(See also Overview of Myeloproliferative Neoplasms Overview of Myeloproliferative Neoplasms Myeloproliferative neoplasms are clonal proliferations of bone marrow stem cells, which can manifest as an increased number of platelets, red blood cells (RBCs), or white blood cells (WBCs)... read more .)
Etiology of Essential Thrombocythemia
Essential thrombocythemia is a clonal hematopoietic stem cell disorder that causes increased platelet production. Essential thrombocythemia usually occurs wiith increased incidence after age 50.
A Janus kinase 2 (JAK2) enzyme mutation, JAK2V617F, is present in about 50% of patients; JAK2 is a member of the tyrosine kinase family of enzymes and is involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF). Other patients have mutations in exon 9 of the calreticulin gene (CALR), and a few have acquired somatic thrombopoietin receptor gene mutations (MPL).
Pathophysiology of Essential Thrombocythemia
Thrombocythemia may lead to
Large vessel thrombosis
Microvascular occlusions involve small vessels of the distal extremities (causing erythromelalgia Erythromelalgia Erythromelalgia is distressing paroxysmal vasodilation of small arteries in the feet and hands and, less commonly, in the face, ears, or knees; it causes burning pain, increased skin temperature... read more ), the eye (causing ocular migraine), or the central nervous system (causing transient ischemic attacks Transient Ischemic Attack (TIA) A transient ischemic attack (TIA) is focal brain ischemia that causes sudden, transient neurologic deficits and is not accompanied by permanent brain infarction (eg, negative results on diffusion-weighted... read more ). Not all patients experience microvascular symptoms even when platelet counts are high.
Whether the risk of large vessel thrombosis causing deep venous thrombosis or pulmonary embolism is increased in essential thrombocythemia is unclear, particularly because platelets are primarily involved in arterial thrombosis and there is no correlation between the platelet count and large vessel thrombosis. Large vessel thrombosis is more likely to occur in patients with masked polycythemia vera Polycythemia Vera Polycythemia vera is a chronic myeloproliferative neoplasm characterized by an increase in morphologically normal red cells (its hallmark), but also white cells and platelets. Ten to 15% of... read more .
Bleeding is more likely with extreme thrombocytosis (ie, about 1.5 million platelets/mcL [1.5 million × 109/L]); it is due to an acquired deficiency of von Willebrand factor caused because the platelets adsorb and proteolyze high molecular weight von Willebrand multimers, causing an acquired von Willebrand syndrome Von Willebrand Disease Von Willebrand disease (VWD) is a hereditary quantitative deficiency or functional abnormality of von Willebrand factor (VWF), which causes platelet dysfunction. Bleeding tendency is usually... read more .
Symptoms and Signs of Essential Thrombocythemia
Common symptoms are
Bruising and bleeding
Paresthesias of the hands and feet (erythromelalgia)
Bleeding is usually mild, rarely spontaneous, and manifests as epistaxis, easy bruisability, or gastrointestinal bleeding. However, serious bleeding may occur in a small percentage of cases with extreme thrombocytosis.
Erythromelalgia (burning pain in hands and feet, with warmth, erythema, and sometimes digital ischemia) may occur.
Transient ischemic attacks cause neurologic deficits depending upon which part of the brain is affected.
The spleen may be palpable but significant splenomegaly is unusual and should suggest another myeloproliferative neoplasm.
Diagnosis of Essential Thrombocythemia
Complete blood count (CBC) and peripheral blood smear
Exclusion of causes of secondary thrombocytosis and other myeloproliferative neoplasms
JAK2 mutation and, if negative, CALR or MPL mutation analysis
Rarely, bone marrow aspirate and biopsy
The platelet count is > 450,000/mcL (> 450,000 × 109/L), but can be >1,000,000/mcL (> 1,000,000 × 109/L). The platelet count may decrease during pregnancy. The peripheral smear may show giant platelets and megakaryocyte fragments.
