Anemia (anemia) is defined as the amount of hemoglobin (Hb), red blood cell (RBC) count, and hematocrit (HCT) per unit volume of blood in peripheral blood that is below the lower limit of normal values in comparable populations, of which hemoglobin is the most reliable and the most common laboratory indicator used to diagnose anemia in clinical practice. Age, gender and altitude of long-term residence can affect hemoglobin concentration. The domestic criteria for the diagnosis of anemia are generally set as follows: adult male hemoglobin <120g/L, red blood cells <4.5×1012/L and hematocrit <0.42; adult female hemoglobin <110g/L, red blood cells <4.0×1012/L and hematocrit <0.37. The diagnostic criteria for anemia in pregnant women are set as follows: hemoglobin <100g/L, red blood cells <4.0×1012/L and hematocrit <0.37 because of the increase of plasma volume and physiological dilution of blood in the middle and late pregnancy. The hemoglobin concentration and erythrocyte count and erythrocyte volume are related to the state of blood dilution, and any conditions that can lead to a relative decrease in plasma volume, such as severe diarrhea, massive burns, hypertonic fluid peritoneal dialysis, long-term fluid intake restriction and diabetic acidosis, can cause blood concentration and a relative increase in the above indicators. On the contrary, any pathological conditions that cause a state of water retention, such as congestive heart failure, hypoproteinemia or acute nephritis, can cause hemodilution, resulting in a relative decrease in the above indicators. Therefore, various influencing factors should be considered comprehensively when diagnosing anemia to avoid misdiagnosis.
Etiology and pathogenesis]
Anemia is not an independent disease, but a clinical manifestation. A variety of diseases can cause anemia. The etiology and pathogenesis of anemia are complex and varied, so only the general contents of the pathogenesis of anemia are covered here.
I. Reduced erythropoiesis
Erythropoiesis originates from pluripotent hematopoietic stem cells. Erythropoietin acts at the level of red lineage-directed progenitor cells to promote erythropoiesis. The common mechanisms of reduced erythropoiesis are.
(i) bone marrow failure: including reduced quantity or defective quality of hematopoietic stem cells, such as aplastic anemia and Fanconi anemia.
(ii) Ineffective hematopoiesis: such as myelodysplastic syndromes.
③ bone marrow suppression: damage to hematopoietic stem cells and progenitor cells caused by radiotherapy or chemotherapy of tumors.
④ bone marrow infiltration: invasion of bone marrow such as hematological malignancy, tumor bone marrow metastasis, bone marrow fibrosis or sclerosis can directly cause reduction of effective hematopoietic tissue in bone marrow.
(v) Decreased hematopoietic stimulating factors: decreased renal synthesis of erythropoietin in chronic renal failure.
(vi) Abnormal hematopoietic microenvironment: little is known about the exact significance of the hematopoietic microenvironment in the pathogenesis of anemia, but there is evidence of a role in the pathogenesis of certain anemias such as aplastic anemia.
(vii) Deficiency of hematopoietic substances: deficiency of folic acid and/or vitamin B12 leads to impaired cellular DNA synthesis and causes megaloblastic anemia. Iron is an important substance for the synthesis of hemoglobin, and iron deficiency can cause iron deficiency anemia.
Excessive destruction of red blood cells
The common feature of this type of anemia is the shortened life span of red blood cells, which is called hemolytic anemia.
(1) Intrinsic defects of red blood cells: abnormalities or defects in the basic structure of red blood cells, including cell membranes, metabolic enzymes and hemoglobin, can cause shortening of their life span.
②External erythrocyte factors: including physical, chemical, drug, metabolic toxins, biotoxins, infections and other non-immune and immune factors. The latter are mainly mediated through humoral immune antibodies causing red blood cell destruction.
Third, blood loss
It includes acute and chronic blood loss. Acute blood loss mainly causes hemodynamic changes, while chronic blood loss is the most common cause of anemia.
The etiology and pathogenesis of anemia are complex and varied, sometimes as a result of the superposition of multiple factors. Clinicians should not be satisfied with the initial diagnosis of anemia, but should carefully search for the cause of anemia in order to take targeted and effective treatment.
Clinical manifestations]
In addition to the manifestations of the disease causing anemia, the clinical manifestations of anemia itself mainly depend on the following factors.
① The reduction of the oxygen-carrying capacity of the blood.
② The degree of change in total blood volume.
③ The rate of development of the above two factors and the compensatory capacity of the respiratory and circulatory system. In some slow-onset anemias such as iron deficiency anemia and chronic aplastic anemia, if the cardiopulmonary compensatory function is good, the patient’s hemoglobin falls to 80g/L or even lower before symptoms appear. Conversely, if the anemia develops rapidly and exceeds the compensatory capacity, the patient may develop obvious clinical manifestations. For example, in patients with acute blood loss, a 20% decrease in total blood volume can cause pallor, tachycardia and hypotension, and a 50% decrease can lead to shock and death, when the clinical manifestations are more often due to a decrease in effective blood volume.
