paroxysmal nocturnal hemoglobinuria in children
Introduction
Introduction to paroxysmal nocturnal hemoglobinuria in children Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic hemolytic disease caused by acquired hematopoietic stem cell gene mutation leading to erythrocyte membrane disease. Clinically, intermittent intravascular hemolysis, hemoglobinuria, after sleep Hemolysis is characterized by aggravation. Both men and women can be ill, more men, more common in young adults, rarely seen in childhood. basic knowledge Sickness ratio: 0.0001% Susceptible people: children Mode of infection: non-infectious Complications: cholelithiasis thrombosis abdominal pain anemia leukemia
Cause
The cause of paroxysmal nocturnal hemoglobinuria in children
(1) Causes of the disease
It is currently believed that the cause of PNH is acquired acquired hematopoietic stem cell gene mutation, peripheral blood of normal and abnormal red blood cells, granulocytes, monocytes and platelets in PNH patients, suggesting that abnormal cells originate from a clone in the bone marrow. The study found that women with heterozygous G6PD mutations showed abnormal PNH erythrocytes with an isoenzyme, which is located on the X chromosome. It is speculated that these abnormal cells originate from a single progenitor cell with the above isozyme. This finding and a large number of studies in recent years have strongly supported the view that abnormal cell populations originated from single progenitor cells. The exact cause of gene mutations in hematopoietic stem cells is still unclear. Clinically, PNH and aplastic anemia can be transformed or coexisted. Therefore, it is speculated that the possible pathogenesis is that a certain mutagenic source causes mutations in hematopoietic stem cells, plus viruses, certain drugs and other factors lead to immune dysfunction, which causes normal hematopoietic stem cells to be damaged and reduced, and mutant hematopoietic stem cells have an opportunity. Proliferation and disease, this theory still needs research to confirm,
(two) pathogenesis
1. Pathophysiology The pathophysiology of PNH is mainly related to the lack of a group of glycositol phospholipid (GPI) connexin on the cell membrane surface; and the lack of GPI connexin is secondary to the defect of GPI anchor synthesis.
(1) GPI anchor synthesis defects: almost all PNH patients have abnormal pig/ gene (located in Xp22), which can cause N-acetylglucosamine to be added to phosphatidylinositol, and thus can not form a complete GPI anchor,
(2) GPI connexin deficiency: It has been found that at least 15 proteins in abnormal cells of PNH patients have different degrees of deficiency, which is closely related to the function of abnormal cells. These proteins can be divided into complement defense proteins and immune molecules. Enzymes, receptors, and granulocyte proteins with unknown functions,
2. Pathogenesis It is currently believed that the main reason for the increased sensitivity of red blood cells to complement hemolytic activity in PNH patients is that the cell membrane lacks both CD55 and CD59 membrane proteins, resulting in a weakened regulation of membrane surface complement activation. CD55 is also known as decay acceleration. Decasure accelerating factor (DAF) can increase the rate of dissociation or decay of invertase complex. The lack of CD55 on the membrane of abnormal PNH increases the activity of invertase, thus causing more C3 to deposit on the membrane. CD59 is also called reaction. Membrane inhibitor of reactive lysis (MIRL), which inhibits the interaction between C8 and C9 during complement activation. CD59 deficiency on PNH erythrocytes can lead to increased sensitivity of red blood cells to complement hemolysis; CD59 deficiency on abnormal platelets does not cause platelet destruction, but mainly plays a role in PNH complicated with venous thrombosis. Because of the dysregulation of the formation of poly C9 complexes on PNH platelets, more C9 complexes are inserted into the membrane. More thromboxane is produced, and abnormal platelets of PNH are particularly sensitive to thromboxane, so PNH patients are susceptible Concurrent thrombosis, deficiencies of Fc receptor III (CDl6a) in granulocytes of patients with PNH can make patients susceptible to infection, especially blood-borne infections. The reduction of acetylcholinesterase activity is one of the characteristics of this disease, and the degree of acetylcholinesterase activity of PNH erythrocytes is reduced. Parallel to the severity of the disease, it is currently believed that the decrease in enzyme activity may be secondary to erythrocyte membrane lipid abnormalities, independent of hemolysis, other proteins of PNH cells, such as CD58, CD14, CDw52, acetylcholinesterase, leukocyte alkaline phosphatase The significance of loss of urokinase receptor and folate receptor is unknown. 3. PNH red blood cells are divided into three types according to the sensitivity of red blood cells to complement hemolysis. PNH red blood cells can be divided into three types:
(1) extremely sensitive red blood cells: its sensitivity to complement hemolysis is 25 to 30 times that of normal red blood cells.