Essential thrombocythemia is a diagnosis of exclusion and should be considered in patients in whom common reactive causes of thrombocytosis Reactive Thrombocytosis (Secondary Thrombocythemia) Reactive thrombocytosis is an elevated platelet count (> 450,000/mcL [> 450,000 × 109/L]) that develops secondary to another disorder. (See also Overview of Myeloproliferative... read more and other myeloproliferative neoplasms are excluded.
Some myelodysplastic syndromes Myelodysplastic Syndrome (MDS) The myelodysplastic syndrome (MDS) is group of clonal hematopoietic stem cell disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular... read more (eg, refractory anemia with ringed sideroblasts and thrombocytosis [RARS-T], and the 5q- syndrome) may present with elevated platelet count. If cytopenias are identified, myelodysplastic syndrome Myelodysplastic Syndrome (MDS) The myelodysplastic syndrome (MDS) is group of clonal hematopoietic stem cell disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular... read more should be considered.
If essential thrombocythemia is suspected, complete blood count (CBC), peripheral blood smear, and iron studies should be measured.
Genetic studies should also be done, including a quantitative JAK2 V617F assay (by next-generation sequencing [NGS] or quantitative polymerase chain reaction), along with a BCR-ABL assay to exclude chronic myeloid leukemia Chronic Myeloid Leukemia (CML) Chronic myeloid leukemia (CML) occurs when a pluripotent stem cell undergoes malignant transformation and clonal myeloproliferation, leading to a striking overproduction of mature and immature... read more (CML, which can manifest with thrombocytosis alone). If the JAK2 and BCR-ABL assays are negative, CALR and MPL mutation assays should be done. Some patients test negative for all three mutations; many have rare variants of the myeloproliferative neoplasm driver mutations and others have germline mutations.
The diagnosis of essential thrombocythemia is suggested by normal hematocrit, white blood cell count, mean corpuscular volume (MCV), and iron studies, as well as absence of the BCR-ABL translocation.
Mutation analysis should always be quantitative because the driver gene allele burden in JAK2 V617F-positive essential thrombocythemia does not exceed 50%. A quantitative allele burden > 50% suggests polycythemia vera Polycythemia Vera Polycythemia vera is a chronic myeloproliferative neoplasm characterized by an increase in morphologically normal red cells (its hallmark), but also white cells and platelets. Ten to 15% of... read more or primary myelofibrosis Primary Myelofibrosis Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and anemia with nucleated and teardrop-shaped red blood cells. Diagnosis... read more . However, a quantitative allele burden < 50% does not definitely exclude polycythemia vera or primary myelofibrosis because these two disorders can present with thrombocytosis alone, and in polycythemia vera, plasma volume expansion can mask the presence of an expanded red cell mass. Also, in about 25% of patients (primarily women) with what initially appears to be essential thrombocythemia, transformation to overt polycythemia vera occurs over time, leading to an increase in hematocrit and an increase in the JAK2V617F allele burden.
World Health Organization guidelines suggest that a bone marrow biopsy showing increased numbers of enlarged, mature megakaryocytes is required for a diagnosis of essential thrombocythemia, but this criterion has never been validated prospectively, and a marrow examination will not distinguish essential thrombocythemia from polycythemia vera. The allele burden is usually >50% in polycythemia vera and primary myelofibrosis.
Prognosis for Essential Thrombocythemia
Life expectancy is normal. Although symptoms are common, the course of the disease is usually benign. Serious arterial thrombotic complications are rare but can be life-threatening. Leukemic transformation occurs in < 2% of patients but may increase after exposure to cytotoxic therapy, including hydroxyurea. Some patients develop secondary myelofibrosis, particularly men with the JAK2V617F or CALR type 1 mutations.
Treatment of Essential Thrombocythemia
Platelet-lowering drugs (eg, hydroxyurea, interferon, anagrelide)
Rarely cytotoxic agents
Rarely stem cell transplantation
For mild vasomotor symptoms (eg, headache, mild digital ischemia, erythromelalgia) in low-risk patients who are > 60 years old and do not have the Jak2 mutation, aspirin 81 mg orally once a day is usually sufficient, but a higher dose may be used if necessary. Severe migraine may require platelet count reduction for control. The utility of aspirin during pregnancy is unproven and may provoke bleeding in patients with essential thrombocythemia and the CALR mutation. Women with essential thrombocythemia are thought to have a higher incidence of fetal loss in the first trimester.
