Candidate of Medical Sciences, Associate Professor V.A. Tkachev
Hemolytic anemia (HA) is a group name for diseases whose common feature is increased destruction of erythrocytes, causing, on the one hand, anemia and increased formation of erythrocyte decay products, and on the other, reactively enhanced erythropoiesis.
Currently, there are classifications of GA , which are based on their division depending on the location of hemolysis (intravascular or intracellular), endo- and exoerythrocyte hemolytic factors of their origin (congenital, acquired).
However, with the same form of HA, intracellular and intravascular hemolysis, erythrocyte and extra-erythrocyte hemolytic factors can be observed simultaneously. According to the classification proposed by L.I. Idelson et al., it is most justified to distinguish two main groups of GA: hereditary (congenital) and acquired. Hereditary GA are united by the genetic principle, but differ significantly in etiology, pathogenesis and clinical picture.
Hereditary (congenital) HA :
1. Membranopathy of erythrocytes:
2. Enzymopenic (fermentopenic) associated with enzyme deficiency:
§ pentose-phosphate cycle;
§ involved in the formation of oxidation and reduction of glutathione;
§ involved in the use of ATP;
§ involved in the synthesis of porphyrins.
Acquired GA :
2. Acquired membranopathies:
§ paroxysmal nocturnal hemoglobinuria;
§ Spur cell anemia.
3. Associated with mechanical damage to red blood cells:
§ marching hemoglobinuria;
§ arising from prosthetic heart valves.
Clinically, intracellular hemolysis , occurring in the cells of the phagocytic system, and intravascular , which occurs in the vascular bed, are distinguished.
Increased intracellular breakdown of red blood cells leads to the development of a characteristic triad of clinical signs – anemia, jaundice and splenomegaly . The bone marrow is able to increase erythropoiesis by 6–8 times compared to the norm, therefore, increased destruction of erythrocytes with a shortening of their average lifespan to 20 days is not always manifested by anemia. Prolonged hemolysis or its increase due to the shortening of the life span of erythrocytes less than 15–20 days leads to the development of anemia. The number of platelets during intracellular hemolysis is not changed. The clinical picture is characterized by general weakness, fatigue, shortness of breath, decreased ability to work.
Jaundice is manifested by an increase in the content of indirect bilirubin in the blood serum due to the increased formation of bile pigments from hemoglobin released during hemolysis of red blood cells. In cases of slight hemolysis, when the liver has time to remove excess bilirubin from the blood, jaundice may not develop. With a combination of jaundice and anemia, the skin acquires a lemon-yellow color. Increased excretion of bilirubin in the bile (pleiochromia) often causes the formation of gallbladder and bile duct stones . The increased formation of urobilinogen and its excretion in the urine leads to a dark color of the urine. The release of stercobilinogen also increases, the feces acquire a dark brown color.
Splenomegaly in HA results from hyperplasia of the phagocytic cell system . Usually it does not increase to a large size and is palpated at the edge of the costal arch .
Hemolytic crisis with intracellular hemolysis does not reach the same degree of severity as with intravascular hemolysis, but can be the cause of death of the patient. Sometimes, as a result of exhaustion, a temporary insufficiency of erythropoiesis develops – a hypoplastic crisis lasting 7–15 days, which poses a serious danger to the patient’s life.
Intravascular hemolysis is manifested by a hemolytic crisis, the main symptoms of which are rapidly developing general weakness, a sharp increase in temperature, shortness of breath, severe headache in the lower back and abdomen, nausea, vomiting with bile, and sometimes dark liquid stools. The condition of patients is severe, sometimes comatose, severe tachycardia. The color of the skin is lemon-yellow, the mucous membranes are pale. In some cases, there is an increase in the spleen, less often – an increase in the liver . A specific sign of a crisis is black or dark urine ( hemoglobinuria ). In some cases, oligo- and anuria occur up to the development of acute renal failure , which is a consequence of disseminated intravascular coagulation due to the ingress of erythrocyte thromboplastic factor released from erythrocytes into the vascular bed. Sometimes there is a hemorrhagic syndrome in the form of petechiae and small bruises on the skin. Mucosal bleeding may occur. Thrombocytopenia is determined in the blood. With hemolysis of moderate intensity, the hemolytic crisis is easier, acute renal failure does not develop. In some cases, intravascular hemolysis is manifested by a slight darkening of the urine and mild icterus.
