🩺 BSH Thrombocytosis Guideline 2025

Interactive Learning Platform - Investigation and Management without JAK2, CALR or MPL Mutations

Professional Education Evidence-Based #BloodDoctor

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πŸ“š Welcome to the Interactive Learning Platform

Learning Objectives

  1. Understand the approach to investigating thrombocytosis without classical MPN driver mutations
  2. Recognize when to perform bone marrow biopsy and extended genomic testing
  3. Apply the new diagnostic terminology (ITUS, ITAM, CTUS)
  4. Develop risk-stratified management strategies
  5. Differentiate between reactive and clonal thrombocytosis

Why This Guideline Matters

The Clinical Challenge

  • 10-15% of essential thrombocythaemia (ET) cases are "triple-negative"
  • >80% of all thrombocytosis is secondary (reactive)
  • Significant practice variation exists in investigation strategies
  • Previous guidelines focused on mutation-positive cases

What You'll Learn

This interactive platform will guide you through:

  • βœ“ Systematic approach to thrombocytosis investigation
  • βœ“ When and when NOT to perform extensive testing
  • βœ“ Novel diagnostic categories and their clinical implications
  • βœ“ Evidence-based management recommendations
  • βœ“ Real-world case scenarios

How to Use This Platform

πŸ’‘ Learning Tips:

  • Navigate through sections using the menu above
  • Complete each section to track your progress
  • Hover over technical termsLike this! Definitions appear when you hover. for quick definitions
  • Test your knowledge with interactive quizzes
  • Apply learning through clinical case scenarios
  • Mark sections as complete to unlock achievements!

πŸ”¬ Aetiology of Thrombocytosis

Overview: Four Main Categories

THROMBOCYTOSIS (Platelets >450Γ—10⁹/L)
↓
Reactive (>80%)
Clonal Myeloid
Clonal Haematopoiesis
Hereditary

1. Reactive (Secondary) Thrombocytosis

Pathophysiology

Thrombopoietin (TPO) is the primary regulator:

  • Produced by the liver
  • Cleared via receptors (TPOR/MPL) on megakaryocytes and platelets
  • Plasma TPO regulated by platelet mass
  • Acute phase reactants (IL-6) increase hepatic TPO production
Category Common Causes
Deficiency/Loss Iron deficiency, bleeding
Inflammation Infection, autoimmune disease, malignancy
Tissue Damage Trauma, surgery, burns
Splenic Hyposplenism, splenectomy
Metabolic Obesity, metabolic syndrome
Drug-Related TPO agonists, ESAs, chemotherapy recovery

2. Clonal Myeloid Disorders

Classical MPNs - Driver Mutations

  • JAK2 V617F: 50-60% of ET
  • CALR exon 9 frameshift: 25-35% of ET
  • MPL exon 10 variants: 5-10% of ET
  • Triple-negative ET: 10-15% of ET

Triple-Negative ET Characteristics

  • βœ“ Predominantly young females
  • βœ“ Most lack definitive clonal evidence
  • βœ“ Lower myelofibrotic transformation risk
  • βœ“ Lower thrombosis risk
  • βœ“ Highly favourable survival

3. Clonal Haematopoiesis (CH)

Definition: Presence of clonal blood cell populations in otherwise healthy individuals

Common genes: DNMT3A, TET2, ASXL1

Prevalence:

  • ~10% of individuals >70 years (conventional sequencing)
  • >66% with sensitive sequencing (VAF <1%)

Clinical significance: May indicate emergent haematological malignancy, especially if:

  • High VAF (>10%)
  • Multiple pathogenic variants
  • Younger individuals
  • Additional cytopenias

4. Hereditary Thrombocytosis

Gene Key Features Clinical Implications
JAK2 germline Various variants (V617I, R564Q/L, etc.) Variable thrombotic risk
MPL germline S505N, P106L, R170H, etc. S505N: high thrombotic risk, fibrosis progression
THPO Various regulatory variants May associate with distal limb defects
SH2B3 Biallelic variants Autoimmune features, hepatosplenomegaly

πŸ” Investigation Approach

⚠️ Critical First Principle

Over 80% of thrombocytosis is REACTIVE - thorough exclusion of secondary causes is fundamental!

