What Is Essential Thrombocythemia?

Primary thrombocytosis is one of a group of relatively chronic myeloproliferative diseases, also known as "hemorrhagic", "true" or "idiopathic" thrombocytosis. Similar to other myeloproliferative diseases, this disease is a pluripotent hematopoietic stem cell clone disease. It is characterized by an abnormal proliferation of megakaryocytes in the bone marrow and a significant increase in platelet count. The main clinical manifestations are bleeding and thrombosis.

Basic Information

nickname

Hemorrhagic thrombocytosis, true thrombocytosis, idiopathic thrombocytosis

English name

primary thrombocytosis

Visiting department

Hematology

Common causes

Clonal proliferation of a single abnormal pluripotent stem cell

Common symptoms

Spontaneous bleeding tendency and / or thrombosis

Causes of Primary Thrombocytosis

Primary thrombocytosis is a disease caused by the clonal proliferation of a single abnormal pluripotent stem cell. The clonal nature was established because an isozyme of glucose-6-phosphate dehydrogenase (G-6-PD) was found in a red blood cell line in a female case of this disease, which manifested as two types of G-6-PD "A "And" B "heterozygotes. The same abnormalities were found in red and granulocyte progenitor cells from another patient. The cause of the main phenotype of the disease in the megakaryocyte-platelet line is unknown. It may be related to the dominant clone's dominant response to megakaryocyte-platelet line regulators. It may also be caused by mutations in pluripotent stem cells that differentiate mainly in the megakaryocyte-platelet lineage. Histological examination and culture of megakaryocytes in vitro showed abnormal expansion of megakaryocyte progenitor cells in the bone marrow of the disease. Patients with bone marrow and blood in vitro cultured megakaryocyte clone forming units (CFU-MEG) were significantly more than normal or secondary thrombocythemia controls, which could be accompanied by abnormal CFU-MEG clone size and intranuclear replication of the nuclei. The growth of CFU-MEG often occurs when the source growth factor is added. A few cases were accompanied by an increase in granulocyte-monocyte colony forming units and erythrocyte colony forming units.

The number of megakaryocytes and the average megakaryocyte capacity of the disease increased. Platelet production can reach 15 times the normal rate. Platelet life is usually normal, and a few cases may be caused by spleen destruction of platelets. The mechanism of massive platelet increase leading to bleeding and thrombosis is uncertain. It is generally believed that abnormal platelet function is the main cause of bleeding, and the decrease of coagulation factor may be one of the reasons in some patients. A significant increase in the number of platelets results in highly aggregated thrombosis. Intrinsic platelet defects include decreased serotonin in platelets, decreased platelet adhesion, and decreased adenosine diphosphate (ADP) and adrenaline-induced platelet aggregation. In this disease, megakaryocytes proliferate not only in the bone marrow, but also involve extramedullary tissues, and megakaryocyte-based hyperplasia can occur in tissues such as liver and spleen. Due to the lower malignancy and slower growth rate, the liver and spleen are often moderately enlarged. No external pathogenic factors related to this disease have been found so far.

Clinical manifestations of primary thrombocythemia

The course of primary thrombocytosis is slow, and many patients are asymptomatic for a long time. The use of automatic blood cell examination equipment increases the chance of diagnosing asymptomatic cases. The main clinical manifestations of this disease are bleeding and thrombosis. Unlike other myeloproliferative diseases, fever, sweating, and weight loss are very rare. On physical examination, about 40% of patients only found splenomegaly, usually mild or moderate swelling. Spleen atrophy and spleen infarction can occur. Swollen lymph nodes are rare.

Bleeding can be spontaneous or caused by trauma or surgery. Spontaneous bleeding is more common in the nasal, oral and gastrointestinal mucosa. There may also be bleeding in the urinary tract and respiratory tract. Cerebral hemorrhage occasionally can cause death. Bleeding symptoms are generally not severe, but severe trauma or bleeding after surgery can be life-threatening. Aspirin or other anti-inflammatory drugs can cause or exacerbate bleeding.

Thrombosis is easy to see in older patients and less common in younger patients. Both arteries and veins can occur, but arterial thrombosis is more common. Cerebrovascular, splenic, mesenteric and finger and toe vessels are the most common sites. Thrombosis generally occurs in small blood vessels, but can also occur in large blood vessels. Finger or toe vascular obstruction can cause local pain, burning sensation, redness, and fever, which can develop into bruising or necrosis. Cerebrovascular thrombosis often causes neurological symptoms, temporary cerebral ischemia, visual disturbances, sensory disturbances, headaches, dizziness, insomnia, etc., and cerebrovascular accidents also occur. Pulmonary thrombosis and myocardial infarction occur. Habitual abortions and abnormal penile erections have also been reported. Itchy skin is less common than true erythrocytosis.

