Introduction to polycythemia vera

Introduction:

Polycythemia vera(referred to as true red) is a kind of chronic myeloproliferative disease with erythrocytosis mainly accompanied by white blood cells and thrombocytosis. The total blood volume is absolutely increased, the blood is thick, and the clinical manifestations are red, purple, dizziness, dizziness and headache. High blood pressure, hepatosplenomegaly, severe blood vessels, bleeding complications, infarction, etc.

Cause:

1.PV is a pluripotent stem cell disease. According to stem cell proliferation and differentiation theory, stem cell abnormalities can directly lead to abnormalities of various hematopoietic cells. Since PV manifests as a whole blood cell in peripheral blood and three lines of cell proliferation in bone marrow histology, it is speculated that PV is a stem cell disease in the 1950s. In 1976, Adamson et al. performed a glucose-6-phosphate dehydrogenase (G-6-PD) isozyme analysis on two women with PV, and found that their skin fibroblasts and lymphocytes contain two types of G-6- PD isoenzyme (GdA/GdB), while peripheral red blood cells, granulocytes, and platelets all contain the same type A G-6-PD (GdA). This suggests that they are derived from stem cells of type A isozyme, thus confirming that PV is an inference of stem cell disease. Using molecular biology techniques such as Southem hybridization and PCR, X-linked gene polymorphism and inactivation pattern analysis confirmed the above conclusions and found that about 80% of female PV patients had peripheral blood neutrophils as monoclonal. T lymphocytes are polyclonal.

2. Cellular and molecular level defects of PV In semi-solid medium, bone marrow cells cultured in PV patients can form spontaneous CFU-E and BFU-E colonies, while normal and secondary hyperplasia patients are none or very There are few spontaneous colonies. Unlike secondary polycythemia, the plasma and urine erythropoietin (EPO) levels in PV patients do not increase, so it is speculated that EPO may be abnormal with EMO signaling, perhaps EPO receptors (EPO-R). It is related to its abnormality, but studies on the structure of EPOY-R in PV patients indicate that there is no abnormal structure of EPO-R gene in PV patients. Recent studies have found that PV-derived progenitor cells are highly sensitive to EPO, insulin-like growth factor 1 (1GF-1), resulting in an uncontrolled production of erythroid cells. As PV patients progress, the increasing number of fibroblasts in the bone marrow is the result of reactive proliferation of platelet-derived growth factor (PDGF) released by megakaryocytes. Pv itself does not involve fibroblasts.

3. A large series of PV cytogenetic studies have shown that about 40% of patients have karyotypic abnormalities. Del(20)(q11), +8 and +9 are common abnormalities at the time of initial diagnosis. These abnormalities can be seen in the course of PV. It has little impact on clinical performance and disease duration and may be related to the disease itself. The chromosomal abnormalities that are currently thought to be associated with PV are del(1)(P11), del(3)(P11;p14), t(1;6)(q11;p21) and t(1;9)(q19; Q14). Since del(20)(q11) is the most common chromosomal abnormality in PV, people are looking for a target gene for PV. A common deletion fragment has been identified and an artificial yeast chromosome spanning this fragment has been constructed. This work is being further studied. Among them.

Familial PV found in Jews of European descent suggests that there may be genetic predispositions in PV. In addition, some people think that PV is caused by the Friend virus variant "erythrocyte proliferative virus" infection. Injecting mouse spleen filtrate containing this virus into normal mice can cause red blood cell volume increase and splenomegaly, but It has not been fully confirmed in humans.

(1) Causes of the disease

The cause of the disease is still unclear. In most patients, the plasma and urine EPO levels did not increase, but decreased significantly. Cell culture showed that the number, affinity and expression of EPO receptors in erythroid progenitor cells of PV patients were not different from those in normal subjects. No abnormality was found in the sequence analysis of EPO gene. The above results showed that there was no EPO receptor in the pathogenesis of the disease. . Modern studies have shown that PV is not an excessive proliferation of normal stem cells, but is caused by abnormal clonal proliferation of single cell origin.

(two) pathogenesis

The pathogenesis of increased proliferation of peripheral blood cells by significant proliferation of bone marrow erythroid cells may be related to the following factors.

