polycythemia vera
Introduction
Introduction to polycythemia vera Polycythemia vera (referred to as true red) is a kind of chronic myeloproliferative disease with erythrocytosis and white blood cells and thrombocytosis. The total blood volume is absolutely increased, the blood is thick, and the clinical manifestations are red, purple and dizzy. , dizziness, headache, high blood pressure, hepatosplenomegaly, severe patients may have blood vessels, bleeding complications, infarction and so on. basic knowledge The proportion of illness: 0.005% Susceptible people: no specific population Mode of infection: non-infectious Complications: myocardial infarction thrombophlebitis splenomegaly
Cause
Causes of polycythemia vera
Causes
Formation of "endogenous" erythroid clones: When bone marrow cultured in vitro, normal bone marrow cells form late erythroid progenitor colonies (CFU-E), EPO is added to the culture medium, and bone marrow cells of PV patients can be added without EPO. Growth, suggesting that the EPO-producing erythrocyte clones of this patient have "tumor" properties. If the bone marrow culture of PV patients is also additionally added with EPO, then in the formed CFU-E, both PV cells and normal cells are present. Red blood cells, indicating that in addition to PV cell clones in PV patients, normal stem cells remain, but their proliferation is inhibited by PV clones. It is believed that abnormal clones of PV originate from a single cell, continue to proliferate, have the advantage of inhibiting normal clones, and have cells. Genetic instability, clinically found cases of PV conversion to acute leukemia.
The erythroid progenitor cells are more sensitive to EPO: when the bone marrow cells of PV patients and normal humans are cultured in stem cells, the same concentration of EPO is added, and the number of early erythroid progenitor colonies (BFU-E) and CFU-E in PV patients are higher than normal. Significantly increased, and the growth of CFU-E was significantly increased when patients did not add EPO. When EPO antibody was added to the culture, the number of CFU-E production in PV patients decreased. The above results suggest that the sensitivity of erythroid progenitor cells to EPO in PV patients is enhanced. This is one of the reasons for the increase in red blood cells.
Apoptosis of pluripotent stem cells: normal red blood cells contain isoforms of two glucose 6-phosphate dehydrogenases (G-6-PD), type A and type B, while red, granulocytes and platelets of PV patients contain only type A In one type, fibroblasts and lymphocytes still contain A, B type G-6-PD isoenzymes, indicating that the disease is a single clonal disease originating from the same pluripotent stem cell level.
Abnormal apoptosis: Some studies have found that the survival time of nucleated red blood cells in PV patients is significantly longer than that in normal people. PV colonies are highly sensitive to IL-3 and SCF, and these factors can delay the apoptosis of erythroid progenitor cells. PV patients and normal controls developed apoptosis in culture conditions lacking cytokines, but PV patients had less apoptosis than normal controls, and this difference may be related to high expression of bcl-2 in PV patients.
Others: Another experiment suggests that there may be a glycoprotein in the serum of PV patients, which can stimulate red blood cell production and stimulate the granulocytes and platelets. It is called bone marrow stimulating factor. The antigenicity of this factor is different from that of EPO, but a small amount of EPO is needed. Participation can work, and its nature needs further study.
Prevention
Polycythemia prevention
The disease belongs to myeloproliferative diseases, and there are no clear preventive measures at present.
Complication
Polycythemia complications Complications, myocardial infarction, thrombophlebitis, splenomegaly
Vascular complications
The incidence rate is 20% to 80%. The Italian PV research group reported that 1213 patients with PV had a thrombosis rate of 40% before or during the follow-up, mainly due to venous thrombosis and thrombophlebitis caused by hypervolemia and hyperviscosity. It can also occur in peripheral arteries, cerebral arteries and coronary arteries, causing severe consequences such as hemiplegia and myocardial infarction. Thrombophlebitis with embolism mainly occurs in the lungs, but mesenteric, liver, spleen and portal veins can also occur, which can cause acute Abdominal disease, hematocrit is significantly increased, with platelets, increased white blood cell count, increased age and previous history of thrombosis and repeated venous bleeding is a risk factor for thrombosis.
