Hemolytic anemia refers to a type of anemia caused by the excessive destruction of red blood cells, leading to a significantly shortened lifespan of red blood cells that exceeds the bone marrow's compensatory capacity for hematopoiesis. When the lifespan of red blood cells is shortened and their destruction increases, but the bone marrow's hematopoietic function can still compensate without resulting in anemia, it is referred to as compensated hemolytic disease.

bubble_chart Etiology

Disease Causes and Classification

1. Based on the cause of red blood cell destruction, hemolytic anemia can be divided into two major categories.

   (1) Hemolytic anemia caused by intrinsic defects of red blood cells

   1. Hereditary
      (1) Abnormalities of red blood cell membrane: such as hereditary spherocytosis, hereditary elliptocytosis, etc.
      (2) Abnormalities of red blood cell enzymes: (1) Defects in enzymes of the anaerobic glycolysis pathway of red blood cells: such as pyruvate kinase deficiency, hexokinase deficiency, etc.; (2) Defects in enzymes of the hexose monophosphate shunt pathway of red blood cells: such as glucose-6-phosphate dehydrogenase deficiency, etc.
      (3) Abnormalities in the quantity or quality of globin chain synthesis: such as thalassemia, hemoglobinopathies, etc.
   2. Acquired: Paroxysmal nocturnal hemoglobinuria (PNH).
   (2) Hemolytic anemia caused by extrinsic abnormalities of red blood cells
   1. Immune hemolytic anemia: (1) Autoimmune hemolytic anemia (AIHA): warm antibody type and cold antibody type; (2) Neonatal alloimmune hemolytic disease; (3) Hemolysis after incompatible blood transfusion; (4) Drug-induced immune hemolytic anemia.
   2. Non-immune hemolytic anemia: (1) Secondary to infections: bacterial, viral, or parasitic infections; (2) Drugs and chemicals: sulfonamides, phenylhydrazine, nitrobenzene, etc.; (3) Physical factors: extensive burns, radiation injury, etc.; (4) Mechanical factors: such as traumatic cardiac hemolytic anemia; microangiopathic hemolytic anemia; march hemoglobinuria. (5) Biological factors: hemolytic snake venom, mushroom poisoning, etc. (6) Secondary to other diseases: tumors, liver disease, kidney disease, hypersplenism, etc.
2. Based on the site of red blood cell destruction, it can be divided into:
   1. Intravascular hemolysis: Red blood cells are mainly destroyed in the circulation.

Pathogenesis

Although normal red blood cells are continuously subjected to mechanical injury during circulation, they can still maintain their integrity. This is related to the biconcave disc shape of normal red blood cells, where their surface area is greater than their corresponding volume. This gives them high deformability, allowing them to pass through microcirculatory channels and splenic sinus wall pores much smaller than their own diameter. This characteristic of red blood cells depends on the structure and function of the red blood cell membrane, the enzymes and energy metabolism within the red blood cells, and the normal structure of hemoglobin. Any abnormality in these three aspects can impair the integrity of red blood cells and lead to hemolysis.

1. Mechanisms of hemolysis caused by red blood cell membrane abnormalities
   1. Loss of deformability: The main condition for maintaining red blood cell deformability is that the surface area of the red blood cell must be greater than its corresponding volume. When there is a defect in the red blood cell membrane, the morphology of the red blood cell changes, and the surface area-to-volume ratio decreases, resulting in poor deformability. Such red blood cells are prone to being trapped in the spleen and destroyed.
   2. Changes in red blood cell membrane permeability: If there is a defect in the red blood cell membrane, the permeability to sodium ions increases, leading to faster and greater influx of sodium ions into the red blood cells, causing osmotic swelling and subsequent hemolysis.
   3. Changes in the chemical composition of the red blood cell membrane: The function and deformability of the red blood cell membrane are related to its normal chemical composition, primarily spectrin, membrane proteins, membrane lipids, and sulfhydryl groups attached to the membrane. Abnormalities in the generation and transformation of these substances can lead to various changes in membrane properties, making the red blood cells more susceptible to destruction.
   4. Red blood cells adsorb agglutinating antibodies, incomplete antibodies, and complement, which injure the cell membrane, making the red blood cells prone to intravascular hemolysis or destruction by the mononuclear phagocyte system.
2. Abnormalities of Enzymes in Red Blood Cells To maintain normal function, red blood cells must obtain energy through glucose metabolism. Their energy is primarily generated via two pathways: anaerobic glycolysis and the hexose monophosphate shunt. Numerous enzymes are involved in these two pathways, with the more significant ones including pyruvate kinase, hexokinase, glucose-6-phosphate dehydrogenase, and glutathione reductase. If defects occur in these enzymes, abnormal energy metabolism in red blood cells can lead to hemolysis.
3. Abnormal Hemoglobin Abnormal hemoglobin is divided into two categories: one is the abnormal molecular structure of globin; the other is the reduced synthesis rate of globin chains. Abnormal hemoglobin makes red blood cells stiff and poorly deformable, prone to destruction and hemolysis.
4. Physical and Mechanical Factors Large-area burns can cause red blood cells to become spherical and easily destroyed. Mechanical injury to red blood cells can occur due to artificial heart valve placement, artificial blood vessels, etc.

