Essential thrombocythaemia is a chronic myeloproliferative neoplasm characterized by sustained clonal proliferation of megakaryocytes in the bone marrow, leading to persistently elevated platelet counts and an increased risk of thrombosis and hemorrhage.

Exam domain	One-glance essentials
Definition / diagnosis	BCR-ABL1-negative clonal MPN with *sustained platelets ≥450 ×10⁹/L* and megakaryocyte proliferation ^[1] Diagnosis requires exclusion of reactive thrombocytosis and other myeloid neoplasms
Epidemiology / risks	Median diagnosis ~60 years; smaller peak in young women ^[1] Thrombotic risk: age > 60, prior thrombosis, JAK2 mutation and cardiovascular risks
Core mechanism	JAK2 (~50–65%), CALR (~25%) or MPL (~3–5%) constitutively activates JAK–STAT → autonomous megakaryopoiesis ^[1]^[2] Clonally abnormal platelets drive thrombosis; extreme counts consume high-molecular-weight VWF
Clinical picture	Up to half asymptomatic; microvascular clues: headache, visual symptoms and *erythromelalgia* ^[1] *Arterial > venous thrombosis*; unusual splanchnic/cerebral sites suggest MPN ^[3] Platelets > 1,000 may cause mucocutaneous bleeding
Investigations	Repeat CBC; exclude infection/inflammation, malignancy, iron deficiency and post-splenectomy state ^[1] *BCR-ABL1 is mandatory* to exclude CML; test JAK2→CALR/MPL ^[1] BM: large mature hyperlobated megakaryocytes; distinguish prefibrotic PMF
Management	*Management follows thrombosis risk, not platelet count alone* ^[1] Low risk: observation/low-dose aspirin; high risk: *hydroxyurea + aspirin* ^[1] Interferon-α is preferred for pregnancy/young patients
Complications	Thrombosis: stroke, MI, DVT/PE and Budd–Chiari/mesenteric thrombosis Acquired vWD with extreme thrombocytosis → paradoxical bleeding ^[3] Post-ET myelofibrosis and AML transformation are each < 5% ^[1]
Prevention / follow-up	Control smoking, hypertension, diabetes and lipids Monitor CBC, symptoms and transformation clues; pregnancy needs aspirin ± IFN and specialist planning
Exam traps	*Do not start aspirin when platelets > 1,000 with bleeding until acquired vWD is excluded* ^[3] Reactive thrombocytosis is much commoner than ET JAK2 positivity does not distinguish ET from PV/PMF—marrow and lineage pattern matter

References

^[1] Lecture slides: GC 086. Splenomegaly.pdf (Essential Thrombocythaemia section) ^[2] Senior notes: Ryan Ho Haemtology.pdf (Essential Thrombocythaemia) ^[3] Senior notes: Block A - Leg swelling and chest pain_ deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (MPN thrombosis and acquired vWD)

Essential Thrombocythaemia (ET)

Essential thrombocythaemia (ET) — let's break the name down:

"Essential" = primary / idiopathic (i.e., not secondary to another cause)
"Thrombocythaemia" → "thrombo" = clot/platelet, "cyt" = cell, "aemia" = in the blood → literally "too many platelet-cells in the blood"

ET is a clonal haematopoietic stem cell disorder classified under the BCR-ABL1-negative myeloproliferative neoplasms (MPNs), characterised by sustained overproduction of platelets (persistently > 450 × 10⁹/L) due to megakaryocyte proliferation, in the absence of a recognisable reactive stimulus. ^[1]^[2]

It is fundamentally a neoplastic condition — a clonal expansion of a mutated haematopoietic stem cell — not simply "too many platelets." The key conceptual point is that the megakaryocytes proliferate autonomously (growth-factor independent), in contrast to reactive thrombocytosis where cytokine-driven signals (e.g., IL-6, thrombopoietin) cause a physiologically appropriate increase.

Key Conceptual Distinction

ET is a diagnosis of exclusion. Before you label someone with ET, you must rigorously exclude reactive (secondary) thrombocytosis — which is far more common — and other primary causes of thrombocytosis (CML, PV, PMF, MDS/MPN overlap syndromes). ^[1]^[3]

2. Epidemiology

Not a common disease — approximately 150 new cases per year in the entire Hong Kong population ^[1]
Incidence: 1–2.5 per 100,000 per year ^[4]
Prevalence: 9–24 per 100,000 (relatively high prevalence because patients with ET have a near-normal life expectancy) ^[4]
Disease incidence increases with age; median age of diagnosis is 60 years ^[1]^[3]^[5]
However, ~20% of patients are diagnosed before age 40 ^[4]^[5]
Female predominance (F:M ≈ 2:1) ^[4]^[5]
There is a small bump in essential thrombocythaemia incidence in younger age groups — actually young women of reproductive age ^[1]

High Yield: The bimodal age distribution (peak at 60s, smaller peak in young women of reproductive age) is a classic exam point. In young women, ET may be discovered incidentally on routine bloods or during pregnancy workup.

ET accounts for roughly one-third of BCR-ABL1-negative MPNs in the developed world ^[4]
The 4 main MPN phenotypes: CML (BCR-ABL +ve), Polycythaemia vera, Essential thrombocythaemia, and Primary myelofibrosis (all BCR-ABL −ve) ^[1]

ET is a sporadic somatic mutation-driven neoplasm in the vast majority of cases. There are no well-established modifiable risk factors (unlike, say, lung cancer with smoking). However, certain factors are relevant:

Factor	Detail
Age	Age > 60 years is the most important risk factor for thrombotic complications and is used directly in risk stratification ^[1]
Prior thromboembolism	History of thromboembolic disease dramatically increases risk of further events ^[1]
JAK2 V617F positivity	Confers higher thrombotic risk compared to CALR-mutated ET ^[4]^[5]
Cardiovascular risk factors	HT, smoking, CHF, high WBC — these compound thrombotic risk ^[1]
Familial MPN	Rare; some families carry germline TPO or c-Mpl mutations causing autosomal dominant hereditary thrombocytosis (not truly ET, but mimics it) ^[4]

Exam Pearl

Unlike reactive thrombocytosis (which is very common and benign), ET carries a genuine risk of both thrombosis and paradoxical bleeding. The key risk factors driving management decisions are age > 60 and prior thromboembolic history. ^[1]

4. Anatomy and Function: Normal Platelet Production (Thrombopoiesis)

To understand ET, you must first understand normal platelet production:

Haematopoietic stem cells (HSCs) in the bone marrow differentiate into megakaryocyte progenitors
These progenitors mature into megakaryocytes — the largest cells in the bone marrow
Megakaryocytes undergo endomitosis (DNA replication without cell division), becoming polyploid (16N–64N), and develop an elaborate demarcation membrane system
Mature megakaryocytes extend proplatelets (long cytoplasmic protrusions) into bone marrow sinusoids
Platelets are released from proplatelets into the circulation
Each megakaryocyte produces ~1,000–3,000 platelets
Normal platelet count: 150–400 × 10⁹/L; lifespan ~7–10 days

Thrombopoietin (TPO) is the principal regulator of platelet production. ^[5]

The signalling pathway:

TPO (produced mainly by the liver) binds to MPL (c-Mpl) receptors on megakaryocytes and HSCs
MPL activation triggers JAK2 (Janus kinase 2) phosphorylation
JAK2 activates STAT5 (Signal Transducer and Activator of Transcription 5)
STAT5 signalling drives increased megakaryocyte development and thrombopoiesis ^[5]

The spleen normally sequesters about one-third of circulating platelets
Post-splenectomy → transient or persistent thrombocytosis (reactive, not ET)
In ET with splenomegaly → extramedullary haematopoiesis may contribute to platelet production

In ET, mutations in JAK2, CALR, or MPL cause constitutive (always-on) activation of this signalling axis, bypassing the need for TPO. The megakaryocytes proliferate autonomously → overproduction of platelets.

5. Aetiology and Pathophysiology

ET is driven by somatic mutations that activate the JAK-STAT signalling pathway in a TPO-independent manner. ^[4]^[5]

Mutation	Frequency	Mechanism
JAK2 V617F	~50–65%	Gain-of-function point mutation in exon 14 of JAK2 → constitutively active tyrosine kinase → unregulated JAK-STAT signal transduction → unregulated myeloproliferation leading to megakaryocyte hyperplasia ^[5]
CALR exon 9	~25%	Calreticulin frameshift mutations → mutant CALR binds and activates MPL in the ER → ligand-independent activation of JAK-STAT pathway. "CALR" = calreticulin, a calcium-binding chaperone protein in the ER
MPL	~3–5%	Mutations in the thrombopoietin receptor itself → constitutive activation without TPO binding. "MPL" = myeloproliferative leukaemia virus oncogene
Triple-negative	~10–15%	Negative for all 3 mutations; may harbour non-canonical mutations (e.g., in JAK2 exon 12, SH2B3/LNK, CBL) or truly unidentified drivers ^[5]

Why Do Different Mutations Cause the Same Disease?

All three driver mutations converge on the same downstream pathway — the JAK-STAT axis. Whether you activate JAK2 directly (JAK2 V617F), activate MPL to then activate JAK2 (CALR mutations), or have a constitutively active MPL (MPL mutations), the end result is the same: TPO-independent megakaryocyte proliferation and excessive platelet production.

5.2 Pathophysiological Consequences

The overproduction of platelets leads to two seemingly paradoxical complications:

Thrombosis: Arterial > Venous ^[1]
Mechanisms:
1. Increased platelet mass → more platelet-endothelial interactions → more platelet activation and aggregation
2. Abnormal platelet function → ET platelets have altered receptor expression (e.g., ↑GPIb, altered arachidonic acid metabolism)
3. Hyperviscosity from extreme cell counts
4. JAK2 V617F specifically increases thrombotic risk — JAK2 is expressed in neutrophils and endothelial cells too, promoting a prothrombotic state via increased neutrophil extracellular traps (NETs) and endothelial activation ^[2]
5. Thrombosis in unusual sites (e.g., mesenteric vein, hepatic vein/Budd-Chiari) — when seeing mesenteric vein thrombosis, screen for JAK2 mutations ^[2]

When platelets are extremely high (usually > 1,000 × 10⁹/L), acquired von Willebrand disease (AvWD) develops ^[1]^[2]
Mechanism: Excess platelets consume excess von Willebrand factor (VWF) → the large VWF multimers that are needed for platelet adhesion under high shear stress are depleted ^[2]
VWF is the "glue" that sticks platelets to damaged endothelium; without it → mucocutaneous bleeding (epistaxis, gingival bleeding, easy bruising, GI bleeding)
This is why extreme thrombocytosis paradoxically causes bleeding, not clotting

"Excess platelets can also result in excess bleeding — not just thrombocytopenia" ^[2]

Critical Clinical Paradox

A common exam trap: students assume more platelets = more clotting. But in ET with platelet count > 1,000 × 10⁹/L, the dominant risk shifts from thrombosis to bleeding due to acquired vWD. When the patient has extreme thrombocytosis with bleeding tendency → want to exclude acquired von Willebrand disease ^[2]. This is when you request a clotting profile including VWF:Ag, VWF:RCo, and ristocetin cofactor activity.

All forms of MPN share the potential to PROGRESS to: ^[1]

Myelofibrosis (post-ET myelofibrosis, PETMF) — risk < 5% ^[1]^[3]
Blastic transformation / Acute leukaemia (AML) — risk < 5% ^[1]^[3]

The transformation risk in ET is the lowest among the three BCR-ABL-negative MPNs (compare: PMF has ~20% leukaemic transformation risk at 10 years).

6. Classification

ET is classified under:

Myeloproliferative Neoplasms (MPN)
├── BCR-ABL1 positive
│   └── Chronic Myeloid Leukaemia (CML)
└── BCR-ABL1 negative
    ├── Polycythaemia Vera (PV) — JAK2 V617F (97%)
    ├── Essential Thrombocythaemia (ET) — JAK2 V617F (50-65%), CALR (25%), MPL (3-5%)
    └── Primary Myelofibrosis (PMF) — JAK2 V617F (50-65%), CALR (25-30%), MPL (5-10%)

"Unlike BCR-ABL and CML, there are no single defining markers for the BCR-ABL-negative MPNs" — diagnosis requires integration of clinical, laboratory, histological, and molecular data ^[1].

