Approach to the patient with thrombocytosis

INTRODUCTION — Thrombocytosis refers to an increased platelet count which, in this review, is >450,000/microL (>450 x 10⁹/L).

This topic discusses our approach to the adult or child with unexplained thrombocytosis.

Clinical manifestations and diagnosis of specific causes of thrombocytosis are discussed separately. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia" and "Overview of the myeloproliferative neoplasms".)

TERMINOLOGY — The following terminology and values are used in this topic:

●Platelets – Platelets are cellular fragments that are derived from megakaryocytes in the bone marrow, as described separately. (See "Platelet biology and mechanism of anti-platelet drugs".)

●Normal platelet count – The normal platelet count in adults and children is 150,000 to 450,000/microL (150 to 450 x 10⁹/L), but the range may vary in clinical laboratories.

●Thrombocytosis – Thrombocytosis is a platelet count >450,000/microL.

CAUSES OF THROMBOCYTOSIS — Thrombocytosis can be caused by either reactive or autonomous processes.

Causes of thrombocytosis vary based on the population studied. As examples, causes of thrombocytosis differ in ambulatory versus hospitalized patients and in infants versus adults.

Reactive thrombocytosis — Reactive processes, also described as secondary thrombocytosis, are caused by processes that are extrinsic to the megakaryocyte. Reactive processes account for most cases of thrombocytosis in all age groups and clinical settings.

Common causes of reactive thrombocytosis (table 1) include:

●Anemia/blood loss – Iron deficiency, blood loss, hemolysis

●Infection – Viral, bacterial, mycobacterial, and fungal causes

●Non-infectious inflammation – Malignancy, rheumatologic conditions, trauma, reactions to medications

●Post-splenectomy – Post-splenectomy or functional asplenia (eg, sickle cell disease)

Mechanisms of reactive thrombocytosis vary with the underlying cause, and may include increased megakaryocyte proliferation/maturation, accelerated platelet release, and/or reduced platelet sequestration/turnover. As examples, asplenia is associated with decreased platelet sequestration/turnover. Blood loss/iron deficiency is associated with increased proliferation of progenitor cells that are common to both platelets and red blood cells. In infections and inflammatory processes, increased production of cytokines stimulate megakaryocyte proliferation, maturation, and/or accelerated platelet release. (See "Megakaryocyte biology and platelet production", section on 'Control of platelet mass'.)

Autonomous thrombocytosis — Autonomous (primary) thrombocytosis is caused by cell-intrinsic mechanisms (ie, processes that lay within the megakaryocyte or its precursor cells).

Most autonomous thrombocytosis in adults is clonal (ie, malignant), and is caused by acquired (somatic) mutations of genes which regulate thrombopoiesis (eg, JAK2, CALR, or MPL) and that are associated with myeloproliferative neoplasms (MPN) and other hematologic malignancies. (See 'Hematologic malignancies' below.)

Thrombocytosis in infants and children may be caused by acquired mutations or, rarely, by inherited (ie, germline) genetic abnormalities associated with familial thrombocytosis syndromes, as described below. (See 'Familial thrombocytosis' below.)

Hematologic malignancies — Hematologic malignancies that are associated with thrombocytosis include:

●Essential thrombocythemia – Essential thrombocythemia (ET) is an MPN that is manifest as thrombocytosis, often in association with vasogenic symptoms (eg, flushing, erythromelalgia) and/or thrombo-hemorrhagic complications. ET is generally caused by an acquired mutation of JAK2, CALR, or MPL. Other clinical manifestations and diagnosis of ET are discussed separately. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia".)

●Polycythemia vera – Polycythemia vera (PV) is an MPN that is manifest as polycythemia (elevated hemoglobin and/or hematocrit) and is often accompanied by thrombocytosis; thrombo-hemorrhagic complications; splenomegaly; pruritus, flushing, erythromelalgia; and/or constitutional symptoms (eg, fever sweats, weight loss). PV is nearly invariably associated with an acquired mutation of JAK2. Other clinical manifestations and diagnosis of PV are discussed separately. (See "Clinical manifestations and diagnosis of polycythemia vera" and "Diagnostic approach to the patient with erythrocytosis/polycythemia".)

●Primary myelofibrosis – Primary myelofibrosis (PMF) is an MPN in which bone marrow fibrosis and a leukoerythroblastic blood smear may be accompanied by thrombocytosis, splenomegaly, thrombo-hemorrhagic complications, and/or constitutional symptoms. Approximately 90 percent of cases have a mutation in JAK2, CALR, or MPL. Clinical manifestations and diagnosis of PMF are discussed separately. (See "Clinical manifestations and diagnosis of primary myelofibrosis".)

●Chronic myeloid leukemia – Chronic myeloid leukemia (CML) is an MPN in which a characteristic chromosomal abnormality, t(9;22), the Philadelphia chromosome, generates the BCR::ABL1 oncogene. CML can rarely present as isolated thrombocytosis but, typically, CML is manifest as an increase of immature myeloid cells in peripheral blood and bone marrow, accompanied by thrombocytosis, polycythemia, and/or splenomegaly. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

●Myelodysplastic syndromes – Myelodysplastic syndromes (MDS) are occasionally associated with thrombocytosis. The 5q- syndrome and MDS/MPN with ring sideroblasts and thrombocytosis are the MDS categories that are most commonly associated with thrombocytosis. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

●Acute myeloid leukemia – Acute myeloid leukemia (AML) is occasionally associated with thrombocytosis. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Pathologic features'.)

Familial thrombocytosis — Familial thrombocytosis (also called familial essential thrombocythemia) refers to rare inherited syndromes that are manifest by thrombocytosis alone (ie, not associated with leukocytosis or polycythemia). Familial thrombocytosis exhibits Mendelian inheritance, high penetrance, and polyclonal hematopoiesis [1]. Activating mutations of the thrombopoietin gene (TPO) or thrombopoietin receptor gene MPL have been described, as discussed in more detail separately. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Familial essential thrombocythemia'.)

Rarely, thrombocytosis is associated with familial PV or PMF; these syndromes exhibit low penetrance, clonal hematopoiesis, and may be associated with JAK2 V617F mutation [1].

INITIAL EVALUATION — Thrombocytosis may be encountered in the course of evaluating other clinical findings or as an incidental abnormality on a complete blood count (CBC) and differential.

Evaluation should include determination of the cause of thrombocytosis and prompt assessment for medical emergencies. Management of complications and emergency conditions should not be delayed by evaluation of the cause of thrombocytosis.

Urgency of evaluation — The urgency of evaluation is guided by the patient's clinical condition, the presence of worrisome findings, and the degree of thrombocytosis.

As examples:

●Clinical emergencies (eg, hemodynamic instability, respiratory compromise) or leukemic blasts on the blood smear generally require hospitalization for urgent evaluation and management.

●Management of associated conditions (eg, thrombosis, bleeding) may require hospitalization and should not be delayed by evaluation of the cause of thrombocytosis.

●The asymptomatic patient without worrisome findings on the blood smear should generally be evaluated as an outpatient.

●The urgency of evaluation is influenced by the level of thrombocytosis. No specific platelet count per se constitutes an emergency, but we suggest evaluating a patient with a platelet count ≥1,000,000/microL within days.

Our approach — All patients with thrombocytosis should have a repeat CBC and differential count, review of the blood smear, history and physical examination, and certain other laboratory tests, as described in the sections that follow (algorithm 1).

Specific causes of thrombocytosis that are identified by the initial evaluation and their management are discussed below. (See 'Diagnosis established by initial evaluation' below.)

Initial evaluation should identify patients who are more likely to have an autonomous (ie, malignant or inherited) disorder rather than a reactive process, because the former will require additional testing, as described below. (See 'Other scenarios' below.)

Patients with the following findings are more likely to have an autonomous cause for thrombocytosis:

●Unexplained vasomotor symptoms (eg, erythromelalgia, flushing, pruritus), constitutional symptoms (eg, unexplained fever, sweats, or weight loss), and/or splenomegaly. Such patients should be evaluated for a potential myeloproliferative neoplasm (MPN), as described below. (See 'Suspected myeloproliferative neoplasm' below.)

●Thrombosis at unusual sites (eg, hepatic vein, inferior vena cava [Budd-Chiari syndrome], portal vein, splenic vein) or multiple sites, thrombosis in younger patients (eg, <45 years), or unprovoked or recurrent thrombosis without other explanation should prompt evaluation for a potential MPN. (See 'Suspected myeloproliferative neoplasm' below.)

●Blood smear that reveals leukemic blasts, leukoerythroblastic features, or other evidence of leukemia or related hematologic malignancy should be referred promptly to a hematologist for further evaluation and management. (See 'Abnormal blood smear' below.)

●Family history of unexplained thrombocytosis should be referred to a hematologist with expertise in inherited hematopoietic disorders. (See 'Familial thrombocytosis' below.)

Management of complications associated with thrombocytosis (eg, bleeding, thrombosis, vasomotor symptoms) is discussed below. (See 'Management' below.)

Complete blood count (CBC) — CBC with differential count should be repeated to confirm the level of thrombocytosis. The urgency of repeat testing is informed by the criteria described above. (See 'Urgency of evaluation' above.)

Spurious thrombocytosis should be excluded by review of the blood smear, as described below. (See 'Blood smear' below.)

When available, prior CBCs (both normal and abnormal) can provide valuable information about the duration and trajectory of thrombocytosis.

Clues to the cause of thrombocytosis may come from other findings on the CBC. As examples, microcytic red blood cells (RBC) may indicate iron deficiency anemia, while neutrophilia may be caused by an infection or an inflammatory condition.

The normal mean platelet volume (MPV) is 9 to 10 femtoL (fL) in most clinical laboratories. The MPV cannot identify the specific cause of thrombocytosis, but MPV ≥11 fL may indicate the presence of abnormal platelets (eg, MPN or familial platelet disorder).

The level of thrombocytosis alone is not sufficient to define the cause. As an example, a platelet count ≥1,000,000/microL may be caused by either a reactive cause or an autonomous (malignant) process. As an example, a single institution study reported that three-quarters of 280 consecutive patients with a platelet count >1,000,000/microL had an underlying reactive process [2]. In general, less extreme thrombocytosis is most commonly due reactive causes, such as iron deficiency, infectious or non-infectious inflammatory conditions, or recovery from thrombocytopenia (eg, after chemotherapy or vitamin repletion).

Blood smear — The blood smear should be reviewed to assess platelet morphology, detect other hematologic abnormalities, and exclude spurious thrombocytosis (pseudothrombocytosis).

Findings from the blood smear that may be useful in the evaluation of thrombocytosis include:

●Platelets – Platelet abnormalities include (see "Evaluation of the peripheral blood smear", section on 'Platelets'):

•Large platelets (up to the size of normal RBCs) may reflect a malignant process (eg, MPN), younger platelets associated with a reactive process (eg, excessive platelet destruction), or a familial platelet disorder.

•Giant platelets (ie, larger than normal RBCs) may be seen with malignant or familial disorders, and less commonly with reactive thrombocytosis.

•Giant platelets, platelet conglomerates, bizarre forms, megakaryocytic fragments, and platelet hypogranularity may be seen in some cases of malignant (picture 1) or familial thrombocytosis.

●Other lineages – Examples of abnormal findings in other lineages include:

•Howell-Jolly bodies (picture 2) and/or nucleated RBCs (picture 3) may be seen with asplenia (surgical or functional). (See "Evaluation of the peripheral blood smear", section on 'Red cell inclusions and other changes'.)

•Myelophthisic disorders often produce leukoerythroblastic blood picture (picture 4) with teardrop-shaped RBCs, nucleated RBCs, and immature granulocytes. This suggests an infiltrative process in the bone marrow. (See "Evaluation of the peripheral blood smear", section on 'Leukoerythroblastic smear'.)

•Immature leukocytes (eg, myeloblasts, promyelocytes, myelocytes) may be seen with chronic myeloid leukemia (picture 5) or other MPNs. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Peripheral blood' and "Overview of the myeloproliferative neoplasms".)

•Dysplastic neutrophils or the Pelger-Huet anomaly (picture 6) suggest the presence of a myelodysplastic syndrome. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Blood smear'.)

●Spurious thrombocytosis – Spurious thrombocytosis (pseudothrombocytosis) refers to an elevated platelet count on the CBC that does not correspond to the estimate from the blood smear. Multiplying by 10,000/microL the average number of platelets per high power field (hpf; under 100X oil immersion) provides a rough estimate of the platelet count. As an example, if the average number platelets is 25 per hpf, the platelet count would be estimated as 250,000/microL.

Conditions that may cause spurious thrombocytosis include:

•Mixed cryoglobulinemia – Patients with mixed cryoglobulinemia may have a temperature-dependent increase in platelet count when blood samples are tested at ≤30°C because of precipitated cryoglobulin particles that are counted as platelets in automated cell counters [3]. This effect disappears if the blood sample is maintained at body temperature until testing.

•Cytoplasmic fragments – Rarely, circulating cytoplasmic fragments (eg, leukemia or lymphoma cells) or fragmented RBCs (eg, from severe hemolysis or burns) may be erroneously interpreted as platelets by automated cell counters [4-6].

History and examination — History should evaluate the following in relation to causes or complications of thrombocytosis:

●Recent trauma or surgery

●Prior surgical removal of the spleen

●Findings suggesting infection or inflammation

●History of bleeding (eg, menorrhagia, gastrointestinal) or iron deficiency

●History of arterial and/or venous thrombosis

●Medications

●Smoking and alcohol consumption

●Prior diagnosis of a chronic hematologic disorder

●Unexplained fever, sweats, weight loss, fatigue, or other systemic complaints suggesting malignancy

Physical examination should seek evidence of cutaneous or mucosal bleeding/bruising, lymphadenopathy, hepatosplenomegaly, and findings suggestive of arterial or venous thrombosis.

Other laboratory studies — Other laboratory studies useful for the initial evaluation of thrombocytosis follow:

●Iron studies – Serum ferritin should be included in the initial evaluation of thrombocytosis (algorithm 1); some experts also include serum iron and iron binding capacity. Evaluation of iron studies is discussed separately. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)

•A low serum ferritin level (eg, <15 ng/mL) is diagnostic of iron deficiency, with a specificity approaching 100 percent. Patients with iron deficiency and anemia typically have microcytic, hypochromic RBCs on the CBC and blood smear (picture 7).

•Elevated ferritin may reflect an inflammatory condition (ferritin is an acute phase reactant) or iron overload.

In select patients, other laboratory tests may be useful. Examples include:

●Inflammatory markers – Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) may be useful in a patient suspected of having an inflammatory process, but who lacks other characteristic findings (eg, neutrophilia, toxic granulations, or Dohle bodies (picture 8)).

ESR and/or CRP should be normal with uncomplicated autonomous thrombocytosis, but elevated in most cases of reactive thrombocytosis. However, normal values for ESR and CRP do not exclude a reactive process.

We suggest not routinely testing the following in the initial evaluation of thrombocytosis:

●Serum chemistries – We do not routinely obtain liver or kidney function tests because they rarely identify a cause of thrombocytosis.

Pseudohyperkalemia (artifactual elevation of potassium in serum but not in plasma) may be seen with thrombocytosis. Pseudohyperkalemia can occur when large numbers of platelets aggregate in vitro; this artifact does not occur in the patient and does not cause clinical problems. Pseudohyperkalemia can be confirmed by simultaneously testing the serum and plasma levels of potassium. (See "Causes and evaluation of hyperkalemia in adults", section on 'Pseudohyperkalemia'.)

●Platelet function testing – Platelet function studies do not identify the cause of thrombocytosis, but may be abnormal in some disorders, such as MPNs. Platelet function testing is discussed separately. (See "Platelet function testing".)

●Flow cytometry – Flow cytometry is generally not useful for defining the cause of thrombocytosis, unless other findings suggest the presence of acute leukemia or related disorders. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

●Cytokines – There is no evidence that serum levels of thrombopoietin (TPO) or other cytokines can identify the cause of thrombocytosis or distinguish reactive from autonomous processes [7-10].

FURTHER EVALUATION — Our approach to further evaluation is guided by whether findings from the initial evaluation define a cause of thrombocytosis.

The initial evaluation may identify more than one possible cause of thrombocytosis. As an example, a patient may have thrombocytosis in the setting of iron deficiency due to an underlying gastrointestinal malignancy. Remediable causes (eg, iron deficiency) should be treated while the underlying condition (eg, cancer) is addressed.

Management of medical complications (eg, hemorrhage, thrombosis) and emergencies must take place even as the diagnostic evaluation is proceeding. (See 'Management' below.)

Diagnosis established by initial evaluation — For many patients, the initial evaluation will define the cause of thrombocytosis.

No further testing or follow-up is required if one or two subsequent complete blood counts (CBCs) reveal that the platelet count has responded as expected in the setting of reactive thrombocytosis. The interval between confirmatory CBCs will vary with clinical setting, as described below.

As examples:

●Iron deficiency – If iron repletion leads to normalization of the platelet count within one to two months. (See "Treatment of iron deficiency anemia in adults", section on 'Response to iron supplementation'.)

●Infection – If thrombocytosis resolves with observation or treatment of an infection. The period for resolution of thrombocytosis will vary with the type and duration of infection. As examples, thrombocytosis should resolve within two weeks of a viral infection but may persist for months or years with chronic infections.

●Recovery from thrombocytopenia – Rebound thrombocytosis following resolution of thrombocytopenia caused by cytotoxic chemotherapy, vitamin deficiency (eg, folate, vitamin B12), excessive alcohol consumption, or immune thrombocytopenia should resolve within two to four weeks.

●Inflammation – Thrombocytosis may persist in the setting of ongoing inflammation from a rheumatologic condition, cancer, or other chronic inflammatory condition. Further evaluation of thrombocytosis is not required if the platelet count does not rise significantly in the setting of ongoing inflammation.

●Asplenia – Persistent thrombocytosis should be anticipated after surgical splenectomy or functional asplenia (eg, sickle cell disease), but other contributing factors should be considered if the platelet count rises significantly after establishing a stable level of thrombocytosis.

Other scenarios — For conditions that are not explained by the initial evaluation and for patients with reactive thrombocytosis that does not respond as expected, further testing is guided by clinical findings, as described below.

Suspected myeloproliferative neoplasm — Patients with vasomotor or constitutional symptoms, splenomegaly, and/or an unusual thrombotic presentation should be evaluated for a myeloproliferative neoplasm (MPN) (algorithm 1), as discussed above. (See 'Our approach' above.)

In this setting, we suggest the following tests of peripheral blood:

●Mutation analysis of JAK2, CALR, and MPL to detect essential thrombocythemia (ET), polycythemia vera (PV), or primary myelofibrosis (PMF). Details of testing for Philadelphia chromosome-negative MPNs are provided separately. (See "Overview of the myeloproliferative neoplasms", section on 'Mutations in PV, ET, and PMF'.)

●Molecular testing for BCR::ABL1 or cytogenetic testing (eg, karyotype, fluorescence in situ hybridization [FISH]) for t(9;22) (Philadelphia chromosome) to diagnose chronic myeloid leukemia (CML), as discussed separately. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

An acceptable alternative is referral to a hematologist for this testing. Patients who are diagnosed with an MPN, and those suspected of having an MPN but with unrevealing molecular/cytogenetic analysis should be referred for hematology consultation.

Abnormal blood smear — Detection of worrisome findings on the blood smear requires prompt evaluation (algorithm 1). (See "Evaluation of the peripheral blood smear", section on 'Worrisome findings'.)

Examples include:

●Circulating leukemic blasts requires prompt referral to hematology for evaluation of possible acute leukemia. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

●Leukoerythroblastic findings (eg, nucleated red blood cells, teardrop cells) suggest a myelophthisic process (eg, PMF or other bone marrow infiltrative disorder), and requires prompt referral to hematology for further evaluation and management. (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Evaluation and diagnosis'.)

Familial thrombocytosis — For patients with an unexplained family history of thrombocytosis who are suspected of having familial thrombocytosis/essential thrombocythemia, we suggest referral to a hematologist with expertise in such conditions. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Familial essential thrombocythemia'.)

Referral to hematology — Referral to a hematologist is not required when the diagnosis is defined by the initial evaluation and the platelet count responds as expected to observation or treatment. (See 'Diagnosis established by initial evaluation' above.)

Patients with thrombocytosis who may benefit from referral to hematology include those whose (see 'Other scenarios' above):

●Platelet count does not respond as expected to observation and/or treatment of a reactive cause of thrombocytosis

●Diagnosis was not defined by initial evaluation

●Myeloproliferative neoplasm or other primary hematologic disorder was detected by molecular testing, or is suspected (see 'Our approach' above)

●Family history of unexplained thrombocytosis

Most patients with thrombocytosis do not require bone marrow examination, but those who may require bone marrow examination include:

●Essential thrombocythemia, polycythemia vera, primary myelofibrosis, or chronic myeloid leukemia defined by molecular and/or cytogenetic testing (see 'Suspected myeloproliferative neoplasm' above)

●Leukoerythroblastic features that suggest primary myelofibrosis or other bone marrow infiltrative disorder (see 'Abnormal blood smear' above)

MANAGEMENT — Management of thrombocytosis, related symptoms, and complications is informed by the underlying cause and the level and trajectory of the platelet count, as follows:

●Reactive thrombocytosis:

•Asymptomatic patients – For patients whose diagnosis was established by the initial evaluation and whose platelet count responded as anticipated, no further evaluation or management is required, as described above. (See 'Diagnosis established by initial evaluation' above.)

•Persistent/worsening thrombocytosis – For patients with persistent/worsening thrombocytosis, or whose platelet count did not respond as anticipated in the setting of a reactive process (eg, infection, inflammatory conditions, cancer), other contributing factors should be considered; referral to hematology may be helpful.

•Hemorrhage – Management of bleeding is guided by the location and severity of bleeding, as with other patients.

•Thrombosis – Arterial or venous thrombosis is managed according to the nature of the thrombotic event, with anticoagulation, thrombolysis, and/or other therapeutic interventions. Management is not altered based on the platelet count, per se.

We suggest not treating reactive thrombocytosis with aspirin, cytoreductive therapy, or plateletpheresis, regardless of the level of the platelet count because there is no evidence of benefit in this setting.

●Autonomous thrombocytosis – Management is guided by the underlying disease process and any associated symptoms or complications.

Management of the platelet count, vasogenic or constitutional symptoms, and/or thrombosis is described separately. (See "Essential thrombocythemia: Treatment and prognosis", section on 'Acquired von Willebrand syndrome' and "Polycythemia vera and secondary polycythemia: Treatment and prognosis".)

Patients with extreme thrombocytosis (>1,000,000/microL) in the setting of an myeloproliferative neoplasm may have excessive bleeding from acquired von Willebrand disease; diagnosis and management of this syndrome is discussed separately. (See "Essential thrombocythemia: Treatment and prognosis", section on 'Acquired von Willebrand syndrome'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myeloproliferative neoplasms".)

SUMMARY

●Thrombocytosis – Thrombocytosis is defined as a platelet count >450,000/microL (>450 x 10⁹/L) in adults and children. (See 'Terminology' above.)

●Causes – Thrombocytosis can be caused by:

•Reactive processes – Platelet counts increase with iron deficiency, splenectomy, and in response to infectious, inflammatory, or malignant conditions. (See 'Reactive thrombocytosis' above.)

•Autonomous processes – Essential thrombocythemia, polycythemia vera, and other myeloproliferative neoplasms cause unregulated, clonal proliferation of hematopoietic stem and progenitor cells. (See 'Autonomous thrombocytosis' above.)

●Evaluation – Initial evaluation (algorithm 1) should seek to distinguish reactive thrombocytosis from an autonomous process, based upon:

•Clinical – History of bleeding, thrombosis, vasomotor symptoms (eg, erythromelalgia, flushing, pruritus), constitutional symptoms (eg, unexplained fever, sweats, or weight loss), iron deficiency anemia, and examination for splenomegaly

•Laboratory

-Complete blood count (CBC)

-Blood smear

-Serum ferritin

●Further evaluation and management – Further studies and management are guided by findings from the initial evaluation.

Scenarios include:

•Evidence of iron deficiency – Thrombocytosis may be due to iron deficiency in patients with a history of blood loss (eg, gastrointestinal bleeding, menorrhagia, multiple pregnancies), hypochromic/microcytic anemia, or low serum ferritin (eg, <15 ng/mL).

The source of blood loss should be investigated, and the platelet count should be re-evaluated after iron repletion. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

•Inflammatory causes – The patient with an apparent infectious or other inflammatory cause of thrombocytosis should be evaluated as clinically indicated and the underlying disorder addressed.

•Post-splenectomy – No further investigation is warranted for thrombocytosis after splenectomy.

•Suspected hematologic malignancy – Essential thrombocythemia, polycythemia vera, or another myeloproliferative neoplasm or hematologic malignancy should be suspected in a patient with erythromelalgia, pruritus, constitutional symptoms, splenomegaly, or an abnormal blood smear (eg, nucleated red blood cells, teardrop cells, blasts).  

Further evaluation for an myeloproliferative neoplasm or other hematologic malignancy should include testing for mutated JAK2, CALR, MPL, and BCR::ABL1, as described separately. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia" and "Overview of the myeloproliferative neoplasms".)

•Family history of thrombocytosis – An inherited disorder may be suspected in an individual with primary relatives who have unexplained thrombocytosis, leukemias, or characteristic skeletal, skin, or other somatic anomalies. Evaluation and diagnosis of familial causes of thrombocytosis are described separately. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Familial essential thrombocythemia'.)