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essential thrombocythemia

Etiology: - idiopathic Epidemiology: - less common than secondary thrombocytosis - 20% of patients with essential thrombocythemia are < 40 years of age [2] Genetics: - ~50% associated with JAK2 V617F mutation - autosomal dominant form associated with defects in THPO Clinical manifestations: 1) 2/3 of patients with essential thrombocytosis are asymptomatic 2) arterial thrombosis a) transient cerebral ischemia, syncope b) digital ischemia c) occlusion of coronary or mesenteric vessels d) erythromelalgia - dysethesia of palms & soles [2] e) livedo reticularis f) headache, visual symptoms 3) venous thrombosis a) portal vein b) hepatic vein c) splenic vein 4) hemorrhage (50% of patients with essential thrombocytosis) a) generally involves mucous membranes or skin - resembles von Willebrand's disease type 2 b) gastrointestinal hemorrhage c) when platelet count > 1,000,000/uL 5) splenomegaly (50%) [2] 6) hepatomegaly (20%) [2] Laboratory: 1) complete blood count (CBC)* a) elevated platelet count (> 450,00-600,000/uL) b) platelet count can exceed 1E06/uL for primary or secondary thrombocytosis c) normal red cell volume (MCV) d) hemoglobin < 13 g/dL e) leukocyte count elevated in 1/2 of patients with essential thrombocythemia f) basophilia may be noted [2] 2) impaired platelet aggregation response to: a) epinephrine b) collagen c) adenosine diphosphate 3) ristocetin cofactor activity (vWF) - low value is contraindication for aspirin [12] 4) hyperkalemia if platelets > 1E06/mm3 a) lysis of platelets or leukocytes during clot formation & retraction b) determine plasma K+ rather than serum K+ 5) bone marrow biopsy a) increase in megakaryocytes b) presence of adequate iron c) absence of collagen fibrosis d) absence of Philadelphia chromosome or other bcl-abl gene rearrangements 46) stem cell culture - spontaneous growth of megakaryocyte colony forming units in essential thrombocythemia 7) JAK2 V627F mutation (50%) 8) calreticulin (CALR) gene mutation 9) thrombopoietin (MPL) receptor gene mutation * case presented [2] with normal platelet count Diagnosis: - essential thrombocythemia a) elevated platelet count (> 600,000/uL) on 2 different occasions separated by at least 1 month in connection with bone marrow findings 1] hypercellular bone marrow with morphologically abnormal megakaryocytic hyperplasia in connection with elevated platelet count 2] absence of Philadelphia chromosome b) exclusion of secondary causes of thrombocytosis Complications: 1) risks for transformation to leukemia at 10, 20, & 30 years are 1%, 8%, & 24%, respectively [4] 2) risks for any myeloid transformation (leukemia, myelodysplastic syndrome, myeloid metaplasia, or polycythemia vera) are 9%, 28%, & 59%, respectively [4] - treatment with cytoreductive drugs does not affect risk of myeloid transformation [4] 3) hemorrhagic complications [2] 4) arterial thrombosis &/or venous thrombosis occur in 20-30% of patients with essential thrombocythemia [2] Differential diagnosis: - iron deficiency - hemorrhage - cancer - infection - chronic inflammatory disease Management: 1) asymptomatic patients younger than 60 years of age without history of thrombosis can be observed if platelet counts are < 1,000,000/uL [2] 2) indications for treatment* [2] - patients > 60 years of age - platelet count > 1,000,000/uL - history of thrombosis - increased risk for thrombosis due to cardiovascular risk, i.e.hypertension, diabetes mellitus 3) treatment a) hydroxyurea 500-2000 mg QD + aspirin 81 mg QD - lowers risk of arterial thrombosis & bleeding regardless of platelet count achieved [2] b) anagrelide + aspirin may be less effective than hydroxyurea + aspirin in preventing thrombosis [2,5] c) interferon-alpha if pregnant - 3 million units SC d) previous guideline: lower platelet count to < 400,000/uL 4) smoking cessation 5) control of platelet count, plateletpheresis a) acute ischemic events b) platelet count > 1,500,000/uL 6) aspirin & dipyridamole are controversial a) may lead to serious hemorrhage b) may protect against thrombosis c) aspirin 81 mg QD 1] indicated in patients with thrombosis despite adequate platelet count control 2] may be used to treat erythromelalgia [2] 7) platelet pheresis or platelet transfusion may be required with hemorrhage 8) treat thrombosis with anticoagulation * essential thrombocythemia discovered incidentally on routine health examination requires treatment if indications for treatment are satisfied [2] despite a lack of guidelines for screening

General

thrombocytosis (thrombocythemia)

References

  1. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1763
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 16, 17, 18. American College of Physicians, Philadelphia 1998, 2006, 2012, 2015, 2018 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. Schiller G, in: UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  4. Wolanskyj AP, Schwager SM, McClure RF, Larson DR, Tefferi A. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc. 2006 Feb;81(2):159-66. PMID: 16471068
  5. Geriatrics at your Fingertips, 13th edition, 2011 Reuben DB et al (eds) American Geriatric Society
  6. Beer PA, Green AR. Pathogenesis and management of essential thrombocythemia. Hematology Am Soc Hematol Educ Program. 2009:621-8 PMID: 20008247
  7. Barbui T, Carobbio A, Rambaldi A, Finazzi G. Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor? Blood. 2009 Jul 23;114(4):759-63. PMID: 19372254
  8. Passamonti F, Thiele J, Girodon F et al A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment. Blood. 2012 Aug 9;120(6):1197-201 PMID: 22740446
  9. Tefferi A Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013 Jun;88(6):507-16 PMID: 23695894
  10. NEJM Knowledge+ Question of the Week. Aug 29, 2017 https://knowledgeplus.nejm.org/question-of-week/1108/
  11. Harrison CN, Campbell PJ, Buck G et al Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005 Jul 7;353(1):33-45. PMID: 16000354 Free Article
  12. NEJM Knowledge+ Hematology