enrolled in a prospective observational study. Blood, 105, 2664 \200\22370. 10. Lengfelder, E. et al. (2000). Interferon alpha in the treatment of polycythemia vera. Ann Hematol, 79, 103 \200\2239. 11. Silver, R.T. (2006). Long-term eff ects of the treatment of polycytemia vera with recombinant interferon alpha. Cancer, 107, 451 \200\2238. 276 CHAPTER 7 Myeloproliferative neoplasms 12. Landolfi , R. et al. (2006). Thrombosis and bleeding in polycythemia vera and essential thrombocythemia: pathogenetic mechanisms and prevention. Best Pract Res Clin Hematol, 19, 6 17 \200\22333. 13. Robinson, S. et al. (2005). The management and outcome of 18 pregnancies in women with polycythemia vera. Haematologica, 90, 1477 \200\22383. 14. McMullin, M.F. et al. (2005). Guidelines for the diagnosis, investigation and managemen t of polycythemia/erythrocytosis. Brit J Haematol, 130, 174 \200\22395. 15. Passamonti, F. (2012). How I treat polycythemia vera. Blood; 120, 275 \200\22384. 16. V erstovsek, S. et al. (2010). Durable responses with the JAK1/JAK2 inhibitor, INCB018424, in patients with polycythemia vera (PV) and essential thrombocythemia (ET) refractory or into lerant to hydroxyurea (HU) [abstract]. Blood (ASH Annual Meeting Abstracts), 116, 313. Further reading Barosi, G. et al. (2009). Response criteria for essential thrombocythemia a nd polycythemia vera: result of a European LeukemiaNet consensus conference. Blood, 113(20) , 4829 \200\22333. 277 MANAGEMENT OF PV 278 CHAPTER 7 Myeloproliferative neoplasms Secondary erythrocytosis See causes of 2 erythrocytosis in E Table 7.1, p.264. Eff ects of the i red cell mass \200 i peripheral vascular resistance. \200 d cardiac o utput. \200 d systemic O2 transportation resulting in, e.g. d cerebral blood fl ow and O2 and glucose delivery to the brain. Thromboembolic complications also occur. Thus \200\230compensatory \200\231 erythrocytosis is a pathological rather than physiological condition. Symptoms Non-specifi c and those of the underlying cause (particularly if cardiac or pulmon ary) may predominate. Pruritus, splenomegaly, or the presence of leucocytosis or thrombocyt osis suggest the alternative diagnosis of PV. Investigations As listed under PV, notably JAK2 mutation analysis, serum EPO, arte- rial O2 saturation, renal and hepatic function, urinalysis, renal ultrasound and, if necessary, ab dominal CT. Treatment The aim of therapy must be correction of the underlying cause where pos- sible an d reduction of the RCM. Venesection is the treatment of choice and if possible should be co ntinued until a target Hct is achieved. The indications for venesection and recommended tar get Hct vary with the underlying cause:1 \200 High O2 affi nity haemoglobins: Indications \200\224dizziness, dyspnoea or angina, thrombosis, comparable family member with thrombosis; target Hct <0.60 or if thrombosis or symptoms wit h Hct <0.60, target <0.52. Hypoxic pulmonary disease: Indications \200\224symptoms of hyperviscosity or Hct >0.56; target Hct 0.50 \200\2230.52. Cyanotic congenital heart disease: Indications \200\224 chest and abdominal pain, myalgia and weakness, fatigue, headache, blurred vision, amaurosis fugax, paraesthesiae, slow mentation and i vis cosity; target individualized; isovolaemic venesection for symptoms. Avoid Fe defi ciency w hich may compromise O2 delivery. \200 Post-renal transplant erythrocytosis: Indication \200\224failure to respond to ACE inhibitor or angiotensin II receptor antagonist; target Hct <0.45. In patients with cyanotic congenital heart disease, pulmonary disease or high O2 affi nity hemoglobin, the benefi t of venesection can be determined by symptomatic response or by usi ng the serum EPO level as a measure of tissue hypoxia. Myelosuppressive therapy is not indicated in any of these disorders. Reference 1. McMullin, M.F. et al. (2005). Guidelines for the diagnosis, investigation and management of polycythemia/erythrocytosis. Brit J Haematol, 130, 174 \200\22395. 279 RELATIVE ERYTHROCYTOSIS Relative erythrocytosis Elevation of Hb and Hct with n or minimally i RBC mass and n or d p lasma volume defi nes RE. Apparent polycythaemia, spurious poly- cythaemia, pseudopolycytha emia, stress erythrocytosis and Gaisbock \200\231s syndrome (RE associated with hypertensio n and nephropathy) are syn- onymous terms for this disorder. However the existence of chron ic plasma contraction is contentious. Etiology Unclear. Some cases may represent extreme ends of n ranges for red cell and plasma volumes, but in most obesity, cigarette smoking, and hypertension are present singly or in combination. Haemoconcentration from dehydration or diuretic therapy should be excluded. Investigations \200 FBC generally shows only modest i Hct. Confi rm persistence with at least 2 measurements over a 3-month period. Serum EPO usually n; may be d. \200 