Stage 1: Initial Clinical Assessment & Testing

Clinical History & Examination

Symptoms: Headaches, erythromelalgia, microvascular disturbances
Risk Factors: Cardiovascular risks, thrombotic/haemorrhagic history
Family History: Thrombocytosis, MPN, malignancy
Examination: BMI, splenomegaly, signs of systemic disease

First-Line Investigations

Test Purpose
Blood Film Spurious thrombocytosis, other myeloid features
Iron Studies Exclude iron deficiency
CRP Inflammatory markers
CXR (age >40) Malignancy screening
Abdominal US If splenomegaly suspected
JAK2, CALR, MPL MPN driver mutations (peripheral blood)
BCR::ABL1 If triple-negative (exclude CML)

⚠️ Important Note

Serum TPO levels do NOT distinguish reactive from clonal thrombocytosis and are NOT routinely recommended.

Stage 2: When to Perform Comprehensive Investigations

βœ… GRADE 1C - Strong Recommendation

Perform BM biopsy + NGS-MGP +/- cytogenetics if:

  • Age >60 years, OR
  • Age 40-60 with significant cardiovascular risk factors*, OR
  • Prior vascular event(s), OR
  • Platelets >1500Γ—10⁹/L

*Hypertension, diabetes, hypercholesterolaemia on therapy, or high QRISK3 score

πŸ€” GRADE 2C - Consider Offering

May offer BM biopsy + NGS-MGP +/- cytogenetics if:

  • Age <60 years without significant vascular risk, BUT
  • Platelets 600-1500Γ—10⁹/L AND/OR
  • Unexplained pertinent symptoms (headaches, erythromelalgia)

❌ NOT Required

BM biopsy and additional genomics NOT needed if:

  • Age <60 years
  • No previous vascular events
  • No cardiovascular risk factors or symptoms
  • Mild thrombocytosis (<600Γ—10⁹/L)

BUT: Secondary causes MUST be fully excluded!

Bone Marrow Histology

Key Features of ET:

  • Megakaryocyte proliferation
  • Increased enlarged, mature megakaryocytes
  • Hyperlobated nuclei (characteristic finding)

Limitations:

  • Subjective interpretation (18% diagnosis changes after expert review)
  • Borderline features common in triple-negative cases
  • Inter-observer variability exists

πŸ’‘ Best Practice

All BM histology should undergo expert haematopathologist review within a multidisciplinary team (MDT) setting, integrating molecular and clinical features.

Next-Generation Sequencing (NGS) Myeloid Gene Panel

NHS England Minimum Panel Includes:

ASXL1, CALR, CBL, CSF3R, CUX1, DNMT3A, EZH2, HRAS, IDH1, IDH2, IKZF1, JAK2, KIT, KRAS, MPL, NFE2, NRAS, RUNX1, SETBP1, SF3B1, SH2B3, SRSF2, TET2, TP53, U2AF1, ZRSR2

Findings in Triple-Negative Thrombocytosis:

  • 70-85% negative
  • Non-canonical JAK2/MPL variants (minority)
  • Putative pathogenic germline variants
  • Variants in CH-associated genes

Paediatric Considerations

πŸ‘Ά Special Considerations for Children

  • >50% of paediatric ET is triple-negative
  • Low complication rates
  • Higher platelet thresholds:
    • 650Γ—10⁹/L at 2 months
    • Decreasing to 450Γ—10⁹/L by 6 years
  • Additional tests: Parental blood counts, inherited thrombocytosis panel
  • Higher BM threshold: Consider 800-1000Γ—10⁹/L in asymptomatic children

πŸ“‹ Novel Diagnostic Terminology

🎯 Why New Terms?