(2) Moderately sensitive red blood cells: it is 3 to 5 times more sensitive to complement than normal red blood cells.
(3) Normal red blood cells. Clinically, about 78% of PNK patients have both (1) and (3) cells, and about 9% of both cells (1) and (2) exist simultaneously, and the remaining patients coexist (2) And (3) two kinds of cells, very few patients only (2) cells, the severity of clinical manifestations is related to (1) the proportion of cell population, in general, when (1) cells account for 20% to 50% Hemoglobinuria can occur at the time, but (2) the proportion of cells is high, the clinical manifestations are mostly light, and hemoglobinuria may not occur. In addition, the proportion of sensitive red blood cells in some patients may change with the development of the disease; After several months or years, the proportion of sensitive red blood cells is reduced, and the condition is reduced or alleviated.
4. Inducing hemolysis factors The disease is aggravated during sleep. The cause is unknown. It is believed that blood flow in the tissues and organs may be increased due to slow blood flow during sleep, causing blood to become acidic and causing hemolysis. In addition, infection, especially Viral infections, drugs (such as aspirin, chlorpromazine, ammonium chloride, furantan, iron, etc.), blood transfusion, surgery, fatigue, trauma, etc. can induce hemolysis.
Prevention
Pediatric paroxysmal nocturnal hemoglobinuria prevention
The exact cause of acquired genetic mutations in hematopoietic stem cells is still unclear, infections, especially viral infections, drugs (such as aspirin, chlorpromazine, ammonium chloride, furantan, iron, etc.), blood transfusion, surgery, fatigue , trauma, etc. can induce hemolysis, therefore, prevention and treatment of the above incentives is conducive to the prevention of the onset of disease.
Complication
Pediatric paroxysmal nocturnal hemoglobinuria complications Complications cholelithiasis thrombosis abdominal pain anemia leukemia
Due to long-term hemolysis, it can cause cholelithiasis. The interaction between the platelet membrane and plasma complement of this disease is abnormal, resulting in hypercoagulability of the blood and causing thrombosis. Thrombosis of the lower extremity vein and mesenteric vein is more common, and abdominal vein embolism occurs. Acute abdominal pain like acute abdomen, if portal vein embolism can cause portal hypertension or even liver failure, long-term hemoglobinuria can cause hemosiderin in the kidney, resulting in hemosiderin, long-term hemoglobinuria and iron-containing blood Luteinuria can cause iron loss in the body, resulting in iron deficiency anemia, due to thrombocytopenia and abnormal function, but there is a tendency to hemorrhage, due to excessive long-term red blood cell destruction or excessive blood transfusion can cause jaundice or skin pigmentation, liver and spleen Swelling, some may have clinical manifestations of aplastic anemia, and a small number of patients can be converted to acute leukemia or myelofibrosis.
Symptom
Pediatric paroxysmal nocturnal hemoglobinuria symptoms common symptoms jaundice cold war hemoglobin urine color red sauce or soy sauce black urine
The onset is slow, the first symptom is anemia of different severity. Most patients have hemoglobinuria. The urine is soy sauce or brown, but 25% of patients have no hemoglobinuria during the course of the disease. Hemoglobinuria occurs after nighttime sleep. Early morning When you wake up, it is heavier, the afternoon is lighter, and sleep during the day can also cause seizures. The episodes are often accompanied by chills, fever, headache, abdominal pain, low back pain and other symptoms. The onset of hemoglobinuria varies greatly, and some occasionally occur, some Frequent seizures, often accompanied by jaundice, the cause of seizures are more common with infections, drugs, transfusion reactions, fatigue and surgery can be induced, the amount of hemolysis is related to many factors:
1. Size of abnormal clones The proportion of complement-sensitive red blood cells in the blood circulation varies greatly, ranging from 1% to 90%. These cells are at risk of hemolysis.
