Hemolytic anemia overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]
Overview
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.
Historical Perspective
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.
Classification
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.
Pathophysiology
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.
Causes
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.
Differentiating Hemolytic Anemia from Other Diseases
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.
Epidemiology and Demographics
In general, hemolytic anemia is a relatively rare condition. The incidence and prevalence are fairly low.
Risk Factors
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.
Screening
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.
Natural History, Complications, and Prognosis
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.
Diagnosis
History and Symptoms
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.
Physical Examination
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 Findings
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.
X ray
There are no X ray findings associated with hemolytic anemia.
CT scan
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 scan
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.
Echocardiography or Ultrasound
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.
Other Imaging Findings
There are no other imaging findings associated with hemolytic anemia.
Other Diagnostic Studies
Other possible diagnostic studies in the workup for hemolytic anemia include ferritin, urine hemosiderin, and flow cytometry.
Treatment
Medical Therapy
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.
Surgery
Splenectomy is a surgical option for hemolytic anemia. Importantly, there are many risks with splenectomy. These risks must be weighed against the potential benefits.
Prevention
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.