Current WHO/ICC classifications have limitations for triple-negative cases:

  • Histological interpretation is subjective
  • Triple-negative ET has distinctive natural history vs. mutation-positive ET
  • No category exists for thrombocytosis without reactive cause OR typical ET morphology
  • Patient counselling challenging when extrapolating from mutation-positive data

Four New Diagnostic Categories

NO Clonal Marker
Normal Megakaryocytes
↓
ITUS
Atypical Megakaryocytes
↓
ITAM
Clonal Marker Present
Normal Megakaryocytes
↓
CTUS
Atypical Megakaryocytes
↓
Triple-negative ET with clonal marker(s)

1. ITUS - Idiopathic Thrombocytosis of Undetermined Significance

Diagnostic Criteria:

  • βœ“ Persistent* thrombocytosis >450Γ—10⁹/L, no reactive cause
  • βœ“ Negative broad genomic analysis (NGS-MGP)
  • βœ“ Histology: normal or increased megakaryocytes WITHOUT significant morphological atypia

Clinical Implications:

  • No evidence of clonal process
  • Uncertain aetiology
  • Likely indolent course

Management:

  • NO routine antiplatelet therapy
  • Annual FBC surveillance
  • Re-evaluate if significant change in counts, new vascular events, or at age 60

2. ITAM - Idiopathic Thrombocytosis with Atypical Megakaryocytes

Diagnostic Criteria:

  • βœ“ Persistent* thrombocytosis >450Γ—10⁹/L, no reactive cause
  • βœ“ Negative broad genomic analysis (NGS-MGP) and cytogenetics
  • βœ“ Histology: increased megakaryocytes with large forms showing hyperlobated nuclei

Alternative term: "Triple-negative ET without clonal markers" (aligns with WHO terminology)

Management:

  • Consider aspirin if age >60 or cardiovascular risk factors
  • Consider cytoreduction if:
    • Age >60
    • Vascular event where thrombocytosis implicated
    • Platelets >1500Γ—10⁹/L
    • Refractory symptoms
    • Multiple cardiovascular risk factors
  • Preferred agent: Interferon-alpha (no DNA-damaging mechanism)

3. CTUS - Clonal Thrombocytosis of Undetermined Significance

Diagnostic Criteria:

  • βœ“ Persistent* thrombocytosis >450Γ—10⁹/L, no reactive cause
  • βœ“ Positive for somatic mutations in CH driver genes (NOT JAK2/CALR/MPL)
    • VAF β‰₯2% (β‰₯4% for X-linked in males)
    • OR clonal cytogenetic abnormality
  • βœ“ Histology: normal or increased megakaryocytes WITHOUT ET-like atypia
  • βœ“ No features of other myeloid neoplasm

Clinical Implications:

  • Evidence of clonal haematopoiesis
  • Falls outside current WHO/ICC classifications
  • Uncertain natural history and vascular risk
  • Unknown progression risk to classical ET

Management:

  • Conservative cytoreduction threshold - only if pronounced thrombocytosis contributing to symptoms or unexplained vascular event
  • Cardiovascular risk optimization crucial (especially smoking cessation)
  • Could consider aspirin if age >60 or cardiovascular risks
  • Counsel patients that benefits of therapy are uncertain

4. Triple-Negative ET with Clonal Marker(s)

Diagnostic Criteria:

  • βœ“ Persistent* thrombocytosis >450Γ—10⁹/L, no reactive cause
  • βœ“ Positive for mutations in CH driver genes (NOT JAK2/CALR/MPL), VAF β‰₯2%
    • OR clonal cytogenetic abnormality
  • βœ“ Histology: increased megakaryocytes with large forms showing hyperlobated nuclei
  • βœ“ No features of other myeloid neoplasm

Clinical Implications:

  • Clonal marker supports ET diagnosis (WHO minor criterion)
  • Subcategorization distinguishes from cases without clonal markers

Management:

  • Follow ITAM guidance
  • Low threshold for repeat BM/genomic assessment if atypical features develop

⚠️ Important Notes

*Persistence: Thrombocytosis must be persistent for at least 3 months before confirming diagnosis. Longer surveillance may be preferable for mild/variable thrombocytosis.