2.MDS
As a complication of PV has attracted people's attention, those:
1 standard treatment quickly spleen.
2 no obvious bone marrow fibrous tissue hyperplasia.
3 bone marrow is extremely active (<90%) with myeloid, erythroid and megakaryocytic three-line hyperplasia.
4 Peripheral blood mononuclear cell count > 1 × 109 / L, hyperplastic abnormal myeloid cells infiltrated the liver and spleen, suggesting that MDS may occur.
Symptom
Symptoms of polycythemia syndrome Common symptoms Hemorrhagic tendency Booger nosebleeds Red blood cells Digestive head fainting Hemorrhoids Thrombosis Increased sputum High viscosity syndrome
The onset of the disease is insidious, often in the asymptomatic period of several months to several years, often found during blood tests, and some cases are diagnosed after thrombosis and bleeding symptoms, many symptoms and signs with blood volume and blood Related to the increase in viscosity, the earliest symptoms are often related to blood circulation disorders and nervous system symptoms. The main clinical manifestations are as follows.
Skin change
It is characterized by reddening of the skin, especially in the face, neck and extremities, mucosal congestion, pale blue, Osler describes the symptoms as "summer as rose red, winter as indigo blue", common capillaries Expansion, gum bleeding and nasal discharge, also see skin blemishes, purpura, sputum, hemosiderin deposition, rosacea and spoon-shaped nails, 50% of patients suffer from water-borne itching, itching caused by bath or shower, burning Or itching, usually lasts for 30 to 60 minutes. Irrespective of water temperature, itching can occur regardless of water, and histamine in blood and skin increases.
2. The nervous system
Headache is the most common, 50% of patients have this performance, can be associated with dizziness, dizziness and tinnitus, fatigue, forgetfulness, limb numbness, sweating, etc., severe cases may have blind spots, diplopia and blurred vision and other visual abnormalities, there may be Angina pectoris and intermittent claudication, a small number of patients with cerebrovascular accident as the first manifestation of the diagnosis, the group of symptoms mainly due to increased red blood cell count, increased blood volume and increased blood viscosity caused by vasodilation, slow blood stasis and tissue hypoxia of.
3. Bleeding
The incidence rate <10%, mainly due to vascular congestion, endovascular damage, reduction of platelet factor 3, etc., platelet dysfunction and abnormal blood coagulation mechanism lead to bleeding tendency, usually nose bleeding, gum bleeding and skin spots on the mucous membrane The ecchymosis can also show gastrointestinal bleeding, bleeding after tooth extraction, and more menstrual flow.
4. The performance of histamine increased
This disease with increased granulosa cells, basophils also increased, the latter is rich in histamine, increased histamine release can cause peptic ulcer, so the incidence of peptic ulcer in this patient is 10% to 16%, compared with normal people 4 to 5 times higher, ulcers caused by upper gastrointestinal bleeding are more common, can be life-threatening, skin itching is also common, 40% occur in hot water bath, 10% can be associated with urticaria.
5. Other
The disease causes excessive proliferation of bone marrow cells, which makes nucleic acid metabolism too high, blood uric acid concentration rises, and a small number of patients may develop uric acid nephropathy, which is characterized by urinary stones and renal colic or gouty arthritis. Some patients may have gallstones, obstructive Jaundice and biliary colic, the most common signs are blood, facial, nasal, ear, lip, palm and conjunctival congestion, reddish, such as drunk, retinal and oral mucosa also showed congestion, about 70% of patients Arterial blood pressure is elevated, about 75% of patients may have splenomegaly, usually moderate to severe swelling, and have a certain differential diagnosis with secondary polycythemia. About 40% of patients may have hepatomegaly, with disease The development of the swelling gradually became apparent.