2. The degree of abnormality of red blood cells is also very different, which is related to the difference in the content of complement defense protein on the cell membrane surface.
3. The degree of complement activation, infection, transfusion reaction, etc. can cause complement activation. Characteristic sleep hemolysis may be related to complement activation caused by endotoxin absorption through the intestine. Long-term hemoglobinuria can cause renal hemosiderin deposition. The cause of hemosiderin, long-term hemoglobinuria and hemosiderin can cause iron loss in the body, resulting in iron deficiency anemia, some patients have bleeding tendency due to the reduction of platelets and their dysfunction, such as Hemorrhage, nosebleeds and skin hemorrhage, etc., frequent hemoglobinuria, due to excessive long-term red blood cell destruction or excessive blood transfusion can cause mild jaundice or skin pigmentation, liver and spleen often mildly enlarged, some patients can be in the course of the disease In the clinical manifestations of aplastic anemia, a small number of patients can be converted to acute leukemia or myelofibrosis.
Examine
Examination of paroxysmal nocturnal hemoglobinuria in children
1. The blood picture is mostly positive cell pigmented anemia. If the iron deficiency is combined, it is a small cell hypochromic anemia. The reticulocytes often increase and sometimes decrease; the number of white blood cells is often decreased, the infection is often increased, and the platelets are often reduced.
2. Bone marrow and bone marrow culture Different patients or the same patient may have different bone marrow images in different stages. Most patients have active bone marrow hyperplasia, mainly young and middle red blood cells and late red blood cells, which are more common in hemoglobinuria; In a small number of patients, the bone marrow hyperplasia is reduced or severely reduced. It is more common in hemoglobinuria. The bone marrow iron staining is often negative. However, after multiple transfusions or low myeloid hyperplasia, the bone marrow iron is normal or increased. CFU-E can often be found in bone marrow culture. The number of colonies with CFU-GM and the like is less than normal.
3. Urine examination showed hemoglobinuria, occult blood test was positive, and hemosiderin (Rous test) test was positive.
4. Special hemolysis test
(1) Acid hemolysis test (Ham test): The principle is: PNH abnormal red blood cells after acidified serum (pH 6.2), easily ruptured by complement activation activated complement attack, this test has strong specificity, positive is An important basis for diagnosing this disease, the sensitivity of the test depends on the concentration of magnesium ions in the serum. If the concentration of magnesium ions in the serum is raised to 5 mmol/L, the sensitivity of the experiment can be improved, but the test is difficult to detect. Small abnormal cell populations and red blood cells that are moderately sensitive to complement.
(2) Sucrose hemolysis test: This is a simple screening test. The principle is that in the sucrose solution with low ion concentration, the binding of complement serum to the erythrocyte membrane is strengthened, causing the defect of the erythrocyte membrane and causing the hemoglobin in the red blood cells to overflow. Hemolysis, this test is more sensitive than acid hemolysis test, but the specificity is poor, such as megaloblastic anemia, immune hemolytic anemia and granulocyte leukemia can be positive.
(3) venom factor hemolysis test: This experiment also has strong specificity, sensitivity is stronger than Ham, slightly worse than sulphur water hemolysis experiment, the principle is a venom factor extracted from cobra (no hemolysis itself) in serum Synergistically, the PNH abnormal red blood cells are ruptured and activated by activation of the complement bypass, and normal red blood cells are not.
(4) Complement hemolysis sensitivity test: By observing the amount of complement required for hemolysis of antibody-sensitized red blood cells, the proportion of abnormal red blood cells and their sensitivity to complement hemolysis can be determined.
