Primary Thrombocythemia

A rare blood disorder characterized by the overproduction of platelets in the bone marrow

Table of Contents

Quick Facts

Prevalence
2-3 per 100,000 people annually
Age of Onset
Most common at 50-60 years
Gender Distribution
More common in women
ICD-10 Code
D47.3

Overview

Primary thrombocythemia, also known as essential thrombocythemia (ET), is a rare chronic blood disorder characterized by the overproduction of platelets by the bone marrow. This condition belongs to a group of diseases called myeloproliferative neoplasms, where the bone marrow makes too many of one or more types of blood cells. In primary thrombocythemia, the abnormal increase in platelets can lead to both bleeding and clotting complications.

The condition typically progresses slowly and many patients may have no symptoms for years. When the platelet count becomes extremely elevated, usually above 600,000 per microliter (normal range is 150,000-400,000), patients may experience various symptoms related to abnormal blood clotting or bleeding. Despite being a chronic condition, with proper management, most people with primary thrombocythemia can lead normal, active lives.

Primary thrombocythemia differs from secondary thrombocytosis, where elevated platelet counts occur as a reaction to another condition such as infection, inflammation, or iron deficiency. In primary thrombocythemia, the elevated platelet production is due to a clonal disorder of the hematopoietic stem cells, often associated with genetic mutations such as JAK2, CALR, or MPL mutations.

Symptoms

Many people with primary thrombocythemia have no symptoms at diagnosis and the condition is discovered incidentally during routine blood tests. When symptoms do occur, they can range from mild to severe and are typically related to blood clotting or bleeding complications.

Common Symptoms

  • Dizziness - Often due to altered blood flow to the brain
  • Fatigue - A common complaint affecting daily activities
  • Flatulence - May occur due to gastrointestinal blood flow issues

Thrombotic Symptoms

Symptoms related to blood clot formation include:

  • Headaches: Often severe and persistent
  • Visual disturbances: Blurred vision, seeing spots or flashing lights
  • Chest pain: May indicate cardiac involvement
  • Numbness or tingling: Particularly in hands and feet
  • Erythromelalgia: Burning pain and redness in hands or feet
  • Transient ischemic attacks (TIAs): Mini-strokes with temporary symptoms

Bleeding Symptoms

Paradoxically, despite high platelet counts, bleeding can occur:

  • Easy bruising
  • Nosebleeds (epistaxis)
  • Bleeding gums
  • Gastrointestinal bleeding
  • Heavy menstrual periods in women
  • Prolonged bleeding after injury or surgery

Other Symptoms

  • Enlarged spleen (splenomegaly): Occurs in about 20-40% of patients
  • Abdominal discomfort: Due to spleen enlargement
  • Skin itching (pruritus): Especially after warm baths
  • Livedo reticularis: Lacy, purplish skin discoloration
  • Night sweats: Less common but may occur

Causes

Primary thrombocythemia is caused by acquired genetic mutations in blood-forming cells in the bone marrow. These mutations lead to the overproduction of platelets. The condition is not inherited and cannot be passed from parent to child.

Genetic Mutations

Three main genetic mutations have been identified in primary thrombocythemia:

JAK2 Mutation

  • Found in approximately 50-60% of patients
  • The JAK2 V617F mutation causes constant activation of JAK2 protein
  • Leads to increased cell proliferation and survival
  • Associated with higher risk of thrombotic events

CALR Mutation

  • Present in about 25-35% of patients
  • Calreticulin gene mutations
  • Generally associated with younger age at diagnosis
  • Lower risk of thrombosis compared to JAK2 mutations

MPL Mutation

  • Found in approximately 3-5% of patients
  • Affects the thrombopoietin receptor
  • Can be associated with higher platelet counts

Triple-Negative Cases

About 10-15% of patients have none of these three mutations, termed "triple-negative." These cases may have other yet-to-be-discovered mutations or different mechanisms causing the disease.