The revised IPSET-thrombosis model is used to stratify thrombotic risk and guide treatment:

Risk Category	Criteria	Annual Thrombosis Rate
Very low	Age ≤ 60, no thrombosis history, JAK2 wild-type	~1%
Low	Age ≤ 60, no thrombosis history, JAK2 mutant	~2%
Intermediate	Age > 60, no thrombosis history, JAK2 wild-type	~2%
High	Age > 60 with JAK2 mutation, OR any prior thrombosis	~4%

Exam High Yield: Risk Stratification Drives Management

The two most important variables: Age > 60 and history of thromboembolic disease — these define high-risk ET. JAK2 positivity adds additional risk even in younger patients. ^[1]^[4]

Feature	PV	ET	PMF
Defining cytosis	↑↑Hb/Hct (M > 16.5/49%, F > 16/48%)	↑↑Plt (≥ 450)	↓Hb, variable WBC & Plt
PBS	Erythrocytosis	Thrombocytosis	Leucoerythroblastic picture, tear-drop cells
BM	Hypercellularity with trilineage growth ("panmyelosis")	Hypercellularity with megakaryocyte lineage	Dry tap; megakaryocytic proliferation & atypia, fibrosis
Characteristic Sx	Facial plethora, aquagenic pruritus	Vasomotor symptoms, erythromelalgia	Severe fatigue, massive splenomegaly
JAK2 V617F	97%	~50–65%	~50–65%
Splenomegaly	Moderate	Mild (if any)	Massive
Transformation risk	Moderate	Low (< 5%)	High (~20%)

^[3]^[4]

7. Clinical Features

Symptom	Pathophysiological Basis
Asymptomatic (up to 50%)	ET is often discovered incidentally on routine blood tests showing isolated thrombocytosis. The platelets, while excessive, may be functionally adequate and not yet causing symptoms ^[1]^[4]
Headache	Microvascular thrombosis and hyperviscosity in cerebral microvasculature → transient ischaemia of cerebral tissue ^[1]^[4]
Dizziness / lightheadedness	Same mechanism — microvascular occlusion in posterior circulation and vestibular apparatus ^[3]^[4]
Transient visual disturbances (scintillating scotomata, amaurosis fugax)	Microthrombotic occlusion of retinal or ophthalmic artery branches; transient retinal ischaemia ^[4]
Syncope	Severe microvascular or macrovascular cerebral hypoperfusion ^[4]
Erythromelalgia	"Burning pain in hands and feet" — pathognomonic of MPN. Due to platelet-mediated arteriolar inflammation and microvascular thrombosis in acral vessels. The small arterioles become occluded by platelet thrombi → tissue ischaemia → burning pain with erythema and warmth. Responds dramatically to aspirin ^[1]^[3]^[4]
Acral paraesthesia	Microvascular ischaemia of digital nerves from platelet microthrombi ^[4]
Chest pain (atypical)	Microvascular coronary thrombosis or coronary artery thrombosis → angina-type symptoms ^[3]
Stroke symptoms (hemiparesis, aphasia)	Macrovascular arterial thrombosis of cerebral arteries (MCA most commonly) ^[3]
Peripheral vascular disease symptoms (claudication)	Arterial thrombosis in lower limb vessels ^[3]
DVT/PE symptoms (leg swelling, pleuritic chest pain, dyspnoea)	Venous thrombosis; though arterial > venous in ET ^[1]
Unusual site thrombosis (abdominal pain from mesenteric/portal/hepatic vein thrombosis)	When seeing mesenteric vein thrombosis, screen for JAK2 mutations ^[2]. Budd-Chiari syndrome (hepatic vein thrombosis) is a classic MPN association
Bleeding (epistaxis, gum bleeding, easy bruising, menorrhagia, GI bleed)	Paradoxical bleeding, especially when Plt > 1,000 × 10⁹/L — due to acquired vWD (consumption of large VWF multimers by excess platelets) ^[1]^[2]^[3]
Livedo reticularis	Microvascular thrombosis in dermal venules → mottled, net-like purplish discolouration of skin ^[4]
Pregnancy complications (1st trimester miscarriage, stillbirth, pre-eclampsia, IUGR, premature delivery)	Placental microinfarction from platelet thrombi; impaired uteroplacental perfusion ^[4]

Sign	Pathophysiological Basis
Often no physical signs	ET is characteristically indolent; physical examination may be entirely normal
Mild splenomegaly (in ~20-50%)	Extramedullary haematopoiesis (EMH) — when the bone marrow proliferative drive is excessive, haematopoietic stem cells "seed" the spleen and produce cells there. Also, increased platelet/cell turnover → splenic workload increases. Splenomegaly in ET is typically mild (unlike PMF where it is massive) ^[1]^[3]
Erythromelalgia (red, warm, painful extremities)	Visible erythema and warmth of digits/palms/soles due to platelet-mediated arteriolar microthrombosis and secondary inflammation ^[3]^[4]
Digital ischaemia / gangrene (rare)	Severe arterial thrombosis of digital arteries → critical ischaemia
Ecchymoses, petechiae	If acquired vWD present (Plt > 1,000) → mucocutaneous bleeding pattern ^[2]
Livedo reticularis	Mottled, lace-like purplish pattern on skin from microvascular occlusion ^[4]
Neurological focal signs (if stroke has occurred)	Large-vessel arterial thrombosis → cerebral infarction
Signs of DVT (unilateral leg swelling, warmth, tenderness)	Venous thrombosis complication

Clinical Pearl: ET vs. Reactive Thrombocytosis at the Bedside

A few bedside clues favour ET over reactive thrombocytosis:

Splenomegaly (reactive thrombocytosis does NOT cause splenomegaly from the thrombocytosis itself — if splenomegaly is present, think primary)
Erythromelalgia — virtually pathognomonic for MPN
Thrombosis in unusual sites (mesenteric, hepatic, portal veins)
Bleeding despite high platelets (acquired vWD)
No obvious reactive cause (no infection, inflammation, iron deficiency, recent surgery)

Unlike PMF (where constitutional symptoms like drenching night sweats, weight loss, and severe fatigue dominate), ET typically has few or no constitutional symptoms
If significant constitutional symptoms are present, consider whether the patient is transforming to myelofibrosis (post-ET MF)

8. Important Pathophysiological Concepts (Expanded)

Unlike most prothrombotic states (e.g., Factor V Leiden, antiphospholipid syndrome) which predominantly cause venous thrombosis, ET causes arterial > venous thrombosis ^[1]. This is because:

Platelets are the primary mediators of arterial thrombosis — in high-shear arterial circulation, platelet adhesion and aggregation are the initiating steps (cf. venous thrombosis which is more fibrin/coagulation factor-dependent)
In ET, the massively increased platelet mass and their abnormal activation state directly promote arterial thrombus formation
JAK2 V617F in particular upregulates platelet-neutrophil interactions and endothelial adhesion molecules, further promoting arterial events

JAK2 mutation-positive ET carries higher thrombotic risk than CALR-mutated ET ^[2]^[4]. This is because:

JAK2 V617F is expressed not only in megakaryocytes but also in neutrophils, monocytes, and endothelial cells
In neutrophils: promotes NETosis (neutrophil extracellular traps) → pro-thrombotic
In endothelial cells: increases expression of adhesion molecules (P-selectin, tissue factor)
In platelets: increased activation, aggregation, and thromboxane A2 generation
CALR mutations, by contrast, are more "megakaryocyte-restricted" in their effects → fewer systemic prothrombotic consequences

When platelet count exceeds ~1,000 × 10⁹/L: ^[2]

The massively increased platelet surface area adsorbs large VWF multimers from the plasma
Additionally, high-shear forces generated by the increased cellular mass promote ADAMTS13-mediated cleavage of large VWF multimers
The result: selective depletion of high-molecular-weight VWF multimers (which are the most haemostatically active)
The VWF ristocetin cofactor activity (VWF:RCo) drops disproportionately to VWF:Ag
Clinical presentation mimics Type 2A VWD → mucocutaneous bleeding

Key investigation: when extreme thrombocytosis + bleeding → check VWF:Ag, VWF:RCo, Factor VIII, and ristocetin-induced platelet aggregation ^[2]

The spleen is not typically massively enlarged in ET (contrast with PMF or CML)
When splenomegaly is present in ET, it is usually mild and due to:
- Extramedullary haematopoiesis
- Increased red cell/platelet pooling
A massive spleen in the context of thrombocytosis should raise suspicion for PMF or CML, not ET ^[1]

High Yield Summary

Essential Thrombocythaemia — Key Points Before Diagnosis/Management:

Definition: Clonal MPN with sustained platelet count ≥ 450 × 10⁹/L due to autonomous megakaryocyte proliferation
Epidemiology: Median age 60, F > M (2:1), 150 new cases/year in HK, near-normal life expectancy
Driver mutations: JAK2 V617F (~50-65%), CALR exon 9 (~25%), MPL (~3-5%), triple-negative (~10-15%) — all converge on JAK-STAT pathway
Diagnosis by exclusion: Must exclude reactive thrombocytosis (infection, inflammation, iron deficiency, malignancy, post-splenectomy) and other MPNs (CML, PV, PMF)
Clinical features:
- Up to 50% asymptomatic — incidental finding
- Microvascular symptoms: headache, dizziness, erythromelalgia (pathognomonic)
- Thrombosis: Arterial > Venous — stroke, MI, PVD; unusual sites (mesenteric, hepatic vein)
- Paradoxical bleeding when Plt > 1,000 → acquired vWD (consumption of VWF multimers)
Risk stratification: Age > 60 and prior thrombosis = high risk; JAK2 positivity adds further risk
Transformation risk: < 5% to myelofibrosis, < 5% to AML — lowest among BCR-ABL-negative MPNs
Key exam trap: Extreme thrombocytosis causes BLEEDING (not more clotting) due to acquired vWD

Active Recall - Essential Thrombocythaemia (Definition, Epidemiology, Pathophysiology, Clinical Features)

Differential Diagnosis of Thrombocytosis

The single most important concept before you even think about ET is this: ET is a diagnosis by exclusion ^[1]^[3]. Reactive (secondary) thrombocytosis is far more common than primary thrombocytosis — perhaps 80-90% of all elevated platelet counts you encounter in clinical practice are reactive. Your job is to systematically exclude the common reactive causes and the other primary (clonal) causes before landing on ET.

Let's think about this from first principles. The platelet count can be elevated because:

Something is driving the bone marrow to make more platelets (reactive — cytokine-driven, especially IL-6, IL-11, and TPO)
The bone marrow is autonomously making too many platelets due to a clonal stem cell defect (primary/neoplastic)
Platelets are being redistributed (e.g., post-splenectomy — the one-third of platelets normally pooled in the spleen are now all in the circulation)

The GC lecture slide frames ET diagnosis as: "Diagnosis by exclusion → infections, inflammations, malignancy, iron deficiency → Bone marrow to exclude CML and other MPN/MDS" ^[1]

This gives us the two-tier framework to work through:

Two-Tier Approach to Thrombocytosis DDx

Tier 1: Exclude reactive (secondary) thrombocytosis — these are the common everyday causes (infections, inflammations, malignancy, iron deficiency, tissue damage, post-splenectomy)

Tier 2: Among primary causes, distinguish ET from other clonal disorders — CML, PV, PMF, MDS/MPN overlap, and MDS with ring sideroblasts and thrombocytosis (MDS-RS-T)

Reactive thrombocytosis involves cytokine-driven platelet production by non-neoplastic megakaryocytes ^[5]. The platelets produced are functionally normal, and the thrombocytosis resolves when the underlying stimulus is treated. Crucially, reactive thrombocytosis almost never causes thrombosis or bleeding — this is a key clinical differentiator from ET.

Category	Examples	Mechanism (Why does it cause thrombocytosis?)
Infection (acute and chronic)	Pneumonia, UTI, osteomyelitis, TB, abscess	IL-6 is released as an acute-phase cytokine during infection → IL-6 stimulates hepatic TPO production AND directly stimulates megakaryopoiesis → more platelets. Also, IL-6 drives the acute-phase response (CRP, fibrinogen) — platelets are essentially "honorary acute-phase reactants"
Inflammation (acute and chronic)	Rheumatoid arthritis, IBD (Crohn's, UC), vasculitis	Same IL-6-mediated mechanism. Chronic inflammation = chronic IL-6 elevation = sustained thrombocytosis. This is why RA patients commonly have platelets of 500-600
Iron-deficiency anaemia	Chronic blood loss (menorrhagia, GI bleed), dietary deficiency	The mechanism is debated but likely involves: (1) TPO and EPO share structural homology → in iron deficiency, high EPO levels may cross-react with MPL receptors on megakaryocytes; (2) iron deficiency itself may directly stimulate megakaryopoiesis; (3) reactive thrombocytosis as a general marrow response to anaemia stress. In HK, always check ferritin when you see thrombocytosis ^[1]^[7]
Malignancy	Hodgkin's lymphoma, metastatic cancer	Tumour-derived IL-6, TPO, and other cytokines drive reactive megakaryopoiesis. Some solid tumours (especially lung, GI) produce paraneoplastic thrombocytosis
Tissue damage / post-surgical	Post-splenectomy, major surgery, severe trauma, burns	Post-splenectomy: the spleen normally pools ~⅓ of platelets → after removal, these re-enter the circulation → immediate rise. Also, spleen is a site of platelet destruction → removal prolongs platelet lifespan. Additionally, surgical stress → IL-6 release → further platelet production. The post-splenectomy rise is typically transient but can persist
Acute blood loss	GI haemorrhage, trauma	Marrow compensatory response: blood loss → hypoxia/stress → EPO surge, which also stimulates megakaryopoiesis; simultaneously, IL-6 from tissue damage drives platelet production
Haemolytic anaemia	Any cause	Compensatory marrow expansion for red cells also "spills over" to megakaryocyte lineage; cytokine milieu favours multilineage expansion
Rebound thrombocytosis	Recovery from B12/folate deficiency, recovery from chemotherapy, recovery after alcohol cessation	During the deficiency/suppression, megakaryopoiesis is suppressed → when the stimulus is removed, the marrow "overshoots" in recovery → transient thrombocytosis. This is analogous to reticulocytosis during recovery from anaemia

From the GC lecture slide — the four categories to exclude are: infections, inflammations, malignancy, iron deficiency ^[1]. These are the most common and the ones examiners expect you to rattle off.