JAK2-V617F mutation \210\222ve. \200 RCM studies n ow rarely performed as PV excluded by sEPO and JAK2 analysis, however can be useful here. Demonstrate n RCM and d plasma volume in 733%; most h ave high n RCM and low n plasma volume. Important to exclude renal disease and arterial hypoxaemia. \200 BM biopsy not usually ne cessary but normal when carried out. Management \200 Involves dealing with reversible associated features, i.e. weight reduction, cessation of smoking, control of i BP (without thiazide diuretic), reduction of alcohol intake, and reduction in stress (where possible). Correction of these factors may r esult in spontaneous improvement. Venesection is not standard management; however, it is suggested that patients with recent thrombosis or Hct levels chronically >0.54 should be considered f or venesection.1 Monitor untreated patients to exclude further i in Hct. Natural history and treatment \200 Not clear. Retrospective analysis appears to suggest a n i incidence of vaso-occlusive episodes that may relate to associated risk factors in the lifestyle of the patients rather than the i PCV. Low-dose aspirin (75mg/d) advisable for patients with overt thrombotic risks and no GI contraindication. No role for myelosuppressive therapy. \200 Many patients improve with the simple measures specifi ed. \200 Follow-up can be done in primary care. Reference 1. McMullin, M.F. et al. (2005). Guidelines for the diagnosis, investigation and management of polycythemia/erythrocytosis. Brit J Haematol, 130, 174 \200\22395. 280 CHAPTER 7 Myeloproliferative neoplasms Idiopathic erythrocytosis Heterogeneous group with absolute erythrocytosis (i RCM) but no c lear cause for 1 or 2 erythrocytosis. Some patients formerly given this diagnosis have been shown to have JAK2 exon 12 mutations. \200 May be physiological variant: extreme \200\230high-normal \200\231 values. \200 5 \200\22310% showed defi nite features of PV a fter several years of follow-up. Others develop clear evidence of SE, e.g. sleep apnoea. \200 Long-term follow-up is requi red in these patients. \200 Venesection to a Hct <0.45 has been recommended because of an incidence of fatal thromboembolic and haemorrhagic events similar to PV.1 Myelosuppressive therapy is contraindicated. Reference 1. McMullin, M.F. et al. (2005). Guidelines for the diagnosis, investigation and management of polycythemia/erythrocytosis. Brit J Haematol, 130, 174 \200\22395. 281 ESSENTIAL THROMBOCYTHAEMIA Essential thrombocythaemia ET (syn. 1 or idiopathic thrombocythaemia) is characterized by persis- tent thrombocytosis that is neither reactive (i.e. 2 to another condition) nor d ue to another myeloproliferative neoplasm or a myelodysplastic disorder. It is a diagnosis of exclusion and is biologically heterogeneous. Incidence True incidence unknown but probably up to 3 per 100,000 annually;1 slight excess in \231\200; median age at diagnosis 60 years; frequently occurs <40 years; very rare <20 years. Pathogenesis Etiology unknown. No association with radiation, drugs, chemicals, or viral in fection. Heterogeneous pathogenesis. The JAK2-V617F muta- tion is found in 750% of patients with ET,2 though it is not clear how this mutation produces 3 diff erent clinical phenotyp es of MPN. The mutation load in ET is lower than in PV and IMF and very rarely shows homozy gous JAK2 mutation.3,4 Further diff erences are lower gene dosage in ET, generally stable f requency of the JAK2-V617F mutant allele over time, and higher expression in platelets than in neutrophils.5 There is evidence of clonality in some patients with JAK2-V617F \210\222 ve ET including the presence of a mutation of the thrombopoietin (TPO) receptor (MPL). Soma tic mutations of codon 515 at the transmem- brane \200\223juxtamembrane junction of MPL (MP L-W515L or MPL-W515K) have been identifi ed in about 10% of JAK2-V617F \210\222ve PMF pati ents and 1% with JAK2-V617F \210\222ve ET.6 Hereditary thrombocytosis has been described d ue to mutations causing hypersensitivity of MPL to TPO7 or i translation of TPO from mRNA.8 ET patients with the JAK2-V617F mutation may have a higher frequency of thrombotic complic ations and it has been suggested that they have a clinical phenotype similar to PV and a di ff erent clinical course from ET patients without the mutation.9 Platelets in ET are often functionally abnormal showing impaired aggre- gation in vitro. High platelet counts (>1000 \227 109/L) are associated with an acquired von Willebrand syndrome.10 The mechanism may b e i catabolism of large-molecular-weight multimers; reduction in the platelet count correct s the abnormality and reduces haemorrhagic epi- sodes.10,11 Clinical features \200 Diagnosis often follows detection of thrombocytosis on a routine FBC; up to 50% patients are asymptomatic. Others may present with \200\230vasomotor \200 \231, thrombotic, and/or haemorrhagic symptoms. Vasomotor symptoms occur in 40%: headache, light headedness, syncope, atypical chest pain, visual upset, paraesthesiae, livedo reticularis, and erythromelalgia (erythema and burning discomfort in hands or feet due to digital microvascular occlusion). 