Primary thrombocythemia test

Platelet counts exceed 600 × 10 ⁹ / L, most patients exceed 1000 × 10 ⁹ / L, and cases have reached 14000 × 10 ⁹ / L. Platelets often have morphological abnormalities: giant platelets, peculiar platelets, platelets stained in light blue, and platelets with reduced granules are all visible. The average platelet volume increased. Megakaryocyte debris can also appear in blood smears. Red blood cells are usually normal, and cases of chronic blood loss can be small cell hypochromic anemia. In the presence of spleen atrophy, Hao-periosome, target red blood cells, and abnormal red blood cells can appear. May have mild anemia, hemoglobin is rarely less than 100g / L. Hemoglobin can be elevated in some patients, but the red blood cell volume is normal. White blood cell counts often increase, usually between 15 and 40 × 10 ⁹ / L. Occasionally, neutral neutrophils and late blasts were seen. Neutrophil alkaline phosphatase scores are generally normal, with occasional decreases or increases.

Myeloproliferation is active or markedly active, megakaryocyte cell lines are significantly increased, and both primitive and naive megakaryocytes are increased, the latter being the case. Megakaryocytes can appear in clusters, and platelets often accumulate in large quantities. Most patients have no cytogenetic abnormalities, and some cases have abnormal chromosomes. If the Ph chromosome or Bcr / Abl fusion gene is present, it is chronic myelogenous leukemia. Although these reported cases do not have significant increase in white blood cells and other characteristics of chronic myelogenous leukemia, the development of the course is more inclined to chronic myelogenous leukemia. The patient died of accelerated phase or acute change.

Platelet life expectancy in this disease is generally normal, sometimes slightly shortened. Platelet function may be reduced, especially epinephrine-induced platelet aggregation. Spontaneous aggregation may also occur with enhanced platelet aggregation. The bleeding time can be prolonged normally or slightly. Coagulation tests are usually normal. In some cases, the level of plasma von Willebrand factor (von Willebrand factor) is reduced or the subunit structure is abnormal. Other platelet defects include a reduction in the number of dense bodies and their contents ADP, adenosine triphosphate (ATP) and serotonin (acquired storage pool disease), reduced -adrenergic receptors, impaired membrane coagulation activity, and epoxidation Reduced enzyme activity, abnormal membrane glycoproteins, enhanced Fc receptors, and decreased prostaglandin D ₂ receptors have been reported. But these deficiencies have not been shown to be linked to hemostatic complications.

Blood uric acid and vitamin B ₁₂ often increase. The occurrence of pseudohyperkalemia in some patients is related to the release of potassium by a large number of platelet destruction.

Diagnosis of primary thrombocythemia

The significant increase in unexplained platelets should be considered, and the diagnosis can be made after excluding other myeloproliferative diseases and secondary thrombocytosis. The diagnostic criteria proposed by Murphy and others are for reference: platelet count above 600 × 10 / L; hemoglobin 130g / L or normal red blood cell volume (male <36ml / kg, female <32ml / kg); normal bone marrow iron staining Or the iron test treatment is ineffective (hemoglobin rise less than 10g / L after 1 month of iron treatment); no Ph chromosome; bone marrow pathological examination without collagen fibers, or without splenomegaly, immature granulocytes and red blood cells when the collagen fibers are smaller than biopsy 1/3 of the area; non-reactive thrombocytosis.

Differential diagnosis of primary thrombocythemia

Differentiation of this disease from other myeloproliferative diseases: Polycythemia vera is easy to identify when there is an increase in red blood cells and increased red blood cell capacity. When the blood volume is not significantly increased during iron deficiency and platelets are significantly increased, iron treatment can be used to make typical true red blood cells The characteristics of the disease appear. Chronic myelogenous leukemia is sometimes difficult to distinguish from this disease with a significant increase in platelets, but the examination of the Ph chromosome or Bcr / Abl fusion gene is sufficient to distinguish it. Primary bone marrow fibrosis has significant splenomegaly, typical extramedullary hematopoiesis, immature granulocytes and immature red blood cells, and extensive collagen fibers in pathological examination of bone marrow. There are characteristic differences in myeloproliferative diseases, and it is not difficult to identify them. Occasionally, some cases show "overlapping" syndromes that are difficult to identify.