Why Is Reactive Thrombocytosis Benign?

Students often ask: "If the platelet count is 800 from iron deficiency, won't the patient clot?" The answer is almost always no. Reactively produced platelets are functionally normal and produced at a regulated pace. There is no clonal abnormality driving abnormal platelet activation, no JAK2-mediated neutrophil/endothelial activation, and no altered platelet receptor expression. The thrombotic risk is essentially that of the underlying condition, not of the platelet count itself. This is a crucial conceptual distinction from ET.

Once reactive causes are excluded, you must differentiate ET from other clonal haematopoietic disorders that can present with an elevated platelet count. The GC lecture slide specifies: "Bone marrow to exclude CML and other MPN/MDS" ^[1].

Condition	Key Distinguishing Features	Why It Mimics ET
Chronic Myeloid Leukaemia (CML)	Defined by Philadelphia chromosome t(9;22) / BCR-ABL1 fusion gene ^[8]. Massive leukocytosis with bimodal distribution (neutrophils + myelocytes), basophilia, massive splenomegaly. "No t(9;22), not CML" ^[8]	CML can present with significant thrombocytosis (platelets may be > 1,000). In fact, rare CML cases present with isolated thrombocytosis before overt leukocytosis develops. This is why BCR-ABL1/Philadelphia chromosome testing is mandatory in any workup of primary thrombocytosis — missing CML is a dangerous error because CML has specific targeted therapy (TKIs)
Polycythaemia Vera (PV)	Hb > 16.5 (M) / > 16 (F), Hct > 49% (M) / > 48% (F) ^[3]^[9]. JAK2 V617F in 97% ^[3]. Low EPO. Facial plethora, aquagenic pruritus, hyperviscosity symptoms	PV frequently has concurrent thrombocytosis. Some "masked PV" cases present with prominent thrombocytosis but only borderline Hb — iron deficiency can mask the erythrocytosis. The WHO criteria require checking Hb/Hct carefully. If both Hb and platelets are elevated → think PV first, not ET
Primary Myelofibrosis (PMF)	Leucoerythroblastic blood picture, tear-drop cells on PBS ^[6]. Dry tap on BM aspirate; biopsy shows megakaryocytic proliferation and atypia with fibrosis ^[6]. Massive splenomegaly, constitutional symptoms (night sweats, weight loss, severe fatigue)	Early/prefibrotic PMF can present with thrombocytosis and minimal fibrosis, closely mimicking ET. The distinction is important because PMF has a much worse prognosis (higher transformation risk, ~20% to AML). BM biopsy morphology is the key differentiator — PMF megakaryocytes show characteristic atypia (cloud-like nuclei, dense clustering)
MDS/MPN overlap syndromes	MDS with ring sideroblasts and thrombocytosis (MDS-RS-T, previously called RARS-T). Dysplastic features in ≥ 1 lineage + ring sideroblasts ≥ 15% + platelets ≥ 450. Often SF3B1 mutated	Presents with thrombocytosis and may have JAK2 mutation, but has concurrent dysplasia (especially in erythroid lineage) and ring sideroblasts on BM iron stain. The prognosis and management differ from ET
MDS with isolated del(5q)	Macrocytic anaemia, hypolobated megakaryocytes, thrombocytosis (paradoxically), del(5q) on cytogenetics	Can present with modest thrombocytosis. Cytogenetics is diagnostic
CML in chronic phase with thrombocytosis-predominant presentation	Repeat: some CML patients present with platelets > 1,000 but relatively modest leukocytosis — the "thrombocythaemic variant of CML." BCR-ABL1 must be checked	This is the most dangerous mimicker because TKI therapy is curative for CML but would be wrong for ET

The Most Dangerous Mimicker: CML

Never diagnose ET without excluding CML. Some CML cases present with predominant thrombocytosis and only mild leukocytosis. BCR-ABL1/Philadelphia chromosome testing is non-negotiable in any patient with persistent thrombocytosis being evaluated for a primary cause. Missing CML deprives the patient of targeted TKI therapy (imatinib, dasatinib, etc.) that transforms prognosis. ^[1]^[8]

Understanding why you order each test is essential:

Investigation	What It Rules In/Out	Rationale
CBC with differential	Reactive vs. primary; CML (leukocytosis, basophilia); PV (↑ Hb/Hct); PMF (anaemia, variable counts)	The starting point. In ET, the defining finding is isolated persistent thrombocytosis (Plt ≥ 450) ^[1]^[4]. Other lineages should be near-normal. If WBC is markedly elevated → think CML or PV
Peripheral blood smear (PBS)	CML: bimodal distribution of neutrophils and myelocytes, basophilia ^[8]^[7]. PMF: leucoerythroblastic picture, tear-drop cells ^[6]. Blasts → acute leukaemia. Dysplasia → MDS	Morphology tells you a huge amount. In ET, the PBS typically shows thrombocytosis with large, hypergranular platelets and occasional giant platelets, but no significant dysplasia, no tear-drop cells, no blasts
CRP/ESR	Reactive thrombocytosis (infection/inflammation)	If CRP/ESR are markedly elevated, reactive thrombocytosis is more likely. In ET, inflammatory markers should be normal (unless there is a coincidental infection)
Ferritin / Iron studies	Iron-deficiency anaemia as a reactive cause ^[1]	Iron deficiency is extremely common and an important reactive cause. Also, iron deficiency can mask PV (low iron → can't make enough Hb → Hb appears "normal" but patient actually has masked PV with thrombocytosis)
BCR-ABL1 / Philadelphia chromosome	CML — must be excluded ^[1]^[8]	Cytogenetics or molecular testing (FISH, RT-PCR). If positive → CML, not ET. Period.
JAK2 V617F, CALR, MPL mutation testing	Supports clonal/primary nature of thrombocytosis; prognostic stratification	JAK2 V617F in ~50%, CALR ~25%, MPL ~3-5% ^[1]^[4]^[5]. Having one of these mutations strongly supports a primary MPN. However, JAK2 is shared among PV (97%), ET, and PMF — so a positive JAK2 alone doesn't distinguish between them
Bone marrow biopsy	Exclude CML and other MPN/MDS ^[1]. Distinguish ET from prefibrotic PMF (most critical distinction)	ET BM: hypercellularity with megakaryocyte lineage proliferation; megakaryocytes are large, mature, with hyperlobated "staghorn" nuclei, dispersed singly or in loose clusters ^[6]. PMF BM: megakaryocytes with bizarre atypia, tight clustering, cloud-like nuclei, with reticulin fibrosis. CML BM: granulocytic hyperplasia with small hypolobated megakaryocytes
Serum EPO	Distinguishes PV (low EPO) from secondary polycythaemia (high EPO)	Relevant when Hb is borderline-high. Low EPO + ↑ Hb → PV, not ET
LDH, urate	Elevated in any MPN due to high cell turnover; markedly elevated in PMF and blast transformation	Non-specific but supportive of clonal disorder if elevated

This is the single hardest differential diagnosis in clinical haematology practice, and it matters enormously because:

Prefibrotic PMF has significantly higher risks of progression to overt myelofibrosis (~12% at 15 years vs ~4% in ET) and leukaemic transformation (~12% vs ~3%)
The distinction rests almost entirely on bone marrow morphology — there are no blood tests or molecular markers that reliably separate them

Feature	ET	Prefibrotic PMF
Megakaryocyte morphology	Large, mature, hyperlobated ("staghorn") nuclei; dispersed singly or in loose clusters	Atypical, with cloud-like/bulbous/hypolobated nuclei; tight clustering near bone trabeculae
Reticulin fibrosis	Grade 0-1 (minimal or absent)	Grade 0-1 initially but often grade 1
Marrow cellularity	Increased, predominantly megakaryocytic	Increased, with more granulocytic proliferation
Anaemia	Absent (Hb normal)	May have mild anaemia
LDH	Normal or mildly elevated	Often elevated
Splenomegaly	Absent or mild	May be moderate
Constitutional symptoms	Absent	May be present even early

Exam Pearl: ET vs Prefibrotic PMF

If an exam question describes bone marrow with large mature megakaryocytes with hyperlobated nuclei, no significant fibrosis, and normal haemoglobin → that is ET. If there is megakaryocyte atypia with tight clustering and any grade of fibrosis → think prefibrotic PMF. The morphological distinction requires an experienced haematopathologist.

PV can masquerade as ET when iron deficiency coexists ^[3]^[9]:

Iron deficiency restricts erythropoiesis → Hb/Hct may not reach the PV diagnostic thresholds
But platelets are still elevated → looks like isolated thrombocytosis → misdiagnosed as ET
Clue: JAK2 V617F positive (97% in PV, ~50% in ET) + low EPO + iron-deficient state
If in doubt, replete iron and re-check Hb/Hct — if it rises above PV thresholds, it was masked PV all along

A rare but important differential, especially in young patients:

Familial ET cases may be due to autosomal dominant inheritance with germline TPO or c-Mpl mutations ^[4]
These cause constitutive TPO signalling → lifelong thrombocytosis
Key clues: family history of elevated platelets, elevated serum TPO levels, absence of somatic JAK2/CALR/MPL mutations
Important to distinguish from true clonal ET because the management differs (lower thrombotic risk, no transformation risk)

When presented with a patient with thrombocytosis on an exam:

Is there an obvious reactive cause? → Check CRP, ESR, ferritin, infection screen, surgical/trauma history
Is it CML? → BCR-ABL1 / Philadelphia chromosome — mandatory ^[1]^[8]
Is it PV with concurrent thrombocytosis? → Check Hb/Hct (gender-specific cutoffs), EPO level
Is it PMF (prefibrotic)? → BM biopsy for megakaryocyte morphology and fibrosis grading; check for leucoerythroblastic picture on PBS
Is it MDS/MPN overlap? → BM biopsy for dysplasia, ring sideroblasts, cytogenetics
Only after all of these are excluded → ET is diagnosed ^[1]^[3]

From the GC lecture slide: "Diagnosis by exclusion → infections, inflammations, malignancy, iron deficiency → Bone marrow to exclude CML and other MPN/MDS → JAK2 V617F mutation in ~50%, CALR, MPL → Plt persistently > 450" ^[1]

High Yield Summary — Differential Diagnosis of ET

ET is a diagnosis of exclusion — must systematically exclude reactive and other primary causes
Reactive thrombocytosis (80-90% of all thrombocytosis): infections, inflammations, malignancy, iron deficiency, post-splenectomy ^[1] — benign, resolves with treatment of underlying cause, almost never causes thrombosis
Primary (clonal) mimickers of ET:
- CML — most dangerous to miss; BCR-ABL1 testing is mandatory ^[1]^[8]
- PV — check Hb/Hct and EPO; beware "masked PV" with concurrent iron deficiency ^[3]^[9]
- Prefibrotic PMF — hardest to distinguish; relies on BM morphology (megakaryocyte atypia, clustering, fibrosis) — worse prognosis than ET
- MDS/MPN overlap (MDS-RS-T) — look for dysplasia and ring sideroblasts
Key investigations for DDx: CBC + PBS, CRP/ESR, ferritin, BCR-ABL1, JAK2/CALR/MPL, BM biopsy, EPO
Reactive thrombocytosis is benign because platelets are functionally normal and non-clonal; ET platelets are clonally abnormal with altered function
Familial thrombocytosis (germline TPO/c-Mpl mutations) is rare but important in young patients ^[4]

Active Recall - Differential Diagnosis of Thrombocytosis / ET

References

^[1] Lecture slides: GC 086. Splenomegaly.pdf (Essential Thrombocythaemia section and Polycythaemia Vera section) ^[2] Senior notes: Block A - Leg swelling and chest pain_ deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (MPN-associated thrombosis section) ^[3] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (Essential Thrombocythaemia and Polycythaemia Vera sections) ^[4] Senior notes: Ryan Ho Haemtology.pdf (Section 3.3.2.3 Essential Thrombocythaemia) ^[5] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (ET section, differential diagnosis of thrombocytosis table) ^[6] Senior notes: Maksim Medicine Notes.pdf (PV, ET, PMF comparison table) ^[7] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (CML PBS findings, iron deficiency PBS) ^[8] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (CML section) ^[9] Lecture slides: GC 086. Splenomegaly.pdf (Polycythaemia Vera section — Hb/Hct diagnostic thresholds)

Diagnostic Criteria for Essential Thrombocythaemia

ET is a clonal neoplasm that looks deceptively simple — "just high platelets." But as we've established, the differential is broad and the mimickers are consequential (missing CML deprives the patient of TKIs; misclassifying prefibrotic PMF as ET gives false reassurance about prognosis). Formal diagnostic criteria exist to standardise the diagnostic process and ensure that every clinician systematically excludes the right things before labelling someone with ET.

The GC lecture slide frames ET as a "diagnosis by exclusion → infections, inflammations, malignancy, iron deficiency → Bone marrow to exclude CML and other MPN/MDS → JAK2 V617F mutation in ~50%, CALR, MPL → Plt persistently > 450" ^[1]

WHO 2022 / ICC 2022 Diagnostic Criteria for ET

The current standard is the WHO 5th edition (2022) and the parallel International Consensus Classification (ICC, 2022) criteria, which are virtually identical for ET. The framework uses major and minor criteria.

