Primary Thrombocytosis (PT) is also known as Essential Thrombocytosis (ET) or Hemorrhagic Thrombocytosis (HTH). It is a clonal pluripotent stem cell disorder and a type of myeloproliferative disease. It is characterized by an excessive proliferation of bone marrow megakaryocytes and a marked increase in the number and quality of platelets in the peripheral blood. The main clinical manifestations are spontaneous bleeding tendencies and/or thrombosis; splenomegaly may be present in about half of the patients. Primary thrombocythemia was first reported by Di Guglielmo in 1920. The incidence of this disease is low, and it used to be considered one of the least common of all myeloproliferative disorders. However, recent studies have found that this disease is not rare and is even more common than true erythropoietic disease. The standardized incidence of PT in all populations reported by the European Standard Population Statistics (ESP) and World Standard Population Statistics (WSP) in 1999-2000 was 1.65/100,000 and 1.13/100,000, respectively. The incidence in China is unknown, and only 22 cases of this disease were treated in Peking Union Medical College Hospital from 1938 to 1995. The disease can develop in a wide range of ages, from 2 to 90 years old, with an average age of 60 years and a predilection for patients between 50 and 70 years old. According to a group of data from the southeastern region of England, the age of onset of the disease ranged from 21 to 99 years, with a mean age of 73 years and 31% of those younger than 65 years. The incidence in each age group was 0.07/100,000 in the 16-24 years group, 0.37/100,000 in the 25-34 years group, 1.26/100,000 in the 35-44 years group, 1.3/100,000 in the 45-54 years group, 2.52/100,000 in the 55-64 years group, 6.51/100,000 in the 65-74 years group, 12.82/100,000 in the 75-84 years group, and 11.82/100,000 in the 85 years and older group. million, and 11.1/100,000 in the group aged 85 years or older. Primary thrombocythemia shows a predominantly female onset of myeloproliferative disorders, with a male:female ratio of approximately 0.76:1. Section 2 Etiology and pathogenesis I. Etiology and pathogenesis 1. The study of G6PD isoenzymes revealed that erythrocytes, neutrophils and platelets of patients with primary thrombocythemia have only one isoenzyme, while non-hematopoietic cells such as fibroblasts have two types of G6PD isoenzymes, type A and type B, in a heterogeneous pattern. Thus, the disease is considered to be a clonal disease of pluripotent stem cells. In addition, the disease is closely related to other myeloproliferative disorders and can co-exist and transform with each other, suggesting that the lesion occurs at the pluripotent stem cell level. Due to the abnormality of pluripotent stem cells, which leads to the continuous proliferation of megakaryocytes in the bone marrow, the platelet yield can be on average 6 times higher than normal. This, together with the release of excessive platelets from the spleen and liver storage fraction into the peripheral blood, and the fact that the platelet lifespan of patients with this disease is mostly in the normal range, leads to a significantly higher platelet count. ②. Molecular studies on tyrosine kinases: Recent studies have shown that JAK2, as a kinase system with tyrosine kinase activity, has a very important role in the pathogenesis of myeloproliferative disorders. When JAK2V617F mutation occurs, JAK2V617F acts as a constitutive tyrosine kinase and activates the JAK-STAT signaling system, leading to abnormal proliferation of myeloid cells, especially when JAK2V617F is co-expressed with erythropoietin receptor (EPOR), thrombopoietin receptor (MPL) or granulocyte colony-stimulating factor receptor (G-CSFR The incidence of JAK2V617F mutations in patients with primary thrombocythemia ranges from 23% to 72%, with an average of about 50%. The presence of this mutated gene can be detected by using different methods, such as conventional DNA sequencing, pyrophosphate sequencing, dissociation curve analysis, allele-specific PCR methods and BasXI restriction digestion analysis, etc. Good results can be obtained to varying degrees, with quantitative PCR methods being preferred. 