Hemolytic anemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]

Hemolytic anemia is the anemia that occurs due to destruction of the red blood cells either intravascularly or extravascularly. Extravascular hemolytic anemia is more common than the intravascular hemolytic anemia. Hemolytic anemia may be acquired or inherited due to enzyme defects that lead to the RBCs hemolysis. Pathophysiology of most hemolytic anemia involves two mechanisms of red blood cells hemolysis either complement activated autoantibodies or non complement activated autoantibodies. Various drugs ,as anti cancer drugs, also lead to immune-mediated hemolysis. Red blood cell membrane and enzyme defects is the main cause of non immune mediated hemolysis. The causes of the hemolytic anemia include intrinsic and extrinsic factors. Hemolytic anemia must be differentiated from other conditions that affect the RBCs as nutritional deficiencies and thalassemias. Hemolytic anemia is a relatively rare condition. The incidence and prevalence are fairly low. The risks factors of hemolytic anemia can be categorized as oxidative stress, mechanical injury, and genetic conditions. The natural history of hemolytic anemia depend on the underlying cause of hemolytic anemia, some types of hemolytic anemia with good prognosis and others have poor prognosis. Symptoms and physical examination of hemolytic anemia are reflecting the RBCs hemolysis, hemoglobin break down, and the release of their products in the circulation. Jaundice, hepatomegaly, and splenomegaly are the most common signs are seen in hemolytic anemia. Serum tests include LDH, haptoglobin, bilirubin, and reticulocyte count are important in the diagnosis of hemolytic anemia. CT scan, MRI scan, and ultrasound imaging can be helpful in assessment of the splenomegaly in cases of hemolytic anemia. Typical treatment of hemolytic anemia include corticosteroids or non-steroidal immunosuppressants. Splenectomy is the second line of treatment of hemolytic anemia.

The history of hemolytic anemia dates back to the 16th century, when the initial experiments were conducted on transfusion of blood. Soon after, the development of the simple microscope revolutionized the study of red blood cells, as red blood cells could be directly observed. After multiple patients began to present with jaundice and splenomegaly, it was observed that there was an association between these symptoms and the destruction of red blood cells. Eventually, it was determined that hemolytic anemia was largely due to immune-mediated mechanisms leading to destruction of red blood cells. Since the 1980s, various immunosuppressive medications have been developed to help treat hemolytic anemia.

Hemolytic anemia can be divided into intravascular and extravascular based on whether the destruction of RBCs occurs in the vessels or outside the vessels, usually in spleen and liver. Extravascular hemolytic anemia is more common than intravascular hemolytic anemia. There are many types ofhemolytic anemias and the general classification of hemolytic anemia is either acquired or inherited (genetic). Genetic conditions include red blood cellmembrane or enzyme defects that predispose the red blood cells to hemolysis.

The pathophysiology of most hemolytic anemia involves complement-activated autoantibodies or non-complement-activated autoantibodies, which result indestruction of red blood cells. The underlying mechanisms is based on immune dysregulation between self and non-self. Numerous drugs including novel anti-cancer therapeutics, can result in immune-mediated hemolysis. On the other hand, the pathophysiology of non-immune-mediated hemolysis relates to structural factors, such as red blood cell membrane and enzyme defects which confer fragility towards red blood cells. In the setting of defects ofred blood cell membranes or anti-oxidant enzymes, there is increased risk for red blood cell destruction.

The causes for hemolytic anemia can be divided into intracorpuscular or extracorpuscular causes. The intrinsic causes are commonly due to hereditarycauses whereas the extrinsic causes are commonly acquired. Drugs are another major cause of hemolysis. In the era of immunotherapy for cancer, drug-related causes are becoming increasingly important to recognize.

The differential diagnosis for hemolytic anemia is broad and includes a variety of conditions that affect red blood cells. Nutritional deficiencies andthalassemias are important components of the differentiation. Certain laboratory tests and physical exam features can help to distinguish these conditions. The treatment of these conditions are quite different, so it is important to distinguish hemolytic anemia from other causes of anemia or other conditions that present similarly.

In general, hemolytic anemia is a relatively rare condition. The incidence and prevalence are fairly low.

Risks factors for hemolytic anemia involve insults to red blood cells or defects within red blood cells. Broadly, the risks factors can be categorized asoxidative stress, mechanical injury, and genetic conditions.