ET diagnostic criteria: 4 Major criteria, OR first 3 Major + 1 Minor criterion ^[3]

#	Major Criterion	Rationale (Why This Criterion?)
1	Platelet count ≥ 450 × 10⁹/L	This is the defining haematological abnormality. The threshold of 450 (not 400) was chosen because it captures clinically significant clonal thrombocytosis while excluding most normal variation. "Plt persistently > 450" ^[1]. The word "persistently" is key — a single elevated reading is not sufficient; you need sustained elevation, typically confirmed on repeat testing over weeks
2	Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobated nuclei. No significant increase or left-shift in neutrophil granulopoiesis or erythropoiesis, and very rarely minor (grade 1) increase in reticulin fibres	This is the morphological criterion that separates ET from prefibrotic PMF (which has megakaryocyte atypia and clustering) and from PV (which shows panmyelosis = trilineage hyperplasia). "Bone marrow to exclude CML and other MPN/MDS" ^[1]. The classic ET megakaryocytes are large, mature, with deeply lobulated "staghorn" nuclei, dispersed individually or in loose clusters — NOT the tight clusters of atypical forms with cloud-like nuclei seen in PMF ^[6]
3	Not meeting WHO criteria for BCR-ABL1+ CML, PV, PMF, MDS, or other myeloid neoplasm	This is the exclusion criterion — the formal requirement to rule out everything else. "Diagnosis by exclusion" ^[1]. It means you must check BCR-ABL1, Hb/Hct (to exclude PV), and assess for MDS features
4	Presence of JAK2, CALR, or MPL mutation	Finding one of these driver mutations provides molecular evidence of clonality, strongly supporting a primary (neoplastic) rather than reactive process. "JAK2 V617F mutation in ~50%, CALR, MPL" ^[1]^[4]^[5]

#	Minor Criterion	Rationale
1	Presence of a clonal marker (e.g., abnormal karyotype) OR absence of evidence for reactive thrombocytosis	If all three driver mutations are negative ("triple-negative" ET, ~10–15%), you cannot satisfy Major Criterion 4. In that case, you need either another clonal marker (e.g., an acquired cytogenetic abnormality found on BM karyotyping) or convincing demonstration that no reactive cause exists. This is the "safety net" for triple-negative patients

How to Apply the Criteria — A Mental Shortcut

Route 1 (mutation-positive, ~85-90% of cases): Plt ≥ 450 + characteristic BM morphology + excluded other neoplasms + JAK2/CALR/MPL mutation → 4 Major criteria met → ET diagnosed

Route 2 (triple-negative, ~10-15%): Plt ≥ 450 + characteristic BM morphology + excluded other neoplasms + no reactive cause identified (or another clonal marker found) → 3 Major + 1 Minor → ET diagnosed

The mnemonic for ET criteria: "4M or 3M + 1m" ^[3]

Common Exam Mistake

Students often forget that bone marrow biopsy is a MAJOR criterion for ET diagnosis. You cannot formally diagnose ET on blood tests and molecular markers alone — the BM is needed to (1) confirm megakaryocyte-lineage proliferation and (2) exclude prefibrotic PMF, MDS, and CML. In practice, some low-risk patients with classic presentations may be managed without BM biopsy, but this does not satisfy WHO criteria.

Understanding how the criteria differ across MPNs helps you grasp why each criterion exists:

Criterion	ET	PV	PMF
Defining blood count	Plt ≥ 450	Hb > 16.5 M / > 16 F; Hct > 49% M / > 48% F ^[9]	Anaemia, variable Plt/WBC
BM morphology	Megakaryocyte-lineage hyperplasia; large, mature, hyperlobated megakaryocytes	Panmyelosis (trilineage growth) ^[6]	Megakaryocyte atypia + reticulin/collagen fibrosis; dry tap ^[3]^[6]
Molecular	JAK2/CALR/MPL	JAK2 V617F (97%), JAK2 exon 12 (3%)	JAK2/CALR/MPL
Criteria format	4M or 3M + 1m	3M or 2M + 1m	3M + 1m (requires all 3 major + at least 1 minor)
Key exclusion	PV, CML, PMF, MDS	Secondary polycythaemia	CML, PV, ET, MDS, other
Minor criteria	Clonal marker or absence of reactive cause	Subnormal EPO	Anaemia, leucoerythroblastic PBS, ↑LDH, splenomegaly

^[3]^[6]

Here is the step-by-step approach when you encounter a patient with an elevated platelet count:

Key Algorithmic Points

Always repeat the CBC — a single elevated platelet count is not enough. Confirm persistence.
Always check CRP/ESR and ferritin first — reactive causes are the commonest and cheapest to exclude.
BCR-ABL1 must be done before molecular MPN testing — CML is the most dangerous mimicker ^[1]^[8].
Hb/Hct must be assessed before calling it ET — masked PV presents with thrombocytosis when iron deficiency suppresses erythrocytosis ^[3]^[9].
BM biopsy is essential — it is the only way to distinguish ET from prefibrotic PMF ^[1]^[3].

Investigation Modalities: Key Findings and Interpretations

Why: The starting point for any haematological evaluation. In ET, the CBC provides the defining abnormality and helps exclude other MPNs.

Parameter	Expected in ET	Interpretation / What to Watch For
Platelet count	≥ 450 × 10⁹/L, sustained ^[1]^[4]	Must be persistently elevated (not a one-off). Counts can range from 450 to > 2,000. When Plt > 1,000, think about acquired vWD risk ^[2]
Haemoglobin	Normal	If Hb is elevated → consider PV. If Hb is low with borderline iron studies → consider masked PV. PV thresholds: M > 16.5 g/dL / Hct > 49%; F > 16 g/dL / Hct > 48% ^[9]
WBC	Normal or mildly elevated	Marked leukocytosis (> 25) with basophilia → think CML ^[8]. Mild neutrophilia is acceptable in ET. Elevated WBC in ET is an independent cardiovascular risk factor ^[1]
Haematocrit	Normal	Elevated Hct → PV

Why: Morphology tells you what the automated counter cannot. The workup framework is MCICM = Morphology (PBS, BM), Cytochemistry, Immunophenotype, Cytogenetics, Molecular genetics ^[10]

Finding	Significance
Large/giant platelets, platelet anisocytosis	Suggestive of clonal megakaryopoiesis (megakaryocytes with altered ploidy produce larger platelets). Also seen in ITP (increased turnover), but context differs
Hypergranular platelets	May be seen in ET — reflects abnormal megakaryocyte maturation
No blasts	Rules out acute leukaemia / blast transformation
No tear-drop cells, no nucleated RBCs	Leucoerythroblastic picture + tear-drop cells = PMF or marrow infiltration ^[6]^[10]. Their ABSENCE supports ET over PMF
No bimodal myelocyte-neutrophil distribution, no basophilia	This pattern = CML ^[7]^[8]. Absence supports ET
No dysplastic forms	Rules out MDS/MPN overlap

Pseudohyperkalemia with Thrombocytosis

A practical pearl: thrombocytosis can cause pseudohyperkalemia ^[11]. When blood clots in a serum tube, the excessive platelets release intracellular potassium during clotting → artefactually elevated K⁺. Always use heparinised plasma (not serum) for potassium measurement in patients with marked thrombocytosis. If you see "hyperkalemia" in a thrombocytosis patient with no clinical reason, check the sample type.

Why: To exclude reactive thrombocytosis.

Finding	Interpretation
Normal CRP/ESR	Supports primary rather than reactive thrombocytosis
Elevated CRP/ESR	Reactive thrombocytosis likely — but does NOT exclude coexistent ET (a patient can have ET AND get an infection). If thrombocytosis persists after the reactive cause resolves → investigate for primary cause

Why: Two reasons:

Iron-deficiency anaemia is a common reactive cause of thrombocytosis
Iron deficiency can mask PV — restricts erythropoiesis so Hb stays below PV thresholds

Finding	Interpretation
Low ferritin	Iron deficiency is present. May be the cause of reactive thrombocytosis, OR may be masking PV. Replete iron and re-check Hb/Hct
Normal ferritin	Iron deficiency is not the cause; proceed with primary workup

Why: This is a non-negotiable exclusion criterion. "No t(9;22), not CML" ^[8]. Bone marrow to exclude CML ^[1].

Method	Details
RT-PCR for BCR-ABL1	Most sensitive method; detects the fusion transcript. Quantitative RT-PCR also used for monitoring CML treatment response
FISH for BCR-ABL1	Detects the fusion gene on interphase or metaphase cells; slightly less sensitive than RT-PCR but very reliable
Conventional cytogenetics	Karyotyping from BM aspirate to detect t(9;22) and any additional cytogenetic abnormalities

Result	Interpretation
BCR-ABL1 positive	CML, not ET. Manage with TKI therapy (imatinib, dasatinib, nilotinib)
BCR-ABL1 negative	CML excluded. Proceed with JAK2/CALR/MPL testing

Why: These are the driver mutations of BCR-ABL1-negative MPNs. Finding one provides strong evidence of clonality and is Major Criterion 4 for ET diagnosis.

Mutation	Test Method	Expected in ET	Significance
JAK2 V617F	Allele-specific PCR, quantitative PCR	Positive in ~50–65% ^[1]^[4]^[5]	Supports clonality. Also present in PV (97%) and PMF (50–65%), so does NOT distinguish between them. JAK2+ ET carries higher thrombotic risk than CALR+ ET ^[2]
CALR exon 9	Fragment analysis / Sanger sequencing	Positive in ~20–25% ^[4]^[5]	Almost exclusively seen in ET and PMF (not PV). Associated with younger age, higher platelet count, lower WBC, and lower thrombotic risk compared to JAK2+ ET
MPL (W515L/K)	Sanger sequencing / targeted NGS	Positive in ~3–5% ^[4]^[5]	Supports clonality. Also seen in PMF
Triple-negative	All three negative	~10–15% ^[5]	Clonality harder to prove. Requires either another clonal marker or exclusion of reactive causes (Minor Criterion). Consider extended NGS panel for non-canonical mutations

From the GC lecture: "JAK2 V617F mutation in ~50%, CALR, MPL" ^[1] — know these frequencies.

Why: To distinguish PV from ET when Hb is borderline.

Finding	Interpretation
Low EPO	Suggests PV (the bone marrow is making red cells autonomously, so the feedback loop suppresses EPO). "Low EPO → not EPO driven" ^[3]^[9]
Normal EPO	Compatible with ET (the red cell line is NOT autonomously overproducing, so the EPO-feedback loop is intact)
High EPO	Secondary polycythaemia (compensatory EPO elevation) — not ET

Why: BM biopsy is Major Criterion 2. It is the only investigation that can reliably distinguish ET from prefibrotic PMF, confirm the characteristic megakaryocyte morphology, and exclude MDS.

The BM examination is done at the posterior iliac crest (preferred site). Both aspirate and trephine biopsy should be performed. ^[10]

Component	Technique	What You Get From It
Aspirate	Suction of liquid marrow → smeared on slides	Cytology (cell morphology), flow cytometry, cytogenetic analysis (karyotype, FISH), molecular genetics
Trephine biopsy	Core of bone + marrow tissue → fixed, sectioned, stained	Histological architecture, cellularity assessment, reticulin/fibrosis grading, immunohistochemistry

Key BM Findings in ET vs. Mimickers

Feature	ET	Prefibrotic PMF	PV	CML
Cellularity	Hypercellular, mainly megakaryocyte lineage ^[6]	Hypercellular, multilineage	Panmyelosis (trilineage) ^[6]	Markedly hypercellular, granulocytic
Megakaryocyte size	Large, mature	Variable, often large but also small atypical forms	Variable	Small, hypolobated ^[8]
Megakaryocyte nuclei	Deeply hyperlobated "staghorn"	Cloud-like / bulbous / hypolobated, bizarre atypia	Pleomorphic, all sizes	Small, hypolobated
Megakaryocyte arrangement	Dispersed singly or in loose clusters	Tight clusters, often adjacent to trabeculae and sinusoids	Loose clusters or dispersed	Clusters of small forms
Reticulin fibrosis	Grade 0–1 (absent or minimal)	Grade 0–1 initially but often progresses	Grade 0–1 initially	Variable
Granulopoiesis	Not significantly increased	Often increased	Increased	Markedly increased, bimodal distribution ^[8]
Erythropoiesis	Normal	Variable, may be reduced	Increased	Moderately reduced

The Critical BM Distinction: ET vs Prefibrotic PMF

This is the single most important morphological distinction in the ET workup. It has major prognostic implications:

ET: 10-year leukaemic transformation ~2–4%, 10-year fibrotic transformation ~4%
Prefibrotic PMF: 10-year leukaemic transformation ~12%, 10-year fibrotic transformation ~12%

The distinction rests on megakaryocyte morphology and arrangement — ET has large, mature, deeply lobulated megakaryocytes dispersed individually, while prefibrotic PMF has atypical forms with cloud-like nuclei in tight clusters. An experienced haematopathologist review is essential. ^[3]

Why: To detect the Philadelphia chromosome (final CML exclusion), identify any additional chromosomal abnormalities that may serve as clonal markers (relevant for triple-negative patients), and provide prognostic information.