Pathophysiology

The mutations lead to:

  • Abnormal megakaryocyte proliferation in bone marrow
  • Increased platelet production
  • Altered platelet function
  • Potential progression to myelofibrosis or acute leukemia (rare)

Risk Factors

While the exact cause of the genetic mutations in primary thrombocythemia is unknown, several factors may influence the risk of developing the condition or experiencing complications:

Demographic Factors

  • Age: Most common in people aged 50-70 years, though can occur at any age
  • Gender: Slightly more common in women, particularly in younger age groups
  • Ethnicity: No significant ethnic predisposition identified

Risk Factors for Complications

Certain factors increase the risk of thrombotic or bleeding complications:

High-Risk Features

  • Age over 60 years
  • Previous thrombotic events
  • JAK2 mutation positivity
  • Cardiovascular risk factors (hypertension, diabetes, smoking)
  • Very high platelet counts (>1,500,000/μL)

Cardiovascular Risk Factors

Environmental Factors

While not directly causative, certain factors may be associated:

  • Previous exposure to radiation (rare)
  • Exposure to certain chemicals (benzene, though not definitively proven)
  • No known dietary or lifestyle factors directly cause the condition

Diagnosis

Diagnosing primary thrombocythemia requires excluding other causes of elevated platelet counts and confirming the presence of a clonal disorder. The diagnostic process follows specific criteria established by the World Health Organization (WHO).

Diagnostic Criteria

The 2016 WHO criteria for diagnosing primary thrombocythemia include:

  1. Platelet count ≥450,000/μL persistently
  2. Bone marrow biopsy showing proliferation mainly of megakaryocytes
  3. Not meeting criteria for other myeloproliferative neoplasms
  4. Presence of JAK2, CALR, or MPL mutation, or in absence of these, no evidence of reactive thrombocytosis

Laboratory Tests

Complete Blood Count (CBC)

  • Elevated platelet count (>450,000/μL)
  • Normal or slightly elevated white blood cell count
  • Normal or slightly low red blood cell count
  • Blood smear examination showing increased platelets

Genetic Testing

  • JAK2 V617F mutation analysis
  • CALR mutation testing if JAK2 negative
  • MPL mutation testing if JAK2 and CALR negative
  • BCR-ABL testing to exclude chronic myeloid leukemia

Bone Marrow Biopsy

Essential for definitive diagnosis:

  • Increased number of mature megakaryocytes
  • Normal cellularity for age
  • No significant fibrosis
  • No evidence of other myeloproliferative disorders

Additional Tests

  • Iron studies: To exclude iron deficiency
  • Inflammatory markers: ESR, CRP to rule out inflammation
  • Liver and kidney function: Baseline assessment
  • Coagulation studies: PT, PTT, fibrinogen
  • Platelet function tests: If bleeding symptoms present

Differential Diagnosis

Conditions to exclude include:

  • Reactive thrombocytosis (infection, inflammation, malignancy)
  • Other myeloproliferative neoplasms
  • Myelodysplastic syndromes
  • Chronic myeloid leukemia
  • Iron deficiency anemia

Treatment Options

Treatment for primary thrombocythemia aims to reduce the risk of thrombotic and bleeding complications while managing symptoms. The approach is individualized based on risk stratification, age, symptoms, and patient preferences.

Risk Stratification

Patients are categorized into risk groups:

  • Low-risk: Age <60 years, no history of thrombosis, no JAK2 mutation
  • Intermediate-risk: JAK2 positive but no other risk factors
  • High-risk: Age ≥60 years or history of thrombosis

Low-Risk Patients

Observation

  • Regular monitoring without specific therapy
  • Low-dose aspirin (81-100mg daily) if no contraindications
  • Management of cardiovascular risk factors
  • Regular blood counts every 3-6 months

High-Risk Patients

Cytoreductive Therapy

First-line options include:

Hydroxyurea (Hydroxycarbamide)
  • Most commonly used first-line agent
  • Reduces platelet count effectively
  • Starting dose: 15-20 mg/kg/day
  • Side effects: skin changes, leg ulcers, nail changes
Interferon-alpha
  • Preferred in younger patients and pregnancy
  • Pegylated forms available (weekly injections)
  • Side effects: flu-like symptoms, depression, fatigue
  • Can achieve molecular remissions in some patients
Anagrelide
  • Specifically reduces platelet count
  • Second-line therapy or in combination
  • Side effects: headaches, palpitations, fluid retention
  • Requires cardiac monitoring