There is no major role for screening for hemolytic anemia. In some cases, testing for G6PD deficiency can be done if a patient will be receiving medications that are known to precipitate oxidative stress.

In general, the natural history, complications, and prognosis depend on the underlying cause of hemolytic anemia. Some types of hemolytic anemia have a transient course with few complications and excellent prognosis. Some types of hemolytic anemia have a lifelong course with many complications and poor prognosis.

The symptoms of hemolysis mostly relate to (1) red blood cell loss and (2) release of hemoglobin and its breakdown products into the circulation. The breakdown products of hemoglobin will accumulate in the blood causing jaundice and be excreted in the urine causing the urine to become dark brown in color.

The physical examination findings of hemolytic anemia reflect (1) red blood cell loss and (2) the release of hemoglobin and its breakdown productions into the circulation. Typical exam findings include jaundice, pallor, splenomegaly, and hepatomegaly.

Laboratory evaluation begins with examination of the peripheral blood smear. Serum tests include LDH, haptoglobin, bilirubin, and reticulocyte count. A combination of all of these tests can give insight into whether or note hemolytic anemia is present and, if present, the degree of hemolysis. The osmotic fragility test is less commonly used but can also be used to assess for predisposition to hemolysis.

There are no X ray findings associated with hemolytic anemia.

CT scan of the spleen can be useful to assess for the splenomegaly. Suggestive findings of splenomegaly include increased the spleen lengthining, loss of the splenic notches, and extension of the spleen below the lower third pole of the kidney.

MRI of the spleen can also be useful to assess for splenomegaly in cases of hemolytic anemia. However, this is a far more costly test compared to ultrasound or CT.

Ultrasound of the spleen may be used to help assess for splenomegaly in cases of hemolytic anemia. Ultrasound’s benifit is in giving more precisive measurement of the size of the spleen in comparison to palpation by physical examination.

There are no other imaging findings associated with hemolytic anemia. 

Other possible diagnostic studies in the workup for hemolytic anemia include ferritin, urine hemosiderin, and flow cytometry.

Medical therapy focuses on immunosuppression. Typical treatment options include corticosteroids or non-steroidal immunosuppressants. Non-steroidal immunosuppressants include rituximab, azathioprine, mycophenolate mofetil, cyclophosphamide, and other agents. The advantage to the use of non-steroidal immunosuppressants is that patients can be spared of adverse effects of steroids like bone loss, cataracts, and glaucoma.

Splenectomy is a surgical option for hemolytic anemia. Importantly, there are many risks with splenectomy. These risks must be weighed against the potential benefits.

There is a small role for preventive measures in hemolytic anemia. Primary prevention focuses on preventing the disease onset before the disease process begins. Avoidance of hemolysis triggers a primary prevention measure.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]

The history of hemolytic anemia dates back to the 16th century, when the initial experiments were conducted on transfusion of blood. Soon after, the development of the simple microscope revolutionized the study of red blood cells, as red blood cells could be directly observed. After multiple patients began to present with jaundice and splenomegaly, it was observed that there was an association between these symptoms and the destruction of red blood cells. Eventually, it was determined that hemolytic anemia was largely due to immune-mediated mechanisms leading to destruction of red blood cells. Since the 1980s, various immunosuppressive medications have been developed to help treat hemolytic anemia.

• In the mid-1500s, seminal experiments were conducted by Richard Lower and Jean-Baptiste Denis on transfusion of blood.^[1]

• In 1661, Malpighi observed red blood cells using a microscope and noted that red blood cells were within capillaries.^[1]

• In 1663, Swammerdam described minute globules in the blood of a frog.^[1]

• In 1673, van Leeuwenhoek described red blood cells in detail.^[1]

• In 1769, Morgagni described the case of a priest who developed hemolytic anemia symptoms, which included red urine, pallor, and splenomegaly. However, since simple microscopes could not show red blood cells in detail, further perspective about hemolytic anemia could not be gained.^[1]

• In 1843, Andral proposed the idea that anemia was due to possible destruction of blood, which we now know as hemolysis.^[1]

• In 1854, Dressler described the case of a 10-year-old child who developed hemolytic anemia upon exposure to cold weather. The boy developed red urine, and exam of his urine under the microscope showed a brown pigment with no red blood cells.

• In 1871, Vanlair and Masius describes a patient who had anemia, splenomegaly, and red urine. They showed that jaundice as a clinical symptoms was due to destruction of red blood cells.^[1] They noted microcytes (small cells) in the blood.

