A. Causes

1. Reactive Thrombocytosis (RT)
   1. Acute reactions to various stimuli
   2. Platelet counts >400K/µL are common in community screening (~1%)
   3. 92% of patients with single count >400K/µL return to normal range on repeat count
2. Transient Conditions causing RT
   1. Response to exercise
   2. Dehydration
   3. Recovery from thrombocytopenia
   4. Acute infections (see also below)
   5. Acute blood loss
   6. Myocardial infarction
3. Chronic Conditions causing RT
   1. Effects on Erythrocytes
   2. Asplenia
   3. Cancers - particularly with inflammatory comment
   4. Autoimmune Disease
   5. Iron deficiency anemia
4. Effects on Erythrocytes
   1. Iron Deficiency anemia
   2. Hemolysis
   3. Hemorrhage
5. Neoplasm
   1. Carcinomas
   2. Hodgkin's Disease
   3. Certain non-Hodgkin lymphomas (particularly with high IL-6 levels)
   4. Infection such as cold viruses, pneumonias, abscess, endocarditis
6. Autoimmune Disease
   1. Rheumatoid Arthritis
   2. Wegener's granulomatosis
   3. Inflammatory Bowel Disease
   4. Other Vasculitides
7. Granulomatous Disease
   1. Tuberculosis
   2. Sarcoidosis
8. Drug Reactions
   1. Vincristine
   2. All-trans retinoic acid
   3. Cytokines
   4. Growth factors
9. Essential Thrombocythemia (ET) [2]
   1. ET is a myeloproliferative disorder
   2. Prevalence ~35 in 100,000 persons
   3. ~1% of patients with platelet count >400K/µL develop ET over 5 years

B. Symptoms

1. Arterial Thrombosis
   1. Transient Ischemic Attacks (TIA) and stroke fairly common
   2. Myocardial infarction
   3. Renal Dysfunction
   4. Mesenteric ischemia
2. Weakness, Dizziness
3. Paresthesias
4. Bleeding: Epistaxis, easy bruising, GI bleeding, intracranial bleed
5. Splenomegaly (60% of patients)
6. Symptoms much more common in ET than other disorders
   1. Reactive thrombocythemia rarely has symptoms
   2. Rarely need to treat reactive thrombocythemia, even with platelets >1 million/µL

C. Pathophysiology

1. Thrombopoietin (TPO) and Interleukin 6 are the major regulators of platelet levels
2. Reactive Thrombocytosis
   1. TPO levels are high or inappropriately normal in reactive thrombocytosis [1]
   2. Reactive thrombocytosis may be due to IL-6 or other factors [3]
3. Essential (Clonal) Thrombocythemia
   1. TPO levels are also elevated or inappropriately high in essential (clonal) thrombocythemia
   2. c-Mpl abnormalities in essential thrombocythemia leads to reduced binding of TPO
   3. Malignant thrombocytosis is due to a humoral factor, probably not IL-6 [4]
   4. Essential thrombocythemia (ET) is due to abnormal lineage proliferation [5]

D. Diagnosis

1. No current way to definitively diagnose ET from RT
2. TPO levels generally high or inappropriately normal in both
3. IL6 and CRP levels typically elevated in RT but not in ET
4. Systemic disease usually present in RT, not causative in ET
5. Bone marrow evaluation is critical in sustained RT to rule out ET
6. Presence of thrombotic, vascular and bleeding complications much more common in ET

E. Essential Thrombocythemia (ET) [5]

1. One of the chronic myeloproliferative disorders
   1. Thrombocythemia also frequently occurs in polycythemia vera (PCV)
   2. Some cases of ET may actually represent prefibrotic idiopathic myelofbirosis or PCV
   3. ~50% of cases due to mutation of signalling kinase JAK2
   4. JAK2+ mutant ET is easier to diagnose than normal JAK2
2. Diagnosis of JAK2 Mutant ET
   1. Platelet count >450K/µL
   2. Mutation in JAK2
   3. No other myeloid cancer, especially JAK2+ PCV, myelofibrosis, or myelodysplasia (MDS)
3. Diagnosis of JAK2 Normal ET
   1. Platelet count >450K/µL
   2. Normal JAK2
   3. No reactive cause for thrombocytosis
   4. Normal ferritin (>20µg/L)
   5. No other myeloid cancer, especially CML, myelofibrosis, PCV, or MDS
4. Symptomatic Disease
   1. Thrombosis - especially vasomotor symptoms, deep vein thrombosis, pulmonary embolism
   2. Hemorrhage - due to dysfunctional platelets
   3. Rare transformation to acute leukemia or myeloid metaplasia
   4. Budd-Chiari Syndrome (hepatic vein thrombosis) and portal vein thrombosis increased in ET
5. Indications for Treatment
   1. Asymptomatic patients - usually treat only for platelet counts >1.0-1.2 Million / µL
   2. Secondary Treatment (after an event) - maintain platelet count <600K/µL
   3. Generally treat with for higher risk: age >60 or cardiovascular risk factors
   4. Platelets >1.5 million/µL should generally be treated with cytoreduction
6. Acute Treatment of Thrombotic complications
   1. Heparin is an activator of antithrombin, an anticoagulant
   2. Give IV or SC (APTT increased 1.4-2.0X)
   3. Autoimmune destruction of platelets may also occur
   4. Warfarin (Coumadin®) may be used longer term
7. Agents for Chronic Therapy
   1. Hydroxyurea - first line for platelet count reduction
   2. Anagrelide - alternative first line for platelet count reduction
   3. Alkylating agents - generally used when hydroxurea and anagrelide have failed
   4. Aspirin
   5. Dipyridamole
8. Hydroxyurea (Hydrea®) [7]
   1. Myelosuppressive therapy
   2. Dose is 10-15mg/kg/day
   3. Very effective for reduction of platelet counts, maintain <600K/µL
   4. Overall well tolerated, and significantly decreases risk for recurrent events
   5. Reduces risk of thrombosis in high risk patients from ~24% to <4%
   6. Hydroxyurea confers increased late risk of leukemia
   7. Other side effects: mucocutaneous lesions, neutropenia (reversible), GI complaints
9. Anagrelide (Agrylin®) [8]
   1. Reasonable alternative for patients resistant or intolerant to HU
   2. Blocks maturation of megakaryocytes and decreases platelet production
   3. Inhibits platelet cyclic AMP phosphodiesterase
   4. Hepatic metablism, excreted in urine, elimination half-life 76 hours
   5. Dose is 0.5mg po qid or 1mg bid; maximum is 2.5mg qid
   6. Responses within 7-14 days; effects are reversible within a few days
   7. Patients do not become refractory to this agent
10. Alkylating Agents: busulfan, melphalan

References

1. Schafer AI. 2004. NEJM. 350(12):1211
2. Ruggeri M, Tosetto A, Frezzato M, Rodeghiero F. 2003. Ann Intern Med. 139(6):470
3. Tefferi A, Ho TC, Ahmann GJ, et al. 1994. Am J Med. 97(4):374
4. Estrov Z, Talpaz M, Mavligit G, et al. 1995. Am J Med. 98(6):551
5. Campbell PJ and Green AR. 2006. NEJM. 355(23):2452
6. Wang JC, Chen C, Novetsky AD, et al. 1998. Am J Med. 104(5):451
7. Cortelazzo S, Finazzi G, Ruggeri M, et al. 1995. NEJM. 332(17):1132
8. Anagrelide. 1997. Med Let. 39(1016):120