Diagnostics . Laboratory methods play an important and often decisive role in the diagnosis of GA.
On the part of peripheral red blood , normochromic anemia of varying severity is observed. Anemia in chronic hemolysis is moderate, but during a hemolytic crisis it reaches a critical value (20–30 g/l hemoglobin). Blood smears reveal microspherocytosis, which is characteristic of hereditary microspherocytic anemia and autoimmune HA, as well as ovalocytosis, target-shaped (flat, pale erythrocytes with a small amount of hemoglobin in the center of the cell) and sickle-shaped erythrocytes, characteristic of certain forms of HA.
Hemolysis is accompanied by reticulocytosis , reflecting the degree of increased compensatory hematopoiesis in the bone marrow.
The osmotic resistance of erythrocytes (normally maximum in 0.32% NaCl solution, minimum in 0.46%) is reduced only with microspherocytosis.
The leukogram and the number of leukocytes are usually not changed. However, in cases of acute hemolytic crisis, leukocytosis with neutrophilia and a shift of the leukocyte count to the left are observed. With pancytopenia of an immune nature, autoimmune GA is combined with agranulocytosis and thrombocytopenia.
Bone marrow picture. Bone marrow hematopoiesis in GA is characterized by compensatory hyperplasia of the red germ with a pronounced erythroblast-normocytic reaction. In an aplastic crisis, erythroblastopenia is observed in the bone marrow.
Biochemical blood tests include the determination of free hemoglobin, bile pigments and hemosiderin. In chronic hemolysis, the level of free plasma hemoglobin does not increase (40 mg / l). During a hemolytic crisis or with HA that occurs with intravascular hemolysis, free plasma hemoglobin sometimes rises to 1-2 g / l. With significant hemoglobinemia, free hemoglobin appears in the urine ( hemoglobinuria ). Urine becomes black in color. With prolonged hemoglobinemia and hemoglobinuria, characteristic grains of hemosiderin are found in the urine sediment.
With HA, the level of indirect (free) bilirubin in plasma increases (does not exceed 13–50 mg/l). With a mild degree of hemolysis, the level of bilirubin may be low or even normal. Thus, the absence of elevated bilirubinemia does not negate the diagnosis of hemolytic disease. Uncomplicated hemolytic anemia may occur without bilirubinuria. Obstructive jaundice against the background of GA (which is often observed) leads to an increase in direct blood bilirubin, which is also accompanied by bilirubinuria.
The level of urobilinogen in the urine increases with acute hemolysis or hemolytic crisis. In chronic hemolysis, this indicator changes little. Enhanced hemolysis is accompanied by an increase in the amount of stercobilinogen up to 0.5-1.0 and even 4.0 grams per day (at a rate of 0.03-0.3 g / day).
Special tests detect iso- or autoantibodies in serum or on erythrocytes (for example, the Coombs reaction), which confirms the immune character of GA.
Using the isotope label of erythrocytes, it is possible to determine the decrease in their life expectancy and the organs involved in the destruction of erythrocytes.
If a hereditary defect in red blood cells is suspected, the activity of red blood cell enzymes is studied, and a study is carried out for the presence of abnormal hemoglobins.
Hereditary membranopathies are caused by abnormalities in the protein or lipid components of the erythrocyte membrane, which leads to their premature destruction. With microspherocytic membranopathy, erythrocytes take the form of spherocytes, ovalocytic – ovalocytes, acanthocytic – acanthocytes (erythrocytes with spike-like protrusions). The disease is inherited in an autosomal dominant manner.
In the pathogenesis of the disease, particular importance is attached to the reduced content of actomyosin-like protein in the erythrocyte membrane and their partial deprivation of phospholipids and cholesterol, which contributes to the transformation of erythrocytes into microspherocytes. Along with this, spherocytes lose the plasticity of normal erythrocytes and purely mechanically linger in the spleen pulp, since they cannot pass into the venous sinusoids through pores with a diameter of up to 3.5 microns, or they pass with the loss of part of the membrane. Upon reaching certain changes in the structure of the membrane, erythrocytes are absorbed by macrophages of the spleen. This explains the cessation of enhanced hemolysis after splenectomy, despite the preservation of microspherocytic form by erythrocytes.