Examine
Examination of polycythemia vera
Peripheral blood mainly showed red blood cell count, hematocrit, red blood cell volume and hemoglobin increase, hematocrit men>60%, and women>55% of patients often have an absolute increase in red blood cell volume. Therefore, these patients may not have red blood cell volume test. About 50% of patients have increased white blood cells and platelets at the same time. In the early stage, red blood cells often show morphological characteristics of iron deficiency, which are small cells with low pigmentation, and late stage is often characterized by bone marrow fibrosis, which may have 9-large large and small unevenness. And teardrop-shaped red blood cells, late-stage patients, late-myelocytes, about 2 / 3 of patients may have increased basophils, peripheral blood smears often see large platelets, bone marrow examination is often three lines of hyperplasia, may have Reticular fibrosis, neutrophil alkaline phosphatase levels increased by about 70% in patients, 40% of patients increased serum Vit B12 concentration, 70% of patients increased serum Vit B12 binding protein, most patients with uric acid and histamine levels Increased, arterial PO is often lower than normal, the whole blood viscosity is often increased, serum EPO levels are reduced or normal low, PT, aPT and fibrinogen are normal. Platelet count Patients with >1000X109/L may have acquired VWD similar to type II VWD, which is characterized by prolonged bleeding time, VIIIC: VWF is normal, ristocetin cofactor activity is reduced, and large VWF multimers are reduced or absent. Some patients have antithrombin III, protein C and protein S deficiency.
Red blood cell
(1) Red blood cell count and hemoglobin increase: multiple tests of red blood cells > 6.5 × 1012 / L (male) or > 6.0 × 1012 / L (female); hemoglobin > 180g / L (male) or > 170g / L (female) .
(2) Hematocrit increased: male 54%, female 50%, patients often ranged from 55% to 80%.
(3) The blood cell volume was determined by the 51Cr labeling method to be greater than the normal value: male > 36 ml / kg, female > 32 ml / kg.
(4) morphological changes of red blood cells: the morphology of red blood cells changes with the development of the disease. The morphology of early red blood cells is mostly normal or mildly uneven. When the disease develops and the spleen is highly enlarged with active extramedullary hematopoiesis, erythrocytes appear in peripheral blood, and the size of red blood cells , the shape is not equal, visible ellipse, teardrop-like red blood cells and basophilic dot-like red blood cells.
(5) Red blood cell life: Different from the progress of the disease, the disease is normal or slightly shortened at the beginning, and the red blood cell life can be shortened due to the extramedullary hematopoiesis of the spleen and the function of the mononuclear macrophage system.
2. Granulocytes : About 2/3 patients have a moderate increase in white blood cell count, mostly in (12 ~ 25) × 109 / L, often with nuclear left shift, about 65% of patients with increased absolute value of basophils, neutral The granulocyte alkaline phosphatase score is mostly increased, while the scores of patients with secondary erythrocytosis are generally normal.
3. Platelet and coagulation function: platelet count is mostly higher than normal, mostly in (400 ~ 800) × 109 / L, visible volume increase, abnormal platelets and megakaryocyte fragments, platelet life is slightly shortened, its adhesion, aggregation and release The function was reduced, and the bleeding time, prothrombin time, partial thromboplastin time and fibrinogen content were generally normal.
4. Blood volume and blood viscosity : The plasma volume is generally normal or slightly reduced, the total blood volume is increased and the red blood cell capacity is increased, and the blood viscosity is increased, which is 5 to 8 times higher than that of normal people.
5. Bone marrow
(1) The smear showed almost high cell proliferation, decreased fat particles, red, granules, and megakaryocysts, all of which were most prominent in the erythroid system. The number of megakaryocytes increased not only in number but also in morphology.
(2) Iron staining showed that the iron inside and outside the cells decreased or even disappeared, which was speculated to be associated with chronic occult bleeding or increased iron utilization and reduced iron storage.
(3) In the advanced stage of the disease, it may be "dry pumping" due to the proliferation of myelofibrosis. Bone marrow biopsy is more helpful than smear to determine the complications of myelofibrosis. Using reticular fiber staining, 10% can be confirmed. ~20% of patients have an increase in fibrous tissue.
6. Chromosome examination : chromosomal abnormalities in untreated patients are 18% to 26%, most commonly aneuploidy, pseudodiploid and polyploid, chromosomal abnormalities are mostly +8, +9 and 20q-, prolonged with the disease course The incidence of chromosomal abnormalities will gradually increase. Patients with more than 10 years of disease and 87% of abnormal chromosomes. When PV was first diagnosed, patients with abnormal chromosome clones have been found to have shorter survival time than those with normal chromosomes.
7. Erythroblast progenitor cell culture : erythroid progenitor cells of PV patients can form CFU-E without endogenous CFU-E on semi-solid medium, such as the characteristics of erythroid progenitor cells in PV patients. As the basis for the diagnosis of early atypical cases.
8. Determination of erythrocyte growth factor: The use of radioimmunoassay to determine the reduction or absence of erythropoietin in plasma and urine of patients is significantly different from most secondary polycythemia.
9. Others : Most patients with PV have arterial oxygen saturation in the normal range of arterial oxygen saturation >92%, which is helpful to exclude secondary polycythemia caused by cardiopulmonary disease, plasma vitamin B12 binding capacity and vitamin B12. The increase in the former is more obvious, which is related to the release of type I and III cobalamin released by leukocytes and immature granulocytes. Both of these proteins can bind to vitamin B12. The above two measurements are helpful to the disease and secondary. Polycythemia differentiation, and can be used as an indicator of efficacy and disease activity, 40% of patients diagnosed with hyperuricemia and hyperuricemia, 60% of untreated patients with elevated histamine in hematuria, and blood basophils Increased cells.
10. Bone marrow biopsy: manifested as myelofibrosis.
11.B ultrasound: showing liver splenomegaly, kidney stones, gallstones.
12. Others: Select ECG, gastrointestinal endoscopy, X-ray, CT, MRI, etc. according to the condition.
Diagnosis
Diagnosis and diagnosis of polycythemia vera
Diagnosis can be based on medical history, clinical symptoms, and laboratory tests.
Diagnostic criteria
The most important basis for diagnosing PV is erythrocytosis, increased white blood cells, thrombocytosis and splenomegaly. Most patients have only two or three of the above characteristics at the time of presentation. Some patients even have only red blood cells, and occasionally only thrombocytosis or Leukocytosis or splenomegaly, so sometimes PV diagnosis is difficult to establish. In 1975, the PV Study Group (PVSC) proposed a "diagnostic standard, but the diagnostic criteria have been proposed for more than 20 years. Here, some new understanding of some of these contents has been made. Therefore, there are always authors to supplement and revise them.
According to the characteristics of skin changes, the red blood cells of blood cytology are absolutely increased, the hematocrit is 55%-80%, and the white blood cells and platelets are also increased. It can be diagnosed. The standard established by the International PV Research Group (PVSG) in 1986 is simple and easy. For clinical reference and reference, in addition, the country has established corresponding standards according to specific conditions.
1.PVSG standard
(1) Class A standards:
1 increased red blood cell volume (51Cr red blood cell labeling method): male 36ml / kg, female 32ml / kg, 2 arterial oxygen saturation 0.92.
3 splenomegaly.
(2) Class B standards:
1 platelet count > 400 × 109 / L.
2 White blood cell count > 12 × 109 / L (no fever, infection status).
3 Neutrophil alkaline phosphatase score increased (> 100, no fever, infection status).
4 serum vitamin B12 increased > 666pmol / L or unsaturated vitamin B12 increased adhesion > 1628pmol / L.
Any one of the above-mentioned Class A 1+2+3, or Class A 1+2 plus Class B can be diagnosed.
