Hemolytic anemia is anemia that result from increased rate of red blood cell destruction. The term hemolytic anemia or hemolytic disorders is limited to conditions in which the rate of red cell destruction is accelerated and the ability of the bone marrow to respond to the stimulus of anemia is unimpaired.
Pathophysiology of Hemolytic Anemia
Normal bone marrow is capable of increasing its production rate by about 6 to 8 times. With optimal marrow compensation, survival of red cells in circulation can decrease from normal 120 days to as few as 15 to 20 days without anemia developing due to premature destruction of the red cells. Till the time increase in production in the bone marrow compensates the destruction of RBCs, it results in a compensated hemolytic state without anemia being present.
When RBC survival is so short that anemia develops in spite of marked bone marrow hyperactivity, the term hemolytic anemia is used.
Classification of Hemolytic Anemia
Based on clinical presentation
Hemolytic anemia can be classified as inherited or acquired
Based on site of Hemolysis
Intravascular – Within the circulation
Extravascular – In extracellular space, within tissue macrophages
Based on Causation
Iintrinsic defect in the cell itself
Extrinsic agent acts on normal cells.
Most intrinsic defects are inherited and extrinsic ones are acquired. Exceptions include Paroxysmal nocturnal hemoglobinuria (PNH) an acquired disorder characterized by intrinsic red cell defect.
List of Hemolytic Anemias
- Defects in red blood cell membrane
- Hereditary spherocytosis
- Hereditary elliptocytosis
- Hereditary stomatocytosis
- Defective red cell metabolism
- Glucose-6-phosphate dehydrogenase deficiency
- Pyruvate kinase deficiency
- Hexokinase deficiency
- 5’-nucleotidase deficiency
- Defects in globin structure and synthesis
- Thalassemia major
- Sickle-cell disease
- Homozygous and doubly heterozygous hemoglobinopathies
- Unstable hemoglobin disease
- Immune-mediated anemias
- Incompatible blood transfusion
- Hemolytic disease of newborn
- Autoimmune hemolytic anemia
- warm reactive antibodies
- cold reactive antibodies
- Viral and Mycoplasma pneumoniae infection
- Chronic lymphocytic leukemia
- Systemic lupus erythematosus
- Rheumatoid arthritis or other autoimmune diseases
- Cold hemagglutinin disease
- Paroxysmal cold hemoglobinuria (PCH)
- Traumatic and microangiopathic hemolytic anemia
- Prosthetic valves
- Hemolytic –uremic syndrome (HUS)
- Thrombotic thrombocytopenic purpura (TTP)
- Disseminated intravascular coagulation (DIC)
- Infections (malaria, toxoplasmosis, cholera, typhoid fever)
- Chemicals, drugs, and burns
- Paroxysmal nocturnal hemoglobinuria (PNH)
Clinical Presentation of Hemolytic Anemia
The presentation of hemolytic anemia depends on the duration of the process as well as its severity. The presenting features are diverse and are due to anemia, the extent of compensation, previous treatment, and the underlying disorder.
Those patients where the disease is minimal, may be asymptomatic and hemolysis is often found incidentally during routine laboratory testing. Clinical manifestations may include the following:
- Anemia – paleness, fatigue, exertional tiredness
- Tachycardia, dyspnea, angina, and weakness if anemia
- Abdominal pain due to bilirubin gallstones [excessive hemolysis results in rise in bilirubin levels]
- Iron overload or hemosiderosis [generally follows therapy with iron supplementation or follows multiple transfusion] Bronze skin color and diabetes occur in hemosiderosis
- Dark urine may be due to hemoglobinuria
- Patients with thrombotic thrombocytopenic purpura (TTP) may experience fever, neurologic signs, renal failure, and thrombocytopenia
- Leg ulcers due to decreased red blood cell (RBC) deformability and endothelial changes
There might be history of recent use of medications that can cause immune hemolysis. These include penicillin, quinine, quinidine, and L-dopa.
In glucose-6-phosphate dehydrogenase (G6PD) deficiency, oxidant drugs and stress from infections. Fava beans can induce hemolysis in susceptible individuals with the Mediterranean variant of G6PD deficiency.
On examination, there might be tachycardia, tachypnea, and hypotension due to lack of oxygen and decreased vascular volume. These changes occur in all kinds of severe anemia.
Jaundice may be present due to increase in indirect bilirubin in hemolysis.
Some hemolytic anemias like hereditary spherocytosis can have splenomegaly.
Patchy hyperpigmentation, sore tongue, and gastrointestinal symptoms may indicate folate deficiency which occur due to increased folate consumption.