I. Skin and mucous membranes
Pale skin and mucous membranes are the most common signs of anemia. The determination of skin pallor is susceptible to a variety of factors, including ethnic skin color, the depth and nature of skin pigmentation, the degree of dilatation of skin vessels, and the content and nature of subcutaneous tissue fluid. Changes in the color of mucous membranes are more reliable, such as the oral mucosa, lid conjunctiva, lips, and nail bed. Other skin changes in anemia are dryness and lack of color, and decreased elasticity and tone. Changes in the skin appendages include dry and fine hair and thin and brittle nails. In iron deficiency anemia, the nails may be retrorse or spatulate.
Respiratory and circulatory system
Severe anemia can cause tissue hypoxia, resulting in compensatory rapid heartbeat and respiration, especially during physical activity. In rapidly progressing anemia, palpitations and shortness of breath are obvious. In chronic anemia, the symptoms are less severe. Long-term severe anemia can cause hyperdynamic heart failure with water and sodium retention, edema and even ascites. If the heart failure is not corrected, it may eventually lead to left ventricular atrophy. This cardiac abnormality can gradually recover after the anemia is cured. Compared to healthy individuals, anemic patients have increased oxygen debt during normal activity and slower than normal heart rate recovery times. The heart murmur is a frequent sign of anemia and occurs in systole and is most clearly defined in the pulmonary valve area. The heart murmur is usually of moderate intensity, mostly wind-like, but sometimes coarse in nature and can be confused with organic heart valve disease. In addition to accelerated blood flow and vortex formation, the murmur may also be a manifestation of relative mitral and tricuspid valve insufficiency due to cardiac dilatation. Electrocardiographic changes are seen in patients with severe anemia and are characterized by nonspecific changes such as sinus tachycardia, sinus arrhythmia, ST-segment reduction, and T-wave hypoplasia. Severe anemia may be accompanied by atrial fibrillation. All the above ECG changes can return to normal after the anemia is corrected. It is worth noting that arrhythmias in anemic patients should not be simply attributed to anemia itself, but should be further investigated for other possible causes and treated accordingly.
III. Neuromuscular system
Severe anemia is often associated with neurological manifestations such as headache, dizziness, tinnitus, syncope, visual blindness, lethargy, poor concentration and memory loss, which may be a manifestation of cerebral hypoxia. Muscle weakness and easy fatigue are the result of muscle tissue hypoxia. Abnormal sensation is a common symptom of pernicious anemia.
IV. Digestive system
Patients with anemia often have digestive symptoms such as loss of appetite, nausea, bloating, abdominal discomfort, constipation or diarrhea. Some of them are the manifestation of the primary disease and some are the result of anemia. Tongue inflammation and tongue papillae atrophy are mostly seen in pernicious anemia, but also in iron deficiency anemia. Mucositis or painful ulcers in the oral cavity are seen in aplastic anemia and acute leukemia, which are caused by granulocytopenia. Difficulty in swallowing is seen in chronic iron deficiency anemia.
V. Genitourinary system
Patients with anemia have polyuria and low specific gravity urine due to impaired glomerular filtration and renal tubular reabsorption. Severe cases may have mild proteinuria. Female patients of reproductive age may have menstrual cycle disorders, increased or decreased menstrual flow or amenorrhea. Severe anemia is common in patients with hypogonadism.
VI. Other
Patients with anemia are sometimes accompanied by hypothermia, which may be related to the elevated basal metabolism of anemia if no etiology can be found. If the body temperature exceeds 38.5℃, the cause of fever should be investigated, such as infection. Hemolytic anemia with jaundice is characterized by the absence of bile metabolites in the urine. Intravascular hemolysis presents with hemoglobinuria and hyperhemoglobinemia, which may be accompanied by abdominal pain, lumbago and fever.
[Diagnosis].
Anemia is only a symptom, so the diagnostic process of anemia is mainly to identify the cause of the anemia. Until the cause is clearly identified, drugs should not be administered indiscriminately, except for supportive treatment, so as not to delay the correct diagnosis.
I. Medical history
A detailed medical history can provide useful clues for the search of the cause of anemia. In addition to the conventional history, the scope of questioning should include the form of onset, time of onset and duration, dietary habits, past medications, occupational exposure, toxic or chemical exposure, bleeding tendency or history of bleeding, history of chronic diseases, history of menstruation, history of childbirth, history of black stool and change in stool habit, change in weight, change in urine color, family genetic history, and presence of fever, etc., and the importance of each of these items should be evaluated and analyzed separately. The importance of these items should be assessed and analyzed separately.