bubble_chart Clinical Manifestations

The clinical manifestations of hemolytic anemia can vary depending on the cause of hemolysis, the degree of hemolysis, the speed of hemolysis, and the site where hemolysis occurs. Generally, it is classified into acute and chronic types.

1. **Acute Hemolytic Anemia**, such as that caused by transfusion of incompatible blood, has a sudden onset with symptoms including shivering, high fever, headache, lack of strength, soreness in the back and limbs, as well as nausea, vomiting, diarrhea, and abdominal pain. Anemia and jaundice may also appear. If intravascular hemolysis occurs, hemoglobinuria may develop, giving the urine a dark red tea or soy sauce-like appearance. Severe anemia can lead to hypoxia, resulting in rapid breathing, increased heart rate, dysphoria, restlessness, and even heart failure, shock, unconsciousness, or acute renal failure.

2. **Chronic Hemolytic Anemia** usually has a gradual onset with milder symptoms, primarily presenting as clinical manifestations of anemia, such as lack of strength, pallor, dizziness, and shortness of breath. Patients often exhibit three main features: anemia, jaundice, and hepatosplenomegaly. However, it should be noted that not all cases of hemolytic anemia present with jaundice. The presence or absence of jaundice depends on the degree of hemolysis and the liver's ability to process bilirubin. Chronic hemolysis with long-term hyperbilirubinemia may lead to complications such as gallstones and liver dysfunction. Patients with sickle cell anemia may develop leg ulcers that are difficult to heal.

bubble_chart Auxiliary Examination

1. Blood Picture: There is a varying degree of decrease in red blood cells and hemoglobin, generally presenting as normocytic normochromic anemia, but sometimes it may manifest as microcytic hypochromic anemia. Anisocytosis and poikilocytosis are more pronounced, and nucleated red blood cells may occasionally be seen. In certain types of hemolytic anemia, specific morphological red blood cells such as spherocytes, elliptocytes, target cells, and sickle cells may be observed. Reticulocyte count is elevated, with the degree of elevation proportional to the severity and acuity of hemolysis. White blood cell and platelet counts are mostly normal or show a grade I increase; acute massive hemolysis may sometimes induce a leukemoid reaction.
2. Bone Marrow Picture: Bone marrow shows hypercellularity or marked hypercellularity, predominantly with erythroid hyperplasia. Cells at all stages of the erythroid series proliferate, but the increase is mainly in polychromatic and orthochromatic normoblasts. The granulocyte-to-erythrocyte ratio decreases or may even reverse. The granulocytic and megakaryocytic series usually show no significant abnormalities. In a few cases complicated by folic acid deficiency, manifestations similar to megaloblastic anemia may occur. In cases with long-term excessive iron loss due to hemoglobinuria, morphological changes of iron-deficiency anemia may be present.
3. Shortened Red Blood Cell Survival: Shortened red blood cell lifespan is the most reliable evidence of hemolysis. The survival period is commonly measured using radioactive 51Cr-labeled red blood cells. The time taken for the radioactivity of labeled red blood cells in the circulating blood to decrease to half of the injected amount is referred to as T1/2 (51Cr). The normal T1/2 (51Cr) for red blood cells is 25–32 days. A value below this indicates shortened red blood cell survival, i.e., increased hemolysis. This method is limited by technical constraints and is only used in diagnostically challenging cases.
4. Blood Generation and Transformation: In severe hemolysis, serum indirect bilirubin concentration increases. Plasma free hemoglobin levels rise, and serum haptoglobin is significantly reduced or absent. Serum lactate dehydrogenase activity is elevated.

bubble_chart Diagnosis

(1) Clinical manifestations: Anemia accompanied by jaundice, where the anemia worsens as jaundice intensifies and alleviates as jaundice disappears, or sudden onset of severe anemia without clinical manifestations of internal or external bleeding, or anemia accompanied by varying degrees of hepatosplenomegaly and jaundice. The characteristic symptom of acute intravascular hemolysis is hemoglobinuria, manifested as tea-colored or soy-sauce-colored urine.