1. Formation of "endogenous" red blood cell clones When stem cells are cultured in vitro, normal bone marrow cells form late erythroid progenitor colonies (CFU-E), and EPO is added to the culture medium, while bone marrow cells of PV patients do not add EPO. It can grow, suggesting that this patient's red blood cell clone that does not rely on EPO production has "tumor" properties. If the bone marrow culture of PV patients is also supplemented with EPO, in the formed CFU-E, there are both PV cells and normal red blood cells, indicating that in addition to PV cell clones, PV patients still have normal stem cells, but their proliferation is affected. Inhibition of PV cloning. It is currently believed that abnormal clones of PV originate from a single cell, continue to proliferate, have the advantage of inhibiting normal clones, and have cytogenetic instability. Clinically, cases of PV conversion to acute leukemia can be found.

2. 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. The number of early erythroid progenitor colonies (BFU-E) and CFU-E in PV patients are normal. The number of people increased significantly, and the growth of CFU-E was significantly higher than that of patients without EPO. When EPO antibodies were added to the culture, the number of CFU-E production in PV patients decreased. These results suggest that erythroid progenitor cells in PV patients have increased sensitivity to EPO, which is one of the causes of erythrocytosis.

3. Apoptosis of pluripotent stem cells is normal. Normal red blood cells contain isoforms of two kinds of glucose 6-phosphate dehydrogenase (G-6-PD) of type A and type B, while red, granulocytes and platelets of PV patients only contain A. Type I, fibroblasts and lymphocytes still contain A and B type G-6-PD isoenzymes, indicating that the disease is a single clonal disease originating from the same pluripotent stem cell level.

4. Apoptosis abnormalities It has been 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. Cell culture showed that PV patients and normal controls developed apoptosis in the absence of cytokine culture conditions, but PV patients had less apoptosis than normal controls, and this difference may be related to high expression of bcl-2 in PV patients.

5. Other experiments suggest that there may be a glycoprotein in the serum of PV patients, which can stimulate the formation of red blood cells and stimulate the granulocytes and platelets, called bone marrow stimulating factor. The antigenicity of this factor is different from that of EPO, but requires a small amount of EPO to participate. Its nature needs further study.

symptom:

The onset of the disease is insidious, often in the asymptomatic period of several months to several years, often found during blood tests. In some cases, the diagnosis is confirmed after thrombosis and bleeding symptoms. Many symptoms and signs are associated with increased blood volume and blood viscosity. The earliest symptoms are often related to blood circulation disorders and nervous system symptoms. The main clinical manifestations are as follows.

1. Skin changes are characteristic. It is characterized by reddening of the skin, especially on the face, neck and extremities. The mucosa is congested and is light blue. Osler described the symptoms as "summer as rose red, winter as indigo blue". Common telangiectasia, bleeding gums and nasal discharge. See also skin blemishes, cyanosis, sputum, hemosiderin deposition, rosacea and spoon-shaped nails. 50% of patients have watery itching. It can cause itching, burning or itching by shower or shower. Usually lasts for 30 to 60 minutes, regardless of water temperature. Itching can also occur irrespective of water. Histamine is elevated in the blood and in the skin.

2. 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 and so on. In severe cases, visual abnormalities such as blind spots, diplopia, and blurred vision may occur. There may also be angina and intermittent claudication. A small number of patients presented with a cerebrovascular accident as the first manifestation. This group of symptoms is mainly caused by increased erythrocyte count, increased blood volume and increased blood viscosity, vasodilation, slow blood stasis and tissue hypoxia.

3. The incidence of bleeding <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. Common are nosebleeds, bleeding gums and stagnant spots and ecchymoses on the skin mucosa. It can also show gastrointestinal bleeding, bleeding after tooth extraction, and more menstrual flow.

4. The manifestation of elevated histamine The disease is accompanied by an increase in granulosa cells and an increase in basophils, which are rich in histamine. Increased histamine release can cause peptic ulcer, so the incidence of peptic ulcer in this disease patients is 10% to 16%, 4 to 5 times higher than normal people. Upper gastrointestinal bleeding caused by ulcers is more common and can be life-threatening. Itching is also common, with 40% occurring after a hot bath and 10% with urticaria.