• In 1890, Wilson described hemolytic anemia from hereditary spherocytosis. The patient had splenomegaly and quick onset of anemia.

• In 1891, Paul Ehrlich discovered that methylene blue had activity against malaria.^[2]

• In 1900, Minkowski showed that jaundice could be from either hemolytic anemia or liver disease.^[1]

• In 1920, it was noted that primaquine was an effective anti-malarial medication.

• In 1940, Dameshek and Schwartz described acquired hemolytic anemia. They noted that red blood cells had increased fragility and that hemolysins could be released into the circulation.

• In 1944, Race and Weiner showed that Rhesus antigen antibodies could bind to red blood cell surfaces and trigger hemolysis.

• In 1945, the Coombs test, or direct antiglobulin test, was described. This test assesses for antibodies bound to a patient’s cells.

• In 1948, Wagley showed that removal of the spleen could alleviate the destruction of red blood cells, suggesting the spleen was the anatomic location of hemolysis.^[3]

• In 1951, Young and colleagues created the term “autoimmune hemolytic anemia“. Glucocorticoids were used to treat warm autoimmune hemolytic anemia.

• In 1953, there was large-scale use of primaquine for troops in the army in order to protect against malaria, and it was soon noted that soldiers developed abdominal discomfort, anemia, and jaundice.^[2]

• In 1956, Carson’s group showed that people who experienced hemolysis from primaquine had decreased level of G6PD.^[2]

• In 1962, Alving’s group showed that acute hemolytic anemia could be triggered by primaquine.^[2]

• In 1962, Iafusco and Biffa described a case of warm autoimmune hemolytic anemia in a newborn.^[4]

• In 1971, Dacie proposed that hemolytic anemia was due to a failure of immune surveillance, ultimately leading to red blood cell destruction.

• After the 1980s, a variety of immunosuppressive medications were used to treat hemolytic anemias on the basis that this was an immune-mediated phenomenon.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]

Hemolytic anemia can be divided into intravascular and extravascular based on whether the destruction of RBCs occurs in the vessels or outside the vessels, usually in spleen and liver. Extravascular hemolytic anemia is more common than intravascular hemolytic anemia. There are many types of hemolytic anemias and the general classification of hemolytic anemia is either acquired or inherited (genetic). Genetic conditions include red blood cell membrane or enzyme defects that predispose the red blood cells to hemolysis.

• Intravascular: This refers to red blood cell destruction within the blood vessels.
• Extravascular: This refers to red blood cell destruction outside the blood vessels, such as in the liver or spleen.

• Secondary immune hemolytic anemia^[1]
• Idiopathic autoimmune hemolytic anemia
• Non-immune hemolytic anemia caused by chemicals or toxins
• Microangiopathic hemolytic anemia (MAHA)
• Sickle-cell anemia
• Hemoglobin SC disease (similar in symptoms to sickle-cell anemia)
• Thalassemia
• Hemolytic anemia due to G6PD deficiency
• Paroxysmal nocturnal hemoglobinuria (PNH)
• Hereditary elliptocytosis
• Hereditary ovalocytosis
• Hereditary spherocytosis
• Malaria^[2]
• Transfusion of blood from a donor with a different blood type

Hemolytic anemias can be either genetic or acquired.

• Genetic conditions of RBC membrane
  • Hereditary spherocytosis^[3]
  • Hereditary elliptocytosis^[4]
• Genetic conditions of RBC metabolism (enzyme defects)
  • Glucose-6-phosphate dehydrogenase deficiency (G6PD or favism)
  • Pyruvate kinase deficiency
• Genetic conditions of hemoglobin
  • Sickle cell anemia
  • Thalassemia

Acquired hemolytic anemia can be further divided into immune and non-immune mediated.