(2) Laboratory findings

1. Manifestations of excessive red blood cell destruction (1) Increased serum indirect bilirubin, the concentration of which is related to the severity and urgency of hemolysis as well as the liver's ability to conjugate and excrete bilirubin; (2) Urinary urobilinogen excretion is significantly increased during acute hemolysis, but in chronic hemolysis, it only increases when accompanied by impaired liver function and generally does not increase; (3) Fecal urobilinogen excretion increases, but it is easily affected by factors such as constipation; (4) Decreased or absent plasma haptoglobin. The normal range is 700–1500 mg/L plasma. It has the ability to bind free hemoglobin in plasma, forming a haptoglobin-hemoglobin complex, which is processed by liver cells and quickly disappears from the blood due to middle consumptive thirst. Therefore, plasma haptoglobin decreases or disappears in hemolytic anemia. (5) Hemoglobinemia: Normally, plasma contains only trace amounts of free hemoglobin, generally less than 50 mg/L. When massive intravascular hemolysis occurs, this value increases significantly, resulting in hemoglobinemia. (6) Hemoglobinuria: When plasma free hemoglobin exceeds the binding capacity of plasma haptoglobin, the excess hemoglobin is filtered by the glomeruli, leading to hemoglobinuria. (7) Hemosiderinuria: Commonly seen in chronic intravascular hemolysis, especially in PNH. (8) Increased serum lactate dehydrogenase (LDH) activity: This is caused by the release of LDH into plasma due to red blood cell destruction. (9) Increased red blood cell fragments on blood smears; shortened red blood cell survival time.
2. Tests for compensatory erythroid hyperplasia (1) Reticulocytosis is one of the important clinical diagnostic indicators of hemolytic anemia. The more severe the anemia, the higher the reticulocyte count, which can reach 50% or higher during acute and substantial hemolysis. When acute aplastic crisis occurs in hemolytic anemia, the elevated reticulocyte count may drop to the normal range or even disappear. (2) Blood smears may show nucleated red blood cells, basophilic stippling, etc. (3) Significant hyperplasia of erythroblasts in the bone marrow, with frequent mitotic figures and a decreased myeloid-to-erythroid ratio.

1. Detailed history-taking to identify disease cause clues (1) Pay attention to familial inheritance and whether there are similar cases among family members or relatives. (2) Certain hemolytic anemias, such as G6PD deficiency, show regional distribution, mainly seen in Guangdong, Guangxi, Yunnan, Sichuan, and Fujian provinces, while thalassemia is more common in provinces south of the Yangtze River. (3) Note the primary disease, such as autoimmune hemolytic anemia, which may be secondary to lymphoma or systemic lupus erythematosus. Additionally, consider infections, exposure to chemical toxins, dietary or medication history to assist in diagnosis.
2. Observation of red blood cell morphology on blood smears Spherocytes are characteristic of hereditary spherocytosis; elliptocytes accounting for more than 15–30% suggest hereditary elliptocytosis; increased target cells indicate thalassemia, hemoglobin E disease, or hemoglobin C disease; acanthocytes may be seen in congenital abetalipoproteinemia; stomatocytes are seen in hereditary stomatocytosis; increased helmet cells or fragmented red blood cells suggest hemolysis due to physical injury to red blood cells, mainly seen in microvascular nature of disease hemolytic anemia.
3. A positive anti-human globulin test (Coombs test) suggests the presence of incomplete antibodies on red blood cells or in serum, seen in autoimmune hemolytic anemia and alloimmune hemolytic anemia.
4. The acidified serum hemolysis test (Ham test), sucrose hemolysis test, and urine hemosiderin test are positive in PNH.
5. Increased osmotic fragility in the red blood cell osmotic fragility test is seen in hereditary spherocytosis. Decreased red blood cell osmotic fragility is observed in sickle cell anemia, thalassemia, hemoglobin E disease, hemoglobin C disease, etc.
6. Reduced G6PD activity, a methemoglobin reduction test with a reduction rate below 75%, and a positive cyanide-ascorbate test are indicative of G6PD deficiency.
7. Hemoglobin electrophoresis, hemoglobin A2, hemoglobin F testing, and red blood cell inclusion body examination are used to diagnose thalassemia and other conditions. A positive isopropanol test and heat denaturation test are seen in unstable hemoglobinopathies.