5. Other causes of excessive proliferation of bone marrow cells, nucleic acid metabolism is too high, blood uric acid concentration is elevated, a small number of patients may develop uric acid nephropathy, manifested as urinary stones and renal colic or gouty arthritis symptoms. Some patients may have gallstones, obstructive jaundice and biliary colic. The most common signs are congestion of the face, nose, ears, lips, palms, and conjunctiva caused by multiple blood, which are crimson, such as drunkenness. The retina and oral mucosa also showed hyperemia. About 70% of patients have elevated arterial blood pressure. About 75% of patients may have splenomegaly, usually moderate to severe swelling, and have certain differential diagnosis significance with secondary polycythemia. About 40% of patients may have large liver, and with the development of the disease, the swelling is gradually obvious.

【Diagnostic criteria】

The most important basis for diagnosing PV is erythrocytosis, leukopenia, thrombocytosis and splenomegaly. Most patients have only two or three of the above characteristics at the time of presentation. Some patients even have only erythrocytes, and occasionally only thrombocytosis or Leukocytosis or splenomegaly is sometimes difficult to establish for PV diagnosis. In 1975, the PV Research Group (PVSC) proposed the “diagnostic criteria, but the diagnostic criteria have been proposed for more than 20 years. Some of these contents have some new understandings, so the authors continue to supplement and revise them.

Since PV is still a diagnostic diagnosis to date, it can be diagnosed only after the exclusion of secondary polycythemia and apparent polycythemia. The differential diagnosis points are shown in the table below. Laboratory tests can be performed in two phases: the first phase includes complete blood count, urine routine, serum ferritin, VitB12, and folate levels, inosine, liver function tests, blood image analysis, COHb, abdominal ultrasound, and exclusion After the common secondary polycythemia, the second stage examination, including bone marrow biopsy, karyotype analysis, serum EPO level determination, oxygenation curve, lung function test, chest X-ray, electrocardiogram, etc., for further identification and diagnosis.

Indicator PV secondary polycythemia relative erythrocytosis

Splenomegaly

Whether there is leukocytosis

Whether there is thrombocytosis

Whether the first wave abnormality of platelet induced by adrenaline

Increased red blood cell volume and normal

Arterial oxygen saturation is normal, normal and normal

Serum vitamin B12 increased normal and normal

Neutrophil alkaline phosphatase increased normal and normal

Bone marrow whole marrow hyperplasia erythrocytosis hyperplasia normal

EPO level decreases and increases normal

Spontaneous CFU-E growth with or without

According to the characteristics of skin changes, the red blood cells of blood cytology are absolutely increased, and the hematocrit is 55% to 80%. White blood cells and platelets also increased. You can diagnose. The standards developed by the International PV Research Group (PVSG) in 1986 are simple and easy to use for clinical reference and reference. In addition, the country has also established corresponding standards according to specific conditions.

1.PVSG standard

(1) Class A criteria: 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 criteria: 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, mucosa reddish; 2 splenomegaly; 3 hypertension or a history of thrombosis 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 shows hyperplasia is active or active, and the granulocyte, red and megakaryocyte cell lines are 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 the first and second items of (1) plus (2) (the standard is changed to male multiple hemoglobin ≥200g/L, female ≥190g/L), and still needs to have the second (2) Any of the 3rd to 7th items, plus (3) and (4), can be diagnosed.

diagnosis:

Should be differentiated from 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, leading to increased red blood cell compensatory, can be seen in Alpine disease, right-to-left shunt congenital heart disease, chronic lung disease, methemoglobinemia, and carboxyhemoglobin hyperactivity caused by smoking, etc., the patient's oxygen saturation is mostly reduced. The other is erythrocytosis caused by renal erythropoietin or erythropoietin-like substance in kidney tumors and other endocrine tumors. It is found in nephroblastoma, liver cancer, cerebellar tumor, diencephalonoma, kidney cancer, uterine tumor, etc. . Relative polycythemia is caused by a decrease in plasma volume and a relative increase in red blood cell capacity. Peripheral blood red blood cells, hemoglobin and hematocrit increase, but the systemic blood cell volume is normal, common in temporary fluid loss such as dehydration, burns and chronic relative erythrocytosis caused by smoking, drinking, anxiety and hypertension (Gaisbock syndrome) . The specific identification is shown in Table 1.