Finding	Significance
Normal karyotype	Most common in ET (~85%). Compatible with diagnosis
t(9;22)	CML, not ET ^[8]
del(13q), +9, +8, del(20q)	Recurrent cytogenetic abnormalities in MPNs. Support clonality (useful in triple-negative patients)
del(5q) isolated	Consider MDS with isolated del(5q) rather than ET
Complex karyotype	Suggests higher risk of transformation

Investigation	When to Order	Finding / Interpretation
VWF:Ag, VWF:RCo, Factor VIII, ristocetin-induced platelet aggregation	When Plt > 1,000 with bleeding tendency → exclude acquired vWD ^[2]	↓VWF:RCo disproportionate to VWF:Ag = acquired vWD (selective loss of large VWF multimers)
LDH	Baseline in all MPNs	Mildly elevated in ET; markedly elevated → suspect PMF or blast transformation
Serum urate	Baseline	Elevated due to high cell turnover; guides management (allopurinol prophylaxis if needed)
Liver function tests	If hepatomegaly / suspected Budd-Chiari	Deranged LFTs with hepatomegaly → consider hepatic vein thrombosis (Budd-Chiari) as complication of ET
Doppler USS of hepatic/portal/splenic veins	If abdominal pain, hepatomegaly, or suspected unusual-site thrombosis	Thrombosis in unusual sites (hepatic, portal, mesenteric veins) is characteristic of MPN ^[2]
Next-generation sequencing (NGS) panel	Triple-negative patients; prognostic information	Extended panel may detect non-canonical mutations (ASXL1, EZH2, IDH1/2, SRSF2, TP53) — relevant for prognostic risk stratification. ASXL1 and TP53 mutations confer adverse prognosis

Stage	Investigations	Purpose
Stage 1: Confirm and characterise thrombocytosis	CBC with differential, PBS, repeat CBC	Confirm persistent Plt ≥ 450; assess other lineages; morphology
Stage 2: Exclude reactive causes	CRP/ESR, ferritin, iron studies, infection screen, clinical context	Most thrombocytosis is reactive
Stage 3: Exclude CML	BCR-ABL1 (RT-PCR or FISH)	Non-negotiable ^[1]^[8]
Stage 4: Molecular MPN testing	JAK2 V617F, CALR, MPL	Demonstrate clonality; Major Criterion 4
Stage 5: Exclude PV	Hb/Hct (with gender-specific cutoffs), serum EPO, iron studies	Rule out masked PV
Stage 6: Bone marrow examination	Aspirate + trephine biopsy, reticulin stain, cytogenetics	Major Criterion 2; distinguish from prefibrotic PMF, MDS, CML ^[1]
Stage 7: Risk stratification	Age, thrombosis history, mutation status, cardiovascular risk factors	Guides management (covered in next section)
Stage 8: Baseline monitoring	LDH, urate, LFTs, VWF studies (if Plt > 1,000)	Baseline for follow-up; detect complications

High Yield Summary — Diagnostic Criteria and Investigation of ET

WHO 2022 Diagnostic Criteria: 4 Major (4M) or 3 Major + 1 Minor (3M + 1m) ^[3]
- M1: Plt ≥ 450 (sustained)
- M2: BM biopsy showing megakaryocyte-lineage proliferation with large, mature, hyperlobated megakaryocytes
- M3: Not meeting criteria for CML, PV, PMF, MDS, or other myeloid neoplasm
- M4: JAK2, CALR, or MPL mutation
- m1: Clonal marker or absence of reactive cause (for triple-negative patients)
ET is a diagnosis by exclusion — you must exclude reactive causes AND other primary myeloid neoplasms ^[1]
BCR-ABL1 testing is mandatory to exclude CML ^[1]^[8]
BM biopsy is a major criterion — cannot formally diagnose ET without it; critical for distinguishing from prefibrotic PMF
JAK2 V617F in ~50%, CALR ~25%, MPL ~3-5%, triple-negative ~10-15% ^[1]^[4]^[5]
Check Hb/Hct and EPO to exclude PV — beware masked PV with concurrent iron deficiency ^[3]^[9]
When Plt > 1,000 with bleeding → check VWF:Ag, VWF:RCo for acquired vWD ^[2]
Thrombocytosis can cause pseudohyperkalemia — use heparinised plasma for K⁺ ^[11]

Active Recall - Diagnostic Criteria and Investigations for ET

^[1] Lecture slides: GC 086. Splenomegaly.pdf (Essential Thrombocythaemia section) ^[2] Senior notes: Block A - Leg swelling and chest pain_ deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (MPN-associated thrombosis section) ^[3] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (Diagnostic criteria for MPN, ET section) ^[4] Senior notes: Ryan Ho Haemtology.pdf (Section 3.3.2.3 Essential Thrombocythaemia) ^[5] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (ET section) ^[6] Senior notes: Maksim Medicine Notes.pdf (PV, ET, PMF comparison table) ^[7] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (CML PBS findings) ^[8] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (CML section) ^[9] Lecture slides: GC 086. Splenomegaly.pdf (Polycythaemia Vera section) ^[10] Senior notes: Ryan Ho Fundamentals.pdf (Haematological workup, MCICM, BM examination) ^[11] Senior notes: Ryan Ho Chemical Path.pdf (Pseudohyperkalemia)

Management of Essential Thrombocythaemia

The management of ET is not about normalising the platelet count for its own sake. The platelet count itself does not correlate linearly with thrombotic risk (a patient with platelets of 600 and JAK2 mutation may be at higher risk than one with platelets of 900 who is CALR-positive and young). Instead, management is driven by thrombotic risk stratification.

The GC lecture slide states: "Management → thrombosis risk" ^[1]

Think of it this way: ET is a chronic disease with near-normal life expectancy ^[4]. The things that actually kill or disable ET patients are thrombotic events (stroke, MI) and, less commonly, bleeding (acquired vWD) or disease transformation (myelofibrosis, AML). The entire management strategy is designed to prevent thrombosis while avoiding unnecessary treatment toxicity in low-risk patients.

Before you can manage ET, you must stratify risk. The revised International Prognostic Score for ET-Thrombosis (IPSET-thrombosis) is the current standard:

Risk Category	Criteria	Approach
Very Low Risk	Age ≤ 60, no thrombosis history, JAK2 wild-type	Observation ± low-dose aspirin
Low Risk	Age ≤ 60, no thrombosis history, JAK2 mutant	Low-dose aspirin
Intermediate Risk	Age > 60, no thrombosis history, JAK2 wild-type	Low-dose aspirin
High Risk	Age > 60 with JAK2 mutation, OR any prior thrombosis	Cytoreductive therapy + aspirin

From the GC lecture slide — the two key variables driving management: ^[1]

Age > 60 years
History of thromboembolic disease

Additionally: cardiovascular risk modification (HT, smoking, CHF, WBC) ^[1]^[3]

Why These Two Variables?

Age > 60: Older patients have accumulated more atherosclerotic burden, more endothelial dysfunction, and more comorbidities — all amplifying the prothrombotic effect of ET. The absolute thrombotic event rate roughly doubles after age 60.
Prior thrombosis: This is the single strongest predictor of recurrent thrombosis. A patient who has already clotted once has demonstrated that their haemostatic system is tipped towards thrombosis in the context of their particular ET biology.
JAK2 V617F: Adds thrombotic risk by activating neutrophils and endothelial cells (as discussed in pathophysiology). This is why JAK2 status modifies risk in the very-low vs. low and intermediate vs. high categories.

From the GC lecture slide — the treatment algorithm shows indications for cytoreduction in very low/low/intermediate-risk ET: ^[12]

Platelet ≥ 1000 (in general)
Vasomotor symptoms

Treatment Modalities

Indication: Very low-risk patients (age ≤ 60, no thrombosis, JAK2 wild-type, no cardiovascular risk factors)

"Young patients asymptomatic → watch and wait, at most aspirin" ^[3]

Rationale: The annual thrombotic risk in this group is ~1%, which is comparable to the general population. The harms of lifelong medication (even aspirin — GI bleeding risk) may outweigh benefits. These patients need regular monitoring (CBC every 3–6 months) but no active treatment.

Indication: Low-risk and intermediate-risk ET; also added to cytoreductive therapy in high-risk ET

Feature	Detail
Dose	75–100 mg once daily (some centres use 81 mg)
Mechanism	Irreversible inhibition of cyclooxygenase-1 (COX-1) in platelets → blocks thromboxane A₂ (TXA₂) synthesis → TXA₂ is a potent platelet aggregator and vasoconstrictor → inhibiting it reduces platelet activation and aggregation. Because platelets are anucleate, they cannot resynthesise COX-1 → the inhibition lasts the entire platelet lifespan (~7–10 days)
Evidence	Extrapolated from the ECLAP trial in PV (which showed aspirin reduced thrombotic events without excess bleeding) and observational data in ET
Erythromelalgia	Aspirin is dramatically effective for erythromelalgia — this is actually a diagnostic clue. The burning pain and erythema resolve within hours of aspirin because the symptom is driven by platelet TXA₂-mediated microvascular thrombosis

When NOT to Give Aspirin

When Plt > 1,000 × 10⁹/L → check for acquired vWD FIRST before starting aspirin ^[2]^[3]. If acquired vWD is present (↓VWF:RCo), aspirin will further impair haemostasis and worsen bleeding. In this scenario, you must reduce the platelet count first with cytoreductive therapy to < 1,000, then reassess VWF before adding aspirin.

"More concerning for ET is the paradoxical bleeding due to very high platelets → high platelet consumes all the vWF, results in acquired vWD — usually > 1000" ^[3]

Contraindications / Cautions for aspirin in ET:

Active bleeding
Acquired vWD (Plt > 1,000 with ↓VWF:RCo) — withhold until platelet count reduced
History of aspirin hypersensitivity
Active peptic ulcer disease (relative — add PPI cover)
Concurrent anticoagulation (assess bleeding risk)

Twice-daily aspirin: Some evidence suggests that in JAK2-mutated ET, twice-daily low-dose aspirin (e.g., 81 mg BD) may provide better platelet inhibition than once daily, because ET platelets have accelerated turnover (younger platelets entering circulation are uninhibited by the morning dose by evening). This is an evolving area but increasingly adopted in practice.

3. Cytoreductive Therapy

Indication: High-risk ET (age > 60 with JAK2 mutation, OR prior thrombosis) ^[1]^[3]

Additional indications for cytoreduction even in lower-risk categories: ^[12]

Platelet ≥ 1,000 (in general) — to prevent/treat acquired vWD
Vasomotor symptoms unresponsive to aspirin

The goal of cytoreductive therapy is to lower the platelet count (target generally < 400 × 10⁹/L) to reduce thrombotic risk and address symptoms.

"Age > 60 years → HU and aspirin" ^[1]^[3]

Feature	Detail
Drug class	Antimetabolite / ribonucleotide reductase inhibitor
Mechanism	Inhibits ribonucleotide reductase → blocks conversion of ribonucleotides to deoxyribonucleotides → reduces DNA synthesis → preferentially affects rapidly dividing cells (including megakaryocytes) → ↓platelet production
Name breakdown	"Hydroxy" = hydroxyl group, "urea" = the urea backbone of the molecule
Dosing	Typically start at 500 mg–1 g daily, titrate to platelet count response. Target Plt < 400 × 10⁹/L
Onset	Relatively rapid (days to weeks) — platelet count starts to drop within 1–2 weeks
Advantages	Oral, inexpensive, well-tolerated, decades of clinical experience, effective in reducing thrombotic events
Monitoring	Regular CBC (every 2–4 weeks initially, then every 1–3 months) — watch for excessive myelosuppression (anaemia, neutropenia). Also monitor renal and hepatic function

Side effects of hydroxyurea:

Side Effect	Mechanism / Notes
Myelosuppression (anaemia, neutropenia, thrombocytopenia)	Expected — dose-dependent; this is the drug working "too well." Dose-reduce or hold if counts drop too low
Macrocytosis	Impaired DNA synthesis → megaloblastic-like erythropoiesis → ↑MCV. This is expected and NOT an indication to stop the drug. However, if MCV rises markedly, check B12/folate to exclude coexistent deficiency
Mucocutaneous effects	Oral ulcers, skin ulcers (especially leg ulcers), nail changes, skin hyperpigmentation
Leg ulcers	Characteristic side effect — painful lower extremity ulcers that are recalcitrant. May necessitate switching to alternative agent
Potential leukaemogenicity	Controversial. HU is theoretically mutagenic (it interferes with DNA synthesis), but large observational studies have NOT convincingly shown increased leukaemic transformation in ET patients treated with HU alone. The transformation risk is more likely intrinsic to the MPN itself. Still, this theoretical concern drives the preference for interferon in young patients
Teratogenicity	Contraindicated in pregnancy — this is why IFN-alpha is used in pregnant/reproductive-age women ^[1]^[3]

Contraindications for hydroxyurea:

Pregnancy and breastfeeding (teratogenic)
Severe bone marrow suppression / severe cytopenias
Known hypersensitivity

HU resistance/intolerance criteria (ELN definition):

Plt > 600 after 3 months of ≥ 2 g/day HU
OR Plt > 400 AND WBC < 2.5 OR Hb < 10 at any dose
OR leg ulcers or other unacceptable non-haematological toxicity at any dose
→ Switch to second-line agent

"IFN (pregnancy)" ^[1]^[3]