This disease needs to rule out secondary thrombocytosis, the identification points are shown in Table 1.

Table 1 Identification of primary and secondary thrombocytosis

The etiology is secondary to an unknown pathological or physiological factor

Sickness is often temporary

Bleeding and thrombosis are rare and common

Splenomegaly is often impermanent

Platelet count <1000 × 10 / L can> 1000 × 10 / L

Platelet morphology is often normal and often abnormal

White blood cell counts are usually normal in 90% of patients

Bleeding time is usually normal and can be extended

Slightly increased number of megakaryocytes significantly increased

Increase in average megakaryocyte volume reduction

Primary thrombocytosis treatment

Controversy remains as to whether asymptomatic primary thrombocytosis is treated with a reduction in platelet count. In general, there is little evidence that long-term platelet-lowering treatment improves the prognosis of asymptomatic patients. There is consensus that reducing platelets in patients with bleeding or thrombosis can improve symptoms. Patients with finger and toe microvascular ischemia or cerebrovascular ischemia should be actively treated with thrombocytopenia. The goal is to reduce megakaryocyte proliferation and platelet production.

Patients with acute and dangerous bleeding or thrombosis can use the blood cell separator to collect platelets. This method of reducing platelets is short-term, after which a rebound will occur, which needs to be used in conjunction with bone marrow inhibitors. 32P and alkylating agents such as Malfalfa, Malilan, Titipas, and Nitrosin must be used in the past, but now they tend to give up because they may cause leukemia.

The hydroxyurea-based non-alkylating agent bone marrow inhibitor has a very good effect on the disease. The starting dose is 10-30 mg / kg daily. Because it can cause rapid bone marrow suppression, a blood count should be checked within 7 days and monitored later. The maintenance dose needs to be individualized, and the medication dose is adjusted according to the blood cell count. About 80% of patients can reduce platelets to less than 500 × 10 / L within 8 weeks, and can control the number of platelets for a long time.

The myelosuppressive effect of hydroxyurea is relatively light, and severe myelosuppression can be avoided by adjusting the dosage. Some patients have mild gastrointestinal reactions, and some patients may develop oral mucosal ulcers. Similar to other chemotherapeutic drugs that can increase the incidence of leukemia, hydroxyurea also has the side effect of increasing the incidence of leukemia. In patients with primary thrombocytosis treated with hydroxyurea, a large proportion of patients with acute myelogenous leukemia and myelodysplastic syndromes are characterized by chromosome 17p deletion and other 17p-syndromes.

Anagrelide is very effective in reducing platelet counts and is now one of the first-line treatments. It can reduce platelets by inhibiting bone marrow megakaryocyte maturation. The dose required to control platelets is generally about 2.0 to 3.0 mg / day for adults, which can reduce platelet count by half in about 11 days. This medicine does not affect the white blood cell count, and a small amount of blood volume may occur in a small number of patients. Platelet counts can be well controlled during patient medication, but platelet counts increase rapidly after discontinuation of most patients. Side effects include nerve and gastrointestinal symptoms, palpitations, and fluid retention.

Recombinant -interferon is an effective drug for treating this disease, which can inhibit the differentiation of abnormal megakaryocyte clones and reduce the size and doubling of megakaryocytes. In most patients treated with interferon for 1 month, platelet counts can drop to normal or near-normal ranges. The starting dose is subcutaneously injected with 3 million units of interferon per day. After the platelets are close to normal, the dose can be adjusted according to the individual's response and tolerance. Later, subcutaneous injections can be maintained at lower doses 3 times a week for many years. Platelets can increase and relapse after stopping use. Mainly flu-like side effects, may have fever, joint muscle soreness, etc., reducing the dose or antipyretic analgesics can reduce or alleviate. Interferon treatment can be accompanied by a decrease in white blood cell count.
Aspirin is an effective adjuvant therapy, especially for the symptoms of finger, toe ischemia and cerebrovascular ischemia. The disadvantage is that it can cause severe bleeding in some patients, which significantly prolongs the bleeding time, so it should be used with caution.

Prognosis of primary thrombocytosis

The main causes of death were severe bleeding and thrombosis of vital organs. Some cases can turn into chronic myelogenous leukemia, myelofibrosis, or polycythemia vera, and can turn into acute leukemia. Chemotherapy drugs such as 32P or alkylating agents may increase leukemia conversion. The survival curve of patients with primary thrombocytosis is similar to that of the normal population of the same age, and the general patient has a good prognosis.