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Hematology

Thrombocytosis

Overview of Thrombocytosis

  • Definition: An abnormally elevated platelet count in the peripheral blood, generally defined as a platelet count greater than 450 x 10^9/L (450,000/µL)
  • Clinical Significance: Thrombocytosis can increase the risk of thrombosis (blood clots) and, paradoxically, in some cases, bleeding
  • Classification:
    • Reactive (Secondary) Thrombocytosis: The most common type, caused by an underlying condition
    • Essential (Primary) Thrombocythemia: A myeloproliferative neoplasm characterized by sustained thrombocytosis and increased risk of thrombosis and bleeding

Reactive Thrombocytosis (Secondary Thrombocytosis)

  • Definition: An elevated platelet count that occurs as a reaction to an underlying condition. It’s not a primary disorder of the bone marrow
  • Characteristics:
    • Transient: Platelet count usually returns to normal once the underlying condition resolves
    • Mild to Moderate Elevation: Platelet counts are typically less than 1000 x 10^9/L, but this is not a strict cutoff
    • Lack of Clonal Marker: Absence of genetic mutations (e.g., JAK2, CALR, MPL) associated with essential thrombocythemia
  • Common Causes of Reactive Thrombocytosis:
    • Infections:
      • Acute and chronic bacterial infections
      • Fungal infections
      • Viral infections (less common)
    • Inflammation:
      • Autoimmune disorders (e.g., rheumatoid arthritis, inflammatory bowel disease)
      • Vasculitis
      • Acute pancreatitis
      • Tissue injury (e.g., trauma, surgery, burns)
    • Iron Deficiency Anemia (IDA):
      • Platelet count may normalize after iron repletion
    • Hemorrhage:
      • Following acute blood loss, the platelet count may temporarily increase
    • Splenectomy:
      • Removal of the spleen leads to increased platelet counts, as the spleen normally removes senescent platelets
      • Platelet counts can be very high (>1000 x 10^9/L) after splenectomy
    • Rebound Thrombocytosis:
      • Following recovery from thrombocytopenia caused by chemotherapy or bone marrow suppression
    • Malignancy:
      • Certain cancers (e.g., lung, breast, ovarian) can cause reactive thrombocytosis
    • Medications:
      • Corticosteroids
      • Epinephrine
  • Pathophysiology:
    • Increased Thrombopoietin (TPO) Production:
      • Many of the underlying conditions associated with reactive thrombocytosis stimulate the production of thrombopoietin (TPO), the primary regulator of platelet production
      • TPO is produced mainly by the liver and kidneys
      • TPO stimulates megakaryocyte proliferation and differentiation in the bone marrow, leading to increased platelet production
    • Increased Release of Platelets from the Bone Marrow:
      • Inflammatory cytokines can promote the release of platelets from the bone marrow storage pool
    • Decreased Platelet Sequestration:
      • Splenectomy removes the spleen, the main site of platelet destruction and sequestration, leading to increased platelet counts
  • Clinical Features of Reactive Thrombocytosis:
    • Often asymptomatic
    • Symptoms of the underlying condition may be present (e.g., fever, pain, inflammation)
    • Thrombotic or bleeding complications are rare in reactive thrombocytosis, especially when platelet counts are <1000 x 10^9/L
  • Laboratory Findings in Reactive Thrombocytosis:
    • Complete Blood Count (CBC):
      • Elevated platelet count (usually < 1000 x 10^9/L)
      • May see other abnormalities depending on the underlying cause (e.g., elevated WBC count in infection, anemia in iron deficiency)
    • Peripheral Blood Smear:
      • Increased number of platelets
      • Platelets usually appear normal in size and morphology
      • May see other abnormalities related to the underlying condition (e.g., microcytes in iron deficiency)
    • Iron Studies:
      • May be abnormal in iron deficiency anemia (low serum iron and ferritin, high TIBC)
    • Inflammatory Markers:
      • Elevated ESR, CRP, and/or other inflammatory markers
    • JAK2, CALR, and MPL Mutation Testing:
      • Negative: Helps to rule out essential thrombocythemia (ET)

Essential Thrombocythemia (Primary Thrombocythemia)

