A. Introduction. Thrombocytosis is defined as a platelet count >450,000 cells/μL.
B. Etiology of Thrombocytosis
a. Primary. If thrombocytosis is caused by a myeloproliferative neoplasm, the platelets are frequently abnormal and the patient may be prone to both bleeding and clotting events.
b. Secondary. If thrombocytosis is secondary to another disorder (reactive), even patients with extremely high platelet counts (e.g., >1,000,000 cells/μL) are often asymptomatic.
C. Causes of Thrombocytosis
a. Primary causes. Myeloproliferative neoplasm (MPN), specific subtypes of myelodysplastic syndrome (MDS), and MDS/MPN overlap syndromes can increase the platelet count through a clonal proliferation of a hematopoietic progenitor cell (see Chapter 70).
i. MPN: Essential thrombocytosis, polycythemia vera, primary myelofibrosis, chronic myelogenous leukemia
ii. MDS: 5q– syndrome
iii. MDS/MPN overlap: Refractory anemia with ringed sideroblasts and thrombocytosis
b. Secondary causes. Reactive thrombocytosis can result from numerous processes, and is the most common cause of thrombocytosis.
ii. Acute or chronic infections and inflammatory disorders (e.g., Crohn’s disease)
iii. Postsurgical status
iv. Connective tissue disorders
v. Iron deficiency anemia
vii. Recovery of the bone marrow from a stress (e.g., chemotherapy or alcohol)
viii. Acute blood loss
D. Approach to the Patient
a. Patient history
i. Evaluate for bleeding (e.g., gastrointestinal or urogenital blood loss). This may imply possible iron deficiency.
ii. Complete review of symptoms to evaluate for occult malignancy or infection. Specific symptoms of fever, night sweats, or weight loss (commonly called “B” symptoms) may implicate malignancy or chronic infection (e.g., tuberculosis).
iv. Evaluate symptoms caused by thrombocytosis, including thrombosis (primary causes have an increased association with hepatic or portal vein thrombosis), bleeding complications, digital microvascular ischemia and vasomotor symptoms of headache, visual symptoms, or erythromelalgia (burning pain of extremities associated with warmth and redness). Typically, presence of these symptoms indicates a primary cause of thrombocytosis.
b. Physical examination. Perform a thorough physical examination, including a rectal examination if symptoms dictate. Pay special attention to the spleen and lymph nodes because enlargement of these organs may suggest malignancy, MPN, or systemic causes of infection.
c. Laboratory studies can further narrow the differential diagnosis.
i. Iron status including the transferrin saturation and serum ferritin will help evaluate the possibility of iron deficiency anemia and is especially important in patients with a history of gastrointestinal bleeding, or a low mean corpuscular volume (MCV).
ii. Hematocrit and white blood cell (WBC) count. The hematocrit and WBC count are often elevated in patients with myeloproliferative neoplasms, although essential thrombocytosis may result in an isolated elevation of the platelet count.
iii. Peripheral smear. Rarely, automated hematology counters may count small fragmented red blood cells (RBCs) as platelets and report an elevated count. This spurious diagnosis of thrombocytosis can be confirmed by evaluating the peripheral smear. Howell-Jolly bodies, target cells, or abnormally shaped cells on the smear may suggest a postsplenectomy state as a cause of thrombocytosis.
iv. Other tests may be performed if reactive thrombocytosis is suspected (e.g., a purified protein derivative [PPD] test for possible tuberculosis, a computed tomography [CT] scan for suspected intra-abdominal malignancy, or serologic testing for connective tissue diseases). If a reactive cause is ruled out, a bone marrow biopsy may be necessary to look for a primary cause.
v. Molecular analysis. When evaluating for a primary disorder (e.g., MPN), molecular studies for the Janus kinase-2 (JAK2 V617F or exon 12), CALR, and MPL mutations are necessary. Depending on the concomitant laboratory studies, a BCR-ABL polymerase chain reaction (PCR) analysis may be necessary to evaluate for chronic myelogenous leukemia. The absence of these molecular mutations, however, does not rule out a myeloproliferative neoplasm.
vi. Bone marrow biopsy. Primary myeloproliferative disorders often have characteristic morphologic changes seen on bone marrow aspirates and biopsies, including megakaryocytic hyperplasia, with clustering of megakaryocytes. This can also help exclude other secondary diagnoses.
a. Primary causes. MPNs may predispose the patient to both bleeding and thrombosis as a result of abnormal platelet function. Risk stratification models for myeloproliferative neoplasms have been established and will assist in deciding appropriate therapeutic options.
i. Immediate platelet apheresis can be considered in patients with acute life-threatening thromboses or in patients experiencing severe symptoms due to an elevated platelet count.
ii. Low-dose aspirin is often indicated as it can prevent thromboses and limit vasomotor symptoms. When platelet counts exceed 1,000,000 cells/μL, there is an increased risk for bleeding due to functional von Willebrand factor (vWF) deficiency caused by proteolysis of large vWF multimers.
iii. Hydroxyurea or anagrelide can be used for long-term management of patients with significant thrombocytosis or thromboses, or who are otherwise at high risk for complications due to the myeloproliferative neoplasm. However, anagrelide is associated with an elevated risk for arterial thrombosis, venous thrombosis, serious hemorrhage, or death from vascular causes compared with hydroxyurea.
b. Secondary causes. Most causes of reactive thrombocytosis do not require treatment to lower the platelet count. The platelet count usually returns to normal after treatment of the underlying disorder. Patients with reactive thrombocytosis rarely have associated thrombosis, so systemic anticoagulation is often unnecessary.
Suggested Further Readings
Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005;353:33–45.Find this resource:
Michiels JJ, Berneman Z, Schroyens W, Finazzi G, Budde U, van Vliet HHDM. The paradox of platelet activation and impaired function: platelet-von Willebrand factor interactions, and the etiology of thrombotic and hemorrhagic manifestations in essential thrombocythemia and polycythemia vera. Semin Thromb Hemost 2006;32:589–604.Find this resource:
Rumi E, Cazzola M. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood 2017;129:680.Find this resource: