. Therefore, urinary hemosiderin reflects hemoglobinuria and suggests severe or intravascular hemolysis.
Red blood cell survival (chromium-51 [51Cr] survival) is rarely used, but it can definitively demonstrate shortened red blood cell survival (hemolysis). If available, this test can be helpful when the clinical history and laboratory studies cannot establish a diagnosis of hemolysis.
The cold agglutinin titer will be elevated in cold agglutinin disease, with the specific IgM antibody varying according to the underlying disorder. [43] For example, a high titer of anti-I antibody (ie, antibody directed against the I antigen found on normal adult RBCs) occurs in mycoplasmal infections. High titers of anti-i antibody (antibody directed against the i antigen found on fetal cord blood RBCs) have been reported in infectious mononucleosis. An anti-P cold agglutinin may be seen in paroxysmal cold hemoglobinuria.
A G6PD screening can usually detect deficiency of this enzyme, but results can be normal if the reticulocyte count is elevated (reticulocytes contain a considerable amount of G6PD). A positive Heinz body preparation on peripheral smear is suggestive of denatured hemoglobin and thus G6PD deficiency (see the image below).
Supravital stain in hemoglobin H disease reveals Heinz bodies (golf ball appearance).
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Screening for sickle cell disease is performed by demonstrating sickling under reduced conditions (sickle cell preparations) and testing for hemoglobin solubility (see the image 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 may be indicated to diagnose hereditary spherocytosis, hematologic malignancy, and rarer types of hemolytic anemias.
Treatment & Management
Approach Considerations
There are numerous types of hemolytic anemia, and treatment may differ depending on the type of hemolysis. [7, 8, 9, 44, 45, 46, 47, 48] Only the general care of hemolytic anemias and the management of the most commonly encountered hemolytic anemias are discussed here. For discussion of treatment of cold agglutinin hemolytic anemia, see Cold Agglutinin Disease.
Folic acid, corticosteroids, rituximab, and IVIG
Prophylactic folic acid is indicated because active hemolysis can consume folate and cause megaloblastosis.
Corticosteroids are indicated in autoimmune hemolytic anemia (AIHA).
Increasing evidence supports the use of rituximab in AIHA, particularly in warm antibody AIHA. [49, 50, 51] Although rituximab is increasingly used in steroid-refractory warm AIHA, [47] results of a phase III trial in 64 patients support its use as first-line therapy for warm AIHA, in combination with corticosteroids. Birgens et al reported that after 12 months, a satisfactory response was observed in 75% of the patients treated with rituximab and prednisolone, but in 36% of those given prednisolone alone (P = 0.003). After 36 months, about 70% of the patients who had received rituximab and prednisolone were still in remission, compared with about 45% of those in the prednisolone group. [45]
Intravenous immunoglobulin G (IVIG) has been used for patients with AIHA, but only a few patients have responded to this treatment, and the responses have been transient.
Transfusion Therapy
One should avoid transfusions unless absolutely necessary. However, transfusions may be essential for patients with angina or a severely compromised cardiopulmonary status. It is best to administer packed red blood cells slowly to avoid cardiac stress.
In autoimmune hemolytic anemia (AIHA), typing and cross-matching may be difficult. One should use the least incompatible blood if transfusions are indicated. The risk of destruction of transfused blood is high, but the degree of the hemolysis depends on the rate of infusion. Therefore, one should slowly transfuse half units of packed red blood cells to prevent rapid destruction of transfused blood.
Iron overload due to multiple transfusions for chronic anemia (eg, thalassemia or sickle cell disorder) can be treated with chelation therapy. A systematic review that compared the oral iron chelator deferasirox with the oral chelator deferiprone and the traditional parenteral agent deferoxamine found little clinical difference between the 3 chelation agents in terms of removing iron from the blood and liver. [52]
Erythropoietin Therapy
Erythropoietin (EPO) has been used to try to reduce transfusion requirements, with variable outcomes. Settings in which EPO therapy has reduced transfusion requirements include the following:
Children with kidney failure [53]
Autoimmune hemolytic anemia associated with reticulocytopenia [54]
A patient with sickle cell disease undergoing hemodialysis for kidney failure [55]
Jehovah’s Witnesses [56]
Infants with hereditary spherocytosis [57, 58]
However, the ability of EPO to reduce transfusion requirement has been questioned in newborns with hereditary spherocytosis [59] and in post-diarrheal hemolytic uremic syndrome. [60]
There is a general impression that additional studies should be carried out to establish the role and indications for EPO in hemolytic disorders. EPO therapy costs more than transfusions. The potential for EPO-induced cardiovascular complications needs to be considered. EPO has pleiotropic effects and might inhibit macrophages in Salmonella infections. [61] EPO was reported to be helpful in treating cerebral malaria due to its pleiotropic effect and not its hematopoietic action. [62] Hence, EPO should be used judiciously.
Discontinuing Medications
Penicillin and other agents that can cause immune hemolysis should be discontinued in patients who develop hemolysis. The following is a partial list of medications that can cause immune hemolysis:
Penicillin
Cephalothin
Ampicillin
Methicillin
Quinine
Quinidine
One should discontinue oxidant medications such as sulfa drugs in patients with G6PD deficiency or those who have unstable hemoglobins. The following is a partial list of medications and chemicals that should be avoided in G6PD deficiency:
Acetanilide
Furazolidone
Isobutyl nitrite
Nalidixic acid
Naphthalene
Niridazol
Iron Therapy
Iron therapy is contraindicated in most cases of hemolytic anemia. The reason is that iron released from RBCs in most hemolytic anemias is reused and iron stores are not reduced.