  • Definition: A myeloproliferative neoplasm characterized by sustained thrombocytosis and increased risk of thrombosis and bleeding. It’s a primary disorder of the bone marrow
  • Diagnostic Criteria (WHO Criteria):
    • Sustained Platelet Count ≥450 x 10^9/L
    • Bone Marrow Showing Increased Numbers of Megakaryocytes with Abnormal Morphology
      • Increased numbers of large, mature megakaryocytes with hyperlobated nuclei
    • Exclusion of Other MPNs: Absence of criteria for PV, PMF, or CML
    • Presence of a Clonal Marker or Evidence of Clonal Hematopoiesis:
      • JAK2 V617F mutation (present in approximately 50-60% of patients)
      • CALR mutation (present in approximately 25% of patients)
      • MPL mutation (present in approximately 5% of patients)
      • If all three mutations are negative, other evidence of clonality is required
  • Pathophysiology:
    • Mutations in JAK2, CALR, or MPL Genes:
      • These mutations lead to constitutive activation of signaling pathways that control megakaryocyte proliferation and platelet production
      • JAK2 V617F: A point mutation in the JAK2 gene
      • CALR mutations: Insertions or deletions in the CALR gene
      • MPL mutations: Mutations in the MPL gene (thrombopoietin receptor)
    • Megakaryocyte Hyperplasia: Increased numbers of megakaryocytes in the bone marrow
    • Increased Platelet Production: Megakaryocytes produce excessive numbers of platelets
  • Clinical Features:
    • Many patients are asymptomatic at diagnosis
    • Thrombotic Events:
      • Stroke
      • Transient ischemic attack (TIA)
      • Myocardial infarction (heart attack)
      • Deep vein thrombosis (DVT)
      • Pulmonary embolism (PE)
      • Erythromelalgia (burning pain and redness in the extremities)
    • Bleeding Events:
      • Paradoxically, some patients may experience bleeding due to abnormal platelet function
      • Easy bruising
      • Nosebleeds
      • Gastrointestinal bleeding
    • Splenomegaly: Enlarged spleen (less common than in PV or PMF)
    • Constitutional Symptoms: Fatigue, night sweats, weight loss (less common)
  • Laboratory Findings:
    • CBC:
      • Elevated platelet count (sustained >450 x 10^9/L)
      • WBC count: May be normal or slightly elevated
      • RBC count: Usually normal, but may be slightly elevated
    • Peripheral Blood Smear:
      • Thrombocytosis (increased platelets)
      • Large platelets (megathrombocytes)
      • Abnormal platelet morphology (e.g., hypogranular platelets)
    • Bone Marrow Examination:
      • Increased numbers of megakaryocytes with abnormal morphology (e.g., large, hyperlobated nuclei)
      • May see increased granulopoiesis
      • Little or no reticulin fibrosis (unlike primary myelofibrosis)
    • Molecular Testing:
      • Positive for JAK2, CALR, or MPL mutation (in most cases)
  • Treatment:
    • Low-Risk Patients (Low Risk of Thrombosis):
      • Low-Dose Aspirin: To reduce the risk of thrombosis
    • High-Risk Patients (High Risk of Thrombosis):
      • Low-Dose Aspirin
      • Cytoreductive Therapy:
        • Hydroxyurea: To lower the platelet count
        • Anagrelide: Inhibits platelet production
        • Interferon-alpha: May be used in younger patients or pregnant women
    • Risk Stratification:
      • Various risk scoring systems are used to estimate the risk of thrombosis and guide treatment decisions

Distinguishing Reactive Thrombocytosis from Essential Thrombocythemia

Feature Reactive Thrombocytosis Essential Thrombocythemia
Platelet Count Usually < 1000 x 10^9/L ≥450 x 10^9/L
Platelet Morphology Usually normal Large platelets, abnormal morphology
Cause Underlying condition (e.g., infection, inflammation, IDA) Clonal myeloproliferative neoplasm
JAK2, CALR, MPL Negative Often positive
Thrombosis Risk Low Increased
Splenomegaly Absent or mild Can be present (but less prominent than PMF)

General Laboratory Tests for Thrombocytosis

  • Complete Blood Count (CBC) with Peripheral Blood Smear: Essential for diagnosis and classification
  • Iron Studies: To rule out iron deficiency anemia
  • Inflammatory Markers: (ESR, CRP) to assess for underlying inflammation
  • Mutation Testing: (JAK2, CALR, and MPL) to rule out essential thrombocythemia and primary myelofibrosis
  • Bone Marrow Aspiration and Biopsy: May be necessary to evaluate for MPNs or other bone marrow disorders

Key Terms

  • Thrombocytosis: Elevated platelet count
  • Reactive Thrombocytosis: Thrombocytosis due to an underlying condition
  • Essential Thrombocythemia (ET): Clonal MPN with sustained thrombocytosis
  • Myeloproliferative Neoplasm (MPN): Clonal disorder of hematopoietic stem cells
  • JAK2, CALR, MPL: Genes commonly mutated in MPNs
  • Phlebotomy: Removal of blood to reduce red cell mass
  • Hydroxyurea: A chemotherapeutic drug used to suppress bone marrow proliferation
  • Anagrelide: A drug that inhibits platelet production