Minimum VAF threshold: 2% for autosomal genes, 4% for X-linked genes in males (aligns with clonal cytopenia of undetermined significance criteria)

Special Consideration: Very Low VAF JAK2 V617F

If JAK2 V617F detected at VAF <1%:

  • May not meet criteria for ET
  • Consider CTUS-type management if histology non-diagnostic
  • Repeat mutational testing (with VAF) if platelet count rises
  • Could repeat every 2-3 years if stable

πŸ’Š Management Strategies

1. Reactive Thrombocytosis

Primary Strategy: Treat the Underlying Cause

  • βœ“ No routine antiplatelet/anticoagulant therapy unless other indications (GRADE 1C)
  • βœ“ Standard thromboprophylaxis for hospitalized patients per local guidelines
  • βœ“ Monitor FBC to ensure resolution
  • βœ“ Special consideration: Iron deficiency with normal Hct - repeat FBC after iron replacement to exclude PV

2. Hereditary Thrombocytosis

Essential Steps (GRADE 1C):

  • MDT discussion (may include genomics tumor advisory board, clinical genetics)
  • Clinical monitoring for thrombosis, bleeding, myelofibrotic progression
  • Cardiovascular risk factor optimization
  • FBC and blood film monitoring

Aspirin (GRADE 2C) - Consider if:

  • Other cardiovascular risks present
  • Family member with same variant had unexplained thrombotic episode
  • Particular variant associated with high thrombosis incidence

Cytoreduction (GRADE 2C):

  • NOT routine
  • Consider for severe intractable symptoms or recurrent thrombosis

Thrombosis Management (GRADE 1C):

  • Unexplained venous thrombosis: standard anticoagulation protocols
  • Expectation of long-term anticoagulation (if acceptable bleeding risks)

3. ITUS Management

Conservative Approach

  • ❌ No routine antiplatelet therapy unless other standard indications (GRADE 1C)
  • βœ“ Annual FBC surveillance appropriate for most with stable counts (GRADE 2C)
  • βœ“ Community-based intermittent monitoring acceptable
  • βœ“ Pregnancy: standard obstetric VTE prevention guidelines

Re-evaluation Triggers (GRADE 2C):

  • Significant change in blood counts
  • Age 60 years (for younger patients)
  • New unprovoked vascular event
  • Development of MPN-suggestive features

4. ITAM / Triple-Negative ET Management

Risk-Stratified Approach

Aspirin (GRADE 2C) - Consider for:

  • Age >60 years
  • Additional cardiovascular risk factors (hypertension, diabetes, hypercholesterolaemia, smoking)
  • Refractory symptoms

Cytoreduction (GRADE 2B) - Consider for:

  • Age >60 years
  • Thrombotic/haemorrhagic event where thrombocytosis implicated
  • Persistent platelets >1500Γ—10⁹/L
  • Refractory symptoms
  • Multiple cardiovascular risk factors

Agent Selection:

  • Interferon-alpha may be favoured (no DNA-damaging mechanism) if no contraindications
  • No evidence favouring any particular agent otherwise

Platelet Count Targets (GRADE 1C)

Should reflect treatment indication:

  • Symptoms: Aim for resolution
  • Extreme thrombocytosis: <1500Γ—10⁹/L
  • Age/vascular risk without events: <600Γ—10⁹/L
  • Otherwise unexplained vascular events: Normal range

Surgery Considerations (GRADE 2C)

Consider temporary cytoreduction if:

  • Marked thrombocytosis (>1000Γ—10⁹/L)
  • Reduced von Willebrand factor activity levels

5. CTUS Management

More Conservative Than ITAM

Cytoreduction (GRADE 2D):

  • Only if pronounced thrombocytosis thought contributing to:
    • Refractory symptoms, OR
    • Otherwise unexplained vascular event

Cardiovascular Risk Factors:

  • Especially important given CH associations
  • Smoking cessation critical (smoking increases CH risk)

Could consider aspirin based on other indications (cardiovascular disease, risk score)

Patient Counselling:

  • Benefits of aspirin/cytoreduction are uncertain
  • Shared decision-making essential

6. Triple-Negative ET with Clonal Marker(s)

Follow ITAM Guidance

  • Low threshold for repeat BM/genomic assessment if atypical features develop:
    • Unexplained/disproportionate cytopenias on cytoreduction
    • New monocytosis

General Principles Across All Categories

Key Management Principles

  • Optimize cardiovascular risk factors in all patients (GRADE 1B)
  • Expert haematopathologist review essential (GRADE 2B for ITAM)
  • Low threshold for interval repeat assessment if starting therapy
  • Consider re-evaluation if original assessment >5 years ago
  • Individualize decisions based on patient preferences and clinical context

πŸ—ΊοΈ Interactive Diagnostic Algorithm

πŸ’‘ How to Use This Algorithm

Click on each decision node to reveal the next steps. This mirrors the clinical decision-making process.