2. Domestic standards According to China's specific conditions, domestic PV diagnostic standards are formulated:
(1) Clinical manifestations:
1 skin, mucous membranes are red.
2 spleen.
3 There is a history of blood pressure in hypertension or in the course of the disease.
(2) Laboratory inspection:
1 Hemoglobin and red blood cell count increased (male hemoglobin > 180g / L, red blood cells > 6.5 × 1012 / L, women > 170g / L and 6.0 × 1012 / L, respectively).
2 The absolute value of blood cell volume increased, the red blood cell capacity of 51Cr labeling method was >39ml/kg for males and >27ml/kg for females.
3 hematocrit increased, male 0.54, female 0.50.
4 no infection and other reasons caused white blood cell count multiple times >11.0 × 109 / L.
5 platelet count multiple times > 300 × 109 / L.
6 Peripheral blood neutrophil alkaline phosphatase (NAP) score >100.
7 Bone marrow showed that the hyperplasia was obviously active or active, and the granulosa, red and megakaryocyte cell lines all proliferated, especially in erythroid cells.
(3) can exclude secondary polycythemia.
(4) can exclude relative polycythemia.
There are two methods for diagnosing polycythemia vera. It is best to use the A method. If the red blood cell capacity is unconditionally measured, the B method is used.
Method A: It can be diagnosed by having any two of the above categories (1), adding the first and second items of (2), plus (3).
Method B: It has the first item in category (1) plus item (2) (the standard is changed to male multiple hemoglobin 200g/L, female 190g/L), and it still needs to have (2) Any of the 4th to 7th items, plus (3), (4), can diagnose the disease.
Differential diagnosis
Should be associated with high altitude polycythemia, severe cardiopulmonary disease, abnormal hemoglobin disease, certain tumors (adrenal adenoma, liver cancer, kidney cancer, etc.), cysts and vascular abnormalities caused by secondary polycythemia.
1. Secondary and relative polycythemia: Secondary erythrocytosis is common in the following two types of conditions: First, tissue hypoxia or renal ischemia and hypoxia caused by increased EPO secretion, resulting in increased red blood cell compensatory, Seen in mountain sickness, right-to-left shunt congenital heart disease, chronic lung disease, methemoglobinemia, carboxyhemoglobinemia caused by smoking, etc., the patient's oxygen saturation is mostly reduced, the other is kidney tumor And other endocrine tumors caused by autologous secretion of erythropoietin or erythropoietin-like substances caused by polycythemia, found in nephroblastoma, liver cancer, cerebellar tumor, metacephaloma, kidney cancer, uterine tumor, etc., relative polycythemia It is due to the decrease of plasma volume and the relative increase of red blood cell capacity. The peripheral blood red blood cells, hemoglobin and hematocrit increase, but the whole body blood cell volume is normal, which is common in dehydration, burns and other temporary fluid loss and smoking, drinking, anxiety and Chronic relative erythrocytosis (Gaisbock syndrome) caused by hypertension, the specific identification is shown in Table 1.
2. Chronic myeloid leukemia (CML): PV patients often have splenomegaly and granulocytes, and advanced peripheral blood immature granulocytes can be increased, so it needs to be differentiated from CML. The neutrophil alkaline phosphatase score in PV patients is increased. High, Ph1 chromosome and bcr/abl mRNA are negative, while slow granules are just the opposite. Recently, it has been found that chronic granule patients can also spontaneously form CFU-E, so endogenous CFU-E cannot be used to identify PV and slow granules.
3. Myelofibrosis: The clinical manifestations of PV have many similarities with myelofibrosis. The advanced stage of PV can also be followed by myelofibrosis. The main identification is the history and bone marrow biopsy. The bone marrow fibrosis bone marrow pathology shows a significant increase in fibrous tissue. The main manifestation of PV is extramedullary hematopoiesis, and only the late stage is combined with myelofibrosis, and the extent of the lesion is small and to a lesser extent.
