Essential Thrombocythemia

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<p>Essential ThrombocythemiaJennifer Pagliei July 31, 2006</p> <p>Essential ThrombocythemiaAlso called essential thrombocytosis or primary thrombocytosis. First described over 70 years ago. A subgroup of the chronic myeloproliferative disorders (CMPDs). The most common myeloproliferative disorder. The only CMPD that is a diagnosis of exclusion. It is heterogeneous both clinically and biologically.</p> <p>PathogenesisNeither thrombopoietin (TPO), the key hormone in the regulation of megakaryocyte differentiation and proliferation, nor its receptor, c-Mpl, has been implicated cin the pathogenesis of ET. Mutations involving the c-Mpl gene have not been cidentified in ET. Serum TPO levels are inappropriately normal or elevated.</p> <p>A clonal defect in platelet and megakaryocyte expression of ccMpl receptors causes impaired binding of TPO and thus increased bone marrow production of TPO. Also seen in reactive thrombocytosis.</p> <p>EpidemiologyIncidence rate of 2.5 new cases/100,000 people per year. In the US, approximately 6,000 people are diagnosed with ET each year. A female preponderance exists with a female to male ratio of approximately 2:1. The median age at diagnosis is 60 years. Up to 20% of patients are younger than 40 years old.</p> <p>Clinical PresentationUp to 50% of patients may be totally asymptomatic at presentation. The remaining 50% of patients may have vasomotor symptoms, thrombotic events, or hemorrhagic complications.</p> <p>Clinical PresentationVasomotor symptoms include: </p> <p>Headache Lightheadedness Syncope Atypical chest pain Acral paresthesia Livedo reticularis ErythromelalgiaBurning pain of the hands or feet associated with erythema and warmth</p> <p>Transient visual disturbancesAmaurosis fugax Scintillating scotomata Ocular Migraine</p> <p>Vasomotor SymptomsUsually controlled by treatment with low or standard doses of aspirin (40 to 325 mg/day). Some patients may be resistant to antiplatelet therapy and require cytoreductive therapy.</p> <p>ThrombosisA common complication of ET. Incidence rates in ET vary between 9 and 22%. Thrombotic events include: </p> <p>Stroke Transient ischemic attacks Retinal artery or venous occlusions Coronary artery ischemia Pulmonary embolism Hepatic or portal vein thrombosis Deep vein thrombosis Digital ischemia</p> <p>ThrombosisRisk factors include: </p> <p>History of prior thrombosis Age over 60 years Prolonged exposure to substantial degrees of thrombocytosis</p> <p>The role of cardiovascular risk factors is disputed, however, smoking, hypertension, and obesity have been implicated in some studies.</p> <p>HemorrhageA less frequent complication of ET. Incidence rates in ET vary between 3 and 9%. Usually involves spontaneous bleeding at superficial sites such as the skin or mucous membranes of the GI, respiratory, or GU tracts. The risk is significantly associated with:</p> <p>Extreme thrombocytosisPlatelet counts &gt;1 million/microlL, &gt;1.5 million/microL, and &gt;2 million/microL.</p> <p>Aspirin in doses greater than 325 mg/day. Following treatment with NSAIDs.</p> <p>HemorrhageIn some patients with platelet counts &gt;1 million/microL, acquired von Willebrand disease may develop due to a reduction in higher molecular weight multimers of von Willebrand factor. Increased bleeding may occur in such patients, especially when treated with aspirin. Cytoreduction usually corrects both the clinical and laboratory abnormalities.</p> <p>Risk StratificationLow risk - 600,000/microL. Bone marrow biopsy showing proliferation of enlarged, mature megakaryocytes. No evidence of PV, CML, chronic idiopathic myelofibrosis, myelodysplastic syndrome, or reactive thrombocytosis.</p> <p>TreatmentSome patients with ET may have a significantly decreased life expectancy although many have normal life expectancy without associated diseasedisease-related complications. The most frequent symptoms are vasomotor and are easily managed with low dose aspirin (40 to 325 mg/day). Thrombotic events in low-risk patients are lowinfrequent and therefore cytoreductive therapy is not indicated.</p> <p>TreatmentCytoreductive therapy is indicated in high-risk highpatients to prevent thrombosis. The decision to use drug therapy in intermediate risk patients should be made on an individual and may be considered in patients with extreme thrombocytosis (platelets &gt;1.5 million/microL). Bleeding complications are less frequent than thrombosis and may be prevented by the avoidance of doses of aspirin greater than 325 mg/day and avoidance of NSAIDs.</p> <p>Therapeutic AgentsHydroxyurea:</p> <p>Inhibits DNA synthesis by inhibiting the enzyme ribonucleotide reductase, producing a megaloblastic blood picture. Initial dose of 15 mg/kg per day po in divided doses. Dose is adjusted to keep platelets between 100,000 and 400,000/microL. Rapid onset of action, usually within 3-5 days. 3Teratogenic and should not be used in pregnancy, breastbreast-feeding, or women with childbearing potential.</p> <p>HydroxyureaSide effects are usually minimal and may include: </p> <p>Oral ulcers Hyperppigmentation Skin rash Nail changes Leg ulcers Nausea Diarrhea Alopecia Fever Abnormal liver function tests Anemia Neutropenia</p> <p>Therapeutic AgentsAnagrelide:</p> <p>An oral imidazoquinazoline derivative that inhibits platelet aggregation via platelet antianticyclic AMP phosphodiesterase activity. Lowers platelets via interference with megakaryocyte proliferation and maturation, resulting in platelet underproduction. Initial dose is 0.5 mg po tid or qid. Dose is adjusted according to platelet count response and symptomatology.</p> <p>AnagrelideSide effects are mainly related to direct vasodilatory and inotropic effects and include: </p> <p>Headache Palpitations/tachycardia Fluid retention Diarrhea Congestive heart failure</p> <p>Hydroxyurea versus AnagrelideAnagrelide plus aspirin has been shown to carry a higher risk of arterial thrombosis, venous thrombosis, serious hemorrhage, and death from vascular causes, in addition to a significantly higher rate of transformation into myelofibrosis at five years than hydroxyurea plus aspirin. Thus, hydroxyurea plus aspirin is recommended as first line therapy in ET.</p> <p>Therapeutic AgentsAlpha Interferon </p> <p>High cost and toxicity issues. Reserved for use in high-risk women of childbearing highage, pregnant women, and patients failing treatment with hydroxyurea. Reduces the platelet count only in the short-term. shortRestricted to acute cerebrovascular complications, digital ischemia, and rare life-threatening situations. lifeAn alkylating agent. Not available in the US, but used widely in Europe.</p> <p>Platelet apheresis </p> <p>Pipobroman </p> <p>Therapeutic AgentsLow dose aspirin </p> <p>40 to 325 mg/day. Prevents recurrent vascular events in high-risk groups highas well as thrombosis. Effective in treating vasomotor symptoms. Radioactive phosphorus 32P oral or IV IV is used only for patients with a life expectancy estimated to be less than 10 years.</p> <p>Radiophosphorus </p> <p>SummaryET is a member of the family of chronic myeloproliferative disorders. ET is suspected in a patient with: </p> <p>A chronically elevated platelet count. Clinical thrombotic or hemorrhagic symptoms. A mild degree of splenomegaly. Causes of reactive thrombocytosis must be ruled out. Other CMPDs or myelodysplasia must be ruled out.</p> <p>ET is a diagnosis of exclusion, therefore: </p> <p>ReferencesHarrison, Claire. Essential thrombocythemia: challenges and evidence-based management, evidenceBritish Journal of Haematology, 2005. Schaffer, Andrew. Thrombocytosis, NEJM, March 18, 2004. Tefferi, Ayalew. Approach to the patient with thrombocytosis. UpToDate, 2006. Tefferi, Ayalew. Diagnosis and clinical manifestations of essential thrombocythemia, UpToDate, 2006. Tefferi, Ayalwe. Prognosis and treatment of essential thrombocythemia, UpToDate, 2006.</p>