282 CHAPTER 7 Myeloproliferative neoplasms Haemorrhagic symptoms occur in 25% (major <5%): easy bruising, mucosal or GI bleeding, or u nexplained or prolonged bleeding after trauma or surgery. Thrombosis occurs in 720% (major <10%): arterial > venous, e.g. MI, CVA, splenic, or hepatic vein thrombosis. Splenomegaly found in <40% (less common and less marked than in other myeloproliferative disorders). Splenic atrophy may occur from repeated microvascular infarction. \200 Recurrent abortion s and fetal growth retardation due to multiple placental infarctions may occur in young women with ET. Patients presenting with abdominal vein (portal vein) thrombosis should be screened for a possible underlying MPN. Diff erential diagnosis Most cases of isolated thrombocytosis are reactive and <10% are due to a 1 hematological disorder. The overlapping clinical phenotypes of ET, PV. PMF, and C ML can make diagnosis diffi cult. Before a diagnosis of ET is made, causes of reactive thro mbocytosis (RT) must be excluded (discussed on E p.290) by detailed history, examination an d investigation, as must PV, CML, PMF, and MDS with a predominant thrombocytosis which can all mimic ET. Investigations \200 FBC: Platelets persistently >450 \227 109/L (may be as high as 5000 \227 109/L); the degree of thrombocytosis is not a criterion for diff erentiating ET from RT. Hb usually n; may be d with d MCV due to chronic blood loss; WBC usually n. Mean platelet volume (MPV) usually n but can be raised; raised platelet distribution width (PDW). Automated FBC may give erroneous data in severe cases as giant platelets may be counted as RBCs. Blood fi lm: Thrombocytosis, variable shapes and sizes (platelet aniso-poikilo- cytosis), giant platelets, and platelet clumps; megakaryocyte fragments; basophilia may be present; variable degree of RBC abnormality: may be hypochromic and microcytic if Fe defi c ient; may be changes of hyposplenism, e.g. Howell \200\223Jolly bodies. \200 Peripheral b lood mutation screening for JAK2-V617F mutation: Detected in 750% of patients with ET; presence excludes reactive thrombocytosis; absence does not exclude ET. Bear in mind false-+ve results due to highly sensitive allele-specifi c assays and false \210\222ve due to low mutant allele burden especially in ET.12 BM examination: Required to help diff erentiate ET from RT in JAK2-V617F \210\222ve patients and to diff e rentiate ET from other MPNs, notably pre-fi brotic PMF, and from MDS. Aspirate: may show i platelet clumps, i large megakaryocytes with \200\230hypermature \200 \231 appearances, i nuclear lobation, and large cytoplasm; little or no granulocyte or eryt hroid hyperplasia. Fe stores present in 40 \200\22370%. 283 ESSENTIAL THROMBOCYTHAEMIA Trephine biopsy: i megakaryocytes, dispersed throughout the marrow or with loose clustering; large, \200\230hypermature \200\231 with deeply lobated a nd hyperlobated nuclei; bizarre atypical forms seen in PMF not usually seen in ET; little o r no granulocyte or erythroid hyperplasia. Reticulin normal or minimal i (up to 25%); no fi brosis. No dysplastic features. Cytogenetics: abnormal in 5%; no specifi c diagnostic abnormalities; Always Ph \210\222ve. Other tests: Uric acid: i in 25%. \200 Pseudohyperkalaemia: in 25%. \200 ESR and acute phase protein s (CRP and fi brinogen) usually n in ET, often raised in RT but not discriminatory as infl ammation can also occur in patients with ET. Serum ferritin: if low Fe replacement therapy should fail to i Hb to the PV range. 2008 WHO diagnostic criteria for ET12 Availability of the JAK2-V617F clonal marker and an i use of BM histology has resulted in a recommended lower platelet count threshold for the d iag- nosis of ET than the historically used 600 to currently used 450 \227 109/L. Diagnosi s of ET requires that all 4 of these criteria are met (Table 7.5). Table 7.5 WHO diagnostic criteria for ET (2008)12 Persistent elevation of the platelet count \211 450 \227 109/L 1 2 Megakaryocyte proliferation with large and mature morphology; no or little granulocyte or e rythroid proliferation 3 Not meeting WHO criteria for CML, PV, PMF, MDS, or other myeloid neoplasm 4 Demonstration of JAK2-V617F or other clonal marker or in the absence of a clonal marker, no evidence of reactive thrombocytosis Diagnostic algorithm for suspected ET Once RT has been excluded (no reactive cause) by hist ory and examina- tion, the diagnostic algorithm recommended by Teff eri and Vardiman12 and based on the 2008 WHO criteria and 2013 BCSH guidelines may be used in a