Feature	Detail
Drug class	Biological response modifier / cytokine
Mechanism	IFN-α has antiproliferative and immunomodulatory effects on haematopoietic progenitor cells. It directly inhibits megakaryocyte proliferation and differentiation. Additionally, it may preferentially target the clonal (mutant) stem cells, potentially reducing allele burden over time — this is a conceptually important distinction from HU, which is a non-selective cytoreducer
Formulations	Pegylated IFN-α2a (Pegasys) — the pegylated form has a longer half-life, allowing weekly subcutaneous injection instead of daily/thrice-weekly conventional IFN
Indications	Pregnancy or women planning pregnancy (IFN-α is not teratogenic, unlike HU) ^[1]^[3]; young patients where minimising leukaemogenic risk is a priority; patients with HU intolerance/resistance
Advantages	Non-teratogenic, non-leukaemogenic, may reduce molecular allele burden (potential for "disease modification"), can achieve complete haematological and even molecular responses

Side effects of IFN-α:

Side Effect	Mechanism / Notes
Flu-like symptoms	Fever, myalgia, fatigue — especially prominent in first weeks. Due to cytokine storm from immune activation. Often ameliorated by paracetamol premedication and dose titration
Depression / psychiatric effects	IFN-α crosses blood-brain barrier and affects serotonergic neurotransmission → can cause significant depression, irritability, insomnia. Screen for psychiatric history before starting. May necessitate discontinuation
Autoimmune thyroiditis	IFN-α can trigger autoimmune diseases — thyroiditis (both hyper and hypothyroidism) is the most common. Monitor TFTs regularly
Hepatotoxicity	Immune-mediated hepatitis. Monitor LFTs
Cytopenias	Myelosuppression, though generally less than HU
Injection site reactions	SC injection → local erythema, pain

Contraindications for IFN-α:

Decompensated liver disease
Severe psychiatric illness (uncontrolled depression, psychosis)
Active autoimmune hepatitis
Severe cytopenias
Hypersensitivity

IFN-α in Pregnancy: The Rationale

ET in pregnancy is a specific clinical scenario because (1) ET has a peak incidence in young women of reproductive age, (2) pregnancy itself is a prothrombotic state, and (3) ET adds further thrombotic risk including placental microinfarction → miscarriage, IUGR, pre-eclampsia. HU is teratogenic so cannot be used. IFN-α is the cytoreductive agent of choice in pregnancy because it does not cross the placenta significantly and has established safety data in pregnancy (from hepatitis B/C treatment experience). Low-dose aspirin (from 12 weeks) is also typically added.

Feature	Detail
Drug class	Phosphodiesterase III (PDE3) inhibitor and imidazoquinazoline derivative
Name breakdown	"An-" = against, "agrelide" derived from "aggregation" → originally developed as an antiplatelet agent, but found to selectively reduce platelet count
Mechanism	Inhibits megakaryocyte maturation at the post-mitotic stage → reduces platelet production. It does NOT affect WBC or RBC counts significantly (megakaryocyte-selective). Also has PDE3 inhibitory activity → vasodilator and positive inotropic effects
Indications	Second-line for HU-intolerant/resistant patients; occasionally used first-line when HU and IFN-α are both unsuitable
Advantages	Megakaryocyte-selective (doesn't cause anaemia/neutropenia); non-leukaemogenic; oral

Side effects of anagrelide:

Side Effect	Mechanism
Headache	PDE3 inhibition → vasodilation → headache. Very common (> 30%), often limits use
Palpitations / tachycardia	Positive inotropic and chronotropic effects from PDE3 inhibition (same mechanism as milrinone — a PDE3 inhibitor used as an inotrope in heart failure)
Fluid retention / oedema	Vasodilation + cardiac effects
Diarrhoea	GI smooth muscle effects
Cardiac toxicity	Can exacerbate heart failure (positive inotropy → increased myocardial oxygen demand). Arrhythmias reported
Anaemia	Paradoxically, anagrelide can reduce Hb via mechanism not fully understood (possibly inhibition of late erythroid maturation)

Contraindications:

Known cardiovascular disease (heart failure, arrhythmias)
Severe hepatic impairment
Severe renal impairment
Pregnancy (limited safety data)

The PT-1 trial (a landmark RCT) showed that anagrelide + aspirin was inferior to HU + aspirin in high-risk ET — more arterial thrombosis, more haemorrhage, and more transformation to myelofibrosis. This is why anagrelide is second-line, not first-line.

Feature	Detail
Drug class	Alkylating agent
Mechanism	Cross-links DNA → cytotoxic to rapidly dividing cells including megakaryocytes
Indications	Reserved for elderly patients (> 75–80) who are intolerant of HU and IFN-α, and in whom anagrelide is contraindicated (cardiovascular disease). Low doses are effective and well-tolerated in the elderly
Risks	Cumulative myelosuppression, pulmonary fibrosis (rare at low doses), potential leukaemogenicity

Feature	Detail
Drug class	JAK1/JAK2 inhibitor
Mechanism	Directly inhibits the constitutively activated JAK2 kinase → reduces downstream STAT signalling → decreases proliferative drive. Also has potent anti-inflammatory effects (reduces cytokine signalling)
Current role in ET	Not standard first-line for ET. Primarily used in PMF and PV. In ET, ruxolitinib may be considered for patients with refractory symptoms or intolerance to all other lines. Clinical trials ongoing
Key side effects	Myelosuppression (anaemia, thrombocytopenia — ironic in ET), infections (immunosuppression from JAK inhibition), weight gain

"Cardiovascular risk modification (HT, smoking, CHF, WBC)" ^[1]^[3]

This applies to ALL risk categories, not just high-risk patients. The rationale is straightforward: ET provides a prothrombotic substrate, and cardiovascular risk factors provide the triggers. Managing both reduces the absolute event rate synergistically.

Modifiable Factor	Action	Why It Matters in ET
Hypertension	Treat to target (<130/80 mmHg)	Hypertension causes endothelial damage → exposes subendothelial collagen → platelet adhesion in the context of already elevated and abnormally activated platelets
Smoking	Cessation	Smoking promotes endothelial dysfunction, increases platelet activation, raises WBC count — all compound ET thrombotic risk
Hyperlipidaemia	Statin therapy if indicated	Atherosclerotic plaque disruption is a major trigger for arterial thrombosis
Elevated WBC	Monitor; if persistently high, may influence decision towards cytoreduction	Leukocytosis is an independent risk factor for thrombosis in ET — neutrophils contribute to thromboinflammation via NETs and endothelial activation
Diabetes	Optimise glycaemic control	Diabetes accelerates atherosclerosis and endothelial dysfunction
Obesity	Weight management	Increases VTE risk independently

5. Management of Specific Clinical Scenarios

"Paradoxical bleeding in very high platelet (acquired VWD)" ^[1] "When the patient has extreme thrombocytosis with bleeding tendency → want to exclude acquired von Willebrand disease" ^[2]

Step	Action	Rationale
1	Withhold aspirin	Aspirin further impairs haemostasis by blocking the residual platelet function
2	Check VWF:Ag, VWF:RCo, FVIII	Confirm acquired vWD (↓VWF:RCo / VWF:Ag ratio)
3	Cytoreduction to lower Plt < 1,000	Reduce platelet mass → less VWF consumption → VWF levels recover
4	If acute severe bleeding: DDAVP or VWF-containing factor concentrates	DDAVP releases stored VWF from endothelial cells → temporary boost. VWF concentrates replace the depleted factor directly
5	Reassess VWF after Plt < 1,000	If VWF normalises, can restart aspirin

"IFN (pregnancy)" ^[1]^[3]

Aspect	Management
Risk	ET in pregnancy increases risk of 1st trimester miscarriage, placental insufficiency, IUGR, pre-eclampsia, stillbirth ^[4]
Aspirin	Low-dose aspirin (75–150 mg/day) from ~12 weeks gestation to 36 weeks
Cytoreduction	IFN-α is the ONLY safe cytoreductive agent in pregnancy (HU is teratogenic, anagrelide has insufficient safety data) ^[1]^[3]
Target	Plt < 400 before conception if possible; maintain throughout pregnancy
Anticoagulation	LMWH may be added in very high-risk patients (prior thrombosis, prior pregnancy complications)
Postpartum	VTE prophylaxis for 6 weeks postpartum (pregnancy + ET = double prothrombotic state)

Aspect	Management
Arterial thrombosis (stroke, MI)	Standard acute management (thrombolysis/thrombectomy for stroke, PCI for MI) + start/optimise cytoreduction. Long-term: aspirin + cytoreduction
Venous thrombosis (DVT, PE)	Anticoagulation (LMWH → warfarin/DOAC) for standard duration + cytoreduction. The role of DOACs in MPN-associated thrombosis is still being studied but increasingly used
Unusual-site thrombosis (Budd-Chiari, portal/mesenteric vein)	Anticoagulation + cytoreduction. Screen for JAK2 if not already done ^[2]. May need interventional procedures (TIPS for Budd-Chiari)

Transformation	Management
Post-ET myelofibrosis	Manage as per PMF guidelines: ruxolitinib for symptoms/splenomegaly; consider allogeneic stem cell transplant in eligible patients
Blast transformation (AML)	Treat as AML: induction chemotherapy ± allogeneic stem cell transplant. Prognosis is poor

Risk Category	Treatment	Key Points
Very Low	Observation ± aspirin	Watch and wait, at most aspirin ^[3]. Add aspirin if CV risk factors present
Low	Low-dose aspirin	Daily aspirin for JAK2-mutated patients
Intermediate	Low-dose aspirin + CV risk modification	Age > 60 but JAK2 wild-type — aspirin + address modifiable risks
High	HU + aspirin (first-line)	"Age > 60 years → HU and aspirin" ^[1]^[3]. IFN if pregnancy ^[1]^[3]
HU-intolerant / resistant	Anagrelide or IFN-α (second-line)	Anagrelide inferior to HU (PT-1 trial); IFN-α increasingly preferred as second-line in non-pregnant patients too
Plt ≥ 1000 or vasomotor symptoms (any risk category)	Consider cytoreduction	Special indications for cytoreduction even in lower-risk ET ^[12]. Check for acquired vWD before starting aspirin if Plt > 1,000

Parameter	Frequency	Purpose
CBC	Every 2–4 weeks during dose titration; every 1–3 months once stable	Monitor platelet response, check for myelosuppression
PBS	Annually or if CBC changes	Screen for morphological changes suggesting transformation
LDH, urate	Every 6–12 months	Rising LDH may herald transformation to MF or AML
BM biopsy	Not routine; repeat if clinical/lab features suggest transformation	Assess for fibrosis progression
Molecular response	JAK2/CALR allele burden every 6–12 months (especially on IFN-α)	IFN-α may reduce allele burden; rising burden may suggest suboptimal response or transformation
VWF studies	If Plt > 1,000 or if bleeding symptoms develop	Detect/monitor acquired vWD
TFTs	Every 3–6 months (if on IFN-α)	Screen for autoimmune thyroiditis
Cardiovascular assessment	Ongoing	Blood pressure, lipids, glucose, smoking status

High Yield Summary — Management of ET

Management is driven by thrombotic risk, NOT by the platelet count alone ^[1]
Risk stratification: Revised IPSET-thrombosis — key variables are age > 60, prior thrombosis, JAK2 mutation status ^[1]^[3]
Very low / low risk: Observation or aspirin alone; "young patients asymptomatic → watch and wait" ^[3]
High risk: First-line: Hydroxyurea + aspirin ^[1]^[3]
IFN-alpha is the agent of choice in pregnancy (HU is teratogenic) ^[1]^[3]
Cardiovascular risk modification for ALL patients: HT, smoking, CHF, WBC ^[1]^[3]
Plt ≥ 1,000 → check for acquired vWD before giving aspirin; consider cytoreduction even in lower-risk patients ^[2]^[3]^[12]
Vasomotor symptoms are also an indication for cytoreduction in lower-risk categories ^[12]
Second-line: Anagrelide or IFN-α for HU-intolerant/resistant patients. Anagrelide is inferior to HU (PT-1 trial)
Disease transformation (post-ET MF, AML) managed per respective guidelines — prognosis differs markedly from stable ET

Active Recall - Management of Essential Thrombocythaemia

References

^[1] Lecture slides: GC 086. Splenomegaly.pdf (Essential Thrombocythaemia section — management and risk stratification) ^[2] Senior notes: Block A - Leg swelling and chest pain_ deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (MPN-associated thrombosis, acquired vWD) ^[3] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (ET management section) ^[4] Senior notes: Ryan Ho Haemtology.pdf (Section 3.3.2.3 Essential Thrombocythaemia — clinical presentation, pregnancy complications) ^[5] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (ET genetics section) ^[12] Lecture slides: GC 086. Splenomegaly.pdf (Treatment Algorithm slide — Gill H et al. Clin Exp Med 2023; indications for cytoreduction in lower-risk ET)

Complications of Essential Thrombocythaemia

ET has a near-normal life expectancy — median survival is approximately 20 years ^[5]. This means that unlike PMF or AML, the disease itself is indolent. But "indolent" does not mean "harmless." The complications of ET are what drive morbidity and, occasionally, mortality. Every complication connects back to the core pathophysiology: too many clonally abnormal platelets causing either thrombosis or paradoxical bleeding, plus a small but real risk of clonal evolution to worse diseases.

