secondary polycythemia
Introduction
Introduction to secondary polycythemia Secondary polycythemia is caused by an increase in the secretion of erythropoietin (abbreviated as erythropoietin) secondary to other diseases, and the erythrocytosis is divided into erythropoietin compensatory increase according to the characteristics of increased erythropoietin secretion. Non-compensatory increases in two categories. Secondary polycythemia is mainly due to tissue hypoxia, increased secretion of erythropoietin, or due to the development of benign or malignant tumors that produce erythropoietin and the administration of hormone preparations that promote the production of erythropoietin. Newborns can be caused by transplacental transfusion or umbilical cord ligation. Symptoms vary in severity, depending on the primary disease. In addition to increased red blood cells, white blood cells and platelets are more normal. The main treatment for the primary disease. Erythrocytosis is a compensatory phenomenon that does not require treatment. After eradication of the primary disease, erythrocytosis can be cured naturally. If the hematocrit exceeds 65%, the blood viscosity is extremely increased, and blood should be exchanged intermittently from the venous exsanguination with an equal amount of plasma or saline. basic knowledge The proportion of illness: 0.001%-0.003% Susceptible people: no special people Mode of infection: non-infectious Complications: angina
Cause
Causes of secondary polycythemia
Cardiovascular disease (25%):
Congenital heart disease such as tetralogy of Fallot, complete displacement of large blood vessels, often secondary to erythrocytosis, the pathogenesis is due to short circuit of blood circulation, reduce arterial oxygen saturation, stimulate the increase of erythropoietin, promote erythropoiesis Non-purpuric congenital heart disease patients with chronic heart failure, pulmonary congestion and pulmonary ventilatory dysfunction, resulting in long-term hypoxia, erythrocytosis, mitral valve disease and chronic lung disease in acquired heart disease Sexual heart disease is often accompanied by erythrocytosis due to systemic blood circulation disorder and obstruction of lung ventilation, but the degree of erythrocytosis is milder, not as significant as congenital heart disease, in addition to pulmonary arteriovenous fistula, jugular vein and pulmonary vein traffic.
Environmental factors (20%):
The disease is caused by a decrease in atmospheric pressure in the plateau region, and secondary erythrocytosis occurs in the absence of oxygen. The higher the altitude, the lower the atmospheric pressure, the lower the alveolar oxygen pressure, the higher the number of red blood cells, hemoglobin and hematocrit. At an altitude of 3,500 meters above sea level, the incidence of high altitude polycythemia increases with the increase of altitude.
Lung bronchopathy (15%):
Emphysema, long-term bronchial asthma, severe spine of the spine, lateral process, affecting heart, lung function, pulmonary heart disease and multiple pulmonary embolism, due to insufficient oxidation of circulating blood transpulmonary, often secondary to erythrocytosis, about Patients with 50% of chronic lung disease have increased red blood cell volume; in addition, Ayerza syndrome is clinically characterized by chronic progressive bronchial asthma, bronchitis, patients with cyanosis, accompanied by erythrocytosis, and may later have right ventricular hypertrophy and dilatation, and The development of chronic congestive heart failure, the main pathological changes are the hardening of the pulmonary artery and its branches, and some are congenital stenosis or hypoplasia of the pulmonary artery.
Pathogenesis
1. Compensatory increase in erythropoietin
(1) neonatal polycythemia: normal full-term neonatal hemoglobin is 180 ~ 190g / L, red blood cells are 5.7 ~ 6.4 × 1012 / L, hematocrit 53% ~ 54%, this is because the fetus is in the mother Physiological hypoxia, after birth, newborns can directly absorb oxygen from the air, the number of red blood cells gradually decreased, such as neonatal hemoglobin > 220g / L, hematocrit > 60%, can be diagnosed as neonatal erythrocytosis Symptoms, which may be caused by:
1 Placenta is excessively bleed, between twins (fetal transfer syndrome) or between mother and fetus.
2 placental insufficiency, such as over-mature, pregnancy poisoning, placenta previa and so on.
3 endocrine and metabolic abnormalities, such as congenital adrenal hyperplasia, neonatal hyperthyroidism, maternal diabetes.
(2) Pulmonary ventilation syndrome (Pickwickian syndrome): due to the respiratory center affecting patients with poor alveolar ventilation, the clinical features are obesity, hypercapnia, erythrocytosis, patients with lethargy, convulsions, cyanosis, periodicity Breathing, and finally lead to right heart failure, after weight loss in individual cases, the alveolar ventilation can be normal, and the symptoms disappear.