STEP 1: Persistent Isolated Thrombocytosis >450Γ—10⁹/L
Click to expand

⚠️ Important Reminders

  • All BM histology should undergo expert haematopathologist review in MDT setting
  • Consider family history and parental blood counts, especially in children
  • Germline testing if pathogenic variant identified on BM NGS-MGP
  • Threshold for comprehensive testing may be higher in children (e.g., 800-1000Γ—10⁹/L)

πŸ₯ Interactive Case Scenarios

πŸ’‘ Learning Approach

Each case presents a clinical scenario. Try to formulate your approach before revealing the answer!

πŸ“‹ Case 1: Young Woman with Mild Thrombocytosis

Presentation:

  • 35-year-old female
  • Incidental finding: Platelets 550Γ—10⁹/L
  • No symptoms
  • No cardiovascular risk factors
  • No family history of thrombocytosis

Initial Tests:

  • Blood film: Normal
  • Iron studies: Normal
  • CRP: Normal
  • JAK2, CALR, MPL: Negative
  • BCR::ABL1: Negative

Question: What is your next step?

βœ… Answer: Conservative Approach

No additional investigations required

Rationale:

  • Age <60 years
  • No cardiovascular risk factors
  • No prior vascular events
  • Mild thrombocytosis (<600Γ—10⁹/L)
  • Secondary causes excluded

Management Plan:

  • βœ“ Presumptive diagnosis: "Idiopathic thrombocytosis"
  • βœ“ Annual FBC monitoring
  • βœ“ Patient education on symptoms to report
  • βœ“ No routine antiplatelet therapy
  • βœ“ Re-evaluate if:
    • Significant rise in platelet count
    • Age 60 years
    • New unprovoked vascular event

πŸ“‹ Case 2: Older Patient with Moderate Thrombocytosis

Presentation:

  • 65-year-old male
  • Platelets 750Γ—10⁹/L (stable over 6 months)
  • Hypertension on treatment
  • Type 2 diabetes
  • Non-smoker

Initial Tests:

  • JAK2, CALR, MPL: Negative
  • BCR::ABL1: Negative
  • Secondary causes excluded

Question: What investigations should be performed?

βœ… Answer: Comprehensive Investigation Required

Perform: BM biopsy + NGS-MGP + cytogenetics (GRADE 1C)

Rationale:

  • Age >60 years
  • Significant cardiovascular risk factors (hypertension, diabetes)

Possible Outcomes & Management:

  • NGS-MGP negative + normal megakaryocytes β†’ ITUS
    • Conservative management
    • Annual FBC monitoring
    • Optimize cardiovascular risks
  • NGS-MGP negative + atypical megakaryocytes β†’ ITAM
    • Consider aspirin (age >60 + CV risks)
    • Possibly consider cytoreduction if multiple CV risk factors
    • Interferon-alpha may be preferred if needed
  • CH gene mutation (e.g., DNMT3A) + normal megakaryocytes β†’ CTUS
    • Cardiovascular risk optimization crucial
    • Could consider aspirin based on CV risk
    • Conservative cytoreduction threshold
  • CH gene mutation + atypical megakaryocytes β†’ Triple-neg ET with clonal markers
    • Manage as ITAM
    • Low threshold for repeat assessment if atypical features

πŸ“‹ Case 3: Prior Vascular Event

Presentation:

  • 55-year-old female
  • History of unprovoked DVT 2 years ago (currently anticoagulated)
  • Platelets 680Γ—10⁹/L
  • No other cardiovascular risk factors

Initial Tests:

  • JAK2, CALR, MPL: Negative
  • Secondary causes excluded

Question: How should this patient be investigated and managed?