patient with suspe cted ET. Peripheral blood mutation screening for JAK2-V617F \200 V617F +ve: ET, PV, or PMF highly likely. Requires BM biopsy and cytogenetics. V617F \210\222ve: ET and PMF still possible and CML should also be considered. Requires BM biopsy and cytogenetics. Risk factors in ET \200 Thrombosis risk associated with previous thrombosis and age >60 y ears; no clear relationship between marked thrombocytosis and thrombotic risk; presence of leucocytosis is an additional risk factor,13 as is JAK2-V617F mutation positivity and homoz ygosity.7 284 CHAPTER 7 Myeloproliferative neoplasms Hemorrhage associated with extreme thrombocytosis (>1500 \227 109/L) and anti-platelet therapy. Risk strati \201 cation in ET14 Low risk \200 Age <40 years, and \200 No history of th rombosis, and \200 No high-risk features/cardiovascular risk factors. Intermediate risk \200 Neither low risk nor high risk. High risk \200 Age \211 60 years, or \200 Previous history of thrombosis. \200 Plat elets >1500 \227 109/L (though in younger patients higher levels could be accepted). Natural history ET is usually associated with a more favorable prognosis than the other MPN s. It generally follows an indolent course and life expectancy is near normal. The risk of life-threatening complications or of leu- kaemic transformation is very low. However, the r isk of AML has in the past been i by cytotoxic therapy (busulfan and 32P) though the risk i s much less with hydroxycarbamide. Need for therapy must be individu- alized, balancing the risk of therapy against risk of thrombosis or haem- orrhage, FBC results, co-morbidity, an d age. Risk of transformation is low for a patient with ET in the absence of busulfan or 32 P therapy: 2% leukaemic transformation and 4% evolution to myelofi brosis at 15 years.15 De ath due to thrombosis is reported in 11 \200\22325% with a cumula- tive rate of cardiovascu lar events of 2 \200\2233% per patient year with arterial thrombosis accounting for 60 \200 \22370% of events.16 Management Aim is to alleviate symptoms of microvascular disturbance (e.g. head- ache, ligh theadedness, atypical chest pain, or erythromelalgia) and reduce the risks and incidence of thrombotic and haemorrhagic com- plications by use of aspirin and normalization of platele t count (target <450 \227 109/L); balance these risks against the short and long-term risk s of therapy (see Table 7.6). \200 All patients with ET should be advised to make lifesty le changes (smoking, exercise, obesity) to reduce their risk of thrombosis and atherosclerosis and rev ersible cardiovascular risk factors should be treated (hypertension, hypercholesterolaemia) . NSAIDs should be avoided due to risk of hemorrhage. \200 Note: acquired von Willebrand sy ndrome (AvWS) occurs in some patients with ET with >1000 \227 109/L platelets; use aspirin cautiously and consider scre ening for AvWS and cytoreduction prior to aspirin therapy; in symptomatic patients cytoredu ctive therapy usually corrects the clinical symptoms and laboratory abnormality; cytoreduct ion is advised in asymptomatic patients with AvWS only if RiCoF <30%; low- dose aspirin may be used if the RiCoF remains >50%.10 285 ESSENTIAL THROMBOCYTHAEMIA Low-risk patients \200 These patients have no i risk of thrombosis (<2/100 patient years) or hemorrhage (71/100 patient years) compared to age- and sex- matched controls;17 thrombo tic deaths are rare; a \200\230watch and wait \200\231 policy is recommended.14 \200 No added risk with surgery. \200 Cytoreductive therapy should be avoided unless complication s occur. \200 Observation aspirin 75mg/d (if no contraindication). \200 Although the antithrombotic benefi t of low-dose aspirin was demonstrated in the ECLAP study in PV18 there is no evidence to support 1 prophylaxis in asymptomatic low-risk ET; the Italian guidelines do not recommend it19 though others do in the absence of a contraindication.20,21 The risks and benefi ts of low-dose aspirin should be carefully balanced in the individual patient.22 Microvascular symptoms (e.g. erythromelalgia) are an indication for low-dose aspirin and us ually respond promptly (75 \200\223100mg/day).23 Intermediate-risk patients \200 Many patients in this group may simply be treated with lo w- dose aspirin (if no contraindication: previous GI hemorrhage, symptomatic AvWS, or RiCoF >5 0%) and observation. Smokers should be encouraged to stop smoking and obese patients to lose weight to reduce their risks of thrombosis. Cytoreductive therapy: individualize treatment. Might be indicated for patients with marked thrombocytosis (>1500 \227 109/L) associated with a bleeding diathesis, or who are at i r isk of hemorrhage, or have cardiovascular risk factors. The ongoing PT-1 study randomizes between aspirin hydroxycarbamide. If treated: aim for platelet count <450 \227 109/L.24 High-risk patients \200 Aspirin: 7 5 \200\223100mg/d recommended for all high-risk patients; quickly relieves erythromelalgia (2 \200\2234d); extreme caution in patients with marked thrombocytosis, haemorrhagic compli cations or history of peptic ulceration; H2-antagonist or PPIs may be needed; markedly i bl eeding risk with higher aspirin doses. Dipyridamole is an alternative for patients unable t o tolerate aspirin. No data on the use of clopidogrel. Hydroxycarbamide (HC): established as standard treatment of choice in combination with aspi rin (when not contraindicated) for high-risk patients, defi nitely those >60 years. Dose 0. 