Immune-mediated hemolytic anemia (direct Coombs test is positive)

• Autoimmune hemolytic anemia^[5]
  • Warm antibody autoimmune hemolytic anemia
    • Idiopathic
    • Systemic lupus erythematosus (SLE)^[6]
    • Evans’ syndrome (antiplatelet antibodies and haemolytic antibodies)
  • Cold antibody autoimmune hemolytic anemia
    • Idiopathic cold hemagglutinin syndrome
    • Infectious mononucleosis and mycoplasma (atypical) pneumonia
    • Paroxysmal cold hemoglobinuria (rare)^[5]
• Alloimmune hemolytic anemia
  • Haemolytic disease of the newborn (HDN)
    • Rh disease (Rh D)
    • ABO hemolytic disease of the newborn
    • Anti-Kell hemolytic disease of the newborn
    • Rhesus c hemolytic disease of the newborn
    • Rhesus E hemolytic disease of the newborn
    • Other blood group incompatibility (RhC, Rhe, Kidd, Duffy, MN, P and others)
  • Alloimmune hemolytic blood transfusion reactions (ie from a non-compatible blood type)
• Drug induced immune mediated hemolytic anemia
  • Penicillin (high dose)
  • Methyldopa

Non-immune mediated hemolytic anemia (direct Coombs test is negative)^[5]

• Drugs (i.e., some drugs and other ingested substances lead to hemolysis by direct action on RBCs)
• Toxins (e.g., snake venom)
• Trauma
  • Mechanical (heart valves, extensive vascular surgery, and microvascular disease)
• Microangiopathic hemolytic anemia (a specific subtype with causes such as TTP, HUS, DIC, and HELLP syndrome)
• Infections
  • Malaria
  • Babesiosis
  • Septicaemia
• Membrane disorders
  • Paroxysmal nocturnal hemoglobinuria (rare acquired clonal disorder of red blood cell surface proteins)
  • Liver disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]

The pathophysiology of most hemolytic anemia involves complement-activated autoantibodies or non-complement-activated autoantibodies, which result in destruction of red blood cells.^[1] The underlying mechanisms is based on immune dysregulation between self and non-self.^[2] Numerous drugs including novel anti-cancer therapeutics, can result in immune-mediated hemolysis. On the other hand, the pathophysiology of non-immune-mediated hemolysis relates to structural factors, such as red blood cell membrane and enzyme defects which confer fragility towards red blood cells. In the setting of defects of red blood cell membranes or anti-oxidant enzymes, there is increased risk for red blood cell destruction.

Drug-induced hemolysis has large clinical relevance. It occurs when drugs actively provoke red blood cell destruction. Drug-induced hemolytic anemia can occur in an antibody-dependent or antibody-independent manner.

• Antibody-mediated hemolysis: This can occur via IgG or IgM binding to red blood cell membranes.^[3] Complement proteins then fix (or attach) onto IgG or IgM antibodies. This eventually results in recruitment of the membrane attack complex consisting of complement proteins C5-C9.
• Antibody-independent hemolysis: This occurs in the absence of IgG or IgM. It can occur via drug-induced protein adsorption on red blood cells.

Immune-mediated hemolysis is characterized by the presence of antibodies that bind to red blood cell membranes and trigger red blood cell destruction. In warm autoimmune hemolytic anemia, antibodies bind to the red blood cell membrane at 37 degrees Celcius (core body temperature for humans).^[2] The antibodies are usually polyclonal, meaning their specificity is for multiple antigens on red blood cells.^[2] Causes of immune-mediated hemolysis include:

• Drugs: This is one of the most common causes of immune-mediated hemolysis. Of note, there is overlap between drug-induced hemolysis and immune-mediated hemolysis. Specifically, drug-induced hemolysis can be immune-mediated or non-immune-mediated, while immune-mediated hemolysis can be drug-dependent or drug-independent.
  • Penicillin: Penicillin is an antibacterial medication that, in high doses, can induce immune-mediated hemolysis via the hapten mechanism in which antibodies are targeted against the combination of penicillin in association with red blood cells. Complement is activated by the attached antibody leading to the removal of red blood cells by the spleen.
  • Nivolumab: This is an antibody that binds to the PD-1 antigen found on lymphocytes. It is typically used to treat cancers like squamous cell carcinoma of the head and neck, melanoma, hepatocellular cancer, and lung cancer. Nivolumab can trigger significant autoimmune reactions. When the hematologic system is affected, hemolytic anemia can result.^[3]
  • Pembrolizumab: This is an antibody that binds to the PD-1 antigen found on lymphocytes. It is typically used to treat cancers like squamous cell carcinoma of the head and neck, melanoma, urothelial cancer, and lung cancer. Pembrolizumab can trigger significant autoimmune reactions. When the hematologic system is affected, hemolytic anemia can result.^[3]
  • Ipilimumab: This is an antibody that binds to cytotoxic T lymphocyte antigen-4 (CTLA-4) on T cells. CTLA-4 is normally an inhibitor molecule involved in the regulatory T cell response.^[2] CTLA-4 functions in maintaining normal homeostasis. Ipilimumab is commonly used to treat stage III melanoma in the adjuvant setting and stage IV melanoma.
  • Anti-RhD: This is a medication used to treat immune thrombocytopenia purpura (ITP). It works by saturating Fc receptors on splenic macrophages and also inducing a mild hemolysis.^[3]
• Infections: Amongst infectious agents, viruses are most likely to trigger hemolysis, compared to bacteria, parasites, or fungi.
• Autoimmune or rheumatologic disease: Activation of one’s own immune system can result in destruction of red blood cells in an antibody-dependent manner. Females are more likely to develop autoimmune hemolytic anemia.
• Lymphoproliferative disorders: These represent a group of primary bone marrow disorders characterized by rapid proliferation of T cells or B cells. Chronic lymphocytic leukemia (CLL), for example, is a lymphoproliferative disorder that is a known etiology of hemolytic anemia.
• Genetic polymorphisms: Mutations or genetic variants in certains genes, like CTLA-4, can cause hemolytic anemia. Mutations can contribute to autoimmunity.^[2]