2, the study of the mechanism of bleeding: the incidence of bleeding in this disease is about 3.6%~37%, most bleeding events are mild, and the mechanism of its occurrence is unknown. Possible causes are ① platelet function defects, platelet adhesion and aggregation function is reduced, release function is abnormal, platelet adrenergic receptors and prostaglandin D2 are lost, the number of Fc receptors is increased, total platelet glycoprotein (CD36) content and surface expression are increased, thromboxane A2 production is increased, the effectiveness of platelet factor III is decreased, and 5-hydroxytryptamine is reduced. (ii) Abnormal coagulation mechanisms, with bleeding symptoms relatively common in platelet counts >1,000 to 1,500X109/L or more, may be associated with acquired defects in von Willebrand factor (AvWS). In patients with MPD, AvWS manifests as a deletion of von Willebrand factor multimers, resulting in defective protein function and persistently elevated platelet counts. This phenomenon is also present in patients with reactive thrombocytosis, suggesting that the bleeding is caused by an absolute elevation of platelet values rather than by clonal platelet function abnormalities. Once the platelet count falls to normal, plasma levels of von Willebrand factor multimers are subsequently restored and the bleeding tendency improves. However, the exact mechanism of the association between high platelet counts and AvWS is still unclear. Depletion of coagulation factors also contributes to bleeding. (iii) Intravascular thrombosis, which causes infarction at the end of the vessel and bleeding from rupture of the infarcted area. ④Drug factors, in the course of antithrombotic, anticoagulation or antiplatelet therapy, may also trigger severe bleeding. 3. Research on the mechanism of thrombosis: the incidence of thrombosis in this disease is about 11%-25%, and the mechanism is unknown. Thrombotic events are more serious than bleeding events. Arterial thrombosis is more frequent than venous thrombosis, and thrombosis can involve large arteries. Abdominal thrombotic events, erythematous limb pain, and transient neurological events can occur. Possible mechanisms include (1) the role of procoagulant circulating factors, such as the production of unstable factor-thromboxane by activated platelets, which causes a strong aggregation and release reaction of platelets, forming microvascular embolism and further development of thrombosis. (ii) Role of platelets: Histological studies of erythromelalgia have revealed the presence of platelet-dominated arterial microthrombi rich in vWF and small amounts of fibrin, and the high sensitivity of the disease to aspirin suggest an important role of platelets in thrombosis; however, controlling platelet counts alone is not sufficient to prevent most thrombotic complications. (iii) Platelet receptors and platelet activation: The hemostatic response of platelets correlates with the number and quality of platelet surface receptors. A variety of platelet membrane proteins and receptor abnormalities exist in MPD, such as GPIIb/IIIa, GPIb, GPIV, GPVI, epinephrine receptors, and TPO receptor cMPL. It has been shown that platelet glycoprotein polymorphisms are associated with thrombosis; in addition, increased platelet activity, such as increased expression of P-selectin, platelet-reactive protein and activated fibrinogen receptor GPIIb/IIIa, is associated with thrombosis to varying degrees in patients with this disease; platelet activation features also include the formation of platelet particles associated with procoagulant activity; the precise mechanism of platelet activation is unclear and may be due to the presence of lipoxygenase deficiency in patients, increased efficiency of endoperoxide TXA2 production, or due to JAK2 activating mutations, the action of abnormal HCT, turbulence, or increased TPO levels. (iv) Platelet interaction with leukocytes and endothelial cells: measurement of neutrophils, endothelial damage (TM and vWF antigens), and levels of markers of thrombin activation (TAT complex, F1+2, and D-dimer) in patients with ET showed the presence of neutrophil activation, endothelial damage, and hypercoagulation in this disease compared to controls. increased levels of VEGF in patients with ET increased endothelial activation. Activated leukocytes promote blood clotting through the release of granule contents and aggregation with platelets. Those with microvascular thrombotic events have an increased percentage of platelet-leukocyte aggregation, which has a pathogenic role in triggering monocyte TF expression and endothelial activation and injury caused by superoxide anion and inflammatory cell release; this aggregation is also associated with the expression of activation indicators CD11b and CD62P. In addition, CD62P on platelets binds to P-selectin glycoprotein