In acquired hemolytic anemia, the presentation may be acute with acute febrile illness such as fever, body aches, malaise, vomiting, etc. The clinical picture of insidious onset would be similar to chronic hemolytic anemia.
A final diagnosis is established by a two-step process: first, demonstrating that a hemolytic anemia is present and second, determining the specific cause of the condition.
Establishing the presence of hemolytic anemia
- Hemolytic anemia should be suspected when anemia exists in association with signs of increased RBC destruction and /or signs of accelerated RBC production.
Determining the specific cause
After clinical examination, following investigations are carried to reach at a diagnosis
Complete blood count
Hb, RBC count, MCV, MCH, MCHC, RDW, PCV.
It measures the number of young red blood cells in your blood. The test shows whether bone marrow is making red blood cells at the correct rate. In hemolytic anemia, reticulocyte count is high because bone marrow is working hard to replace the destroyed red blood cells.
Liver Function Tests
When red blood cells break down, they release hemoglobin into the bloodstream. The hemoglobin combines with a chemical called haptoglobin. A low level of haptoglobin in the bloodstream is a sign of hemolytic anemia. Hemoglobin is broken down into a compound called bilirubin. High levels of bilirubin in the bloodstream may be a sign of hemolytic anemia. High levels of this compound also occur with some liver and gallbladder diseases. Thus, liver function tests are required to find out what’s causing the high bilirubin levels.
Elevated lactate dehydrogenase is criterion for hemolysis. It is sensitive but not specific since LDH can be released from neoplastic cells, the liver, or from other damaged organs.
A low serum haptoglobin level is another criterion for moderate-to-severe hemolysis.
But, 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.
Peripheral Blood Smear
Cells noted may help with diagnosis.
hereditary spherocytosis, immune-mediated hemolytic anemia
- If considered hereditary – osmotic fragility test, RBC membrane protein studies
- If considered acquired – direct Coombs testing, IgG, C3
- Rule out Paroxysmal cold hemoglobinuria [Donath Landsteiner testing]
Suggests microangiopathic RBC destruction. Consider DIC, TTP, HELLP, HUS, mechanical cardiac valve, vasculitis, malignant hypertension. Increased D-dimer levels in the blood confirm DIC.
Found in sickle cell anemia. Consider sickling test, Hb electrophoresis or high performance liquid chromatography [HPLC]
These are found in thalassemia. ConsiderHb electrophoresis or HPLC
These indicate hereditary stomatocytosis
If considered acquired – lead levels testing
If considered nonacquired – 5’ nucleotidase testing
This is found in cold or warm autoimmune hemolytic anemia. Direct Coombs test should be done.
Unusual red cell inclusions
Consider evaluation for Babesia, malaria or Bartonella
Treatment of Hemolytic Anemia
General Approach to The Treatment
Further exposure to any drug or chemical must stop. In case of infection being the cause, it should be treated specifically.
- Symptomatic treatment can be given by blood transfusion, if there is marked anemia or symptoms of shock.
- Splenectomy can be helpful in conditions like hereditary spherocytosis, or immunohemolytic anemias.
- Steroid therapy is useful in certain forms of immunohemolytic anemias.
- In steroid resistant cases, imunosupression may be considered.
Definitive therapy depends on the cause.
Folic acid is a cofactor for enzymes involved in production of red blood cells.
Active hemolysis can consume folate and cause megaloblastosis. Therefore folic acid supplementation is indicated
Corticosteroids are indicated in autoimmune hemolytic anemia.
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.
Iron overload due to multiple transfusions for chronic anemia (eg, thalassemia or sickle cell disorder) can be treated with chelation therapy. Deferasirox, defriprone and deferoxamine are common chelating agents.
Erythropoietin stimulates red cell production and may help to reduce transfusion requirements. Eyrthropoietin therapy is used in following conditions
- Children with chronic renal failure
- Autoimmune hemolytic anemia associated with reticulocytopenia
- Infants with hereditary spherocytosis
Iron therapy is contraindicated in most cases of hemolytic anemia as the iron released from RBCs in most hemolytic anemias is reused.
But iron may be indicated in patients who have proven iron deficiency by serum iron studies and, bone marrow aspiration.
Splenectomy could be the first choice of treatment in some types of hemolytic anemia, such as hereditary spherocytosis.
In other cases, splenectomy is recommended when other measures have failed
Early Detection of Hemolytic Anemia
In hereditary cases, early detection of hemolytic anemia is desirable.
Screening for sickle cell anemia or G6PD deficiency are part of newborn screening programs at some places. These inherited types of hemolytic anemia can be detected with routine blood tests. Diagnosing these conditions as early as possible is important so that children can get proper treatment.