βœ… Answer: Full Investigation Mandatory

Perform: BM biopsy + NGS-MGP + cytogenetics (GRADE 1C)

Rationale:

  • Prior vascular event (unprovoked DVT)
  • Need to determine if thrombocytosis contributed
  • Diagnosis will influence long-term management

Management Considerations by Diagnosis:

  • If ITAM or Triple-neg ET with clonal markers:
    • Consider cytoreduction (vascular event where thrombocytosis may be implicated)
    • Target platelets to normal range
    • Continue anticoagulation (standard for unprovoked DVT)
    • Assess for thrombophilia if not already done
  • If ITUS or CTUS:
    • More conservative approach
    • Carefully assess other VTE risk factors
    • Continue anticoagulation as per standard VTE guidelines
    • Optimize cardiovascular risk factors

Key Point: Presence of other provoking factors for DVT should be carefully considered when attributing the event to thrombocytosis.

πŸ“‹ Case 4: Extreme Thrombocytosis

Presentation:

  • 42-year-old male
  • Platelets 1800Γ—10⁹/L
  • No symptoms
  • No cardiovascular risk factors

Initial Tests:

  • JAK2, CALR, MPL: Negative
  • Secondary causes excluded

Question: What is your approach?

βœ… Answer: Comprehensive Investigation Regardless of Age

Perform: BM biopsy + NGS-MGP + cytogenetics (GRADE 1C)

Rationale:

  • Platelets >1500Γ—10⁹/L - absolute indication for full workup
  • Even in young patient without risk factors
  • High platelet count itself is a thrombotic and haemorrhagic risk factor

Additional Assessments:

  • Check for acquired von Willebrand syndrome (vWF activity levels)
  • Assess bleeding history

Management:

  • If diagnosis supports MPN (ITAM or triple-neg ET with clonal markers):
    • Consider cytoreduction (platelets >1500 is an indication)
    • Target: <1500Γ—10⁹/L at minimum, possibly <600Γ—10⁹/L
    • Pre-operative cytoreduction for any invasive surgery
  • If ITUS or CTUS:
    • Could consider cytoreduction given extreme thrombocytosis
    • Shared decision-making with patient

πŸ“‹ Case 5: Paediatric Thrombocytosis with Family History

Presentation:

  • 8-year-old child
  • Platelets 700Γ—10⁹/L (stable over 1 year)
  • Mother also has thrombocytosis (platelets 650)
  • No symptoms
  • No bleeding or thrombotic events

Question: What investigations are appropriate?

βœ… Answer: Inherited Thrombocytosis Panel

Investigations (GRADE 1B):

  • Exclude reactive causes
  • Parental blood count testing (mother already known to have thrombocytosis)
  • JAK2, CALR, MPL screening
  • BCR::ABL1
  • Inherited thrombocytosis panel (JAK2, MPL, THPO, SH2B3 germline testing)

BM Biopsy Threshold (GRADE 2C):

  • Higher threshold in children - consider if:
    • Platelets 800-1000Γ—10⁹/L in asymptomatic child
    • OR prior thrombosis/hemorrhage
    • OR pertinent symptoms
  • In this case (asymptomatic, platelets 700), likely not needed initially

If Hereditary Variant Identified:

  • MDT discussion (may include clinical genetics)
  • Clinical monitoring for complications
  • Risk factor optimization
  • Generally no therapy unless complications occur
  • Family counselling

Key Point: >50% of paediatric ET is triple-negative with low complication rates. Conservative approach is appropriate.

🎯 Test Your Knowledge

Question 1: What percentage of thrombocytosis is typically reactive (secondary)?

A) 40-50%
B) >80%
C) 60-70%
D) 30-40%

Question 2: Which gene mutations are considered "classical MPN drivers"?

A) DNMT3A, TET2, ASXL1
B) TP53, KRAS, NRAS
C) JAK2, CALR, MPL
D) BCR::ABL1, PDGFRA, FGFR1

Question 3: In a 35-year-old with platelets 550Γ—10⁹/L, negative JAK2/CALR/MPL, no CV risk - what is recommended?

A) Immediate bone marrow biopsy
B) Start aspirin therapy
C) NGS myeloid gene panel on peripheral blood
D) Annual FBC monitoring, no additional testing

Question 4: What does ITUS stand for?

A) Inherited Thrombocytosis of Uncertain Significance
B) Idiopathic Thrombocytosis of Undetermined Significance
C) Inflammatory Thrombocytosis of Unknown Source
D) Intermediate Thrombocytosis Unspecified Type

Question 5: What minimum VAF threshold is proposed for CTUS diagnosis?