ligand-1 on neutrophils to form an adhesion chain and forms a more solid adhesion with the binding of CD11b to platelet GPIb or fibrinogen bound to platelet GPIIb/IIIa. ⑤ Role of erythrocyte pressure: HCT is the main indicator of whole blood viscosity in vitro, but in vivo hemodynamics and arterial oxygenation also have an impact on rheology. HCT can affect platelet activation and the opportunity for platelets to interact with leukocytes and the vessel wall, and its increase will cause a narrowing of the plasma/platelet area, further exacerbating the procoagulant effect. II. Pathological changes Microvascular thrombotic damage due to extreme platelet proliferation. The spleen is congested and may be extensively embolized, with splenic fibrosis and splenic atrophy in a few cases. Thrombosis can occur in different sites such as lower limb veins, splenic veins, mesenteric veins as well as kidney, lung and brain. With the formation of thrombus, necrosis and/or secondary atrophic lesions may develop at the corresponding sites. The disease may have extra-marrow infiltration and the proliferation of megakaryocyte lineage is not limited to the bone marrow, but may also involve extra-marrow tissues, mainly the liver and spleen. Due to the low malignancy and slow growth rate of the disease, the liver and spleen tend to be mildly or moderately enlarged. Section III Clinical manifestations Primary thrombocytosis occurs in patients aged 50 to 70 years, with an average age of onset of about 60 years, and can also occur in adolescents and infants. The course of the disease is generally slow and often asymptomatic at the onset, and its main clinical manifestations are bleeding and thrombosis. Many patients are occasionally diagnosed by the discovery of thrombocytosis or splenomegaly. About 80% of patients may have unexplained bleeding or thrombosis, of which bleeding is more common and may be spontaneous or abnormal due to trauma or surgery. Spontaneous bleeding is most common in the nose, gums, and gastrointestinal mucosa. Skin bleeding is mostly manifested as petechiae. Bleeding can also occur in the urinary tract, respiratory tract, and other areas, and occasionally cerebral hemorrhage can occur and cause death. The incidence of thrombosis is more commonly reported abroad and less frequently reported in China. In China, about 30% of patients may have venous or arterial thrombosis. Splenic vein, mesenteric vein and deep and superficial veins of lower extremities are good sites for thrombosis, which may cause corresponding clinical symptoms and signs. Vascular embolism of the lower extremities may cause numbness, pain, and even gangrene, and may also manifest as intermittent claudication, erythromelalgia, etc. Mesenteric thrombosis can cause acute abdomen, etc. Thrombosis of the lungs, kidneys, adrenal glands, and brain can be a cause of death. About 30% of patients present with functional or vasodilatory symptoms at the time of presentation, such as vascular headache, dizziness, blurred vision, burning sensation in the palms and soles of the feet, terminal numbness and cyanosis. Non-specific symptoms such as fatigue, weakness and insomnia may also be manifested. Approximately 40% of patients may have hepatomegaly and 80% may have mild or moderate enlargement of the spleen. Asymptomatic splenic infarction may also occur in about 20% of patients with this disease, resulting in splenic atrophy. Section IV Laboratory tests I. Peripheral blood picture 1. Platelet count is significantly elevated, mostly between 1000 and 2000X109/L, occasionally fluctuating between 800 and 1000X109/L, but also up to 3000X109/L or more, with a maximum of 14000X109/L reported. Platelet morphology is generally normal, but giant, small and aberrant platelets and platelets with increased granularity are also seen, often aggregated into piles, occasionally accompanied by megakaryocyte fragments or nuclei. Leukocyte count may be normal or increased, with 95% above 10X109/L, occasionally reaching 40-50X109/L, but generally not exceeding 50X109/L. Neutrophils predominate, with occasional naive granulocytes, and some patients may have increased eosinophils and basophils. Neutrophil alkaline phosphatase score is increased. The red blood cell count is generally normal. 