However, iron therapy is indicated for patients with severe or intravascular hemolysis in which persistent hemoglobinuria has caused substantial iron loss. Before starting iron therapy, one should document iron deficiency by serum iron studies and, possibly, by assessing iron stores in bone marrow aspirates.
Splenectomy
Splenectomy may be the first choice of treatment in some types of hemolytic anemia, such as hereditary spherocytosis. [63] In other cases, such as in AIHA, splenectomy is recommended when other measures have failed. Splenectomy is usually not recommended in hemolytic disorders such as cold agglutinin hemolytic anemia in which hemolysis is intravascular.
Overwhelming postsplenectomy sepsis is a rare but a potentially fatal event, especially during the first 2 years after splenectomy. Patients should be immunized against infections with encapsulated organisms, such as Haemophilus influenzae and Streptococcus pneumoniae, in advance of the procedure. Immunization can be performed post splenectomy.
Deterrence/Prevention of Hemolytic Anemia
The following is a partial list of medications and chemicals that individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency should avoid:
Acetanilid
Furazolidone
Isobutyl nitrite
Nalidixic acid
Naphthalene
Niridazole
Sulfa drugs
The G6PD Deficiency Association has a more comprehensive online list of medications that people with G6PD deficiency should avoid.
Fava beans can cause severe hemolysis in certain populations with the Mediterranean G6PD isoenzyme variant. These patients should avoid eating dishes with fava beans.
Patients should know to avoid medications that caused them to have immune hemolysis. The following is a partial list of medications that can cause immune hemolysis:
Penicillin
Cephalothin
Ampicillin
Methicillin
Quinine
Quinidine
Consultations
A hematology consultation would be helpful in selecting appropriate diagnostic approaches and laboratory tests and in planning and monitoring therapy.
Long-Term Monitoring
One should monitor the hemoglobin level, reticulocyte count, indirect bilirubin value, lactate dehydrogenase (LDH) level, and haptoglobin value in patients with hemolytic anemia to determine the response to therapy. Urine hemoglobin and hemosiderin should be monitored to evaluate recovery in patients with severe or intravascular hemolysis.
Other treatments are as follows:
Folic acid should be recommended for patients with ongoing hemolysis.
Administer oral iron to patients who have become iron deficient due to intravascular hemolysis.
One should taper corticosteroids. Occasionally, patients may have to continue low-dose steroids.
Avoid transfusions unless there is evidence of angina, cardiopulmonary decompensation, or other severe organ impairment.
Medication
Medication Summary
The goals of pharmacotherapy are to reduce morbidity and to prevent complications in patients with hemolytic anemia. Treatment is specific to the type of hemolytic anemia. For example, corticosteroids are usually the first line of treatment in autoimmune hemolytic anemia (AIHA) but are seldom effective in pediatric cold agglutinin disease. Rituximab has been used and can be effective in steroid-resistant AIHA. [49, 51]
Vitamins
Class Summary
Vitamins are essential for normal DNA synthesis and the formation of a number of coenzymes in many metabolic systems.
Folic acid is a cofactor for enzymes involved in production of red blood cells. Administered folic acid replenishes depleted folate stores consumed during chronic hemolysis.
Corticosteroids
Class Summary
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 inhibits phagocytosis of antibody-covered red blood cells. This agent is indicated in some hemolytic disorders such as AIHA.
Iron Salts
Class Summary
Iron therapy is contraindicated in most hemolytic anemias. However, iron therapy is indicated for patients with severe intravascular hemolysis in which persistent hemoglobinuria has caused substantial iron loss.
Ferrous sulfate is the most common and inexpensive form of iron used. Tablets contain 50-60 mg of iron salt. Other ferrous salts are used and may cause less intestinal discomfort because they contain a smaller dose of iron (25-50 mg). Oral solutions of ferrous iron salts are available for use in pediatric populations.
Pyruvate Kinase-R Activators
Class Summary
Mitapivat, a first-in-class pyruvate kinase (PK) activator, improves Hb and reduces transfusion burden in patients with hemolytic anemia associated with PK deficiency by targeting the underlying defect. [6]
PK activator that acts by allosterically binding to pyruvate kinase tetramer and increasing PK activity. Red blood cell (RBC) form of pyruvate kinase (PK-R) is mutated in PK deficiency, which leads to reduced adenosine triphosphate, shortened RBC lifespan, and chronic hemolysis. Indicated for treatment of hemolytic anemia in adults with PK deficiency.
Monoclonal antibody
Antineoplastics, Anti-CD20 Monoclonal Antibodies
Rituximab is a monoclonal antibody directed against the CD20 antigen on the surface of B-lymphocytes. Rituximab binds to CD20 on the cell surface, activating complement-dependent B-cell cytotoxicity; and to human Fc receptors, mediating cell killing through an antibody-dependent cellular toxicity.
Monoclonal Antibodies
Sutimlimab is a humanized immunoglobulin G (IgG4) monoclonal antibody which targets and inhibits complement. Sutimlimab inhibits the classical complement pathway by specifically binding to the complement protein component 1 subcomponent (C1s), which is a serine protease that cleaves C4. Inhibition of the classical complement pathway at the C1s level prevents deposition of complement opsonins on RBC surfaces, resulting in inhibition of hemolysis in cold agglutinin disease.
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