5. GPI connexin detection In general, the expression of CD55 and CD59 in blood cells can be detected by flow cytometry analysis using the corresponding monoclonal antibody, which has the advantage of easy operation in granulocytes and platelets; and in these two cell populations The proportion of abnormal cells is greater than the proportion of abnormal cells in red blood cells, which is related to the normal life of abnormal granulocytes and platelets in the blood circulation. In general, CD59 deficiency is the most common, and CD16 deficiency is the least common. It is currently believed that detecting granulocytes Or GPI-linked protein on erythrocytes is highly sensitive, specific, and reliable. Routine imaging studies, such as chest X-ray, B-ultrasound, attention to lung infection, gallstone and liver, splenomegaly, etc., angiography can be found Venous thrombosis, brain CT examination can find cerebral thrombosis.
Diagnosis
Diagnosis and diagnosis of paroxysmal nocturnal hemoglobinuria in children
diagnosis
According to the clinical manifestations of hemolytic anemia, hemoglobinuria and acid hemolysis test are positive, can be diagnosed, for the manifestation of hyperplastic anemia and the evidence of hemolysis is not obvious, need to follow-up observation to confirm the diagnosis, China's current PNH diagnostic criteria and The diagnostic criteria for aplastic anemia-PNH syndrome are as follows.
1.PNH diagnostic criteria
(1) Clinical manifestations: in line with PNH.
(2) Laboratory tests: Ham test, syrup test, venom factor hemolysis test, urinary occult blood (or urinary hemosiderin) and other experiments can be diagnosed if any of the following conditions are met:
1 or more positive.
2 is a positive, but must have the following conditions: more than two positive, or one positive, but the operation is normal with a negative control, the results are reliable, immediate repeat is still positive; there are other direct or indirect evidence of hemolysis, there is a positive hemoglobin Urinary appearance; can exclude other hemolysis, especially hereditary spherocytosis, autoimmune hemolytic anemia, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and paroxysmal cold hemoglobinuria .
2. Aplastic anemia-PNH syndrome diagnostic criteria for the conversion of aplastic anemia to PNH, or conversion of PNH to aplastic anemia, or both of the characteristics of the disease, are aplastic anemia-PNH syndrome, indicating that the two diseases occur sequentially, or When there are two characteristics of the disease, which is the main clinical manifestations, the syndrome can be subdivided into four cases, and those who can be distinguished should be marked:
(1) Aplastic anemia-PNH: Refers to the original affirmation of aplastic anemia (rather than the early diagnosis of PNH), which is converted to a determinable PNH. The performance of the aplastic anemia is not obvious.
(2) PNH-Aplastic Barrier: Refers to the original positive PNH (instead of the fourth category below), which is converted to a clear aplastic anemia, and the performance of PNH is not obvious.
(3) PNH with aplastic anemia characteristics: It means that the clinical and laboratory examinations indicate that the condition is still PNH-based but accompanied by one or more sites with low bone marrow hyperplasia, megakaryocytes, reticulocytes are not increased, etc. Obstacle performer.
(4) Aplastic anemia with PNH characteristics: Only clinical and laboratory examinations showed that the diseased person was mainly aplastic anemia, but the test results with PNH were positive.
Differential diagnosis
The disease should be differentiated from aplastic anemia, autoimmune anemia, myelodysplastic syndrome (MDS), nutritional megaloblastic anemia and other causes of hemoglobinuria, generally based on the clinical and laboratory of each of the above diseases It is not difficult to identify the characteristics of the examination. If the bone marrow hyperplasia of the aplastic anemia is low, and the abnormal red blood cells like PNH can be detected, or the clinical manifestations of PNH and laboratory examinations are low, the bone marrow hyperplasia is low, and the aplastic anemia-PNH synthesis should be suspected. Some patients with MDS may also have abnormal blood cells similar to PNH, but their basic characteristics and development of the disease are still dominated by MDS, and typical hemoglobinuria or PNH appears rarely.