10%-30% of patients have mildly increased red blood cells, which are multi-stained and of uneven size. Especially in splenic atrophy, red blood cell cytoplasm can appear in Howe’s glial vesicles and basophilic dot color. In case of long-term recurrent bleeding, small cell hypochromic anemia may appear. Bone marrow image Bone marrow aspiration may be blocked by the needle and the phenomenon of “dry aspiration” may occur. The bone marrow is actively or significantly proliferating, with significant proliferation of nucleated cells, mainly megakaryocytes. In normal cases, megakaryocytes account for 0.0058% of the nucleated cells, but in this disease, they can be 0.05% to 5.0%. Both primitive and naive megakaryocytes can be increased, and the increase in granular and plate-producing megakaryocytes is more obvious, with abundant cytoplasm and increased nuclear lobulation. There is a large number of platelets aggregated into piles. Eosinophilic and basophilic granulocytes may also be increased, but there is no leukemic infiltration. Bone marrow biopsies are sometimes associated with mild to moderate fibrous tissue hyperplasia. Bone marrow examination is not very helpful in identifying primary or secondary thrombocytosis, megakaryocyte aggregation may suggest a diagnosis but is not specific, while finding reticulofibrosis is specific but not sensitive. III. Bleeding and coagulation tests Prolonged bleeding time, positive capillary fragility test, shortened prothrombin depletion time, poor clot regression or excessive contraction. Platelet adhesion is reduced, and platelet aggregation is abnormal in about 50% of patients. The aggregation function to both ADP and epinephrine-induced aggregation is reduced, but the response to collagen aggregation is generally normal. The effectiveness of platelet factor 3 is reduced. Prothrombin time is normal or reduced, and prothrombin time is prolonged in the white clay fraction. Prothrombin production may be impaired. IV. Blood biochemical examination Blood uric acid, lactate dehydrogenase and serum acid phosphatase are increased. In some cases, due to platelet destruction, a large amount of potassium ions are released into the blood, which may cause pseudohyperkalemia. V. Other tests The role of cytogenetics in the diagnosis of ET is limited because of the incidence of abnormal clones of only 5%. Chromosomal examination reveals deletion of the long arm of chromosome 21 (21q-) in some patients, and variants of varying lengths of the long arm of chromosome 21 have also been reported. Bone marrow progenitor cell cultures have spontaneous megakaryocyte or erythroid clone formation. The JAK2V617F mutation can be examined in approximately 50% to 70% of ET patients. Section V. Diagnosis and differential diagnosis I. Diagnosis The diagnosis of primary thrombocythemia can be considered when there is a persistent increase in platelets of unknown cause, significant proliferation of megakaryocytes in the bone marrow, massive platelet aggregate formation, splenomegaly, hemorrhage or thrombosis, and other clinical manifestations. The specific diagnostic criteria and their new concepts are described below. (1) Domestic diagnostic criteria 1. Clinical manifestations Symptoms and signs caused by bleeding, splenomegaly, and thrombosis may be present. 1. Laboratory tests ①. Platelet count >1000X109/L. ②. Platelets in piles in blood film with giant platelets. ③.Bone marrow proliferation is active or above, or megakaryocytes are increased, large body and abundant cytoplasm. ④.White blood cell count and neutrophils are increased. ⑤, Aggregation response of platelet adrenaline and collagen may be reduced. Primary thrombocythemia can be diagnosed where clinically consistent, platelets >1000X109/L, other myeloproliferative disorders and secondary thrombocythemia can be excluded. (b) Foreign diagnostic criteria 1. Diagnostic conditions described in foreign textbooks: ①, clinical history of bleeding or/and thrombosis. ②, Splenomegaly. ③, platelet count >1000X109/L, white blood cell count <30x109/L, normal or reduced hemoglobin, but no increase in red blood cell count. ④, Bone marrow hyperplasia, megakaryocyte lineage hyperplasia is obvious. (⑤) Increased leukocytes and platelet alkaline phosphatase. (6) Secondary thrombocytosis and other myeloproliferative disorders can be excluded. 2. Revised diagnostic criteria for primary thrombocytosis by the PVSG: ①. Platelet count >600X109/L. ②. Erythrocyte pressure volume <0.40, or normal erythrocyte volume (<36ml/kg in men and <32ml/kg in women). ③, Positive bone marrow iron staining, or normal serum ferritin or erythrocyte MCV. ④, No Ph1 chromosome or bcr/abl gene rearrangement. ⑤, Bone marrow collagen fibrosis: A, None. B, less than 1/3 of the biopsy specimen area, and no obvious splenomegaly and appearance of naïve granules and red blood cells in peripheral blood. (6) No morphological and cytogenetic evidence of myelodysplastic syndrome. (vii) No cause of reactive thrombocytosis. 