2. Chronic myeloid leukemia (CML) PV patients often have splenomegaly and granulocyte elevation, and the peripheral blood may increase the number of immature granulocytes in the peripheral blood, so it needs to be differentiated from CML. In patients with PV, neutrophil alkaline phosphatase scores increased, Ph1 chromosome and bcr/abl mRNA were negative, while slow granules were just the opposite. Recent studies have found that patients with chronic granules can also spontaneously form CFU-E, so endogenous CFU-E cannot be used to identify PV and slow granules.

3.MyelofibrosisThe 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, while PV is mainly characterized by extramedullary Hematopoietic phenomenon, only the late stage combined with myelofibrosis, and the extent of the lesion is small, to a lesser extent.

complication:

1. The incidence of vascular complications is 20% to 80%. The Italian PV team reported that 1213 patients with PV had a thrombosis rate of 40% before or during follow-up. Mainly due to high blood volume and hyperviscosity caused by venous thrombosis and thrombophlebitis. 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 the mesentery, liver, spleen and portal vein can also occur, which can cause acute abdomen. Hematocrit is significantly elevated, with elevated platelets and white blood cell counts, increased age and previous history of thrombosis and repeated venous bleeding are risk factors for thrombosis.

2. MDS as a complication of PV has drawn increasing attention, those:

1 standard treatment after rapid splenomegaly

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.

treatment:

【Conventional treatment】

PV is often maintained in the plethora of blood for several years and then enters the "depletion" period.

1, azoemia

The treatment of hemolytic phase is to reduce symptoms and reduce embolism and bleeding complications by reducing blood cells. In some patients, red blood cell count and hematocrit are controlled by periodic venous bleeding, and platelet and white blood cell counts are controlled by administration of myelosuppressive drugs. Most patients require both treatments. The advantages and disadvantages of common treatments for PV are shown in the following table:

Advantages and disadvantages of different PV treatment methods

Treatment method advantages and disadvantages

Intravenous bleeding is simple; low risk can not control thrombocytosis and leukocytosis

HydroxyureaControls leukocytosis and thrombocytosis, leading to a low risk of leukemia requiring maintenance therapy

Mailyline is simple to administer; long-term remission can cause long-term bone marrow suppression; may cause leukemia; have long-term toxicity of lung and skin

32P can make thrombocytosis and leukocytosis long-term control expensive, relatively inconvenient to administer; moderate risk of leukemia

Tumor can be taken conveniently; can increase thrombocytosis and leukocytosis to obtain a good control of high risk of leukemia

(1) venous bleeding Generally speaking, venous bleeding from 450 to 500 ml at intervals of 2 to 4 days can reduce the hematocrit (HCT) to normal or near normal. Patients with HCT greater than 64% should have a shorter bleeding interval. Patients with less than 50 kg should have a reduced amount of blood transfusion each time, and a small number of times should be used for bleeding in patients with cardiovascular disease. Venous bleeding can improve symptoms such as headaches, but it does not reduce the number of platelets and white blood cells, and it is also ineffective for skin itching and gout. This method can be used for patients younger than 50 years of age without a history of embolism.

(2) indications for treatment of myelosuppressive drugs with myelosuppressive drugs: 1 platelet count higher than 800X109-1000X109/L; 2 with embolization and bleeding complications; 3 venous bleeding treatment needs more than once a month; 4 severe skin Itching.

Commonly used drugs are:

1 hydroxyurea: need to maintain drug delivery, combined with venous bleeding can reduce embolization complications.

2 Marilyn: 2 to 4 mg per day. After several weeks, the white blood cell count can be reduced to normal. After stopping the drug, the blood cell count remains normal for several months to several years. In a large series of studies, the first remission period in the patients treated with malilan is shown. For 4 years. Because excessive administration can cause severe bone marrow suppression, the daily dose should not exceed 4 mg.

332P: After intravenous administration of 32P2 ~ 4mCi, the disease can be well controlled. After 6 to 8 weeks, the effect can be given again according to the first dose. The biggest side effect of 32P treatment is high-risk treatment-related white blood cells/Myelodysplastic syndromeAnd tumor, 32P treatment patients 10 years of leukemia / myelodysplastic syndrome risk rate of 10%, the incidence of tumor risk is 15%, the risk of leukemia / MDs at 20 noon can be increased to 30%.