bubble_chart Treatment Measures

1. Disease causes and preventive measures for inducing factors: For hemolysis caused by bacterial infections, antibiotics should be used appropriately to rapidly control the infection; for hemolysis induced by chemicals or drugs, the medication should be discontinued immediately; for hemolysis secondary to other diseases, the primary disease should be actively treated. In cases of mismatched blood transfusion, the transfusion should be stopped immediately, all transfusion equipment should be replaced, and measures should be taken to prevent shock and protect renal function.
2. Adrenocortical hormones can suppress antigen-antibody reactions and are primarily indicated for: immune hemolytic anemia, primaquine-induced hemolysis, PNH, and cases of mismatched blood transfusion. Prednisone is commonly used, with a dosage of 40–60 mg/d for adults until hemolysis subsides, followed by gradual dose reduction. The treatment course generally lasts six months, as premature discontinuation or rapid dose reduction can easily lead to relapse. For critical cases, dexamethasone or hydrocortisone may be administered intravenously, switching to oral administration once the condition stabilizes.
3. Immunosuppressants may be added for patients who respond poorly to adrenocortical hormones or require high maintenance doses. Examples include cyclophosphamide and azathioprine. Azathioprine is commonly used at 2–2.5 mg/kg/d. After the condition stabilizes, the dose should be gradually reduced. During treatment, regular blood tests should be conducted, and close attention should be paid to potential bone marrow suppression.
4. Splenectomy is indicated in the following cases: (1) Autoimmune hemolytic anemia requiring high-dose adrenocortical hormone therapy or unresponsive to drug treatment; (2) Hereditary spherocytosis or other types of hemolytic anemia accompanied by hypersplenism; (3) Cases where 51Cr-labeled red cell surface measurements confirm that red cells are primarily destroyed in the spleen; (4) Certain types of hemoglobinopathies or pyruvate kinase deficiency, where splenectomy can prolong red cell lifespan and reduce hemolysis.
5. Blood transfusion may be administered for most acute or chronic hemolytic anemia patients with grade III anemia or during a hemolytic crisis. However, it should be noted that transfusion can activate complement, exacerbating AIHA, PNH, or drug-induced immune complex-mediated hemolytic anemia. To avoid or mitigate post-transfusion hemolytic reactions, such patients should preferably receive saline-washed or frozen red blood cells.
6. Prevention of complications: Early intervention should be taken to prevent complications of hemolysis, such as shock, acute renal failure, and heart failure.

bubble_chart Prevention

1. Conduct in-depth epidemiological investigations, provide genetic counseling, offer marriage guidance, and provide marriage consultation, prenatal diagnosis, and early detection of hereditary diseases for patients with hemolytic anemia related to genetics. Timely artificial late abortion is an effective measure to prevent genetic diseases. Implement family planning, eugenics, and optimal child-rearing to gradually reduce its incidence.
2. Individuals with G6PD deficiency should avoid contact with oxidizing drugs and refrain from consuming fava beans or contact with fava beans or Mongolian snakegourd root.
3. Avoid using known drugs that can induce immune hemolytic anemia.

bubble_chart Differentiation

(1) Acute jaundice hepatitis: This condition is often not accompanied by severe anemia, and there is no active proliferation of erythroblasts. The reticulocyte count does not increase, both direct and indirect bilirubin levels in the serum are elevated, urine bilirubin is positive, and there is no hemoglobinuria. Patients often have a history of hepatitis exposure.

(2) Hemoglobinuria and hematuria or myoglobin hematuria: Urinalysis in these patients reveals intact red blood cells. Myoglobinuria mainly occurs due to severe muscle injury, intense exercise, and can also be seen in cases of electric shock and stirred pulse embolism, among others. Differentiation can be made using spectrophotometry or electrophoresis.

(3) Congenital bilirubin metabolism defects: These often present with chronic jaundice and a family genetic history, caused by defects in liver cell enzymes or impaired uptake, transport, and excretion of bilirubin by hepatocytes. There is no hemolysis or anemia, nor are there signs of increased red blood cell destruction or compensatory hyperplasia.