3. The American Society of Hematology (ASH) recommends the latest diagnostic criteria According to the latest research progress on the molecular pathogenesis of BCR/ABL-negative MPD, the ASH recommends the latest diagnostic criteria for ET, whose conditions include: A1, platelet count >600X109/L for at least two months. A2, Acquired JAK2V617F point mutation. B1, Exclusion of reactive thrombocytosis: e.g., normal inflammatory indicators, etc. B2, no evidence of iron deficiency: stainable iron in bone marrow or normal erythrocyte volume (MCV). B3, no evidence of PV: normal erythrocyte volume with normal iron reserves and normal erythrocyte pressure product (HCT). B4, no evidence of chronic leukemia: no Ph chromosome or BCR/ABL fusion gene. B5, no evidence of myelofibrosis: no collagen fibrosis or reticulofibrosis ≤ grade 2 (applying grade 0 to 4 grading). B6, no evidence of MDS: no significant dysplasia and no MDS-related cytogenetic abnormalities. Meet A1, A2 and B3~B6 for V617F-positive ET; meet A1 and B1~B6 for V617F-negative ET. II. Differential diagnosis Primary thrombocythemia should be differentiated mainly from reactive or secondary thrombocythemia and other myeloproliferative disorders with thrombocythemia. 1. Reactive or secondary thrombocytosis Reactive or secondary thrombocytosis due to various causes is significantly different from ET. The common causes of reactive or secondary thrombocytosis are: (1) physiological: strenuous exercise, childbirth, after epinephrine injection; (2) no splenic state: after splenectomy, splenic atrophy, splenic vein thrombosis; (3) inflammatory diseases: recovery from acute infection, osteomyelitis, tuberculosis, rheumatic fever, ulcerative colitis, nodular disease, rheumatoid arthritis, liver cirrhosis, etc.; ④ tumor: various cancers, Hodgkin’s lymphoma, etc.; ⑤ after acute blood loss, trauma surgery, etc.; ⑥ hemolytic anemia, iron deficiency anemia, iron granulocytic anemia, etc.; ⑦ other: osteoporosis, chronic kidney disease, glycogen storage disease, etc. The main points of differentiation between primary and secondary thrombocythemia are as follows. Table 1: Differentiation points between primary and secondary thrombocytosis Primary Secondary Cause Unknown Secondary to some etiology, physiological factors Disease duration Persistent Mostly transient Platelet count Often >1000×109/L, persistent Generally <1000x109/L, transient Platelet survival time Normal or mildly shortened Generally normal Platelet morphology and function Mostly abnormal Generally normal Bone marrow megakaryocytes Significantly increased and seen as juvenile megakaryocytes Mildly increased Nucleated cells Splenomegaly Common Generally not large Leukocyte count Frequently increased Generally normal For vascular embolism and bleeding Common Rarely seen 2. Other myeloproliferative disorders Myeloproliferative disorders such as true erythroblastosis, chronic granulocytic leukemia and myelofibrosis can be accompanied by thrombocytosis. However, each disease has its own characteristics: true red is highlighted by erythrocytosis; chronic granulocytic leukemia is dominated by infantile granulocytosis and can mostly be detected with Ph1 chromosome and/or BCR/ABL fusion gene; myelofibrosis patients mostly have clinically giant spleen, infantile granulocytes and erythrocytes can be seen in peripheral blood, especially teardrop-like erythrocytes, and bone marrow biopsy has evidence of fibrosis, etc. Section 6 Treatment The treatment of primary thrombocythemia is aimed at reducing the increased platelets to normal or near normal to prevent thrombosis and bleeding. Although the relationship between the degree of platelet elevation and functional abnormalities and the risk of thrombosis and hemorrhage is not clearly established, it is generally accepted that lowering platelet levels can help reduce the risk of complications and, therefore, patients with platelet counts >600X109/L should be treated aggressively if they are: (i) older than 60 years; (ii) or have a previous history of thrombotic/hemorrhagic disease; (iii) or have cardiovascular disease predisposing factors. The rational treatment of primary thrombocythemia is still controversial, and there is a lack of effective clinical treatment measures. The selection of an appropriate treatment plan by risk stratification should be the trend of ET treatment, and