4 Interferon: Recent studies have shown that IFN is an effective drug for the treatment of PV. After 6 to 12 months of treatment, the red blood cell volume of 70% of patients can be controlled, about 20% of patients get partial remission, and 10% are ineffective. The dose was 9×106 to 25×10 6 U/week, and it was subcutaneously injected in 3 times. In addition, platelet count, itchy skin and splenomegaly were significantly improved.

5 dibromopropazone: mainly used in patients with PV with persistent thrombocytopenia and thrombocytopenia, the effective rate is about 70%, the initial dose is 0.5 ~ lmg, PO, 4 times / day, the maintenance amount is 2.5mg /d, the onset time is 17 to 25 days. Because the drug can pass through the placenta, pregnant women are banned, and the drug is ineffective in controlling erythrocytosis and PV-related systemic symptoms.

6 other:HomoharringtonineChinese medicine, such as hyperthyroidism, blood stasis and phlegm, are also effective for some patients.

(3) symptomatic treatment of skin itching venous bleeding / myelosuppressive drugs are often ineffective, because bathing can make it worse, therefore, can advise patients to reduce the number of bathing, psoralen and ultraviolet radiation can relieve skin itching, aspirin and Sepyridine is also effective, but antihistamines are ineffective. Since embolization is the leading cause of death in PV patients, oral prevention with aspirin and dipyridamole can be given.

(4) Choice of treatment plan Because of the high risk of leukemia caused by treatment with Malilan and 32P, venous exsanguination + low-dose aspirin (40mg/d) should be used first, but there is a history of hemorrhage or significant increase of platelets (≥1000X109/L) and acquired. VWD is banned, maintaining HCT below 45%; if the patient has embolism or bleeding, systemic symptoms, refractory severe itchy skin, painful splenomegaly, use rh-IFN-a, 3 million U, 3 per week When the patient's HCT control is not ideal or can not tolerate interferon, start treatment with hydroxyurea, 30mg / kg, orally, changed to 5 ~ 20nw / kg after 1 week, if the HCT is still greater than 47%, then assisted by venous bleeding If the HCT is still unsatisfactory, switch to Malilan, 4-6mg/d, for 4-8 weeks, until the platelet is lower than 300×109/L or the blood cell count is normal, then the drug can be repeated again after the patient relapses. The program; patients treated with Malilan, if there is persistent thrombocytopenia and repeated thrombosis, spleen pain, you can use 32P, and finally choose splenectomy + continuous systemic treatment.

2, the end of the period

In this period, patients may have anemia, significant bone marrow fibrosis and significant splenomegaly, platelet count may increase, normal or decrease, white blood cell count may be significantly increased with the appearance of immature granulocytes in peripheral blood. Because of the ineffectiveness of spleen irradiation, the use of Malilan, hydroxyurine chemotherapy can significantly reduce platelet count, so periodic blood transfusion therapy has become the only treatment.

[prognosis]

PV is a chronic disease that usually lasts 10 to 20 years after diagnosis.

The PVSG study found a median survival of 13.9 years for patients with venous bleeding alone, 11.8 years for 32P patients, and 8.9 years for patients treated with tumors. About 31% of patients died of embolism, 19% died of leukemia, 15% died of other tumors, and 5% died of bleeding or end stage.

(a) treatment

It is the goal of treating PV to inhibit abnormal proliferation of bone marrow erythroid cells, reduce blood volume, reduce blood viscosity, eliminate various symptoms and signs caused by erythrocytosis, reduce thromboembolism and hemorrhagic complications, improve quality of life and prolong survival.

1. Intravenous bloodletting, venous bleeding 2 to 3 times a week, 400ml each time, until HCT is normal. This treatment often relieves symptoms quickly and reduces red blood cell volume, but does not reduce elevated white blood cells and platelets and does not alleviate stubborn skin itching andgoutattack. Those with heart, cerebrovascular disease or history of thrombosis should be careful in bloodletting, 250ml per time, up to 2 times a week, and the target is to maintain 42% to 45% of HCT. In order to prevent thrombosis, intravenous infusion after bloodlettingDextran 40(Low molecular dextran) 500ml. Repeated bloodletting can cause iron deficiency, which needs to be supplemented appropriately.