(3) Hemoglobin disease: due to the increased oxygen affinity of abnormal hemoglobin, it closely binds with oxygen, maintains the state of oxyhemoglobin, and does not easily release oxygen to tissues, causing tissue hypoxia, which can increase erythropoietin and cause erythrocytosis. In this group of cases, the oxygen affinity is increased, the oxygen dissociation curve is shifted to the left, the tissue can be reduced by oxygen, and the tissue oxygen tension is reduced.
(4) abnormal hemorrhagic disease: this group of diseases, including some damage or pathological conditions, hemoglobin uptake or release of oxygen is abnormal, according to the absorption band and characteristics, can be divided into methemoglobinemia, thiohemoglobinemia and Carbon monoxide hemoglobinemia, etc., due to the ability of hemoglobin to lose oxygen binding, can not carry oxygen to the tissue, can also cause mild secondary polycythemia, erythrocytosis caused by smoking is due to some people smoking a lot, long-term exposure to high concentrations In carbon monoxide, inhaled carbon monoxide has a strong affinity for hemoglobin. Carbon monoxide and hemoglobin combine to replace oxygen, causing hypoxia, which may cause mild erythrocytosis, and hematocrit has a certain relationship with smoking consumption. Plasma can be restored after smoking is stopped.
2. Non-compensatory increase in erythropoietin
(1) Kidney disease: Kidney disease secondary to erythrocytosis, especially kidney cancer, followed by polycystic kidney, hydronephrosis, benign renal adenoma, renal sarcoma, kidney tuberculosis, etc., secondary kidney tumor and kidney There are also reports of secondary erythrocytosis in transplantation. The mechanism of erythrocytosis is due to tumors, cysts or accumulated water compressing kidney tissue, obstructing blood flow, causing hypoxia in local tissues, increasing erythropoietin production in the kidney, leading to erythropoietin. Increased production, in addition to the presence of erythropoietin RNA in the fluid of the cyst wall and the fluid of the cyst and the renal cancer tissue of the tumor. If the crude leachate of the tumor tissue is injected into the animal, the erythropoiesis may be stimulated, and the kidney transplant patient may The mechanism that causes erythrocytosis may be related to an increase in erythropoietin caused by kidney damage in the recipient itself.
(2) Other tumors: Hepatocellular carcinoma has been confirmed to have erythrocytosis, and erythropoietin antigen has also been confirmed in liver cancer cells. The erythrocytosis can be improved after liver cancer resection, metastatic liver cancer, hepatic hemangioma, hepatic angiosarcoma, etc. Erythrocytosis, cirrhosis patients occasionally see erythrocytosis, may be associated with hepatocellular carcinoma, in addition to liver tumors, there are cerebellar hemangioblastoma, uterine fibroids, pheochromocytoma, ovarian cancer, etc., individual reports of gastric cancer, prostate Cancer, lung cancer, Hodgkin's disease, esophageal tumors, etc. can affect the secretion of erythropoietin and then erythrocytosis.
Erythrocyte dynamics, hematopoietic cytokinetics is a quantitative study of the dynamic changes of hematopoietic cell population proliferation, differentiation, maturation, distribution and death in the body's hematopoietic tissue, and their physiological and pathological conditions on the body and external regulatory factors In response, erythrocyte production in the body undergoes proliferation and differentiation of hematopoietic cells, proliferation and maturation of red blood cells to late red blood cells and bone marrow reticulocytes, and release of reticulocytes into the peripheral blood to mature into red blood cells. There is a certain amount of red blood cells produced every day, and the same amount of red blood cells are destroyed.
Pluripotent stem cell
In 1961, Till and Mclulloch discovered that bone marrow cells from normal mice were infused into lethal dose-treated mice, and after 8 to 10 days, recipients of mice could produce cells from the erythroid, granulocyte and megakaryocyte lines of the bone marrow. The spleen nodules are composed of Becker. The labeled chromosomes prove that all the cells in each spleen nodule originate from a single cell. Therefore, the spleen nodule-producing cells are called hematopoietic stem cells or pluripotential hematopoietic stem cells. The pluripotent hematopoietic stem cells have a strong ability to proliferate and have the ability to multiply differentiation. The hematopoietic stem cells maintain asymmetry by mitosis, and on the other hand, the progenitor cells are continuously produced.