this plan is being gradually improved. Table 2, Risk stratification of primary thrombocythemia Treatment Patients Treatment All patients Need to control risk factors for vascular events (smoking, hypertension, hyperlipidemia, obesity, etc.) High-risk patients (previous history of thrombosis or low-dose aspirin + hydroxyurea Age >60 years or platelets >1500X109/L) (Anagrelide or interferon can be used as second-line therapy) Intermediate-risk patients Participate in randomized trials (e.g., intermediate-risk group for PT-1) (age 40-60 years, no high-risk factors) or low-dose aspirin (cytostatic agents may be considered if other cardiovascular risk factors are present) Low-risk patients Low-dose aspirin (age <40 years, no high-risk features) < p=""> II. Measures to control platelet counts Rapid and effective reduction of platelet counts and keeping them well controlled are the It is also the basic treatment to prevent complications such as thrombosis and the occurrence of bleeding, and is the preferred method of treatment for this disease. 1, myelosuppressive drugs ①, hydroxyurea is currently one of the first choice of drugs for the treatment of this disease at home and abroad. The daily dose is 1.0g~6.0g, divided into oral doses. The purpose is to reduce the platelets to below 400X109/L, and the efficiency is about 80%. Treatment can be maintained according to the platelet count test results. The side effect is reversible leukocyte reduction. Long-term application may result in erythrocyte megaloblastic transformation due to its inhibitory effect on DNA. About 1/3 of patients may have skin mucosal damage including increased pigmentation, maculopapular rash, nail atrophy, purple papules, oral ulcers, and gastrointestinal discomfort. No leukemogenic effect has been found. (2) Leucovorin is a commonly used and effective drug. It should be used in small doses, starting with 4mg~8mg/d orally in divided doses or once. When the platelet count is reduced to 50% of the initial treatment, the dose should be reduced by half accordingly. When the platelet count decreases to near normal, the drug can be stopped or changed to maintenance dose. Long-term use has a leukemogenic effect, and is now used sparingly. (iii) Azacitidine is used in combination with platelet mono-collection in critically ill patients with combined thrombosis. 0.2~0.4mg/kg can be administered intravenously, followed by platelet mono-collection. After clinical improvement, other myelosuppressive drugs will be used for maintenance. ④, others, azacitidine benzoate 0.1~0.15mg/kg?d, cyclophosphamide 50~100mg/d, levorphanol azacitidine 0.05mg/d, etc. It can be used according to the disease stage or individual sensitivity. The main side effects are the same as those of leucovorin. 2. Radionuclide 32P can be given orally or intravenously at the first dose of 2.3mCi/m2, and then given once after 3 months if necessary. It is generally not advocated for patients under 45 years of age, as 32P may have the potential to induce leukemia. 3.Plateletpheresis, i.e. platelet isolation. Platelets are separated using a blood cell separator in order to rapidly reduce the number of platelets and improve clinical symptoms. It is commonly used in elderly patients with massive acute gastrointestinal bleeding, before pregnancy and delivery, before elective surgery, and when myelosuppressive drugs are ineffective. This method is mostly well tolerated by patients. If the platelet count decreases after mono-collection, the platelets can be maintained at a more normal level with additional drugs. 4, Interferon (Interferon, IFN) Studies have shown that IFN-α in vitro and in vivo has a significant inhibition of BFU-MK and CFU-MK proliferation activity, the total efficiency of its treatment of ET is about 70% ~ 80%, and can effectively reduce the incidence of thrombosis and bleeding complications. The mechanism of action is related to its dual effect of lowering platelet levels and enhancing platelet function. The initial dose of 3 million U is administered subcutaneously three times a week, after which the dose is adjusted according to the patient’s tolerance and the therapeutic effect, and long-term maintenance therapy is required. Side effects are usually mild, and long-term efficacy must be further observed. 