Clinical Practice Guideline



Developed for the

Aerospace Medical Association

by their constituent organization

American Society of Aerospace Medicine Specialists


Overview: Thrombocytosis, also called thrombocythemia, is generally defined as a platelet count greater than a defined upper limit of normal that may vary between 350,000/μl to 600,000/μl, depending on the laboratory or medical reference.  The most common cut off for normal is <450,000/μl.


Elevated platelet counts are often an incidental or unexpected finding on a complete blood count (CBC) conducted to evaluate an unrelated condition.10  For those individuals found to have thrombocytosis without associated bleeding or thrombosis, the first challenge is to find the cause.


The causes of thrombocytosis are separated into two categories:  autonomous (primary) thrombocytosis and reactive (secondary) thrombocytosis.  Autonomous thrombocytosis occurs as a result of myeloproliferative disorders, myelodysplastic disorders, or rarely as a result of a hereditary condition.19  Reactive thrombocytosis is most often a normal physiologic response to coexistent inflammatory condition (e.g., infection, chronic inflammatory condition).  Distinction between these two categories is important since autonomous thrombocytosis is associated with a significantly increased risk for thrombotic or hemorrhagic complications whereas reactive thrombocytosis is not.12


The most important medical complications of thrombocytosis are hemorrhage and thrombotic events.  Thrombosis occurs more frequently in arterial vessels but also occurs in large veins, potentially resulting in deep vein thrombosis, portal vein thrombosis, or pulmonary embolus.10  The most common location for an arterial thrombus is in the brain.10  Platelet counts that exceed 1,500,000/μl have an increased risk of bleeding.5  Thrombocytosis with counts less than 1,000,000/μl are more often associated with thrombosis but the relative platelet count is not proportional to an individual’s risk of thrombosis.11


Thrombocytosis is frequently present without the symptoms of hemorrhage and thrombotic events.  When other symptoms do occur they may be subtle and non-specific.  Microvascular thrombi are thought to be the cause of erythromelalgia, pain and warmth with erythema or mottling of the skin.  Erythromelalgia is usually present on the extremities but may also affect the face.11  Other non-specific symptoms may include headache and paresthesias.


A.  Reactive (secondary) thrombocytosis


The most common reason for an elevated platelet count is reactive thrombocytosis.12  Reactive thrombocytosis is most often a normal physiologic response to a coexistent inflammatory condition or surgery.  Lifetime reactive thrombocytosis may also be present in patients who have had a splenectomy.  Recent studies have found that between 87% and 96% of people found to have platelet counts over 500,000/μl had reactive thrombocytosis.1, 4, 9


Reactive thrombocytosis is generally a self-limiting condition that resolves with the inciting condition.  Thrombosis or bleeding occurs in less than 1% of patients with reactive thrombocytosis.1  The list of conditions that may lead to a reactive thrombocytosis is lengthy.  The platelet count should normalize within days after “correction” of whatever problem caused the thrombocytosis.  A more prolonged elevation of the platelet count suggests an undiagnosed problem, such as a persistent infection.  Common conditions include tissue damage from surgery, infection, malignancy, asplenia, and chronic inflammatory disorders.11  Other conditions associated with transient thrombocytosis include acute blood loss, “rebound” from thrombocytopenia, iron deficiency, and even exercise.10, 11


Reactive thrombocytosis may be a result of a subclinical disorder or occult cancer.  Therefore, asymptomatic patients with thrombocytosis must have a comprehensive physical evaluation for malignancy or other potentially treatable disease.


B.  Autonomous (primary) thrombocytosis


1)  Myeloproliferative disorders.


a)  Polycythemia vera (PV) causes thrombocytosis with an increase in blood viscosity.  Thrombosis in the brain or other vital organs is a significant threat for PV patients.13  PV is not a waiverable condition.


b)  Chronic myeloid leukemia (CML) – The leukemias have many significant medical complicating factors other than thrombocytosis that have the potential for progression and performance decrement.  CML is not a waiverable condition.


c)  The natural history of chronic idiopathic myelofibrosis is associated with marrow failure and transfusion-dependent anemia.  Median survival for this condition is 5 years.  Thrombocytosis associated with chronic idiopathic myelofibrosis is not waiverable.


d)  Essential thrombocytosis (ET) is a diagnosis of exclusion.  No single specific clinical, cytogenic, or molecular test is available for the diagnosis.8  Janus kinase 2 (JAK2) present in 95% of polycythemia vera, is also present in 50% of ET.18  ET should be suspected in the asymptomatic patient found to have a chronically elevated platelet count, especially if the count exceeds 1,000,000/μl.  The criteria for making this diagnosis have recently been updated by the World Health Organization and must include all four of the below items.18 

i.  A platelet count greater than or equal to 450,000/μL.

ii.  A bone marrow biopsy consistent with ET.

iii.  A lack of any criteria for PV, CML, myelofibrosis, or myelodysplastic syndromes.

iv.  The demonstration of a JAK2 mutation or other clonal marker; or in the absence of a clonal marker, no evidence for reactive thrombocytosis.


Most commonly, ET is found incidentally on complete blood counts (CBCs), but less commonly it may be found due to complications.  Complications of ET can generally be categorized into thrombotic, hemorrhagic, or progression into one of the other three myeloproliferative disorders.10  Determinants of an increased risk for complications are generally agreed upon to be age over 40, previous thrombotic event, or presence of cardiac risk factors.  The annual risk of thrombotic complications in a cohort of untreated/treated patients was found to be 6.6%/patient-year.3  In this cohort, the most common thrombotic event was a cerebral arterial thrombosis.  The annual risk of thrombotic and hemorrhagic complications in a cohort of untreated patients with age range of 16-55 was found to be 2.3%/patient-year.17  The risk of hemorrhage or progression to another myeloproliferative disorder is less than that of a thrombotic event.


Treatment of ET is generally categorized into one of two types of therapy.  Aspirin therapy is indicated for relief of erythromelalgia symptoms and to reduce the risk of thrombotic events.  It is very important to emphasize that aspirin therapy in these patients is not without risk.  ET patients with platelet counts over 1,500,000/μl may develop an acquired von Willebrand’s disease.  Aspirin in these patients greatly increases their risk of hemorrhagic complications.  The second category of therapy for ET is cytoreductive therapy.  This category includes the antineoplastic drugs such as the alkylating agent busulfan and the antimetabolite hydroxyurea.  The newest cytoreductive drug indicated for ET is anagrelide.  These drugs are not approved for flying status.  Furthermore, even if one were to reduce the platelet count to normal range with a cytoreductive drug complication rates still exceed acceptable aeromedical standards (probably because the platelets are still qualitatively abnormal). 


2)  Myelodysplastic disorders cause different degrees of cytopenia and abnormal cell maturation.  These patients are therefore at increased risk of anemia, infection, and bleeding which are often refractory to treatment.


3)  Hereditary thrombocytosis is an extremely rare and heterogeneous genetic disorder that presents clinically like ET. 


C.  Non-specific thrombocytosis.  A recent “expert panel” has recommended that a platelet count of 400-450,000 needs no further evaluation.18  Any platelet count > 450,000 does need evaluation.  If there is no evidence of a “reactive” thrombocytosis, then Janus kinase 2 mutation (JAK-2) testing should be done.  A bone marrow biopsy should also be done, which would include testing for the Ph+ chromosome.  Commonly, if these tests are negative, the individual platelet count is between 450,000/μl and 600,000/μl, and no evidence of reactive process then the individual is labeled “non-specific thrombocytosis.”


Aeromedical Concerns:


A.  Essential thrombocytosis.  The most significant aeromedical concern is the greater than 1%/year risk of a thrombotic event (most common cerebral).  Unfortunately the level of thrombocytosis does not predict thrombotic events.  Hemorrhagic complications are seen with elevated thrombocytosis levels (>1.5 million/µl). 


B.  Secondary thrombocytosis.  Thrombotic and hemorrhagic complications do not occur in reactive thrombocytosis unless the underlying condition itself predisposes to such complications (e.g., individuals who are post-operative or with malignancy).12  The elevated platelet count by itself will not cause complications that affect physical or cognitive performance.  For the condition to be labeled a reactive thrombocytosis, a credible underlying etiology must be identified.  Individuals who have had a surgical splenectomy frequently have lifelong reactive thrombocytosis19 and once again do not have an increased risk for thrombosis or bleeding.4 


Medical Work-Up: The approach to an individual found to have an elevated platelet count should begin with an evaluation for reactive thrombocytosis.  In this case, the primary medical problem should be managed first.  Once the platelet count returns to baseline, no disqualifying platelet condition exists and the individual may be returned to flying status as long as the primary medical condition doesn’t require a waiver.


Patients who are asymptomatic and found to have an elevated platelet count require additional testing to rule out autonomous thrombocytosis or an occult illness causing reactive thrombocytosis.  If the history does not identify a risk factor for thrombocytosis, the physical exam should focus on evidence of bleeding or thrombosis.  The spleen may be enlarged in cases of autonomous thrombocytosis. 


If history and physical exam are non-contributory the most useful laboratory tests will be a repeat platelet count, the peripheral blood smear, and serum iron studies including plasma fibrinogen and ferritin.  Other tests that may suggest an occult inflammatory process is present include an erythrocyte sedimentation rate and C-reactive protein levels.  Although platelet production is regulated by the hormone thrombopoeitin, serum thrombopoeitin levels are not helpful in differentiating reactive from autonomous thrombocytosis.19  Additional testing must also include stool for occult blood and chest x-ray for occult malignancy.  Cases of persistent thrombocytosis in an otherwise normal patient must have a formal hematological evaluation.


Aeromedical Disposition (military): Air Force:  The USAF standards require removal from flying status anytime platelets are found to exceed 450,000/μl.  In the case of reactive thrombocytosis, the pilot is returned to flight status once the platelet count has returned to a normal value.  The guide for a waiver request states that the aeromedical summary for an initial waiver should include the following:

      A.  Comprehensive history – to include thrombosis or bleeding episodes (negatives included), symptoms, course of platelet values, treatment, and cardiac risk


      B.  Physical – complete, special attention to skin, neurology and abdomen.

      C.  Current CBC with differential.

      D.  Serum iron, ferritin, fibrinogen, erythrocyte sedimentation rate (ESR), C-reactive protein, occult blood studies, chest x-ray.