2. Proliferation kinetics of CFU-S
Cell proliferation kinetics refers to the process of cell population proliferation, differentiation and death in terms of time and quantity. Cell proliferation is carried out by cell division. The cell cycle refers to the beginning of a cell division and the next division. Throughout the entire process of end-stage, a series of specific biochemical metabolisms are sequentially performed during the various phases of the cell cycle.
(1) G1 phase: generally refers to the completion of cell division, the formation of daughter cells, to the gap between cell DNA replication, so it is also called the pre-replication period, G1 phase DNA is diploid content, mainly in the G1 phase of RNA and The synthesis of proteins and the preparation of metabolism associated with DNA replication can last for hours, tens of hours or days, or even months.
(2) S phase: From the start of DNA replication by the cell to the completion of DNA replication, the DNA content is continuously increased from diploid to 4-fold, and the S phase is 6-8 h.
(3) G2 phase: from the completion of DNA replication, to the gap between the cells and the dividing phase, the G2 phase DNA content is 4 times. In this phase, tubulin synthesis and mitochondrial DNA synthesis, G2 time limit changes Larger and susceptible to various factors.
(4) M phase: for the cell division phase, generally 0.5 to 2 hours.
Erythroid progenitor cell
BFU-E (burst-forming unit-erythroid) is an early erythroid progenitor cell that needs to be cultured for 14 to 20 days in vitro to form colonies. Each colony contains hundreds to tens of thousands of In nuclear cells, BFU-E forms larger colonies, shaped like a blasted firefly, and megakaryocytes, neutral or eosinophils and mononuclear macrophages can be seen in explosive colonies, so it is assumed that early BFU- E is a bidirectional or multi-directional progenitor cell, similar to CFU-S, and BFU-E growth is also dependent on erythropoietin.
CFU-E (colony forming unit-erythroid) is the latest progenitor cell in the erythroid system. EPO is required for survival and proliferation in an in vitro culture system. CFU-E is close to identifiable primitive red blood cells. Human CFU-E can form 8 to 64 colonies composed of nucleated red blood cells in vitro for 7 days. The ratio of CFU-E to BFU-E in normal human bone marrow is 5:1 to 10:1.
4. Kinetic parameters of erythroid cell formation
According to the cell division index of each stage of bone marrow and the DNA synthesis time determined by the in vitro incorporation method of radionuclide, the cycle time of human bone marrow erythroid cells was estimated as: original, early red blood cells were 20h, and medium and young red blood cells were about 2h. Young red blood cells do not have the ability to synthesize DNA, so they are non-proliferating cells. During the whole process, the cell's division index is 3 to 5 times. It is estimated that it takes about 5 days for red blood cells to form new reticulocytes from the bone marrow. time.
5. Red blood cell maturation
The maturation of red blood cells begins with hemoglobin synthesis in the cytoplasm. As the erythroid cells continue to mature, the amount of hemoglobin in each nucleated cell increases, while the RNA content decreases, just in human erythrocytes that have just differentiated from hematopoietic stem cells. The content of hemoglobin is almost zero. In the later maturation process, the hemoglobin content in the cell gradually increases to 14.4pg. After a cell division, although the hemoglobin content in the cell is reduced by half, after a cell cycle, the cell is in the cell. The hemoglobin content is increased from 7.2pg to 21.6pg. The hemoglobin in the cell has a decisive influence on the cleavage phase of red blood cells. Among them, when the hemoglobin content in the daughter cells after the division of the young red blood cells exceeds 13.5pg, the cells lose their continued division. The ability to mature into late red blood cells, and enter the denucleation stage, during the process of red blood cell maturation, DNA and RNA synthesis gradually reduced or disappeared.
In morphology, as the cells mature, the ribosomes gradually decrease, and the organelles gradually degenerate and disappear. As the cells continue to divide and the nucleus becomes smaller, the concentration and disappearance, the cell bodies are relatively increased.
6. Red blood cell denucleation and release
The denucleation of late red blood cells is similar to cell division in biology and morphology. Denucleation can be seen as two unequal divisions, some are reticulocytes, and some are concentrated nuclei without division. The wavy motion of the young red blood cells increases. After several contractions, the nucleus is squeezed to the cytoplasm and then prolapsed. Most of the naked nuclei are phagocytosed by macrophages or lysed in the spleen.
The release of mature red blood cells is the last process of bone marrow erythrocyte hematopoiesis. Electron microscopic observation shows that red blood cells enter the blood through the sinus wall of the bone marrow and the cytoplasm of the endothelial cells. When the red blood cells enter the blood sinus, the deformable cytoplasm enters first. The nucleus remains outside the sinusoid. After the red blood cells enter the sinusoid, the endothelial cells contract and the sinusoidal orifice is closed. Under hypoxia, the sinus wall of the bone marrow can be dilated and the blood flow is increased. Occasionally, a small amount of nucleated red blood cells are seen in the peripheral blood. Escape.