Physical examination
A comprehensive and orderly physical examination is extremely helpful for the diagnosis of the cause of anemia. Skin and mucous membrane examination includes color, rash, ulcers, hair and nail changes. Pallor of the skin and mucous membranes is a common manifestation of anemia and can generally reflect the degree of anemia. Yellow sclera of the skin suggests hemolytic anemia. Special attention should be paid to the presence of sternal pressure pain and generalized superficial lymph nodes and liver and spleen enlargement. Anal and gynecological examinations should not be neglected either, as bleeding hemorrhoids or tumors in this area are common causes of anemia. Heart murmurs can be caused by anemia, but possible organic pathology should be ruled out. Neurological examination should include fundus. Signs of posterior and lateral cord degeneration suggest pernicious anemia.
III. Laboratory tests
It can provide a definite diagnosis for anemia. Routine blood tests can determine the degree and morphological classification of anemia and the cell lineage involved. Reticulocyte count reflects the activity of red blood cell production. Urinalysis should be noted for bilirubin metabolites and occult blood. Hematuria may be a manifestation of renal or urinary tract disease itself, or it may be due to thrombocytopenia or coagulation disorders. Hemoglobinuria is evidence of intravascular hemolysis. Positive fecal occult blood suggests gastrointestinal bleeding.
Bone marrow examination is a major component in the diagnostic process of anemia. There are two types of bone marrow examinations: puncture smear and biopsy. The former focuses on cytologic analysis such as cell proliferation, cell sorting count, presence of abnormal or tumor cells, and number of non-hematopoietic cells. The latter provides pathological information such as the degree of bone marrow proliferation, distribution and area of hematopoietic tissue, bone marrow fibrosis, and tumor metastasis or infiltration. Bone marrow examination can provide a direct basis for changes in erythropoietic activity and causes in anemia. In hemolytic anemia, erythropoiesis is significantly active and the granulocyte/erythrocyte (M/E) ratio can be inverted. Aplastic anemia has an overall decrease in bone marrow hematopoietic activity and an increase in nonhematopoietic cells. In leukemia, the bone marrow appears to have a large number of leukemic cells and normal hematopoietic activity is suppressed. Bone marrow iron staining is a reliable indicator for evaluating the body’s iron reserves, and patients with iron deficiency anemia have significantly reduced or absent extracellular iron. Ringed iron granulocytes are seen in myelodysplastic syndromes and iron granulocytic anemia.
Special laboratory tests related to anemia will be described in the anemia monograph.
Treatment]
The causes of anemia are different, and the treatment should be different according to the disease.
I. Etiological treatment
It is the key to the treatment of anemia. All anemia should be treated on the basis of identifying the cause of the disease in order to achieve the goal of balancing the symptoms and the root cause until it is cured.
Second, supportive treatment
Blood transfusion is an effective treatment for anemia, but because of the side effects and complications, the indications should be strictly controlled. Chronic anemia with hemoglobin below 60g/L is an indication for blood transfusion. Component blood transfusion should be used as much as possible according to the situation. Correction of the patient’s general condition and effective control of infection are also important components of supportive therapy.
Supplementation of elements or factors required for hematopoiesis
Some anemias are caused by the lack of hematopoietic elements or factors, and reasonable supplementation can achieve good results, such as iron deficiency anemia caused by iron deficiency, and megaloblastic anemia caused by vitamin B12 or folic acid deficiency. Vitamin B12 or iron has a certain reserve in the normal organism, and anemia occurs only after its depletion. Therefore, care should be taken to replenish the reserve when treating this type of anemia to avoid recurrence.
IV. Hematopoietic growth factors or hematopoietic stimulating drugs
In renal anemia, erythropoietin biosynthesis is reduced, and exogenous supplementation of this hematopoietic growth factor is effective for treatment. Erythropoietin may also be effective for some chronic diseases of anemia. Androgens have a long history of use in the treatment of chronic aplastic anemia because of their stimulatory and erythropoietin-like effects on bone marrow hematopoiesis.
Some anemias are caused by deficiencies in hematopoietic elements or factors and can be treated well with proper supplementation, such as iron deficiency anemia caused by iron deficiency, and megaloblastic anemia caused by vitamin B12 or folic acid deficiency. Vitamin B12 or iron has a certain reserve in the normal collective, and anemia occurs only after its depletion. Therefore, care should be taken to replenish the reserves when treating this type of anemia to avoid relapse.
V. Immunosuppressants
For anemia whose pathogenesis is related to immunity. Glucocorticoids can be used for autoimmune hemolytic anemia or pure red blood cell aplastic anemia. Some patients with aplastic anemia are effectively treated with anti-thymocyte globulin (ATG) or anti-lymphocyte globulin (ALG) and cyclosporine (CsA).
VI. Allogeneic hematopoietic stem cell transplantation
Applicable to bone marrow hematopoietic failure or certain severe hereditary anemias such as heavy aplastic anemia, dyslipopoietic anemia and sickle cell anemia.
VII. Splenectomy
The spleen is the main site of red blood cell destruction. Certain anemias are indications for splenectomy, including hereditary spherocytosis, hereditary oval erythrocytosis, autoimmune hemolytic anemia and hypersplenism that have failed to respond to medical treatment. Some patients with pure red blood cell aplastic anemia with thymoma may achieve remission after thymectomy.