Due to traditional habits in China, bloodletting therapy has always been difficult to carry out extensively, especially when bleeding is required every week. Therefore, doing a good job of publicity and interpretation is an important part of bloodletting therapy. In particular, it should be emphasized that the proportion of leukemia conversion (only 1.5%) and secondary solid tumors is the lowest, and the adverse reactions are the least, and the median survival time is similar to other therapies, which is 12.6 years. However, the incidence of thromboembolic complications in the first 3 years of bloodletting alone was higher, and there were more patients with myelofibrosis. It must be emphasized that even if the bloodletting treatment alone, the leukemia conversion is lower than other treatments, but it is still significantly higher than the matched normal population. The current consensus is that young patients with stable disease are more suitable for bloodletting and supplemented with low-dose aspirin.

2. Myelosuppressive therapy

(1) Radionuclide therapy: 32P is most used, which inhibits hematopoiesis by releasing beta-rays to prevent nuclear division of bone marrow hematopoietic cells. After the first dose of intravenous injection of 2 ~ 3mci / m2, in most cases, the blood picture returned to normal within 4 to 8 weeks. If the blood picture fails to be corrected after 3 months, the second dose can be administered, and the dose should be increased by 25%. A small number of patients need to be administered for the third time, but the total dose should not be >15 mci within 1 year. 32P can also be administered orally, but the dose should be increased by 25%, divided into 2 times, at intervals of 1 week. The remission rate of 32P treatment can reach 75%-85%, and the curative effect can last for six months to several years, and the incidence of thromboembolic complications can be reduced. The disadvantage is that if the dose is not properly controlled, too much can cause bone marrow suppression. Secondly, the incidence of acute leukemia and solid tumor after treatment was significantly higher than that of venous bloodletting, especially the incidence of long-term acute leukemia was as high as 10.3%. If 32P is used in combination with chemotherapy, the incidence of acute leukemia is higher. In view of the above reasons, 32P is currently mainly used for elderly patients. The median survival of the 32P treatment was 10.9 years.

(2) Chemical treatment:

Hydroxyurea (HU): HU is most commonly used in Europe and America. The dose is 1.5~2g/d. The blood level can reach the normal range within a few weeks, and then it is maintained at 0.5~1.0g/d. The efficacy of HU is short-lived, and it often rebounds quickly after stopping the drug, so it is necessary to continue medication. Once myelosuppression occurs, it can be recovered from days to weeks after stopping the drug. Long-term HU treatment, 5.4% of acute leukemia, although still higher than venous bloodletting, but the safety is relatively good. The incidence of myelofibrosis and mortality in HU was similar to that of venous bleeding, while thromboembolic complications were significantly reduced, only 6%.

2 alkylating agent:Busulfan(Busulfan, myeleukon) is the most widely used in China, with a dose of 4-6 mg/d. It usually takes about one month to control the blood, but the duration of action is significantly longer than HU, so it can be administered intermittently. In some cases, the blood is still basically normal for several months and even years after the drug is stopped. The median remission period can reach 4 years. Intermittent medication can reduce the incidence of long-term acute leukemia, only reported 2%. Another alkylating agent, Chlorambucil (CBl348), was weaker and slower than the white amphibious, with a median survival of 9.1 years. The conversion of acute leukemia is 17%, and another 3.5% of patients have large cell lymphoma, so it has been used less.

3 cephalosporin: It is the first anti-leukemia drug in China, and it is effective for acute and chronic myeloid leukemia. It was found to have good curative effect after being applied to PV in the 1980s. These drugs include cephalosporin and homoharringtonine at a dose of 2 mg/d, either intravenously or intramuscularly, for a course of treatment from 10 to 14 days. Generally, the blood picture drops to normal after 1 to 2 months after stopping the drug, and the curative effect is mostly maintained for 3 to 6 months, and a few can be maintained for more than 1 year. Re-medication after relapse is usually still effective. According to the above dosage and course of treatment, the vast majority of patients do not have myelosuppression, and cardiac toxicity is also rare. Whether the long-term will promote the conversion to leukemia, there is no definitive information. Another report, using an intravenous infusion of 2 to 4 mg per day, continuous or intermittent use of red blood cells and hemoglobin normal, can prolong the remission period of more than 10 months, but some patients may be associated with white blood cells and / or thrombocytopenia.