Cold agglutinins usually bind to the the Ii carbohydrate antigen on red blood cells.^[2] Agglutination usually occurs in the peripheral vasculature in distal capillary beds, where temperature is cool. IgM antibody binds to red blood cells upon exposure to cold, and IgM fixes complement proteins like C1, initiating the classical complement pathway. Subsequent complement proteins include C4, C2, and C3. The membrane attack complex then forms and results in intravascular hemolysis.^[2]

Non-immune hemolysis is characterized by the absence of antibodies in the setting of red blood cell destruction.^[3] Non-immune drug-induced hemolysis can also arise from drug-induced damage to cell volume control mechanisms; for example drugs can directly or indirectly impair volume regulatory mechanisms, which become activated during hypotonic red blood cell swelling to return the cell to a normal volume. The consequence of the drugs actions are irreversible cell swelling and lysis (e.g. ouabain at very high doses). Alternatively, non-immune drug induced hemolysis can occur via oxidative mechanisms. This is particularly likely to occur when there is an enzyme deficiency in the antioxidant defense system of the red blood cells. Red blood cell enzymatic deficiencies are common causes of non-immune-mediated hemolysis.^[4]

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: This is a red blood cell enzyme defect that results in oxidative stress and hemolysis. It is the most common red blood cell enzymatic defect. Antimalarial oxidant drugs like primaquine damages red blood cells in glucose-6-phosphate dehydrogenase deficiency in which the red blood cells are more susceptible to oxidative stress due to reduced NADPH production consequent to the enzyme deficiency. G6PD is the rate-limiting enzyme in the pentose phosphate pathway, or hexose monophosphate shunt. The normal function of G6PD is to confer reductive potential to erythrocytes via NADPH. Oxidation of NADPH to NADP+ in erythrocytes prevents oxidation of other molecules in these cells and thus prevents hemolysis.^[5] Intact G6PD allows for generation of reduced glutathione, which prevents oxidative stress and hemolysis.^[5] In the presence of G6PD deficiency, the stores of glutathione are depleted, and the sulfhydryl groups of hemoglobin and other proteins become oxidized. This creates precipitation of denatured hemoglobin known as Heinz bodies. This leads to irreversible membrane damage and thus hemolysis. Drugs that typically cause hemolysis in patients with G6PD deficiency include:
  • Primiquine and other anti-malarial agents
  • Fava beans
  • Sulfa drugs like trimethoprim-sulfamethoxazole
  • dapsone

• Pyruvate kinase deficiency: This is a red blood cell enzymatic defect that can result in oxidative stress and hemolysis. It is an autosomal recessive disorder. It is the second most common red blood cell enzymatic defect, after G6PD deficiency. Pyruvate kinase is the final enzyme in the glycolysis pathway and converts phosphoenolpyruvate to pyruvate.

• Glucose phosphate isomerase deficiency: This is a red blood cell enzymatic defect that can result in oxidative stress and hemolysis.