The first manifestations of the disease are usually noted in older childhood and adolescence. The course of the disease is very diverse – from subclinical to severe with frequent hemolytic crises. Complaints may be absent: “Sick people are more yellow than sick.” They are caused by anemic hypoxia or attacks of biliary colic in the presence of gallstones. Jaundice is accompanied by the release of intensely colored feces and dark urine. The spleen is enlarged in 50% of patients. Serum bilirubin is always elevated due to the indirect fraction. Significantly increased daily excretion of stercobilin with feces and urobilinogen with urine. The disease is combined with congenital anomalies : tower skull, gothic sky, strabismus, heart defects. Hemolytic crises develop gradually and are provoked by infections or childbirth. Aplastic crises are accompanied by the disappearance of jaundice, the appearance of leuko- and thrombocytopenia. In some patients, bilateral ulcers appear on the skin of the legs as a result of microclotting by spherocytes. Anemia is moderate, sometimes absent due to hemolysis compensation by enhanced erythropoiesis. The hemoglobin content is usually normal or slightly increased. A blood test reveals microspherocytosis, ovalocytosis, or acanthosis. In the bone marrow, pronounced hyperplasia of the erythroblastic germ with signs of accelerated maturation is revealed. The osmotic resistance of erythrocytes in microspherocytic anemia is sharply reduced, while in ovalocyte and acanthocytic anemia it is normal. The lifespan of erythrocytes is significantly reduced. In 30–40% of cases, a complication occurs in the form of biliary colic or obstruction of the bile duct (obstructive jaundice).
The most effective treatment for sphero- and ovalocytic GA is splenectomy . However, microspherocytosis and decreased osmotic stability remain for life. Due to the increased destruction of red blood cells, folic acid must be included in therapy. In patients with aplastic crises or severe hemolysis, packed red cell transfusions are indicated. Splenectomy is not indicated for patients with asymptomatic disease. The operation is performed only in the course of anemia requiring frequent transfusions or in the presence of cholelithiasis. There is no specific therapy for acanthocytosis.
The prognosis for microspherocytic and ovalocytic anemia after splenectomy is favorable, for acanthocytic anemia it is unfavorable.
Enzymopenic hereditary anemia is a group name for GA caused by hereditary deficiency of certain erythrocyte enzymes.
The most common is enzymopenic GA associated with deficiency of glucose-6-phosphate dehydrogenase in erythrocytes. The role of this enzyme is its participation in the restoration of NADP (nicotinamide adenine dinucleotide phosphate), which ensures the regeneration of glutathione (a tripeptide involved in many metabolic processes). Reduced glutathione protects red blood cells from decay upon contact with oxidants, including drugs. Provoke the disease more than 40 types of drugs (antimalarial, sulfonamides, nitrofurans, anti-tuberculosis, antibiotics, analgesics, vitamins C and K, 5-NOC, etc.), vaccines, toxicosis of pregnancy, hepatargia, rickettsial or viral infection, endogenous intoxication (diabetic acidosis ), etc. The clinical picture is varied: from asymptomatic to severe hemolytic crisis.
The following clinical forms are distinguished: acute intravascular hemolysis; favism (GA, caused by the intake of primaquine, sulfonamides, inhalation of the pollen of some plants); acute hemolytic disease of the newborn, not associated with group and Rh incompatibility or with hemoglobinopathies; hereditary chronic (non-spherocytic) hemolytic anemia.
Acute intravascular hemolysis occurs with a picture of hemoglobinuric fever, which is clinically manifested by sudden chills , fever, headache, and vomiting. The main symptoms in this case are severe hemoglobinemia, hyperbilirubinemia, hemoglobinuria, severe anemia with hyperreticulocytosis, hyperleukocytosis, sometimes with a leukemoid reaction. With a favorable course, recovery occurs. In some cases, symptoms of minimal hemolysis are periodically or constantly observed. In the most severe cases, due to the obstruction of nephrons by blood detritus and the deposition of hemosiderin in the tubules of the kidneys, anuria with uremia develops, which leads to death.