3. Itching is difficult to treat with this disease. An antihistamine such as cyproheptadine hydrochloride may be used alone or in combination with cimetidine. Others such as aspirin and PUVA can also be applied.

4. Other treatments In recent years, it has been reported that the use of recombinant interferon alpha (IFN-α) for the treatment of PV has achieved certain effects. It inhibits the proliferation of abnormally cloned hematopoietic progenitor cells and bone marrow fibroblasts, antagonizes platelet-derived growth factor (PDGF) and metastatic growth factor (TGF-β) to reduce myelofibrosis. Because IFNα has a slow onset of action, it is advisable to apply other treatments and use it as a long-term maintenance treatment after the blood picture is significantly improved. The dose of IFNα is 3 million to 5 million U/time, 3 times a week, and the course of treatment is at least 6 to 12 months. The response rate of IFNα alone was 60%. Low dose reportedaspirin(50mg / d) can reduce the production of thromboxane A2 by more than 80%, so it is recommended for long-term application, especially for patients with separate venous bleeding to reduce thromboembolic complications. However, there have been reports of bleeding after application, and laboratory tests that reflect platelet function do not predict the risk of bleeding. Therefore, it is recommended to use a dose of 250mg/d or less, which has been banned in previous history of bleeding.

Various antihistamines have poor effects on refractory pruritus in patients with PV. It has been reported that IFNα has a certain effect, but it has a slower onset. Myelosuppressive therapy can only be relieved after controlling the blood picture. Late PV with myelofibrosis (some people call it PV failure), patients often have spleen, anemia, white blood cells, thrombocytopenia, treatment is very difficult. Radiotherapy in the spleen area has been confirmed to be ineffective, and splenectomy can achieve at least temporary relief. Due to the many complications of surgery, the mortality rate is as high as 25%. Care should be taken and adequately prepared before surgery. People with severe anemia often need regular blood transfusions and can also use androgen. Iron supplementation should be cautious when iron deficiency occurs, which can increase the short-term rapid increase of red blood cells and aggravate the condition.

Patients with PV have surgery for concurrent surgical diseases, including tooth extraction, and postoperative complications are as high as 47%, most of which are bleeding, or thrombotic complications, and the risk is high. Therefore, it is recommended that bloodletting and blood cell replacement should be performed before surgery, and the operation should be performed after the blood picture is obviously improved.

(two) prognosis

Most of PV is slow to develop, and the median life expectancy of untreated patients is 1.5 years, but after various treatments, the median survival period can reach 10 to 15 years.

PV can undergo various transformations during the course of the disease. In the Peking Union Medical College Hospital, 90 patients with PV disease were followed up for more than 3 years. In the course of the disease, 10 patients were transformed into other myeloproliferative diseases and/or acute leukemia with a conversion rate of 16.7%. Some cases can have multiple transformations, such as first to thrombocytopenia (the number of red blood cells and capacity are normal), then converted to myelofibrosis, and eventually converted to acute leukemia. In addition, individual cases can be converted to chronic lymphocytic leukemia. More authors in the literature suggest that after PV is converted to myelofibrosis, 20% to 50% will progress to acute leukemia, the vast majority of which are acute myeloid leukemia. PV can be directly converted into acute leukemia, and can also be converted to acute leukemia through the myelodysplastic syndrome (MDS) stage, both of which account for 50%. Once converted to acute leukemia, various treatments are poorly effective and usually die within a few months.

The first cause of death of PV is thromboembolic complications, accounting for 30% to 40%, of which myocardial infarction accounts for 50%, stroke accounts for 31.5%, and venous thrombosis accounts for 18.5%. Others were acute leukemia (19%), solid tumors (5%), and bleeding (5%). The remaining cases died of advanced bone marrow failure (including myelofibrosis), most of which were due to neutropenia, death from infection, thrombocytopenia, and visceral bleeding.

prevention:

The disease belongs to myeloproliferative diseases, and there are no clear preventive measures at present.