      E.  Hematology consultation to include bone marrow biopsy and clonal markers.


Navy:  No standards exist regarding elevated platelet count.  Individual complications such as thrombosis or other diagnoses causing thrombocytosis such as PV are disqualifying.

Army:  No standards exist regarding elevated platelet count.  Individual complications such as thrombosis or other diagnoses causing thrombocytosis such as PV are disqualifying.


Aeromedical Disposition (civilian): Waivers have been granted for ET.  No standard exists regarding an absolute platelet count that may not be exceeded.  Aeromedical disposition will depend on the presence and/or severity of complications.  Hematologist evaluation and follow up are required for special issuance. 


Waiver Experience (military): Review of the Air Force database through November 2007 showed only six patients with thrombocytosis were considered for waiver; only two were pilots.  Of these two pilots, one case was granted waiver for essential thrombocytosis, not requiring medication.  This case progressed to myelofibrosis and was subsequently disqualified from flying duties. 


Waiver Experience (civilian): There is no single pathology code for thrombocytosis in the FAA’s Aeromedical Certification system so civil aviation experience with this condition cannot be determined at this time.


ICD 9 Code for Thrombocytosis


Essential thrombocythemia (primary thrombocytosis)




Chronic myelomonocytic leukemia


Myelodysplastic syndrome, unspecified


Myelofibrosis with myeloid metaplasia (idiopathic myelofibrosis [chronic])




1.  Aidogan, T, et al.  Incidence and etiology of thrombocytosis in an adult Turkish population.  Platelets.  2006; 17:  328-31.


2.  Barbui T, Barosi G, et al.  Practice guidelines for the therapy of essential thrombocythemia.  A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation.  Haematologica.  2004; 89(2):  215-232.


3.  Cortelazzo S, Viero P, Finazzi G, D’Emilio A, Rodeghiero F, Barbui T.  Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia.  J Clin Oncol.  1990 Mar; 8:  556-62.


4.  Griesshammer M, et al.  Aetiology and clinical significance of thrombocytosis: analysis of 732 patients with an elevated platelet count.  J Intern Med.  1999; 245:  295-300.


5.  Harrison CN, Green AR.  Essential Thrombocythemia.  Hematol Oncol Clin N Am 2003; 17:  1175-90.


6.  Harrison CN, Campbell PJ, Buck G, et al.  Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia.  N Engl J Med.  2005; 353 (1):  334-5.


7.  McIntyre KJ, Hoagland HC, Silverstein MN, Pettitt RM.  Essential thrombocythemia in young adults.  Mayo Clin Proc 1991; 66:  149-54.


8.  Nimer, SD.  Essential Thrombocythemia: Another “Herogeneous Disease” Better Understood?  Blood.  1999; 93:  415-6.


9.  Ruggeri M, Tosetto A, Frezzato M, Rodeghiero F.  The rate of progression to polycythemia vera or essential thrombocythemia in patients with erythrocytosis or thrombocytosis.  Ann Intern Med.  2003; 139:  470-5.


10.  Sanchez, S, Ewton, A.  Essential Thrombocythemia.  A review of diagnostic and pathologic features.  Arch Pathol Lab Med.  2006; 130:  1144-50.


11.  Schafer, AI.  Chapter 111 – Essential Thrombocythemia and Thrombocytosis.  Lichtman MA, et al.  Williams Hematology, 7th ed.  The McGraw-Hill Companies, Inc. 2006.


12.  Schafer, AI.  Thrombocytosis.  N Engl J Med.  2004; 350:  1211-9.


13.  Spivak, JL.  Chapter 95 – Polycythemia vera and other myeloproliferative diseases.  Kasper, DL, et al.  Harrison’s Principles of Internal Medicine, 16th ed.  The McGraw-Hill Companies, Inc.  2005.


14.  Storen EC, Tefferi A.  Long-term use of anagrelide in young patients with essential thrombocythemia.  Blood.  2001; 97(4): 863-866.


15.  Tefferi A.  Diagnosis and clinical manifestations of essential thrombocythemia.  UpToDate.  Online version 15.3, September 13, 2007.


16.  Tefferi A.  Prognosis and treatment of essential thrombocythemia.  UpToDate.  Online version 15.3, May 9, 2007.


17.  Tefferi A, Gangat N, Wolanskyj AP.  Management of extreme thrombocytosis in otherwise low-risk essential thrombocythemia; does number matter?  Blood.  2006; 108:  2493-2494.


18.  Tefferi A, Thiele J, Orazi A, et al.  Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel.  Blood.  2007; 110:  1092-7.


19.  Vannucchi, AM, Barbui T.  Thrombocytosis and Thrombosis.  Hematology Am Soc Hematol Educ Program.  2007:  363-70.


20.  Vardiman JW, Harris NL, Brunning RD.  The World Health Organization (WHO) classification of the myeloid neoplasms.  Blood.  2002; 100(7):  2292-2302.



July 22, 2008