5 \200\2231.5g/d maintenance after higher initial doses aiming to bring platelets <450 \227 109/L. \200 Control of thrombocytosis with HC reduces risk of thrombosis in high-ris k patients (3.6% vs 24% after 27 months in randomized study vs observation)25; HC + aspirin superior to anagrelide + aspirin in the UK MRC PT-1 randomized trial in 809 pa tients with high-risk ET: despite similar d in platelets, d rates of arterial thrombosis, m ajor hemorrhage, transformation to myelofi brosis (3 \227) and treatment withdrawal though i rate of venous thrombosis.26 286 CHAPTER 7 Myeloproliferative neoplasms Can be used in patients <60 years, though many physicians/ centers continue to prefer anagr elide or IFN in this group of patients. Some patients require HC in combination with anagre lide or IFN- to achieve a normal platelet count. Side eff ects: myelosuppression, oral ulceration, rash; contraindicated in pregnancy and breastfeeding; risk of leukemia not i by HC.10,26,27 Up to 10% of patients do not achieve the desired reduction in platelets; others develop unacceptable side eff ects, e.g. leg ulcers, cytopenias, or fever ; a working group has developed criteria to defi ne clinical resistance and intolerance to HC in ET to facilitate analysis of trials and management of individual patients.28 \200 \223 Platelets >600 \227 109/L after 3 months of at least 2g/day HC (2.5g/d if weight >80kg); or \200\223 Platelets >400 \227 109/L and WBC count <2.5 \227109/L at any dose of HC; or \200\223 Platelets >400 \227 109/L and Hb <10g/dL at any dose of HC; or \200\223 Presenc e of leg ulcers or other unacceptable mucocutaneous manifestations at any dose of HC; or \200\223 HC-related fever. Interferon: (start at 3 million units, 3 \227 weekly; usual maintenance 1 \200\2235 millio n units, 3 \227 weekly) can control thrombocytosis due to ET; useful in some younger patie nts and patients intolerant to HC or anagrelide; no risk of leukaemogenesis; 85% response r ate with 54% achieving normal platelet counts; reduction in splenomegaly in 66% with 17% no rmalization of spleen size;19 rarely used due to inconvenience of SC administration and poo r tolerance; drug of choice in pregnancy; pegylated IFN has equal effi cacy and a more conv enient once weekly dose schedule. Anagrelide: commence 500mcg bd, adjust according to response with weekly increments of 500mcg/d to usual therapeutic dose of 2 \200\2233mg/d. Has been p referred in younger patients, though HC often remains the standard treatment. Interferes wi th megakaryocyte diff erentiation; therapeutic eff ect usually seen within 14 \200\22321d; side eff ects: headache (>50%), palpitations (>50%), fl uid retention, diarrhea (15 \200 \22320%); contraindicated in pregnancy and patients with CCF or known cardiac disease. Busulfan: alkylating agent; produces prolonged control of platelet count; i risk of AML; re stricted to patients >75 years unable to comply with regular HC therapy; administer intermi ttently at 4 \200\2236mg/d for 2 \200\2236 weeks until response or as single dose of 0.5 \200\2231mg/ kg repeated if necessary after 2 \200\2233 months. Radioactive phosphorus (32P): may be considered in elderly patients (>75 years) unable to c omply with regular HC therapy; side eff ects: myelosuppression, long-term risk of AML (10%) ; 2.3mCi/m2 IV; may be repeated after 3 \200\2236 months. JAK2-inhibitors: may prove useful for accelerated-phase disease. Given excellent prognosis of ET, the role of JAK2 inhibitors in the majority of ET patients is unclear. 287 ESSENTIAL THROMBOCYTHAEMIA Table 7.6 Treatment for ET20 \231\200 of childbearing age ?Low-dose aspirina Low-dose aspirina IFN- + low-dose aspiri n Risk group Age <60 years Age >60 years ?Low-dose aspirina Not applicable Low risk Intermediate riskb Low-dose aspirina Not applicable High risk Hydroxycarbamide/ IFN- /anagrelidec + low-dose aspirin Hydroxycarbamide + low-dose aspirin a In the absence of a contraindication, including a RiCoF <50%. b Decision to use cytoreduc tive agents in intermediate risk ET should be made on individual patient basis, but not sta ndard. c Choice dependent on guidelines used and sphysican/center preference. ET in pregnancy \200 Close monitoring is recommended in all ET patients (including low- r isk patients). A multidisciplinary approach with close maternal and fetal monitoring is rec ommended. Additional thromboprophylaxis may be indicated. 