Let's work through each complication systematically, grouped by mechanism.

1. Thrombotic Complications (The Dominant Source of Morbidity)

"Thrombosis: Arterial > Venous" ^[1]^[3]

Thrombosis is the most common and most clinically significant complication of ET. The lifetime cumulative thrombotic event rate is approximately 10–25%. Understanding why ET causes thrombosis is crucial — it is not simply "more platelets = more clotting." The thrombotic mechanism is multifactorial:

Increased platelet mass → more platelet-endothelial surface interactions → more activation events
Clonally abnormal platelets → altered receptor expression (↑GPIb, ↑GPIIb/IIIa), increased TXA₂ generation, enhanced aggregation
JAK2 V617F in non-platelet cells → neutrophil activation (NETosis), endothelial P-selectin/tissue factor upregulation → systemic prothrombotic milieu
Blood is more viscous due to the high cell counts ^[2]

Site	Clinical Presentation	Pathophysiological Basis
Cerebral arteries	Stroke (ischaemic — hemiparesis, aphasia, visual field loss), TIA	Platelet thrombus in MCA or vertebrobasilar arteries; can be in-situ thrombosis or artery-to-artery embolism. JAK2-positive patients at highest cerebrovascular risk ^[2]
Coronary arteries	Myocardial infarction (chest pain, troponin rise, ECG changes)	Platelet-rich thrombus on coronary atherosclerotic plaque or microvascular coronary occlusion
Peripheral arteries	Peripheral vascular disease / limb ischaemia (claudication, rest pain, gangrene)	Thrombotic occlusion of iliac, femoral, or distal arteries. Digital ischaemia from small vessel occlusion
Retinal arteries	Amaurosis fugax, retinal artery occlusion	Microthrombotic occlusion of ophthalmic artery branches → transient or permanent visual loss

Site	Clinical Presentation	Why This Site?
Deep veins of legs	DVT (unilateral leg swelling, pain, warmth)	Standard VTE pathophysiology compounded by ET
Pulmonary arteries	PE (dyspnoea, pleuritic chest pain, tachycardia)	Embolisation from DVT; can be massive/submassive
Superficial veins	Superficial thrombophlebitis (palpable cord, erythema)	Common, often overlooked

This is a classic exam topic and a key clinical differentiator of MPN-associated thrombosis from other prothrombotic conditions.

"Occur in peculiar locations → mesenteric vein. Hence, when seeing mesenteric vein thrombosis, will screen for JAK2 mutations" ^[2]

"Patients with this mutation can clot even before developing the cytosis → so even if CBC doesn't show MPN features, still indicated for genetic screening" ^[2]

Site	Clinical Syndrome	Key Points
Hepatic veins	Budd-Chiari syndrome — hepatomegaly, ascites, abdominal pain, liver dysfunction. Can be acute (fulminant liver failure) or chronic (cirrhosis-like)	MPN (especially JAK2-positive ET or PV) is the single most common cause of Budd-Chiari in many series. Always screen for JAK2 in any patient presenting with Budd-Chiari. The hepatic venous outflow obstruction → hepatic congestion → ischaemic hepatocyte necrosis → liver failure
Portal vein	Portal vein thrombosis — abdominal pain, splenomegaly from portal hypertension, variceal bleeding	Portal hypertension develops because venous drainage from the gut/spleen is blocked. Can present as GI variceal haemorrhage — a seemingly paradoxical bleeding complication that is actually caused by thrombosis
Mesenteric veins	Mesenteric vein thrombosis — severe abdominal pain (often out of proportion to examination), nausea/vomiting, bloody diarrhoea if bowel infarction develops	When seeing mesenteric vein thrombosis → screen for JAK2 mutations ^[2]. This is a life-threatening emergency if it progresses to bowel infarction
Splenic vein	Splenic vein thrombosis — left upper quadrant pain, splenomegaly, isolated gastric varices	May exacerbate the splenomegaly already present from extramedullary haematopoiesis
Cerebral venous sinuses	Cerebral venous sinus thrombosis (CVST) — headache, papilloedema, seizures, focal neurological deficits	Unusual presentation of stroke; consider MPN in any young patient with CVST

Key Exam Point: Unusual-Site Thrombosis and JAK2 Screening

Any patient presenting with thrombosis in unusual sites (hepatic, portal, mesenteric, splenic veins, CVST) should be screened for JAK2 V617F mutation, even if the CBC is normal at the time. ^[2] This is because JAK2-mutated clones can cause thrombosis before the cytosis becomes apparent — the prothrombotic effect of mutant neutrophils and endothelial cells operates independently of the platelet count.

These are included as complications because, while often considered "symptoms" of ET, they represent genuine end-organ ischaemic injury from microvascular occlusion:

Manifestation	Mechanism
Erythromelalgia	Platelet thrombi in acral arterioles → tissue ischaemia → burning pain, erythema, warmth of digits. Can progress to digital ulceration or gangrene if untreated
Transient visual disturbances / scintillating scotomata	Microthrombi in retinal arterioles → transient retinal ischaemia
Migraine-like headaches	Microvascular ischaemia in cerebral microvasculature
Transient neurological deficits	TIA-like episodes from microvascular cerebral ischaemia

2. Haemorrhagic Complications

"Paradoxical bleeding in very high platelet (acquired VWD)" ^[1] "More concerning for ET is the paradoxical bleeding due to very high platelets → high platelet consumes all the vWF, results in acquired vWD — usually > 1000" ^[3]

This is the most important haemorrhagic complication and one of the most frequently tested concepts in ET.

Aspect	Detail
When it occurs	Typically when platelet count exceeds ~1,000 × 10⁹/L ^[3]^[4]
Mechanism	Excess platelets consume excess von Willebrand factor (VWF), a clotting factor for platelet adhesion ^[2]. Specifically, the massively increased platelet surface area adsorbs and promotes cleavage of large VWF multimers (which are the haemostatically most active forms). The selective depletion of high-molecular-weight VWF multimers mimics Type 2A VWD
Clinical presentation	Mucocutaneous bleeding pattern — epistaxis, gingival bleeding, easy bruising, menorrhagia, GI bleeding. "Which often presents with bleeding tendency" ^[2]
Diagnosis	↓VWF:RCo (ristocetin cofactor activity) disproportionate to VWF:Ag; ↓ or absent large VWF multimers on multimer gel analysis; may have ↓Factor VIII
Management	Cytoreduction to bring Plt < 1,000 → VWF levels recover. Withhold aspirin. Acute bleeding: DDAVP or VWF-containing concentrates

"Excess platelets can also result in excess bleeding — not just thrombocytopenia" ^[2]

The Clinical Paradox to Remember

More platelets does NOT always equal more clotting. When Plt > 1,000 → the risk shifts from thrombosis to bleeding. This is because the VWF consumption overwhelms the prothrombotic effect of the excess platelets. Giving aspirin to a patient with Plt > 1,000 and acquired vWD will make the bleeding worse, not better. Always check VWF studies before starting or continuing aspirin in extreme thrombocytosis.

Mechanism	Detail
Platelet dysfunction	Even without acquired vWD, ET platelets may have qualitative defects — altered granule content, abnormal receptor signalling — that impair normal haemostatic function
Drug-related bleeding	Aspirin (COX-1 inhibition) and anticoagulants (for treatment of prior thrombosis) further increase bleeding risk, especially in the context of acquired vWD

3. Disease Transformation

"Two downstream complications of essential thrombocythemia — transformation, though risk is low" ^[3] "Risk of transformation to myelofibrosis and AML (< 5%)" ^[1]

ET has the lowest transformation risk among the three BCR-ABL-negative MPNs. However, transformation, when it occurs, dramatically changes the clinical trajectory.

Aspect	Detail
Risk	< 5% at 10–20 years ^[1]^[3]^[5]; 15-year cumulative risk < 5% ^[5]
Mechanism	Clonal evolution: the mutant megakaryocytes progressively release fibrogenic cytokines (PDGF, TGF-β) → stimulate bone marrow fibroblasts → collagen/reticulin deposition → progressive marrow fibrosis → marrow failure. This is the same pathophysiology as primary myelofibrosis, but arising secondarily
Clinical features	Progressive cytopenias (especially anaemia), increasing splenomegaly (extramedullary haematopoiesis), constitutional symptoms (weight loss, night sweats, fatigue), leucoerythroblastic blood picture with tear-drop cells on PBS
Diagnosis	BM biopsy showing ≥ grade 2 reticulin/collagen fibrosis in a patient with prior documented ET, plus at least 2 of: anaemia, leucoerythroblastic PBS, increasing splenomegaly, ↑LDH, constitutional symptoms
Management	Managed as per PMF guidelines: ruxolitinib for splenomegaly/symptoms; allogeneic HSCT for eligible patients (only potentially curative option); supportive care (transfusions, EPO)
Prognosis	Significantly worse than stable ET — median survival 5–7 years after transformation (compared to 20+ years for stable ET)

Aspect	Detail
Risk	< 5% ^[1]^[3]; < 2% at 15 years ^[5]
Mechanism	Acquisition of additional genetic hits in the original clone (TP53 mutations, complex karyotype, epigenetic deregulation) → loss of terminal differentiation → blast accumulation (≥ 20% blasts in blood or marrow = diagnostic of AML). This is "secondary AML" arising from a pre-existing MPN, which has a very different biology and much worse prognosis than de novo AML
Risk factors for transformation	Older age, prolonged disease duration, TP53 mutations, complex karyotype, exposure to alkylating agents (e.g., busulfan — though controversial for hydroxyurea). Triple-negative ET may have higher transformation risk in some studies
Clinical features	Rapid clinical deterioration: severe cytopenias, increasing blast count, fever, bleeding, infection susceptibility
Management	Induction chemotherapy (similar to de novo AML regimens, e.g., "7+3" — cytarabine + daunorubicin) followed by consolidation and allogeneic HSCT if feasible. Response rates are lower than for de novo AML
Prognosis	Very poor — median survival < 6 months. Post-MPN AML is one of the most treatment-resistant forms of AML

Why Is ET's Transformation Risk the Lowest Among MPNs?

Compare: PMF transforms to AML in ~20% of cases at 10 years; PV transforms to myelofibrosis in ~10% and to AML in ~5%. ET's low transformation risk (~2-5% for each) is thought to reflect the relatively limited genomic instability in ET clones — the megakaryocytes differentiate normally (just excessively), so there is less selective pressure for acquiring additional mutations. CALR-mutated ET has particularly low transformation risk compared to JAK2-mutated or triple-negative ET.

"Pregnancy complications: ↑risk of 1st trimester miscarriage, stillbirth, premature delivery, pre-eclampsia, IUGR" ^[4] "Increased risk of 1st trimester pregnancy loss" ^[5]

Complication	Mechanism
First-trimester miscarriage (most common pregnancy complication in ET)	Platelet microthrombi occlude the uteroplacental vasculature → impaired trophoblast invasion and placentation → early pregnancy failure
Stillbirth	Placental infarction from progressive microvascular thrombosis → fetal demise
Intrauterine growth restriction (IUGR)	Chronic placental insufficiency from ongoing microthrombotic damage → reduced nutrient/oxygen delivery to the fetus
Pre-eclampsia	Impaired placentation (similar mechanism to miscarriage) → placental ischaemia → release of anti-angiogenic factors (sFlt-1) → maternal endothelial dysfunction → hypertension, proteinuria
Placental abruption	Thrombosis of decidual vessels → retroplacental haemorrhage → premature placental separation
Premature delivery	Secondary to pre-eclampsia, IUGR, or placental insufficiency necessitating early delivery

While not complications of ET per se, treatment-related complications are clinically important:

Treatment	Complication	Mechanism
Hydroxyurea	Leg ulcers, mucocutaneous toxicity, macrocytosis, myelosuppression	DNA synthesis inhibition → epithelial cell damage; dose-dependent marrow suppression
Hydroxyurea	Theoretical leukaemogenicity	Mutagenic potential from DNA synthesis interference — though large studies have not convincingly demonstrated increased AML risk attributable to HU alone
IFN-α	Depression, autoimmune thyroiditis, flu-like symptoms, hepatotoxicity	CNS serotonin pathway disruption; immune dysregulation; systemic cytokine effects
Anagrelide	Cardiac toxicity (palpitations, HF exacerbation, arrhythmias)	PDE3 inhibition → positive inotropic/chronotropic effects → increased myocardial O₂ demand
Aspirin	GI bleeding	COX-1 inhibition → reduced prostaglandin-mediated gastroprotection. Especially dangerous if patient also has acquired vWD

"Gouty arthritis — ↑uric acid due to increased cellular turnover" ^[13]

Aspect	Detail
Mechanism	ET involves increased megakaryocyte proliferation and platelet turnover → increased purine metabolism (DNA/RNA breakdown) → ↑uric acid production → hyperuricaemia → risk of urate crystal deposition in joints (gout) or kidneys (urate nephropathy/stones)
Clinical presentation	Acute monoarthritis (classically 1st MTP joint), nephrolithiasis, or chronic tophaceous gout
Management	Allopurinol prophylaxis if urate is elevated; adequate hydration; treat acute gout with colchicine/NSAIDs (but avoid NSAIDs if bleeding risk is high or on anticoagulation)

Although splenomegaly in ET is typically mild (unlike PMF), progressive splenic enlargement can cause:

Complication	Mechanism
Abdominal discomfort / early satiety	Physical compression of stomach and adjacent structures
Hypersplenism	Increased splenic pooling/destruction of blood cells → cytopenias (especially in post-ET MF)
Splenic infarction	Thrombosis of intrasplenic vessels → infarction → acute LUQ pain

Complication Category	Key Examples	Approximate Risk / Frequency
Arterial thrombosis	Stroke, MI, PVD, digital ischaemia	9–22% cumulative ^[4]
Venous thrombosis	DVT, PE, superficial thrombophlebitis	Less common than arterial
Unusual-site thrombosis	Budd-Chiari, portal/mesenteric/splenic vein thrombosis, CVST	Screen for JAK2 in any unusual-site thrombosis ^[2]
Haemorrhage / acquired vWD	Mucocutaneous bleeding, GI haemorrhage	3–37% ^[4]; especially when Plt > 1,000 ^[3]
Post-ET myelofibrosis	Marrow fibrosis, cytopenias, splenomegaly	< 5% ^[1]^[3]
Blast transformation (AML)	Acute leukaemia	< 5% ^[1]^[3]; < 2% at 15 years ^[5]
Pregnancy complications	Miscarriage, IUGR, pre-eclampsia, stillbirth	Elevated above baseline ^[4]^[5]
Hyperuricaemia / gout	Gouty arthritis, urate nephropathy	Variable; related to cell turnover
Treatment-related	Leg ulcers (HU), cardiac toxicity (anagrelide), depression (IFN)	Drug-specific

High Yield Summary — Complications of ET

Thrombosis is the dominant complication: Arterial > Venous ^[1]. Includes stroke, MI, PVD, DVT/PE
Unusual-site thrombosis (hepatic, portal, mesenteric veins, CVST) is characteristic of MPN — always screen for JAK2 ^[2]
Paradoxical bleeding when Plt > 1,000 due to acquired vWD — consumption of VWF multimers ^[1]^[2]^[3]
Transformation risk is low: myelofibrosis < 5%, AML < 5% ^[1]^[3] — the lowest among BCR-ABL−ve MPNs
Post-MPN AML has very poor prognosis (median survival < 6 months)
Pregnancy complications: 1st trimester miscarriage (most common), stillbirth, IUGR, pre-eclampsia ^[4]^[5]
Hyperuricaemia/gout: from increased cellular turnover ^[13]
Remember: more platelets does NOT always mean more clotting — extreme thrombocytosis shifts risk towards bleeding ^[2]^[3]
Majority of ET patients have normal life expectancy (median survival ~20 years) ^[5] — complications are what you're managing, not the disease's natural lethality

Active Recall - Complications of Essential Thrombocythaemia

References

^[1] Lecture slides: GC 086. Splenomegaly.pdf (Essential Thrombocythaemia section) ^[2] Senior notes: Block A - Leg swelling and chest pain_ deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (MPN-associated thrombosis, acquired vWD) ^[3] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (ET complications section) ^[4] Senior notes: Ryan Ho Haemtology.pdf (Section 3.3.2.3 Essential Thrombocythaemia — clinical presentation, pregnancy complications, haemorrhage) ^[5] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (ET prognosis and complications sections) ^[13] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (PMF complications section — gouty arthritis from increased cellular turnover, applicable to all MPNs)

High Yield Summary

Essential Thrombocythaemia — Key Points Before Diagnosis/Management:

Definition: Clonal MPN with sustained platelet count ≥ 450 × 10⁹/L due to autonomous megakaryocyte proliferation
Epidemiology: Median age 60, F > M (2:1), 150 new cases/year in HK, near-normal life expectancy
Driver mutations: JAK2 V617F (~50-65%), CALR exon 9 (~25%), MPL (~3-5%), triple-negative (~10-15%) — all converge on JAK-STAT pathway
Diagnosis by exclusion: Must exclude reactive thrombocytosis (infection, inflammation, iron deficiency, malignancy, post-splenectomy) and other MPNs (CML, PV, PMF)
Clinical features:
- Up to 50% asymptomatic — incidental finding
- Microvascular symptoms: headache, dizziness, erythromelalgia (pathognomonic)
- Thrombosis: Arterial > Venous — stroke, MI, PVD; unusual sites (mesenteric, hepatic vein)
- Paradoxical bleeding when Plt > 1,000 → acquired vWD (consumption of VWF multimers)
Risk stratification: Age > 60 and prior thrombosis = high risk; JAK2 positivity adds further risk
Transformation risk: < 5% to myelofibrosis, < 5% to AML — lowest among BCR-ABL-negative MPNs
Key exam trap: Extreme thrombocytosis causes BLEEDING (not more clotting) due to acquired vWD

High Yield Summary — Differential Diagnosis of ET

ET is a diagnosis of exclusion — must systematically exclude reactive and other primary causes
Reactive thrombocytosis (80-90% of all thrombocytosis): infections, inflammations, malignancy, iron deficiency, post-splenectomy ^[1] — benign, resolves with treatment of underlying cause, almost never causes thrombosis
Primary (clonal) mimickers of ET:
- CML — most dangerous to miss; BCR-ABL1 testing is mandatory ^[1]^[8]
- PV — check Hb/Hct and EPO; beware "masked PV" with concurrent iron deficiency ^[3]^[9]
- Prefibrotic PMF — hardest to distinguish; relies on BM morphology (megakaryocyte atypia, clustering, fibrosis) — worse prognosis than ET
- MDS/MPN overlap (MDS-RS-T) — look for dysplasia and ring sideroblasts
Key investigations for DDx: CBC + PBS, CRP/ESR, ferritin, BCR-ABL1, JAK2/CALR/MPL, BM biopsy, EPO
Reactive thrombocytosis is benign because platelets are functionally normal and non-clonal; ET platelets are clonally abnormal with altered function
Familial thrombocytosis (germline TPO/c-Mpl mutations) is rare but important in young patients ^[4]

High Yield Summary — Diagnostic Criteria and Investigation of ET

WHO 2022 Diagnostic Criteria: 4 Major (4M) or 3 Major + 1 Minor (3M + 1m) ^[3]
- M1: Plt ≥ 450 (sustained)
- M2: BM biopsy showing megakaryocyte-lineage proliferation with large, mature, hyperlobated megakaryocytes
- M3: Not meeting criteria for CML, PV, PMF, MDS, or other myeloid neoplasm
- M4: JAK2, CALR, or MPL mutation
- m1: Clonal marker or absence of reactive cause (for triple-negative patients)
ET is a diagnosis by exclusion — you must exclude reactive causes AND other primary myeloid neoplasms ^[1]
BCR-ABL1 testing is mandatory to exclude CML ^[1]^[8]
BM biopsy is a major criterion — cannot formally diagnose ET without it; critical for distinguishing from prefibrotic PMF
JAK2 V617F in ~50%, CALR ~25%, MPL ~3-5%, triple-negative ~10-15% ^[1]^[4]^[5]
Check Hb/Hct and EPO to exclude PV — beware masked PV with concurrent iron deficiency ^[3]^[9]
When Plt > 1,000 with bleeding → check VWF:Ag, VWF:RCo for acquired vWD ^[2]
Thrombocytosis can cause pseudohyperkalemia — use heparinised plasma for K⁺ ^[11]

High Yield Summary — Management of ET

Management is driven by thrombotic risk, NOT by the platelet count alone ^[1]
Risk stratification: Revised IPSET-thrombosis — key variables are age > 60, prior thrombosis, JAK2 mutation status ^[1]^[3]
Very low / low risk: Observation or aspirin alone; "young patients asymptomatic → watch and wait" ^[3]
High risk: First-line: Hydroxyurea + aspirin ^[1]^[3]
IFN-alpha is the agent of choice in pregnancy (HU is teratogenic) ^[1]^[3]
Cardiovascular risk modification for ALL patients: HT, smoking, CHF, WBC ^[1]^[3]
Plt ≥ 1,000 → check for acquired vWD before giving aspirin; consider cytoreduction even in lower-risk patients ^[2]^[3]^[12]
Vasomotor symptoms are also an indication for cytoreduction in lower-risk categories ^[12]
Second-line: Anagrelide or IFN-α for HU-intolerant/resistant patients. Anagrelide is inferior to HU (PT-1 trial)
Disease transformation (post-ET MF, AML) managed per respective guidelines — prognosis differs markedly from stable ET

High Yield Summary — Complications of ET

Thrombosis is the dominant complication: Arterial > Venous ^[1]. Includes stroke, MI, PVD, DVT/PE
Unusual-site thrombosis (hepatic, portal, mesenteric veins, CVST) is characteristic of MPN — always screen for JAK2 ^[2]
Paradoxical bleeding when Plt > 1,000 due to acquired vWD — consumption of VWF multimers ^[1]^[2]^[3]
Transformation risk is low: myelofibrosis < 5%, AML < 5% ^[1]^[3] — the lowest among BCR-ABL−ve MPNs
Post-MPN AML has very poor prognosis (median survival < 6 months)
Pregnancy complications: 1st trimester miscarriage (most common), stillbirth, IUGR, pre-eclampsia ^[4]^[5]
Hyperuricaemia/gout: from increased cellular turnover ^[13]
Remember: more platelets does NOT always mean more clotting — extreme thrombocytosis shifts risk towards bleeding ^[2]^[3]
Majority of ET patients have normal life expectancy (median survival ~20 years) ^[5] — complications are what you're managing, not the disease's natural lethality

Essential Thrombocythaemia

1. Definition

2. Epidemiology

Global and Hong Kong Data

Among MPNs

3. Risk Factors

4. Anatomy and Function: Normal Platelet Production (Thrombopoiesis)

Normal Thrombopoiesis

The TPO–MPL–JAK2–STAT Axis

The Spleen's Role

Why This Matters for ET

5. Aetiology and Pathophysiology

5.1 Molecular Genetics (The "Driver Mutations")

5.2 Pathophysiological Consequences

A. Thrombosis (the dominant risk)

B. Paradoxical Bleeding (with extreme thrombocytosis)

C. Potential for Disease Transformation

6. Classification

6.1 Within the WHO/ICC Classification of MPNs

6.2 Risk Stratification in ET (IPSET — International Prognostic Score for ET)

6.3 Comparison Table: ET vs. Other MPNs

7. Clinical Features

7.1 Symptoms

7.2 Signs

7.3 Constitutional Symptoms

7.4 Symptoms and Signs Organised by System

8. Important Pathophysiological Concepts (Expanded)

8.1 Why Arterial > Venous Thrombosis in ET?

8.2 Why Does JAK2 Mutation Specifically Increase Thrombotic Risk?

8.3 Acquired von Willebrand Disease (AvWD) — Mechanism in Detail

8.4 The Spleen in ET

Active Recall - Essential Thrombocythaemia (Definition, Epidemiology, Pathophysiology, Clinical Features)

References

Structured Classification of Differential Diagnoses

Tier 1: Reactive (Secondary) Thrombocytosis

Tier 2: Primary (Clonal) Causes of Thrombocytosis

Key Differentiating Investigations — Why Each Test Matters

Differential Diagnosis Algorithm

Distinguishing ET from Prefibrotic PMF — The Most Difficult DDx

Distinguishing ET from PV — The "Masked PV" Trap

Hereditary/Familial Thrombocytosis

Summary: Practical DDx Checklist for the Exam

Active Recall - Differential Diagnosis of Thrombocytosis / ET

Diagnostic Criteria for Essential Thrombocythaemia

The Principle: Why Do We Need Formal Diagnostic Criteria?

WHO 2022 / ICC 2022 Diagnostic Criteria for ET

Major Criteria

Minor Criterion

Diagnostic Criteria: Quick Comparison Across BCR-ABL−ve MPNs

Diagnostic Algorithm

Investigation Modalities: Key Findings and Interpretations

1. Complete Blood Count (CBC) with Differential

2. Peripheral Blood Smear (PBS)

3. Inflammatory Markers (CRP, ESR)

4. Iron Studies (Ferritin, Serum Iron, TIBC, Transferrin Saturation)

5. BCR-ABL1 / Philadelphia Chromosome Testing

6. Molecular Testing: JAK2, CALR, MPL

7. Serum Erythropoietin (EPO)

8. Bone Marrow Examination (Aspirate + Trephine Biopsy)

9. Cytogenetics (Conventional Karyotyping from BM)

10. Additional Investigations (As Clinically Indicated)

Putting It All Together: The Complete Investigation Panel for Suspected ET

Active Recall - Diagnostic Criteria and Investigations for ET

References

The Foundational Principle: Risk-Adapted Therapy

Risk Stratification: The IPSET-Thrombosis Model (Revised)

Management Algorithm

Treatment Modalities

1. Observation ("Watch and Wait")

2. Low-Dose Aspirin

3. Cytoreductive Therapy

3a. Hydroxyurea (HU) — First-Line Cytoreductive Agent

3b. Interferon-Alpha (IFN-α) — First-Line Alternative

3c. Anagrelide — Second-Line Agent

3d. Busulfan — Third-Line / Elderly Patients

3e. JAK Inhibitors (Ruxolitinib) — Emerging / Specific Indications

4. Cardiovascular Risk Factor Modification

5. Management of Specific Clinical Scenarios

A. Extreme Thrombocytosis with Bleeding (Acquired vWD)

B. ET in Pregnancy