• Triose phosphate isomerase deficiency: This is a red blood cell enzymatic defect that can result in oxidative stress and hemolysis.^[6] This enzyme normally functions to convert dihydroxyacetone phosphate to glyceraldehyde-3-phosphate, which is a critical step in glycolysis. In addition to causing hemolytic anemia, this condition can cause neuromuscular disease and increased risk for infections.^[6]

Hemolytic anemia causes a compensatory increase in erythropoetin that in turn causes an increase in reticulocyte percentage and absolute reticulocyte count. This results in increased hemoglobin and red blood cell production.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]

The causes for hemolytic anemia can be divided into intracorpuscular or extracorpuscular causes. The intrinsic causes are commonly due to hereditary causes whereas the extrinsic causes are commonly acquired. Drugs are another major cause of hemolysis. In the era of immunotherapy for cancer, drug-related causes are becoming increasingly important to recognize.

The causes of hemolytic anemia can be divided into etiologies that are intrinsic to red blood cell biology or extrinsic to red blood cell biology. Intrinsic, or intracorpuscular, causes include red blood cell membrane defects or enzyme deficiencies. Extrinsic causes include infections, autoimmune conditions, or drugs.

• Paroxysmal nocturnal hemoglobinuria
• Alpha thalassemia
• Hereditary spherocytosis: This is the most common hereditary form of hemolytic anemia.^[1] It is caused by mutations in red blood cell cytoskeletal proteins, such as:
  • Spectrin
  • Ankyrin
  • Band 3
  • Band 4.1
  • Glycophorin
• Hereditary elliptocytosis
• Unstable hemoglobin variants and hemoglobinopathies

• Glucose-6-phosphate dehydrogenase deficiency
• Pyruvate kinase deficiency
• Triose phosphate isomerase deficiency

Extrinsic factors refers to those that are commonly acquired in nature and have an adverse effect on red blood cells.

• Shiga-toxin from enterohemorrhagic E. coli strain O157:H&
• Parvovirus
• Malaria
• Babesia
• Clostridium perfringens

Systemic activation of the immune system due to underlying rheumatologic conditions can result in a predisposition for hemolysis.

• Systemic lupus erythematosus

These are important causes of hemolysis, especially in the era of immunotherapy for cancer. As more immunotherapeutic agents reach the market, it is likely that there will be more cases of iatrogenic hemolytic anemia.

• Pembrolizumab
• Nivolumab
• Ipilimumab
• Durvalumab
• Avelumab
• Dapsone
• Quinines

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]

In general, hemolytic anemia is a relatively rare condition. The incidence and prevalence are fairly low.

• Worldwide, the incidence of autoimmune hemolytic anemia is 0.8 per 100,000 persons.^[1] Some studies suggest that the incidence of autoimmune hemolytic anemia in adults in 1:100,000 persons.^[2] The incidence of hemolytic anemia is lower in children.
• Worldwide, the prevalence of autoimmune hemolytic anemia is 17 per 100,000 persons.^[1]
• Worldwide, the incidence of drug-induced hemolytic anemia is 0.1 per 100,000 persons.^[3]

• Hemolytic anemia affects men and women equally.

• Hemolytic anemia affects all races equally.

• Hemolytic anemia affects adults more commonly than children.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]

Risks factors for hemolytic anemia involve insults to red blood cells or defects within red blood cells. Broadly, the risks factors can be categorized as oxidative stress, mechanical injury, and genetic conditions.

Oxidative stress in the setting of G6PD deficiency:^[1]

• Use of primiquine for malaria treatment
• Use of dapsone for PCP or leprosy treatment
• Consumption of fava beans as part of a Mediterranean diet
• Use of sulfa drugs like trimethoprim-sulfamethoxazole for treatment of skin, urinary tract, or other infections
• Use of phenazopyridine for alleviating symptoms of dysuria
• Use of nitrofurantoin for treatment of a urinary tract infection

Mechanical damage-related risk factors:

• Presence of a mechanical mitral or aortic valve^[2]
• High shear stress from extracorporeal membrane oxygenation (ECMO) circuit in patients undergoing cardiac surgery or with hypoxic respiratory failure^[2]
• Presence of left ventricular assist device for end-stage heart failure^[3]

Genetic conditions affecting red blood cells:

• Hereditary spherocytosis
• Hereditary elliptocytosis
• Paroxysmal nocturnal hemoglobinuria
• Sickle cell disease^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]

There is no major role for screening for hemolytic anemia. In some cases, testing for G6PD deficiency can be done if a patient will be receiving medications that are known to precipitate oxidative stress.