A) β‰₯2% (β‰₯4% for X-linked in males)
B) β‰₯5%
C) β‰₯10%
D) β‰₯1%

Question 6: For ITAM management, which cytoreductive agent may be preferred?

A) Hydroxyurea
B) Anagrelide
C) Interferon-alpha
D) Busulfan

Question 7: What platelet threshold requires comprehensive investigation regardless of age?

A) >600Γ—10⁹/L
B) >800Γ—10⁹/L
C) >1000Γ—10⁹/L
D) >1500Γ—10⁹/L

Question 8: Serum TPO levels in thrombocytosis investigation are:

A) Essential for distinguishing reactive from clonal
B) Recommended in all cases
C) NOT routinely recommended (do not distinguish reactive from clonal)
D) Only useful in hereditary thrombocytosis

Question 9: What is the main difference between ITUS and CTUS?

A) Platelet count level
B) Presence/absence of clonal marker
C) Age of patient
D) Presence of splenomegaly

Question 10: For hereditary thrombocytosis, what is the routine recommendation for cytoreduction?

A) All patients should receive cytoreduction
B) Only if platelets >1500
C) NOT routine; consider only for severe symptoms or recurrent thrombosis
D) If family history of thrombosis

⭐ Key Take-Home Messages

Essential Principles

  • Most thrombocytosis is REACTIVE - thorough exclusion of secondary causes is fundamental
  • Risk-stratified investigation prevents unnecessary testing while identifying high-risk patients
  • New diagnostic framework (ITUS, ITAM, CTUS) provides clinically useful subcategorization
  • Triple-negative ET has distinctive natural history vs mutation-positive ET
  • Management decisions require integration of histology, genomics, and clinical context

Investigation Strategy Summary

Clinical Scenario Recommended Approach
Age <60, no CV risk, platelets <600 Annual FBC monitoring - no BM/NGS needed
Age <60, no CV risk, platelets 600-1500 OR symptoms May offer BM + NGS-MGP +/- cytogenetics
Age >60 OR CV risk/prior events OR platelets >1500 Perform BM + NGS-MGP +/- cytogenetics
Paediatric with family history Parental counts + inherited thrombocytosis panel

Diagnostic Categories at a Glance

ITUS

No clonal marker + Normal MKs

  • No routine antiplatelet
  • Annual FBC surveillance
  • Re-evaluate at age 60 or if change

ITAM

No clonal marker + Atypical MKs

  • Consider aspirin if age >60/CV risks
  • Consider cytoreduction per indications
  • IFN-Ξ± may be preferred

CTUS

Clonal marker + Normal MKs

  • CV risk optimization crucial
  • Conservative cytoreduction threshold
  • Benefits of therapy uncertain

Triple-neg ET with clonal markers

Clonal marker + Atypical MKs

  • Manage as ITAM
  • Low threshold for repeat assessment

Common Pitfalls to Avoid

⚠️ What NOT to Do

  • ❌ Order serum TPO levels (not useful for distinguishing reactive vs clonal)
  • ❌ Perform BM biopsy on every young patient with mild thrombocytosis
  • ❌ Start aspirin routinely for ITUS or CTUS without other indications
  • ❌ Extrapolate thrombotic risk from mutation-positive ET to triple-negative cases
  • ❌ Forget to exclude secondary causes thoroughly
  • ❌ Ignore family history and parental blood counts in children

Future Directions & Research Needs

Knowledge Gaps

  • Natural history and progression rates from CTUS to classical ET
  • Long-term outcomes in ITUS vs ITAM
  • Vascular risk stratification in triple-negative categories
  • Therapeutic trials for aspirin/cytoreduction in triple-negative ET
  • Whole genome sequencing utility in triple-negative thrombocytosis
  • National variant curation database for rare JAK2/MPL variants

Clinical Resources

πŸ“š Additional Resources

  • BSH Website: Guidelines and addenda at b-s-h.org.uk
  • NHS England Genomic Medicine Service: National genomic test directory
  • Patient Support: MPN Voice for patient resources
  • MDT Discussion: Consider referral to specialized MPN centers for complex cases