7. Red blood cell destruction
The normal red blood cell survival time is 100-130 days, so the red blood cells in the body are destroyed by 1/120 per day, 6.25g hemoglobin is decomposed, and the corresponding amount of red blood cells and hemoglobin are formed to maintain the dynamic balance of red blood cell numbers in the body, and the physiological damage of red blood cells. Mainly due to aging, red blood cell senescence, red blood cell hexokinase, phosphoglucose isomerase and other gradual loss of vitality, the metabolic process dependent on these enzymes weakened, red blood cells survived 60 days, the adenosine triphosphate (ATP) content began to decrease , thus leading to energy metabolism disorders, aging red blood cells osmotic fragility increased, deformability reduced, morphologically gradually changed from disk shape to spherical shape, these aging red blood cells in the blood circulation by the impact of blood flow or red blood cells mechanical damage Broken, finally phagocytized by mononuclear macrophages or neutrophils, or red blood cell lysis caused by loss of permeability changes due to various factors. Normally, about 10% of aging red blood cells are destroyed in the blood vessels. The spleen plays an important role. In addition to the spleen, the liver also destroys red blood cells. To one of the sites, other organs of the monocyte-macrophage cells also have the ability to remove abnormal red blood cells, but to a lesser efficiency.
8. Red blood cell production regulation
Under physiological conditions, the total amount of circulating red blood cells is maintained by feedback regulation of the rate of red blood cell production. Between hematopoietic stem cells and mature red blood cells, a complex dynamic balance is formed, which is interlinked and mutually constrained, in erythropoiesis. Erythropoietin plays an important role. Erythropoietin (EP) is a glycoprotein with a molecular weight of 60,000 to 70,000. In serum protein electrophoresis, EP is located in the region of alpha globulin, EP is erythrocyte hematopoiesis. The main role is:
1 Stimulate the proliferation of erythroid committed stem cells in the early stage.
2 promote red differentiation of differentiated stem cells into erythrocytes.
3 stimulate the proliferation of immature red blood cells in bone marrow. These three effects are restricted by the negative feedback of the terminal products of the above process. Androgen can stimulate the production of EP and stimulate the synthesis of heme, and increase the number of EP sensitive cells. The GFU phase of CFU-S enters the DNA synthesis phase, and can also directly act on erythropoiesis.
Large doses of estrogen inhibit the production of EP, and estrogen may inhibit the production of red blood cells by reducing the response of hematopoietic stem cells to EP.
It is generally believed that the increase of red blood cells and the contraction of the spleen when the first arrival in the plateau is released, and the release of stored red blood cells to the peripheral blood is related. The long-term increase of red blood cells in the plateau and the decrease of oxygen pressure in the plateau are in anoxic state and are related to the following factors:
(1) Increase in the level of red blood cell 2,3-diphosphoglycerate: The right shift of the oxygen dissociation curve can reduce the arterial oxygen saturation, which is beneficial to the release of oxygen from the blood to the tissue.
(2) Increased levels of erythropoietin in plasma and urine: increased plasma iron turnover rate, increased reticulocyte count, and increased red blood cell volume and blood volume.
(3) Excessive antidiuretic hormone and adrenocortical hormone secretion decreased, returning to normal levels.
(4) Increased erythropoiesis in the bone marrow: an adaptive mechanism to compensate for hypoxia, in order to increase oxygen carrying capacity and ensure the organization's need for oxygen.
However, erythrocytosis has a certain physiological range. Excessive hyperplasia can cause an increase in blood volume, a decrease in plasma volume, an increase in blood viscosity, and a slow blood flow. These conditions reduce blood oxygenation, tissue hypoxia, and increased cardiac burden. Turned to pathological state, in the chronic hypoxic environment, arterial oxygen saturation decreased, which can stimulate the massive production of erythropoietin, causing excessive proliferation of red blood cells, and excessive increase of 2,3-diphosphoglycerate in red blood cells, so that the lungs Difficulties in oxygen uptake, arterial oxygen saturation decreased further, forming a vicious circle, and finally developed into the disease.