1st trimester spontaneous abortion occurs frequently in young women with ET (25 \200\22340% ) with late pregnancy loss in 10%; abruptio placentae occurs in 3.6% and intrauterine growt h retardation (IUGR) in 4 \200\2235%.29 Maternal thrombosis and hemorrhage are uncommon. \200 High risk in \231\200 with a histo ry of severe complications in a previous pregnancy. Patients with the JAK2-V617F mutation have a higher risk of developing complications in pregnancy; aspirin did not prevent these and may worsen the out come in mutation \210\222ve mothers.30 If possible, stop potentially teratogenic drugs (hydroxycarbamide, anagrelide) at least 3 months before conception. Low-dose aspirin is recommended for pregnant \231\200 with ET with a history of microvascu lar symptoms or a previous adverse pregnancy event; generally low-dose aspirin is given thr oughout pregnancy and for at least 6 weeks after delivery for all \231\200 with ET and PV without contraindications.31 If possible, aspirin should be commenced before conception. LMWH is recommended for prophylaxis and treatment of DVT in selected high-risk pregnant women with ET and a history of late fetal loss, pre-term delive ry, VTE and IUGR (enoxaparin 40mg od, then bd from 16 weeks then od for 6 weeks post-partum ).29 Interferon alfa is cytoreductive treatment of choice when indicated: previous history of ma jor thrombosis or hemorrhage; platelet count >1000 \200\2231500 \227 109/L; familial throm bophilia or cardiovascular risk factors.29 Life-threatening hemorrhage in ET \200 Main sites: skin, mucous membranes, and GIT. \200 Most frequent in patients with platelet counts >1000 \200\2231500 \227 109/L. \200 Sto p antiplatelet agents. \200 Identify site of bleeding. 288 CHAPTER 7 Myeloproliferative neoplasms Hydroxycarbamide 2 \200\2234g/d \227 3 \200\2235d to d platelets (takes 3 \200\2235d for e ff ect). \200 Antifi brinolytic agents, e.g. tranexamic acid may be used. \200 Desmopre ssin/factor VIII concentrate of limited value if evidence of AvWS.10 Platelet transfusion may be helpful if no evidence of AvWS. Arterial thrombosis in ET \200 Commence aspirin 75mg/d (rapid response in TIA and erythromelalgia) if no major contraindication. Cytoreductive therapy to normalize platelet count. Venous thrombosis in ET \200 Commence heparin followed by oral anticoagulant therapy (tar get INR 2.0 \200\2233.0) according to standard protocols. Commence concomitant cytoreductive therapy to reduce risk of recurrence. Monitor platelet count and INR closely because of greater bleeding risk. Surgery in ET \200 i morbidity and mortality risk if surgery undertaken with poor control . \200 Withhold aspirin for at least 5 days before elective surgery if surgically required. Commence/adjust hydroxycarbamide/cytoreductive therapy to achieve platelet count <450 \227 109/L; especially if splenectomy planned. Resume oral cytoreductive therapy as soon as possible post- operatively; resume aspirin 24h after surgery if no excessive bleeding. Consider LWH prophylaxis as per standard protocols. \200 Surgical procedures may require specifi c antithrombotic strategies, e.g. heparin. Monitor patient with ET carefully for he morrhage or thrombosis. Thrombotic risks reduced if platelet count normal. References 1. Johansson, P. et al. (2004). Trends in the incidence of chronic Philadelphia chromosome neg ative (Ph \210\222) myeloproliferative disorders in the city of Gothenberg, Sweden, during 1983 \200\22399. J Intern Med, 256, 161 \200\2235. 2. Baxter, E.J. et al. (2005). Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet, 365, 1054 \200\22361. 3. Scott, L.M. et al. (2006). Progenitors homozygous for the V617F JAK2 mutation occur in m ost patients with polycythemia vera, but not essential thrombocythemia. Blood, 108, 2435 \200\2237. 4. Kralovics, R. et al. (2006). Acquisition of the V617F mutation of JAK2 is a l ate genetic event in a subset of patients with myeloproliferative disorders. Blood, 108, 1377 \200\22380. 5. Moliterno, A.R. et al. (2006) Molecular mimicry in the chronic myeloproliferative disord ers: reciprocity between quantitative JAK2 V617F and Mpl expression. Blood, 108, 3913 \200 \22315. 6. Pardanani, A.D. et al. (2006). MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 118 patients. Blood, 108, 3472 \200\2236. 7. Ding, J. et al. (2004). Familial essential thrombocythemia associated with a dominant- p ositive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopo ietin. Blood, 103, 4198 \200\223200. 8. Wiestner, A. et al. (1998). An activating splice donor mutation in the thrombopoietin ge ne causes hereditary thrombocythemia. Nat Genet, 18, 49 \200\22352. 