Antiplatelet Therapy

  • Low-dose aspirin: Standard for most patients unless contraindicated
  • Clopidogrel: Alternative for aspirin-intolerant patients
  • Dual antiplatelet therapy: In specific high-risk situations

Emergency Treatment

Plateletpheresis

  • Rapid platelet reduction in emergencies
  • Used for acute thrombosis or severe symptoms
  • Temporary effect requiring cytoreductive therapy

Supportive Care

  • Cardiovascular risk management: Control blood pressure, cholesterol, diabetes
  • Smoking cessation: Critical for reducing thrombotic risk
  • Regular exercise: Improves circulation and overall health
  • Hydration: Adequate fluid intake to prevent blood thickening
  • Avoid iron supplements: Unless documented deficiency

Monitoring

Regular follow-up includes:

  • Blood counts every 2-3 months initially, then every 3-6 months
  • Assessment for thrombotic or bleeding symptoms
  • Monitoring for disease progression
  • Evaluation of treatment side effects
  • Annual assessment of cardiovascular risk factors

Prevention

While primary thrombocythemia itself cannot be prevented as it results from acquired genetic mutations, many complications can be prevented or minimized through proper management and lifestyle modifications.

Preventing Thrombotic Complications

  • Medication adherence: Take prescribed antiplatelet or cytoreductive therapy as directed
  • Regular monitoring: Keep all scheduled appointments for blood tests
  • Cardiovascular risk reduction: Control modifiable risk factors
  • Stay active: Regular exercise improves circulation
  • Maintain healthy weight: Reduces strain on cardiovascular system

Lifestyle Modifications

  • Quit smoking: Most important modifiable risk factor
  • Limit alcohol: Moderate consumption only
  • Stay hydrated: Drink plenty of water, especially in hot weather
  • Avoid prolonged immobility: Move regularly during long trips
  • Wear compression stockings: During long flights or periods of sitting

Medical Precautions

  • Inform all healthcare providers about your condition
  • Discuss risks before any surgery or dental procedures
  • Review all medications with your hematologist
  • Avoid medications that affect platelet function unless prescribed
  • Consider medical alert bracelet for emergency situations

Special Situations

Pregnancy Planning

  • Consult with high-risk obstetrics and hematology
  • Switch to pregnancy-safe medications (interferon)
  • Close monitoring throughout pregnancy
  • Plan for delivery with appropriate medical support

Travel Precautions

  • Carry medical documentation
  • Ensure adequate medication supply
  • Know location of medical facilities at destination
  • Consider travel insurance with medical coverage

When to See a Doctor

Patients with primary thrombocythemia should be aware of warning signs that require immediate medical attention as well as symptoms that warrant routine consultation.

Seek Emergency Care For:

  • Sudden severe headache or worst headache of your life
  • Sudden weakness, numbness, or paralysis of face, arm, or leg
  • Sudden confusion or difficulty speaking
  • Sudden vision loss or visual disturbances
  • Chest pain or pressure
  • Difficulty breathing or shortness of breath
  • Severe abdominal pain
  • Signs of stroke or heart attack
  • Uncontrolled bleeding

Contact Your Doctor For:

  • Persistent or worsening headaches
  • Increased fatigue or weakness
  • New or worsening bruising or bleeding
  • Burning pain in hands or feet
  • Persistent dizziness or lightheadedness
  • Abdominal fullness or discomfort
  • Night sweats or unexplained fever
  • Skin changes or persistent itching
  • Side effects from medications

Regular Follow-up

Maintain scheduled appointments for:

  • Routine blood count monitoring
  • Annual comprehensive evaluation
  • Medication adjustments
  • Disease progression assessment
  • Management of other health conditions

References

  1. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. American Journal of Hematology. 2020;95(12):1599-1613.
  2. Arber DA, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405.
  3. Barbui T, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018;32(5):1057-1069.
  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms. Version 3.2023.
  5. Mesa RA, et al. Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): Consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT). Leukemia Research. 2007;31(6):737-740.

Medical Disclaimer: This information is for educational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional for diagnosis and treatment of medical conditions.