Acute hemolytic disease of the newborn is most often provoked by the use of drugs with a potentially hemolytic effect by a pregnant or nursing mother. Clinically (as well as hemolytic disease of the newborn, associated with incompatibility of the blood of the mother and fetus according to the Rh factor or blood type), the disease is characterized by yellowness of the skin and mucous membranes , enlarged liver and spleen . The amount of hemoglobin decreases to 6–8 g/l, the number of erythrocytes to 2–3 million. Reticulocytosis, normomegaloblastosis, anisocytosis, poikilocytosis, and polychromasia are noted.
Hereditary chronic (nonspherocytic) hemolytic anemia can manifest itself from birth, the first months or the first years of life. At the same time, there is pallor with an icteric tinge of the skin and mucous membranes, an increase in the spleen, less often in the liver. Anemia is normochromic macrocytic in nature with the presence of reticulocytosis, bilirubinemia. The course of the disease may be accompanied by hemolytic crises due to medication or intercurrent infection. A frequent complication is calculous x olecystitis .
Treatment of an acute hemolytic crisis is aimed at stopping hemolysis, preventing and eliminating shock and anuria. For this purpose, intravenous infusions of polyglucin, dextran, sodium bicarbonate are carried out. Shown are cardiovascular agents, osmotic diuretics, prednisone. In renal failure, hemodialysis is performed. In severe HA, transfusions of washed and thawed erythrocytes are necessary. With minimal hemolysis, antioxidants are prescribed – vitamin E, riboflavin. In acute hemolytic disease of the newborn, an exchange transfusion is performed. In hereditary chronic hemolytic anemia, splenectomy is effective.
Hemoglobinopathies – GA associated with a violation of the structure or synthesis of hemoglobin. There are hemoglobinopathies caused by an abnormality in the structure of hemoglobin (sickle cell anemia) and caused by a violation of the synthesis of hemoglobin chains (thalassemia).
Sickle cell anemia is caused by a mutation leading to the substitution of thymine for adenine in the 6th codon of the b-gene, as a result of which the encoded valine is replaced by glutamine in the 6th position of the b-chain. Low temperatures increase the crescent of red blood cells. In cold weather, patients may begin crises. The crescent is aggravated by acidosis. Due to the rigidity of sickle-shaped erythrocytes and their adherence to the vascular endothelium, the rheological properties of the blood are disturbed. Pressure in areas with fast blood flow (spleen) leads to hemolysis of pathologically altered erythrocytes. Crises often occur with infections, dehydration, fever, acidosis, starvation, hypoxia, lung diseases. In children, the manifestations of the disease are associated with the addition of pain, while in adults – with damage to organs.
The clinic of the disease is manifested by a hemolytic crisis. The hemoglobin level usually fluctuates from 50 to 110 g/l. Anemia is normochromic, normocytic. There is anisocytosis and poikilocytosis of erythrocytes (sickle and target cells), moderate reticulocytosis , leukocytosis, thrombocytosis. Most patients have a significant increase in serum iron concentration.
There is no effective treatment for sickle cell anemia, so care should be directed at managing complications. Folic acid replacement therapy is recommended to increase erythropoiesis. Prophylactic exchange transfusions of red blood cells can reduce the number of crises. Good results have been obtained with bone marrow transplantation .
Thalassemia is a group of diseases with a hereditary disorder in the synthesis of one or more chains (a-, b-chains) of globin. Due to the imbalance in the production of globin chains, ineffective hematopoiesis, defective hemoglobin production, hemolysis and anemia of varying severity develop. The type of inheritance is codominant.
The pathogenesis is based on a deficiency of the main hemoglobin fraction – HbA (A 1 ) and an increased content of abnormal hemoglobin (HbF, HbA 2 , HbH, etc.).
Morphologically , hyperplasia of the red bone marrow, expansion of the bone marrow spaces, thinning of the compact bone substance (up to pathological fractures), foci of extramedullary hematopoiesis, pronounced spleno- and hepatomegaly are observed.
Clinically , among b-thalassemias, there are major, intermediate, minor and minimal forms. Among the a-thalassemias, hemoglobinopathy H is distinguished. The most striking clinical signs in children with b-thalassemia major are short stature, square skull, thickened nose bridge, protruding zygomatic arches, narrowing of the palpebral fissures as a result of bone marrow hyperplasia. There is icteric coloration of the skin and mucous membranes, fever, secondary hypersplenism may develop. On the part of the blood, there are signs of severe hypochromic anemia (color index 0.5, decrease in hemoglobin to 20–50 g/l) with anisocytosis, poikilocytosis, schizocytosis and target erythrocytes, high reticulocytosis. In the future, there are signs of myocardial dystophy, heart failure, trophic ulceration, liver cirrhosis, pancreatic fibrosis with the development of diabetes mellitus due to hemosiderosis. Other forms of b- and a-thalassemia proceed more benignly.
In the treatment of the disease, transfusions of washed or thawed erythrocytes are used. To increase the level of hemoglobin, a shock course of treatment is used: 8–10 transfusions in 2–3 weeks. Then transfusions are carried out less frequently, every 3-4 weeks at the rate of 20 ml/kg of body weight. Subcutaneous administration of desferal is indicated to obtain maximum urinary iron excretion. Taking ascorbic acid at 50–100 mg/day also increases urinary iron excretion . With a combination of splenomegaly and anemia, a splenectomy is performed.
Forecast. The peak mortality in thalassemia major occurs after the age of 25 years, unless previously treated to increase urinary iron excretion. Bone marrow transplantation performed at an early age using an HLA-matched donor can lead to recovery. With thalassemia intermedia, hemochromatosis and severe bone disorders develop at the age of 30-40.
Acquired hemolytic anemia.
Immunohemolytic anemias are characterized by the presence in the blood of antibodies against antigens of one’s own or transfused (donor) erythrocytes. There are autoimmune GA caused by warm autoantibodies (GAVTA), cold agglutinins (GAVHA), biphasic hemolysins (GAVDH), and autoantibodies when taking certain drugs (GAVL). HA caused by cold and warm autoantibodies is divided into two forms: idiopathic and symptomatic (in the presence of a tumor of the lymphoid tissue, systemic connective tissue diseases in the former and infectious mononucleosis, mycoplasmal pneumonia in the latter).
The etiology of GAVTA and GAVHA is unknown. HAVDH is observed in acute viral infections, less often in syphilis. HAVL develops with the appearance of autoantibodies to the intake of certain drugs (penicillin, streptomycin, PASK, indomethacin, phenacetin, quinine, cephalosporin, tetracycline, aspirin, cefotaxime, leukeran, 5-fluorouracil, isoniazid, rifampicin, thiazides, clonidine ).
The pathogenesis of HAVTA is associated with a change in the erythrocyte membrane under the influence of thermal autoantibodies related to IgG and the formation of a new antigen.
In HAVCA, cold autoantibodies (IgM) with complement are fixed on erythrocytes in small vessels of the distal parts of the body when they are cooled to a temperature below 32°C.
The pathogenetic mechanism for the occurrence of HAVDH is the appearance in the blood of two-phase hemolysins (IgG), which are deposited on erythrocytes when the body is cooled (1st phase) and carry out their hemolysis at a temperature of 37°C (2nd phase).
The pathogenesis of HAVL is based on the mechanism of formation of anti-drug antibodies of the IgG type when the drug is combined with the complements of the erythrocyte surface.
Hemolysis in patients with HAVTA is predominantly extravascular, with HAVHA and HAVL – mixed, with HAVDH – vascular.
The course of GAVTA and GAVHA is chronic with the presence of jaundice, moderate or severe anemia with reticulocytosis and irritated bone marrow. However, GAVHA is characterized by the presence of Raynaud’s syndrome , which does not occur in patients with GAVTA. There is a dark stool and urobilinuria, some enlargement of the spleen and liver. Erythrocytes in HAVCA are little changed, while in patients with HAVTA anisocytosis, micro- and macrocytosis are observed. GAVTA is often complicated by heart attacks of internal organs , GAVHA – by gangrene of the fingers or toes .
In patients with HAVDH, the clinic is characterized by a severe general condition with fever, shortness of breath, headache, pain in muscles, joints, sometimes uncontrollable vomiting, loose stools, jaundice, black urine, moderate enlargement of the spleen and liver, as well as reactive erythropoiesis in the bone marrow. GAVDH is complicated by renal failure, anuria.
