Essential Essential ThrombocythemiaThrombocythemia

Jennifer PaglieiJennifer Pagliei

July 31, 2006July 31, 2006

Essential ThrombocythemiaEssential Thrombocythemia

Also called essential thrombocytosis or primary Also called essential thrombocytosis or primary thrombocytosis.thrombocytosis.

First described over 70 years ago.First described over 70 years ago.

A subgroup of the chronic myeloproliferative A subgroup of the chronic myeloproliferative disorders (CMPDs).disorders (CMPDs).

The most common myeloproliferative disorder.The most common myeloproliferative disorder.

The only CMPD that is a diagnosis of exclusion.The only CMPD that is a diagnosis of exclusion.

It is heterogeneous both clinically and It is heterogeneous both clinically and biologically.biologically.

PathogenesisPathogenesis

Neither thrombopoietin (TPO), the key hormone in the Neither thrombopoietin (TPO), the key hormone in the regulation of megakaryocyte differentiation and regulation of megakaryocyte differentiation and proliferation, nor its receptor, c-Mpl, has been implicated proliferation, nor its receptor, c-Mpl, has been implicated in the pathogenesis of ET.in the pathogenesis of ET.Mutations involving the c-Mpl gene have not been Mutations involving the c-Mpl gene have not been identified in ET.identified in ET.Serum TPO levels are inappropriately normal or Serum TPO levels are inappropriately normal or elevated.elevated.

A clonal defect in platelet and megakaryocyte expression of c-A clonal defect in platelet and megakaryocyte expression of c-Mpl receptors causes impaired binding of TPO and thus Mpl receptors causes impaired binding of TPO and thus increased bone marrow production of TPO.increased bone marrow production of TPO.

Also seen in reactive thrombocytosis.Also seen in reactive thrombocytosis.

EpidemiologyEpidemiology

Incidence rate of 2.5 new cases/100,000 Incidence rate of 2.5 new cases/100,000 people per year.people per year.In the US, approximately 6,000 people are In the US, approximately 6,000 people are diagnosed with ET each year.diagnosed with ET each year.A female preponderance exists with a A female preponderance exists with a female to male ratio of approximately 2:1.female to male ratio of approximately 2:1.The median age at diagnosis is 60 years.The median age at diagnosis is 60 years.Up to 20% of patients are younger than 40 Up to 20% of patients are younger than 40 years old.years old.

Clinical PresentationClinical Presentation

Up to 50% of patients may be totally Up to 50% of patients may be totally asymptomatic at presentation.asymptomatic at presentation.

The remaining 50% of patients may have The remaining 50% of patients may have “vasomotor” symptoms, thrombotic events, “vasomotor” symptoms, thrombotic events, or hemorrhagic complications.or hemorrhagic complications.

Clinical PresentationClinical Presentation

Vasomotor symptoms include:Vasomotor symptoms include: HeadacheHeadache LightheadednessLightheadedness Syncope Syncope Atypical chest painAtypical chest pain Acral paresthesiaAcral paresthesia Livedo reticularisLivedo reticularis Erythromelalgia Erythromelalgia

Burning pain of the hands or feet associated with erythema and Burning pain of the hands or feet associated with erythema and warmthwarmth

Transient visual disturbancesTransient visual disturbancesAmaurosis fugaxAmaurosis fugaxScintillating scotomataScintillating scotomataOcular MigraineOcular Migraine

Vasomotor SymptomsVasomotor Symptoms

Usually controlled by treatment with low or Usually controlled by treatment with low or standard doses of aspirin (40 to 325 standard doses of aspirin (40 to 325 mg/day).mg/day).

Some patients may be resistant to Some patients may be resistant to antiplatelet therapy and require antiplatelet therapy and require cytoreductive therapy.cytoreductive therapy.

ThrombosisThrombosis

A common complication of ET.A common complication of ET.Incidence rates in ET vary between 9 and 22%.Incidence rates in ET vary between 9 and 22%.Thrombotic events include:Thrombotic events include: StrokeStroke Transient ischemic attacksTransient ischemic attacks Retinal artery or venous occlusionsRetinal artery or venous occlusions Coronary artery ischemiaCoronary artery ischemia Pulmonary embolismPulmonary embolism Hepatic or portal vein thrombosisHepatic or portal vein thrombosis Deep vein thrombosisDeep vein thrombosis Digital ischemia Digital ischemia

ThrombosisThrombosis

Risk factors include:Risk factors include: History of prior thrombosisHistory of prior thrombosis Age over 60 yearsAge over 60 years Prolonged exposure to substantial degrees of Prolonged exposure to substantial degrees of

thrombocytosisthrombocytosis

The role of cardiovascular risk factors is The role of cardiovascular risk factors is disputed, however, smoking, hypertension, disputed, however, smoking, hypertension, and obesity have been implicated in some and obesity have been implicated in some studies.studies.

HemorrhageHemorrhage

A less frequent complication of ET.A less frequent complication of ET.Incidence rates in ET vary between 3 and 9%.Incidence rates in ET vary between 3 and 9%.Usually involves spontaneous bleeding at Usually involves spontaneous bleeding at superficial sites such as the skin or mucous superficial sites such as the skin or mucous membranes of the GI, respiratory, or GU tracts.membranes of the GI, respiratory, or GU tracts.The risk is significantly associated with:The risk is significantly associated with: Extreme thrombocytosisExtreme thrombocytosis

Platelet counts >1 million/microlL, >1.5 million/microL, and Platelet counts >1 million/microlL, >1.5 million/microL, and >2 million/microL.>2 million/microL.

Aspirin in doses greater than 325 mg/day.Aspirin in doses greater than 325 mg/day. Following treatment with NSAIDs.Following treatment with NSAIDs.

HemorrhageHemorrhage

In some patients with platelet counts >1 In some patients with platelet counts >1 million/microL, acquired von Willebrand disease million/microL, acquired von Willebrand disease may develop due to a reduction in higher may develop due to a reduction in higher molecular weight multimers of von Willebrand molecular weight multimers of von Willebrand factor.factor.

Increased bleeding may occur in such patients, Increased bleeding may occur in such patients, especially when treated with aspirin.especially when treated with aspirin.

Cytoreduction usually corrects both the clinical Cytoreduction usually corrects both the clinical and laboratory abnormalities.and laboratory abnormalities.

Risk StratificationRisk Stratification

Low risk - <2% risk of thrombosis over 4 yearsLow risk - <2% risk of thrombosis over 4 years Age <60 yearsAge <60 years No previous history of thrombosisNo previous history of thrombosis Platelet count <1,500,000/microLPlatelet count <1,500,000/microL No cardiovascular risk factors No cardiovascular risk factors

High riskHigh risk Age >60 yearsAge >60 years A previous history of thrombosisA previous history of thrombosis

Intermediate riskIntermediate risk Patients who do not qualify for either the low or high Patients who do not qualify for either the low or high

risk groupsrisk groups

Disease TransformationDisease Transformation

ET may transform into:ET may transform into: Polychthemia vera (PV)Polychthemia vera (PV) Agnogenic Myeloid Metaplasia (AMM)Agnogenic Myeloid Metaplasia (AMM) Acute myeloid leukemia (AML)Acute myeloid leukemia (AML) Myelofibrosis with myeloid metaplasia (MMM)Myelofibrosis with myeloid metaplasia (MMM)

It is not clear whether specific therapy for It is not clear whether specific therapy for ET, including hydroxyurea or anagrelide, ET, including hydroxyurea or anagrelide, modifies the risk of fibrotic transformation.modifies the risk of fibrotic transformation.

PregnancyPregnancy

Results in spontaneous abortions Results in spontaneous abortions approximately 45% of the time, primarily approximately 45% of the time, primarily occurring in the first trimester.occurring in the first trimester.

The occurrence of abortions cannot be The occurrence of abortions cannot be predicted from the disease course, platelet predicted from the disease course, platelet count, or specific therapy.count, or specific therapy.

Aspirin is associated with a decreased Aspirin is associated with a decreased incidence of miscarriage.incidence of miscarriage.

Physical ExamPhysical Exam

Palpable splenomegalyPalpable splenomegaly Present in 25 to 48% of patients at diagnosis.Present in 25 to 48% of patients at diagnosis. Usually only modest in degree.Usually only modest in degree.

Hepatomegaly and lymphadenopathy are Hepatomegaly and lymphadenopathy are uncommon.uncommon.

Differential DiagnosisDifferential Diagnosis

Includes:Includes: Reactive thrombocytosisReactive thrombocytosis Familial essential thrombocythemiaFamilial essential thrombocythemia Chronic myelogenous leukemia (CML)Chronic myelogenous leukemia (CML) Polychthemia vera (PV)Polychthemia vera (PV) Agnogenic Myeloid Metaplasia (AMM)Agnogenic Myeloid Metaplasia (AMM)

DiagnosisDiagnosis

ET is a diagnosis of exclusion.ET is a diagnosis of exclusion.May be diagnosed in patients with persistent May be diagnosed in patients with persistent thrombocytosis only in the absence of a known thrombocytosis only in the absence of a known cause of reactive or clonal thrombocytosis.cause of reactive or clonal thrombocytosis.There are no laboratory findings that are There are no laboratory findings that are pathognomonic for ET.pathognomonic for ET.Peripheral blood smear and bone marrow biopsy Peripheral blood smear and bone marrow biopsy may show clusters of giant platelets, may show clusters of giant platelets, megakaryocyte clusters, and/or mild reticulin megakaryocyte clusters, and/or mild reticulin fibrosis.fibrosis.

Peripheral Smear and Bone Peripheral Smear and Bone Marrow BiopsyMarrow Biopsy

DiagnosisDiagnosis

Confirm thrombocytosis by repeating CBC.Confirm thrombocytosis by repeating CBC.Examine the peripheral blood smear to exclude spurious Examine the peripheral blood smear to exclude spurious thrombocytosis.thrombocytosis.Perform a complete history and physical exam.Perform a complete history and physical exam.Attempt to determine the duration of thrombocytosis.Attempt to determine the duration of thrombocytosis.Obtain a serum ferritin concentration, ESR, CRP, and Obtain a serum ferritin concentration, ESR, CRP, and plasma fibrinogen level to evaluate for reactive plasma fibrinogen level to evaluate for reactive thrombocytosis.thrombocytosis.

Consider testing for the JAK2 mutation.Consider testing for the JAK2 mutation.

Perform a bone marrow biopsy with reticulin staining and Perform a bone marrow biopsy with reticulin staining and cytogenetic studies to distinguish among the CMPDs.cytogenetic studies to distinguish among the CMPDs.

DiagnosisDiagnosis

JAK2 mutation: JAK2 mutation: Present in approximately 50% of ET patients.Present in approximately 50% of ET patients. Differentiates patients with myeloproliferative Differentiates patients with myeloproliferative

disease-associated thrombocytosis from disease-associated thrombocytosis from those with reactive thrombocytosis.those with reactive thrombocytosis.

However, it does not allow differentiation However, it does not allow differentiation among ET, PV, and AMM.among ET, PV, and AMM.

Presence of the mutation does not appear to Presence of the mutation does not appear to carry significant treatment or prognosis carry significant treatment or prognosis relevant information.relevant information.

Diagnostic CriteriaDiagnostic Criteria

The Polycythemia Vera Study Group (PVSG) The Polycythemia Vera Study Group (PVSG) criteria include:criteria include: A consistently elevated platelet count >600,000/ A consistently elevated platelet count >600,000/

microL. microL. Megakaryocytic hyperplasia on bone marrow Megakaryocytic hyperplasia on bone marrow

aspiration and biopsy.aspiration and biopsy. Absence of the Philadelphia chromosome on routine Absence of the Philadelphia chromosome on routine

cytogenetic study.cytogenetic study.Molecular studies of the BCR/ABL gene rearrangement are Molecular studies of the BCR/ABL gene rearrangement are now recommended to exclude cytogenetically masked cases now recommended to exclude cytogenetically masked cases of CML.of CML.

Diagnostic CriteriaDiagnostic Criteria

Absence of infection, inflammation, and other Absence of infection, inflammation, and other causes of reactive thrombocytosis. causes of reactive thrombocytosis.

Absence of peripheral blood, bone marrow, Absence of peripheral blood, bone marrow, and karyotypic evidence for a myelodysplastic and karyotypic evidence for a myelodysplastic disorder or AMM.disorder or AMM.

Normal iron stores, as evidenced by normal Normal iron stores, as evidenced by normal serum ferritin and normal red cell mean serum ferritin and normal red cell mean corpuscular volume. corpuscular volume.

Diagnostic CriteriaDiagnostic Criteria

The PSVG criteria are the “gold standard” The PSVG criteria are the “gold standard” for the diagnosis of ET.for the diagnosis of ET.The World Health Organization (WHO) The World Health Organization (WHO) criteria are similar and include:criteria are similar and include: A sustained platelet count >600,000/microL.A sustained platelet count >600,000/microL. Bone marrow biopsy showing proliferation of Bone marrow biopsy showing proliferation of

enlarged, mature megakaryocytes.enlarged, mature megakaryocytes. No evidence of PV, CML, chronic idiopathic No evidence of PV, CML, chronic idiopathic

myelofibrosis, myelodysplastic syndrome, or myelofibrosis, myelodysplastic syndrome, or reactive thrombocytosis.reactive thrombocytosis.

TreatmentTreatment

Some patients with ET may have a significantly Some patients with ET may have a significantly decreased life expectancy although many have decreased life expectancy although many have normal life expectancy without associated normal life expectancy without associated disease-related complications.disease-related complications.

The most frequent symptoms are vasomotor and The most frequent symptoms are vasomotor and are easily managed with low dose aspirin (40 to are easily managed with low dose aspirin (40 to 325 mg/day).325 mg/day).

Thrombotic events in low-risk patients are Thrombotic events in low-risk patients are infrequent and therefore cytoreductive therapy is infrequent and therefore cytoreductive therapy is not indicated.not indicated.

TreatmentTreatment

Cytoreductive therapy is indicated in high-risk Cytoreductive therapy is indicated in high-risk patients to prevent thrombosis.patients to prevent thrombosis.

The decision to use drug therapy in intermediate The decision to use drug therapy in intermediate risk patients should be made on an individual risk patients should be made on an individual and may be considered in patients with extreme and may be considered in patients with extreme thrombocytosis (platelets >1.5 million/microL).thrombocytosis (platelets >1.5 million/microL).

Bleeding complications are less frequent than Bleeding complications are less frequent than thrombosis and may be prevented by the thrombosis and may be prevented by the avoidance of doses of aspirin greater than 325 avoidance of doses of aspirin greater than 325 mg/day and avoidance of NSAIDs.mg/day and avoidance of NSAIDs.

Therapeutic AgentsTherapeutic Agents

Hydroxyurea:Hydroxyurea: Inhibits DNA synthesis by inhibiting the enzyme Inhibits DNA synthesis by inhibiting the enzyme

ribonucleotide reductase, producing a megaloblastic ribonucleotide reductase, producing a megaloblastic blood picture.blood picture.

Initial dose of 15 mg/kg per day po in divided doses.Initial dose of 15 mg/kg per day po in divided doses. Dose is adjusted to keep platelets between 100,000 Dose is adjusted to keep platelets between 100,000

and 400,000/microL.and 400,000/microL. Rapid onset of action, usually within 3-5 days.Rapid onset of action, usually within 3-5 days. Teratogenic and should not be used in pregnancy, Teratogenic and should not be used in pregnancy,

breast-feeding, or women with childbearing potential.breast-feeding, or women with childbearing potential.

HydroxyureaHydroxyurea

Side effects are usually minimal and may include:Side effects are usually minimal and may include: Oral ulcersOral ulcers HyperppigmentationHyperppigmentation Skin rashSkin rash Nail changesNail changes Leg ulcersLeg ulcers NauseaNausea DiarrheaDiarrhea AlopeciaAlopecia FeverFever Abnormal liver function testsAbnormal liver function tests AnemiaAnemia NeutropeniaNeutropenia

Therapeutic AgentsTherapeutic Agents

Anagrelide:Anagrelide: An oral imidazoquinazoline derivative that An oral imidazoquinazoline derivative that

inhibits platelet aggregation via platelet anti-inhibits platelet aggregation via platelet anti-cyclic AMP phosphodiesterase activity.cyclic AMP phosphodiesterase activity.

Lowers platelets via interference with Lowers platelets via interference with megakaryocyte proliferation and maturation, megakaryocyte proliferation and maturation, resulting in platelet underproduction.resulting in platelet underproduction.

Initial dose is 0.5 mg po tid or qid.Initial dose is 0.5 mg po tid or qid. Dose is adjusted according to platelet count Dose is adjusted according to platelet count

response and symptomatology.response and symptomatology.

AnagrelideAnagrelide

Side effects are mainly related to direct Side effects are mainly related to direct vasodilatory and inotropic effects and vasodilatory and inotropic effects and include:include: HeadacheHeadache Palpitations/tachycardiaPalpitations/tachycardia Fluid retentionFluid retention DiarrheaDiarrhea Congestive heart failureCongestive heart failure

Hydroxyurea versus AnagrelideHydroxyurea versus Anagrelide

Anagrelide plus aspirin has been shown to Anagrelide plus aspirin has been shown to carry a higher risk of arterial thrombosis, carry a higher risk of arterial thrombosis, venous thrombosis, serious hemorrhage, venous thrombosis, serious hemorrhage, and death from vascular causes, in and death from vascular causes, in addition to a significantly higher rate of addition to a significantly higher rate of transformation into myelofibrosis at five transformation into myelofibrosis at five years than hydroxyurea plus aspirin.years than hydroxyurea plus aspirin.Thus, hydroxyurea plus aspirin is Thus, hydroxyurea plus aspirin is recommended as first line therapy in ET. recommended as first line therapy in ET.

Therapeutic AgentsTherapeutic Agents

Alpha InterferonAlpha Interferon High cost and toxicity issues.High cost and toxicity issues. Reserved for use in high-risk women of childbearing Reserved for use in high-risk women of childbearing

age, pregnant women, and patients failing treatment age, pregnant women, and patients failing treatment with hydroxyurea.with hydroxyurea.

Platelet apheresisPlatelet apheresis Reduces the platelet count only in the short-term.Reduces the platelet count only in the short-term. Restricted to acute cerebrovascular complications, Restricted to acute cerebrovascular complications,

digital ischemia, and rare life-threatening situations.digital ischemia, and rare life-threatening situations.

PipobromanPipobroman An alkylating agent.An alkylating agent. Not available in the US, but used widely in Europe.Not available in the US, but used widely in Europe.

Therapeutic AgentsTherapeutic Agents

Low dose aspirinLow dose aspirin 40 to 325 mg/day. 40 to 325 mg/day. Prevents recurrent vascular events in high-risk groups Prevents recurrent vascular events in high-risk groups

as well as thrombosis.as well as thrombosis. Effective in treating vasomotor symptoms.Effective in treating vasomotor symptoms.

RadiophosphorusRadiophosphorus Radioactive phosphorus 32P oral or IVRadioactive phosphorus 32P oral or IV IV is used only for patients with a life expectancy IV is used only for patients with a life expectancy

estimated to be less than 10 years.estimated to be less than 10 years.

SummarySummary

ET is a member of the family of chronic ET is a member of the family of chronic myeloproliferative disorders.myeloproliferative disorders.

ET is suspected in a patient with:ET is suspected in a patient with: A chronically elevated platelet count.A chronically elevated platelet count. Clinical thrombotic or hemorrhagic symptoms.Clinical thrombotic or hemorrhagic symptoms. A mild degree of splenomegaly.A mild degree of splenomegaly.

ET is a diagnosis of exclusion, therefore:ET is a diagnosis of exclusion, therefore: Causes of reactive thrombocytosis must be ruled out.Causes of reactive thrombocytosis must be ruled out. Other CMPDs or myelodysplasia must be ruled out.Other CMPDs or myelodysplasia must be ruled out.

ReferencesReferences

Harrison, Claire. Essential thrombocythemia: Harrison, Claire. Essential thrombocythemia: challenges and evidence-based management, challenges and evidence-based management, British Journal of Haematology, 2005.British Journal of Haematology, 2005.Schaffer, Andrew. Thrombocytosis, NEJM, Schaffer, Andrew. Thrombocytosis, NEJM, March 18, 2004.March 18, 2004.Tefferi, Ayalew. Approach to the patient with Tefferi, Ayalew. Approach to the patient with thrombocytosis. UpToDate, 2006.thrombocytosis. UpToDate, 2006.Tefferi, Ayalew. Diagnosis and clinical Tefferi, Ayalew. Diagnosis and clinical manifestations of essential thrombocythemia, manifestations of essential thrombocythemia, UpToDate, 2006.UpToDate, 2006.Tefferi, Ayalwe. Prognosis and treatment of Tefferi, Ayalwe. Prognosis and treatment of essential thrombocythemia, UpToDate, 2006.essential thrombocythemia, UpToDate, 2006.