5, Anagrelide Anagrelide is a cinchona derivative, which can inhibit periodic ribulose phosphodiesterase and phosphodiesterase A2. Early on, it was mainly used as a platelet aggregation inhibitor, but later it was found that its platelet-lowering effect was more prominent. Its mechanism of action is to selectively act on megakaryocytes and reduce platelets by preventing the maturation of megakaryocytes, and it has obvious efficacy in treating various MPDs with increased platelets. Dosage: The starting dose is 1~2.0mg daily, the average time to reduce platelets by half is 17 days, and the average time to reduce platelets to <400x109/L is 21 days. The maintenance dose is 1.5~4.0mg per day. this drug has no leukemogenic and carcinogenic effects and has few side effects. III. Anti-platelet aggregation measures Platelet aggregation is closely related to thrombosis, and the use of anti-platelet aggregation drugs can help improve the patient's symptoms. There is a report that aspirin 0.3g, 4 times/day and pansentine 50mg, 4 times/day, taken orally at the same time, normalized platelet aggregation in 4 out of 6 patients. Another group reported that oral administration of aspirin 0.5g once every other day normalized platelet aggregation and improved finger and toe pain in 20 of 22 patients. Aspirin has the ability to interfere with platelet prostaglandin cyclooxygenase and may reduce erythromelalgia in thrombocythemia. Erythromelalgia is caused by platelet aggregation in the blood vessels, resulting in swelling of the endothelium of small arteries and clotting or fibrosis. These changes can be reversed by the use of aspirin. Therefore, aspirin is recommended for patients with this disease. Other related drugs are dipyridamole and indomethacin. Heparin or bicoumarins anticoagulants can be used in the presence of thrombosis. Harrison et al. compared the effect of hydroxyurea plus low-dose aspirin with anagrelide plus low-dose aspirin in the treatment of high-risk ET patients with venous thrombotic events. 809 ET patients were observed and followed up for 39 months and found that the former was associated with arterial thrombosis, myocardial infarction, transient cerebral ischemia, severe bleeding, and a shift to bone marrow The incidence of arterial thrombosis, myocardial infarction, transient cerebral ischemia, severe hemorrhage, and transformation to bone marrow fibrosis was significantly lower in the former than in the latter, but was significantly higher in venous thrombosis. Since a large number of platelets are retained in the spleen, surgical excision will increase the risk of bleeding and thrombosis, therefore, it is generally considered contraindicated to excise the spleen. V. Management of young people and pregnant patients There are reports in the literature that young patients have a better prognosis. A group of 56 young patients with a mean age of 29 years, ranging from 12 to 40 years, were followed up for 5 years. 70% were diagnosed by incidental finding of thrombocytosis. During the 5-year follow-up period, significant thrombotic complications were reported in only 10% of cases. Complications of severe bleeding and thrombosis have also been reported in 23% of young patients. It has been suggested that no specific treatment is needed for young asymptomatic individuals and that treatment is only appropriate for patients with cardiovascular risk factors. The rate of miscarriage in the first 3 months of pregnancy is 47%, but is not related to the platelet count or to the presence of specific treatment. Complications other than increased early miscarriage are rare. Therefore, no treatment is needed for asymptomatic women of pregnancy or childbearing age. However, given the different degrees of hypercoagulability that may exist in pregnant women, the moderate application of antiplatelet aggregation drugs may also be necessary, especially in the middle and late stages of pregnancy. Section VII Course and prognosis Unlike other myeloproliferative disorders, patients with prothrombocytosis have a small chance (<5%) of transforming into acute leukemia and therefore have only a slightly shorter survival compared to normal subjects. The main poor prognosis is related to serious complications such as thrombotic and hemorrhagic. The course of the disease varies according to the degree of thrombocytosis. Most cases progress slowly, maintaining a benign course for many years, especially in young people without a tendency to bleeding and thrombosis, and myelosuppressive drugs are not always required. About half of the patients survive for more than 5 years. Older patients with recurrent bleeding and thrombosis have a poorer prognosis. Life-threatening complications such as severe thromboembolism and bleeding are the main causes of death from this disease.