HAVL proceeds acutely with a predominance of mild and moderate forms. After discontinuation of the drug, all antibodies quickly disappear.
The diagnosis is based on the detection of immunoglobulins attached to the erythrocyte, the complement component, cold or drug antibodies using a direct antiglobulin test (Coombs reaction ).
Treatment of rapid hemolysis in patients with HAVTA is carried out by transfusion of erythrocytes. In all cases, corticosteroids are prescribed, which quickly remove or stop hemolysis: prednisolone 60–100 mg per day. With contraindications to corticosteroids, a splenectomy is performed. If they are ineffective , cytostatics are prescribed: cyclophosphamide 60 mg / m 2 or azathioprine 80 mg / m 2 for 3-6 months.
Warming is the appropriate treatment for patients with HAVCA . In severe cases, cytostatics are prescribed: chlorbutin 2.5-5 mg per day, cyclophosphamide 400 mg every other day or in combination with corticosteroids. Plasmapheresis is shown (obtaining blood plasma with the return of formed elements to the bloodstream.).
Treatment of patients with HAVDH consists in the exclusion of low temperatures . Transfusions of erythrocytes are indicated only in 50% of patients. For skin manifestations, desensitizing drugs are prescribed. Treatment is carried out only with an exacerbation of the disease, when the concentration of hemoglobin drops to a low level.
The main therapeutic measure in HAVL is the abolition of drugs . Transfusions are prescribed only for severe forms that threaten the life of the patient. Corticosteroids are not indicated.
Forecast. With HAVTA, a 10-year survival rate is observed in 70% of patients. Patients with GAVHA with post-infectious syndrome do not require treatment. Patients with HAVDH are usually self-limited. In cases of HAVL, there may be fatal renal failure as a result of the appearance of circulating immune complexes in the blood.
Isoimmune hemolytic anemia can develop in newborns with incompatibility of blood groups and Rh of the fetus and mother, as well as a complication of blood transfusions that are incompatible according to the AB0 and Rh system (post-transfusion GA).
Pathogenesis. When the fetal erythrocytes pass through the placenta, the mother is immunized and antibodies are formed that enter the fetal circulation, causing the destruction of its erythrocytes. The most common cause of hemolysis is the D-antigen of the Rh-blood group system. AB0 incompatibility between mother and fetus also plays a role in the occurrence of hemolytic disease of the newborn. In severe hemolysis, compensatory stimulation of erythropoiesis in the liver occurs, which leads to the development of portal and umbilical venous hypertension, edema of the hypertrophied placenta. Due to a violation of the supply of nutrition to the fetus, severe hypoproteinemia develops. As a result of portal hypertension, hypoalbuminemia, fetal ascites develops, turning into anasarca , which causes the ineffectiveness of postpartum resuscitation of the fetus. In most cases, intrauterine death occurs. If a child is born, jaundice develops within the first 24 hours, and bilirubinemia peaks on days 4–5 of life. In surviving children, as a result of hyperbilirubinemia, irreversible changes in the nervous system develop: deafness, asymmetric spasticity. For hemolytic disease of the newborn , hepatosplenomegaly, anemia, and reticulocytosis are typical. The first examination of the mother for the content of IgG antibodies should be carried out at the 16th week of pregnancy, the second – at 28–32 weeks. With an antibody titer of 1:16 (suspicion of the presence of IgG antibodies), amniocentesis should be recommended (puncture of the fetal bladder to extract amniotic fluid for diagnostic purposes or to terminate a pregnancy for medical reasons).
The goal of therapy is to prevent bilirubin neurotoxicity. Transfusion therapy for newborns begins when the level of hemoglobin in cord blood is less than 130 g / l (at a rate of 140 g / l) and the concentration of bilirubin is above 40 μmol / l. The donor’s blood must be 0(I) group (Rh-negative) and matched using an indirect Coombs test with mother’s serum. In total, 500-600 ml of donor erythrocytes are used. Specific prophylaxis for Rh-negative women is carried out during childbirth or no later than 48 hours after them with anti-Rh 0 anti-D-immunoglobulin (Rh 0 IgG) at a dose of 200-300 mcg.