Asymptomatic patients who use tobacco or have cardiovascular disease or cardiovascular risk factors are also treated with aspirin. The use of aspirin for cardiovascular prophylaxis in the absence of cardiovascular disease or risk factors in patients > 65 years of age is associated with an unacceptable incidence of adverse effects. Contrary to some published literature, there is no proof that asymptomatic patients > 65 years with thrombocytosis benefit from aspirin therapy.
Aminocaproic acid or tranexamic acid is effective for controlling hemorrhage due to acquired von Willebrand syndrome during minor procedures such as dental work. Major procedures may require optimization of platelet counts.
JAK-2 inhibitors such as ruxolitinib may be effective for the treatment of essential thrombocythemia.
Allogeneic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more is rarely used in essential thrombocythemia but can be effective if there is transformation to acute leukemia.
Lowering platelet count
Because prognosis is usually good and there is no correlation between degree of thrombocytosis and thrombosis, potentially toxic drugs that lower the platelet count should not be used just to normalize the platelet count in asymptomatic patients. Generally agreed-upon indications for platelet-lowering therapy include
Cardiovascular risk factors
Transient ischemic attacks
Need for a surgical procedure in patients with extreme thrombocytosis and low ristocetin cofactor activity
Sometimes severe migraine
However, there are no data that prove cytotoxic therapy to reduce the platelet count lowers thrombotic risk or improves survival.
Drugs used to lower platelet count include anagrelide, interferon alfa-2b, and hydroxyurea. Hydroxyurea is generally considered the drug of choice for short-term use but has no benefit and is myelotoxic when used long-term. Because anagrelide and hydroxyurea cross the placenta, they are not used during pregnancy; interferon alfa-2a can be used in pregnant women when necessary. Interferon is the safest therapy for migraine when dedicated migraine drugs are not effective. Anagrelide should be used with caution in older patients because of its effects on the cardiovascular system (eg, palpitations, arrhythmias) and the kidneys (eg, fluid retention, renal failure).
Hydroxyurea should be prescribed only by specialists familiar with its use and monitoring. It is started at a dose of 500 to 1000 mg orally once a day. Patients are monitored with a weekly CBC. If the WBC count falls to < 4000/mcL (< 4 × 109/L), hydroxyurea is withheld and reinstituted at 50% of the dose when the value normalizes. When a steady state is achieved, the interval between CBCs is lengthened to 2 weeks and then to 4 weeks. The aim is relief of symptoms rather than platelet count normalization. Too-rapid withdrawal of hydroxyurea can result in rapid rebound and platelet cycling.
Some studies have suggested that ruxolitinib, a drug that is used in polycythemia vera and primary myelofibrosis, may be useful in patients with essential thrombocythemia who are resistant to other treatments.
Platelet removal (plateletpheresis) has been used in rare patients with serious hemorrhage or recurrent thrombosis or before emergency surgery to immediately reduce the platelet count. However, plateletpheresis is rarely necessary. Its effects are transient with prompt rebound in the platelet count. Hydroxyurea or anagrelide do not provide an immediate effect but should be started at the same time as plateletpheresis.
Essential thrombocythemia is a clonal abnormality of a multipotent hematopoietic stem cell resulting in increased platelets.
Patients are at risk of microvascular thrombosis and hemorrhage.
Essential thrombocythemia is a diagnosis of exclusion; in particular, other myeloproliferative neoplasms and reactive (secondary) thrombocytosis must be ruled out.
Asymptomatic patients require no therapy. Aspirin is usually effective for microvascular events (ocular migraine, erythromelalgia and transient ischemic attacks).
Some patients with extreme thrombocytosis require more aggressive treatment to control the platelet count; such measures include interferon alpha, hydroxyurea, anagrelide, and plateletpheresis.