In some cases, screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency can be done to determine if a patient is at risk for hemolytic anemia. Primaquine, sulfa drugs, and fava beans can trigger hemolytic crises in the setting of G6PD deficiency.^[1] Rasburicase has also been shown to trigger hemolytic episodes, so G6PD screening is important prior to administration of rasburicase.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

The differential diagnosis for hemolytic anemia is broad and includes a variety of conditions that affect red blood cells. Nutritional deficiencies and thalassemias are important components of the differentiation. Certain laboratory tests and physical exam features can help to distinguish these conditions. The treatment of these conditions are quite different, so it is important to distinguish hemolytic anemia from other causes of anemia or other conditions that present similarly.

Table legend: HELLP, hemolysis/elevated liver enzymes/low platelets; TTP, thrombotic thrombocytopenic purpura; CLL, chronic lymphocytic leukemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

In general, the natural history, complications, and prognosis depend on the underlying cause of hemolytic anemia. Some types of hemolytic anemia have a transient course with few complications and excellent prognosis. Some types of hemolytic anemia have a lifelong course with many complications and poor prognosis.

The natural history depends on the etiology of the hemolytic anemia.

• Drug-induced hemolytic anemia: This tends to be transient, if the etiology is identified. Once the drug is introduced, the hemolysis typically begins within a few days. Once the offending agent is discontinued, the hemolysis begins to abate. The course is usually mild. There are typically no long-term complications from this type of hemolysis. Serologic tests, such as the direct antiglobulin test, or Coomb’s test, can persist despite clinical resolution of symptoms.
• Autoimmune hemolytic anemia: This can have a lifelong course if the etiology is not identified. This can have an unpredictable course of relapses^[1] and remissions.
• Warm autoimmune hemolytic anemia in children: This has a self-limited course when treated with steroids.^[1] Steroids usually result in a rapid remission, especially if a high dose or induction dose is used. Relpases are unusual. The estimated mortality rate is 10-30%.
• Hereditary etiologies of hemolytic anemia: Such etiologies include G6PD deficiency, red blood cell membrane defects, or red blood cell enzyme defects. These tend to manifest with lifelong symptoms, as these are difficult to cure. Patients with these types of hemolytic anemia have lifelong risk.
• Cold agglutinin disease: This condition results in hemolysis in the presence of cold temperatures. The hemolysis begins upon exposure to cold then abates after cold temperatures are no longer present. Post-infection cold agglutinin disease typically lasts for weeks to months then resolves. Serological tests such, as the Donath-Landsteiner antibody, can persist despite clinical resolution of the hemolytic anemia.^[2]

The complications depend on the specific type of hemolytic anemia.

• Cardiovascular collapse: This refers to failure of the heart to produce a sufficient blood pressure to maintain normal homeostasis and oxygen delivery. This can lead to death from hypoxia and hypoxemia within a short period of time.
• Exacerbation of cardiopulmonary conditions: Hemolytic anemia can result in high-output cardiac failure, which refers to the inability of the circulatory system to meet the demands of exercising tissue, despite a high cardiac output. Hemolytic anemia can also exacerbate lung disease, since the capillary beds in the pulmonary circulation function to load oxygen onto hemoglobin for delivery to tissue beds.
• Exacerbation of neurologic conditions: Hemolytic anemia can contribute to cerebrovascular disease, or strokes, since the brain requires oxygen for survival of neurons.
• Myocardial infarction: Myocardial infarction, or heart attack, occurs if the anemia is severe such that the oxygen-carrying capacity is reduced to the coronary tissue. For this reason, patients with coronary artery disease should be transfused packed red blood cells if hemoglobin is less than 8 g/dl, compared to the conventional threshold of 7 g/dl for the general population.
• Transfusion dependence: This occurs when a patient requires repeated transfusions with packed red blood cells in order to maintain hemoglobin within an acceptable range, such as greater than 7 g/dl. Complications of transfusion include:
  • Transfusion-associated circulatory overload (TACO)^[3] For this reason, a restricted transfusion strategy is preferred over a liberal strategy.^[4]
  • Transfusion-related acute lung injury (TRALI)^[3]
  • Iron overload, or hemosiderosis
  • Transfusion reaction due to ABO blood group incompatibility

The outcome depends on the type and cause of hemolytic anemia.

• Drug-induced hemolytic anemia: The prognosis of this type of anemia is typically favorable if the offending agent is discontinued.
• Cold agglutinin disease: This has a generally good prognosis. Patients typically survive for many years. In the case of an associated lymphoma, the prognosis can be much worse depending the type of lymphoma.^[1]

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