Prevention
Secondary erythrocytosis prevention
Prevention: It is necessary to keep the patient's daily life, keep the mood comfortable, treat the disease correctly, and establish the confidence to overcome the disease. Otherwise, the illness will easily worsen the illness. Diet should be light, eat spicy and hot products. When the disease is in the middle and late stages, the condition is often mixed with the image of the virtual and the real. Therefore, it is necessary to prevent overwork and injury, or to reinforce the exogenous evils after labor.
Complication
Secondary polycythemia complications Complications
Sometimes you can have angina. Clinically, angina is often divided into two types: stable angina and unstable angina. Stable angina pectoris means that the onset of angina pectoris remains relatively stable over a period of time, both induced by fatigue, with no significant changes in seizure characteristics, and is a stable and afflicted angina pectoris. Unstable angina includes angina pectoris, spontaneous angina pectoris, post-infarction angina pectoris, variant angina pectoris, and labor-induced angina pectoris. The main features are unstable pain, long duration, and the risk of spontaneous seizures can easily evolve into myocardial infarction. Unstable angina is different from stable angina. It belongs to acute coronary syndrome and often requires urgent treatment. It is very close to non-ST-segment elevation myocardial infarction, so it is generally discussed together.
Symptom
Symptoms of secondary polycythemia Symptoms Common symptoms Deficiency erythrocytosis Head swelling Congestive angina pectoris Heart squint Dizziness Plateau Multi-blood face
1. The manifestation of erythrocytosis
Common symptoms include dizziness, head swelling, headache, fatigue, palpitations, insomnia, vertigo, fear of heat, sweating, etc. Sometimes angina, facial, finger, lip and auricle are dark red to bun, mucous membrane and conjunctival hyperemia Vasodilation.
2. Symptoms and signs of the primary disease
According to the history of the primary disease, physical examination laboratory data and red blood cell count, hemoglobin, hematocrit increased, red blood cell volume is higher than normal, erythropoietin increased or normal, and the diagnosis of primary polycythemia can be diagnosed.
Examine
Examination of secondary polycythemia
1. Peripheral blood: hemoglobin, red blood cell count, hematocrit, red blood cell volume is higher than normal, but white blood cell and platelet counts are generally normal.
2. Arterial oxygen saturation: can cause a decrease in cardiopulmonary disorders, etc., but normal in cancer patients.
3. Increased red blood cell volume determination, decreased plasma volume or normal.
4. Determination of vitamin B12: Quantification in serum is increased or normal.
5. Neutral alkaline phosphate (NAP) is normal.
6. Histamine levels were not determined to increase histamine.
7. Chromosome detection: Secondary erythrocytosis generally has no chromosomal abnormalities.
8. Hematopoietic stem cell culture: There is no spontaneous hematopoietic stem cell colony formation in secondary erythrocytosis.
9. Determination of serum erythropoietin (EPO): in patients with secondary polycythemia due to low blood oxygenation in the arteries, usually elevated EPO levels; or secondary to malignant tumors, such as liver cancer or kidney cancer can cause abnormal erythropoiesis Increased.
Diagnosis
Diagnosis and diagnosis of secondary polycythemia
According to the history of the primary disease, physical examination laboratory data and red blood cell count, hemoglobin, hematocrit increased, red blood cell capacity is higher than normal, erythropoietin increased or normal, the diagnosis of primary polycythemia can be diagnosed.
Differential diagnosis:
Mainly differentiated from polycythemia vera and relative polycythemia.
Polycythemia vera: a chronic myeloproliferative disorder characterized by abnormal proliferation of red blood cells. It may be caused by the hematopoietic stem cells being free from the normal control of erythropoietin, or by the increased sensitivity of hematopoietic stem cells to erythropoietin and the stimulation of abnormal myeloproliferative factors. It is characterized by red blood cell volume, total blood volume and increased blood viscosity. In the course of the disease, there are varying degrees of splenomegaly, myeloid metaplasia, and myelofibrosis. The disease is mainly caused by skin mucosal plaque, stagnation or visceral hemorrhage, which belongs to the category of "blood syndrome" of traditional Chinese medicine. The main cause of hepatosplenomegaly is the "accumulation" category of traditional Chinese medicine.
Relative polycythemia: the cause of dehydration and insufficient water intake, mainly the symptoms of hypovolemia, gastrointestinal failure in severe cases of Gaisbock, smoking history in most cases, the age of onset of patients is mild, more common in men, most of the weight is more than normal, common Symptoms include mild headache, dizziness, neurasthenia, anxiety, facial and lip conjunctiva and oral mucosa red and purple congestion, spleen is not swollen, half of the patients have high blood pressure, and hypertension is also common in the course of the disease.