9. Campbell, P.J. et al. (2005). Defi nition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. La ncet, 366, 1945 \200\22353. 289 ESSENTIAL THROMBOCYTHAEMIA 10. Elliot, M.A. and Teff eri, A. (2005). Thrombosis and hemorrhage in polycythemia vera an d essential thrombocythaemia. Br J Haematol, 128, 275 \200\22390. 11. Budde, U. and van Genderen, P.J. (1997). Acquired von Willebrand disease in patients wi th high platelet counts. SeminThromb Hemost, 23, 425 \200\22331. 12. Teff eri, A. and Vardiman, J.W. (2008). Classifi cation and diagnosis of myeloprolifera tive neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic al gorithms. Leukemia, 22, 14 \200\22322. 13. Carobbio, A. et al. (2007). Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation statu s. Blood, 109, 2310 \200\22313. 14. Finazzi, G. and Barbui, T. (2005). Risk-adapted therapy in essential thrombocythemia an d polycythemia vera. Blood Rev, 19, 243 \200\22352. 15. Passamonti, F. et al. (2004). Life expectancy and prognostic factors for survival in pa tients with polycythemia vera and essential thrombocythemia. Am J Med, 117, 755 \200\22361. 16. Vannucchi, A.M. and Barbui, T. (2007). Thrombocytosis and thrombosis Hematology 2007, 363 \200\22370. 17. Ruggeri, M. et al. (1998). No treatment for low risk thrombocythaemia: results from a prospective study. Br J Haematol, 103, 772 \200\2237. 18. Landolfi , R. et al. (2004). Effi cacy and safety of low dose aspirin in poilycythemia vera. N Engl J Med, 350, 114 \200\22324. 19. Barbui, T. et al. (2004). Practice guidelines for the therapy of essential thrombocythe mia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hem atology and the Italian Group for Bone Marrow Transplantation. Haematologica, 89, 215 \200 \22332. 20. Teff eri, A. and Barbui, T. (2005). bcr/abl \200\223negative, classic myeloproliferativ e disorders: diagnosis and treatment. Mayo Clin Proc, 80, 1220 \200\22332. 21. Campbell, P.J. and Green, A.R. (2005). Management of polycythemia vera and essential thrombocythemia. Hematology, 2005, 201 \200\2238. 22. Landolfi , R. and Di Gennaro, L. (2008). Prevention of thrombosis in polycythemia vera and essential thrombocythemia. Haematologica, 93, 331 \200\2235. 23. McCarthy, L. et al. (2002). Erythromelalgia due to essential thrombocthemia. Transfusio n, 42, 1245. 24. Cortelazzo, S. et al. (1995). Hydroxyurea for patients with essential thrombocythemia a nd a high risk of thrombosis. N Engl J Med, 332, 1132 \200\2236. 25. Harrison, C.N. et al. (2005). Hydroxyurea compared with anagrelide in high-risk essenti al thrombocythemia. N Engl J Med, 353, 33 \200\22345. 26. Finazzi, G. et al. (2005). Acute leukemia in polycythaemia vera: an analysis of 1638 pa tients enrolled in a prospective observational study. Blood, 105, 2664 \200\22370. 27. Barosi, G. et al. (2007). A unifi ed defi nition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an internationa l working group. Leukemia, 21, 277 \200\22380 plus corrigenda 21, 1135. 28. Barbui, T. and Finazzi, G. (2006). Myeloproliferative disease in pregnancy and other management issues. Hematology, 2006, 246 \200\22352. 29. Passamonti, F. et al. (2007). Increased risk of pregnancy complications in patients wit h essential thrombocythemia carrying the JAK2 (617V>F) mutation. Blood, 110, 485 \200\2239. 30. Harrison, C. (2005). Pregnancy and its management in the Philadelphia-negative myeloproliferative diseases. Br J Haematol, 129, 293 \200\223306. 31. Beer, P. et al. (2011). How I treat essential thrombocythemia. Blood, 117, 1472 \200 \22382. Further reading Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoie tic and Lymphoid Tissues, 4th ed. Lyon: IARC. 290 CHAPTER 7 Myeloproliferative neoplasms Reactive thrombocytosis Platelet counts of >450 \227 109/L occur as a reactive phenomenon and maybe seen in: \200 Infection. \200 Following surgery. \200 Post splenectomy or f unctional asplenia. \200 Malignancy, e.g. occult carcinoma. \200 Trauma. \200 Chronic infl ammatory states, e.g. collagen disorders. \200 Blood loss. \200 Fe defi ciency. \200 Haemolytic anemia. \200 Rebound in response to haematinics and/or chemotherapy. \200 Any severely ill patient on ITU. Raised platelet count in clonal hematological disorders occurs in CML, ET, PV, PMF, and als o in MDS (esp. 5q \210\222 syndrome). In RT platelets are usually <1000 \227 109/L but lev els of 1500 \227 109/L may occur. Platelet morphology usually normal but diff erentiation from ET relies on full clinical evaluation. BM examination if done reveals i megakaryocytes with n morphology. RT is generally not associated with an i risk of thrombosis or haemor- rhage and no specifi c treatment is required. However, short-term anti- coagulant or antiplatelet therapy is ad vised for marked thrombocytosis occurring in the immediate post-splenectomy period as an i incidence of thrombosis has been described in this situation. Improvement or resolution of the underlying cause usually results in normalization of the p latelet count in RT. 291 REACTIVE THROMBOCYTOSIS 292 CHAPTER 7 Myeloproliferative neoplasms Primary myelo \201 brosis 1 myelofi brosis (syns. idiopathic myelofi brosis (IMF), myelofi brosis with myeloid meta plasia) is a MPN characterized by marrow fi brosis, splenomegaly, extramedullary haematopoi esis, and teardrop poikilo- cytes and leucoerythroblastosis in the peripheral blood fi lm. Cases of myelofi brosis (MF) that evolve from PV (10 \200\22315% evolve into MF) or ET (72% evolve to MF) are designated post-PV myelofi brosis and post-ET myelofi brosis respectivel y. The term PMF is reserved for de novo cases. Incidence Rare disorder; 75 cases per million per annum; predominantly elderly patients (me dian 65 years); aff ects \231\202 and \231\200 equally. Pathogenesis \200 PMF is a clonal neoplastic proliferation arising from an early haematopoietic stem cell that leads to marked hyperplasia of morphologically abnormal megak aryocytes and clonal monocytes that stimulate reactive fi brosis of the BM. The JAK2-V617F mutation has been found in up to 58% of patients with PMF;1 it is homozygous in 13% of patients with PMF compared to 30% with PV and rare in ET.2,3 Presence of JAK2-V617F may correlate with poorer survival in PMF;4 homozygosity is associat ed with more frequent unfavorable cytogenetic abnormalities.5 The MPL-W515L or MPL-W515K mutation of the transmembrane domain of the thrombopoietin recep tor (cMPL) has been detected in 9% of patients with JAK2-V617F \210\222ve PMF; these mutat ions can co-exist in the same patient; 30% of patients with a cMPL mutation also have the J AK2-V617F mutation;6 the burden of each mutation appears to remain constant over time.7 Patients with MPL-W515L/K mutations may be older, have more severe anemia, and be more likely to require transfusion support.8 750% of patients with clinically similar PMF have no detectable mutation of JAK2 or cMPL, so these mutations cannot be the only cause of PMF and other gene tic events clearly contribute to the development of PMF; gains of genetic material occur in >50% of patients, most commonly 9p, 2q, 3p, 4, 12q, and 13q.9 PMF fi broblasts are non-clonal; fi brosis is a reactive process in response to cytokines r eleased by clonal megakaryocytes and monocytes, notably TGF- ,10 PDGF, IL-1, EGF, calmodul in, and bFGF may also play a role. Exaggeration of normal BM reticulin pattern progresses to intense collagen fi brosis that d isrupts and fi nally obliterates normal marrow architecture; ultimately osteosclerosis may develop. High levels of endothelial progenitors appear in PB in the prefi brotic phase and haematopoietic progenitors (CD34 cells) increase as PMF advances which facilitate s seeding of extramedullary haematopoiesis.11 293 PRIMARY MYELOFIBROSIS Extramedullary haematopoiesis develops in spleen and/or liver, and occasionally other sites , e.g. lymph nodes, skin, and serosal surfaces. Marrow fi brosis can also occur 2 to other disorders: a minority may follow chemotherapy or radiotherapy; can develop in response to chronic myeloproliferat ive disorders, myelodysplasia, and 2 to carcinomatous involvement. Clinical features and presentation \200 720% may be asymptomatic at diagnosis: mild abnor malities identifi ed on routine FBC or splenomegaly on clinical examination. 70 \200\22380% are diagnosed in the fi brotic stage; most present with symptoms of progress ive anemia and hepatosplenomegaly associated with hypercatabolic features of fatigue, weigh t loss, night sweats, and low-grade fever. Abdominal discomfort (heavy sensation in left upper quadrant), early satiety and/or dyspeps ia from pressure eff ects of splenic enlargement may prompt presentation. Symptoms and signs of marrow failure: lethargy, infections, bleeding. \200 Splenomegaly i s almost universal (>90%): moderate-to-massive (35%) enlargement; variable hepatomegaly (up to 70%); lymphadenopathy is uncommon (<10%). Gout in 75%; portal hypertension, pleural eff usion, and ascites (due to portal hypertension or peritoneal seeding) also occur. 20 \200\22330% of patients with PMF are diagnosed in pre-fi brotic stage which may clinical ly mimic ET; it evolves from hyperproliferation of megakaryocytes with moderate-to-marked t hrombocytosis (88% \211 500 \227 109/L), occasionally with thrombosis or bleeding, mild anemia, mild-to-moderate leucocytosis, and no or modest splenomegaly (15%) to classical fi brotic PMF.12 Investigations and diagnosis \200 FBC: Hb usually d or n (<10g/dL in 60%); normochromic n ormocytic indices; WBC may be d, n or i (730%; rarely >100 \227 109/L); basophilia and eosinophilia in 10 \200\22330%; platelets usually d or n; occasionally i. Blood fi lm: