Primary Myelofibrosis
Primary myelofibrosis is a chronic myeloproliferative neoplasm characterized by clonal hematopoietic stem cell proliferation with progressive bone marrow fibrosis, extramedullary hematopoiesis, and peripheral blood cytopenias with leukoerythroblastic changes.
Primary Myelofibrosis (PMF)
Primary myelofibrosis (PMF) is a chronic Philadelphia-negative myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis (reticulin/collagen deposition) and splenomegaly [1][2][3].
Let's break the name down:
- Primary → arises de novo (not secondary to another MPN like PV or ET)
- Myelo- → from Greek myelos = marrow
- Fibrosis → from Latin fibra = fibre; excessive deposition of fibrous connective tissue
The defining features are:
- Dysregulated myeloproliferation = atypical megakaryocytic hyperplasia and proliferation [4]
- Reactive deposition of fibrous connective tissue (reticulin or collagen) in the bone marrow, often with osteosclerosis [4]
- Development of extramedullary haematopoiesis (haematopoiesis occurring outside the bone marrow, principally in the spleen and liver) [1][3][5]
Key Conceptual Point
PMF is NOT a neoplasm of fibroblasts. The fibroblasts depositing collagen in the marrow are NOT clonal — they are reactive. The clonal abnormality lies in the haematopoietic stem cell, specifically the megakaryocytic lineage, which produces cytokines that stimulate the fibroblasts [1][3][5]. Think of it as: the megakaryocytes are the "boss" giving bad orders, and the fibroblasts are the innocent "workers" following those orders.
Where PMF Fits Within Myeloproliferative Neoplasms
MPN are clonal haematopoietic stem cell disorders characterized by the overproduction of mature cells of myeloid lineages [1]. Unlike myelodysplastic syndromes (MDS), the cells in MPN are not dysplastic — they undergo full maturation but may be functionally abnormal [4].
All forms of MPN share the potential to progress to myelofibrosis (post-PV MF, post-ET MF) and blastic transformation (AML) [1].
WHO classification of MPNs [4][5]:
| MPN Subtype | Defining Mutation | Predominant Lineage |
|---|---|---|
| Chronic Myeloid Leukaemia (CML) | BCR-ABL1 (Philadelphia chromosome) | Granulocytic (WBC ↑↑) |
| Polycythaemia Vera (PV) | JAK2 V617F (97%), JAK2 exon 12 (3%) | Erythroid (Hb ↑↑) |
| Essential Thrombocythaemia (ET) | JAK2 (50%), CALR (25%), MPL (3-5%) | Megakaryocytic (Plt ↑↑) |
| Primary Myelofibrosis (PMF) | JAK2 (60-65%), CALR (20-25%), MPL (7%) | Megakaryocytic → fibrosis |
The 4 main phenotypes of MPN: BCR-ABL +ve = CML; BCR-ABL -ve = PV, ET, PMF. The most common molecular marker associated with the Ph-negative MPNs is JAK2 V617F [1].
High Yield: CML is defined by Philadelphia chromosome / BCR-ABL1. The other three (PV, ET, PMF) are "Philadelphia-negative MPNs" and share overlapping driver mutations (JAK2, CALR, MPL).
PMF is the least common form of the MPNs [4][5].
| Parameter | Detail |
|---|---|
| Incidence | ~1.5 per 100,000/year (US data); ~150 new cases per year in the entire HK population [1][5] |
| Sex | Male predominance (M:F ≈ 6:1) [4] |
| Age at diagnosis | Median age = 67 years; disease incidence increases with age [1][4][5] |
| Younger patients | 5–17% of patients are diagnosed before age 40–50 [4] |
In Hong Kong, ~150 new cases per year of MPN occur in the entire population. The median age for all three Ph-negative MPNs is 65–70 years. Disease increases with age [1].
Exam Point
If asked "which MPN is least common?", the answer is PMF. If asked "which MPN has the worst prognosis?", the answer is also PMF (median survival 3–5 years without transplant) [3].
PMF is largely a sporadic disease. Identified risk factors include [4]:
- Age — incidence increases with advancing age (median 67 years)
- Male sex — M:F ≈ 6:1
- Environmental exposure:
- Thorium dioxide exposure (historical radiographic contrast agent — Thorotrast)
- Petroleum manufacturing plants (toluene and benzene) — benzene is a well-known myelotoxin and carcinogen
- Ionizing radiation
- Prior MPN — PV or ET can transform into secondary myelofibrosis (post-PV MF, post-ET MF), but this is classified separately from primary myelofibrosis
- Genetic predisposition — rare familial MPNs have been described, though the vast majority are sporadic
Anatomy & Function: The Bone Marrow and Spleen
Understanding PMF requires understanding where blood is made and why it moves.
- The bone marrow is the primary site of haematopoiesis in adults
- It contains haematopoietic stem cells (HSCs) embedded in a stromal microenvironment of fibroblasts, adipocytes, endothelial cells, and extracellular matrix (reticulin fibres)
- The stroma provides structural support and growth factor signalling (e.g., stem cell factor, thrombopoietin)
- Reticulin is a type III collagen fibre forming a delicate meshwork that supports haematopoietic cells. In PMF, this reticulin becomes excessively deposited → marrow fibrosis
- The spleen normally functions in:
- Filtration of old/damaged RBCs (red pulp)
- Immune surveillance (white pulp — lymphoid tissue)
- Reservoir for platelets (~⅓ of total platelet pool) and some RBCs
- During fetal life, the spleen is a site of haematopoiesis. In PMF, the spleen is "re-activated" for extramedullary haematopoiesis (EMH), though this is ineffective [1][3]
- When the bone marrow fails (fibrosis), HSCs migrate to the spleen and liver → EMH
- However, no significant or functional haematopoiesis occurs even in this situation [3]
- This is an important concept: even if you remove the spleen, it will not impair blood production capability [3]
- EMH can also occur at other sites: could go to spine, cause cord compression [3], paravertebral masses, pleura, peritoneum, skin, lymph nodes
Etiology
A. Primary Myelofibrosis — Driver Mutations
The pathogenesis of PMF centres on acquired somatic mutations in haematopoietic stem cells that constitutively activate the JAK-STAT signalling pathway.
- JAK = Janus Activated Kinase (named after the two-faced Roman god Janus, because JAK proteins have two kinase-like domains)
- JAK2 is a non-receptor tyrosine kinase that normally transduces signals from haematopoietic growth factor receptors (EPO-R, TPO-R/MPL, G-CSF-R)
- The V617F point mutation (valine → phenylalanine at position 617) in exon 14 is a gain-of-function mutation → constitutively active JAK2 → continuous activation of downstream STAT5/STAT3, PI3K/AKT, and RAS/MAPK pathways → unregulated myeloproliferation
- This is the same mutation found in PV (97%) and ET (50%), which is why these diseases can share overlapping features and transform into one another
- CALR = Calreticulin — a calcium-binding chaperone protein in the endoplasmic reticulum
- Mutant CALR binds to MPL (TPO receptor) on the cell surface → constitutive activation of JAK-STAT signalling (same downstream pathway as JAK2 mutation, but through a different mechanism)
- CALR mutations occur in MPNs without JAK2 or MPL mutations [4]
- Generally associated with better prognosis compared to JAK2 mutation
- MPL = Myeloproliferative Leukemia virus oncogene (also known as the thrombopoietin receptor, c-Mpl)
- Gain-of-function mutations in MPL (most commonly W515L/K) → constitutive activation of JAK-STAT pathway independent of TPO binding
- Results in megakaryocyte hyperplasia and subsequent fibrosis
- Negative for JAK2, CALR, and MPL mutations
- May harbour other mutations (e.g., ASXL1, TET2, SRSF2, EZH2, IDH1/2)
- Carries the worst prognosis among all molecular subtypes
Molecular Hierarchy of PMF
All three driver mutations (JAK2, CALR, MPL) converge on the same pathway: constitutive activation of JAK-STAT signalling → unregulated myeloproliferation, especially of the megakaryocytic lineage. The mutations are mutually exclusive — a patient will have one or none.
Prognosis by mutation (best to worst): CALR > JAK2 > MPL > Triple-negative
These do not define the disease but worsen outcomes and are used in prognostic scoring:
- ASXL1 (Additional Sex Combs Like 1) — epigenetic regulator; most important adverse prognostic marker in PMF
- EZH2 — Polycomb group protein (histone methyltransferase); loss-of-function
- SRSF2, U2AF1 — spliceosome mutations
- IDH1/IDH2 — isocitrate dehydrogenase mutations (also seen in AML and gliomas)
- TET2 — epigenetic regulator
Other causes of myelofibrosis (secondary myelofibrosis) [4]:
| Category | Examples |
|---|---|
| MPN transformation | Post-PV MF, Post-ET MF |
| Other haematological malignancies | MDS, AML, ALL, CML, Lymphoma, Multiple myeloma |
| Metastatic cancers | Breast cancer, Prostate cancer |
| Autoimmune disorders | SLE |
| Granulomatous disorders | Tuberculosis, Sarcoidosis |
| Environmental exposure | Thorium dioxide, benzene/toluene, ionizing radiation |
High Yield for HK context: TB-related granulomatous myelofibrosis should be considered in Hong Kong given the relatively higher TB prevalence.
Pathophysiology
This is the core of understanding PMF. Let's build it step by step.
- An acquired somatic mutation (JAK2/CALR/MPL) occurs in a haematopoietic stem cell
- This leads to constitutive activation of JAK-STAT signalling → clonal expansion, especially of the megakaryocytic lineage
- The fibroblasts causing collagen deposition in PMF ARE NOT CLONAL [3]
- The issue comes from the "boss" of the fibroblasts, which are the megakaryocytes [3]
- Abnormal megakaryocytes release cytokines (PDGF and TGF-β) which stimulate fibroblast proliferation and collagen deposition [3][5]
- Additional cytokines released:
- PDGF (Platelet-Derived Growth Factor) → fibroblast proliferation
- TGF-β (Transforming Growth Factor-beta) → collagen synthesis + inhibits normal haematopoiesis
- bFGF (basic Fibroblast Growth Factor) → angiogenesis
- VEGF (Vascular Endothelial Growth Factor) → angiogenesis + increased marrow vascularity
- OPG (Osteoprotegerin) → osteosclerosis
- Reticulin fibres → collagen fibres → osteosclerosis (new bone formation)
- The fibrotic marrow progressively replaces normal haematopoietic tissue
- This leads to marrow failure → cytopenias (anaemia, thrombocytopenia, leukopenia)
- Fibrotic BM unable to function and HSC move to spleen and liver (extramedullary haematopoiesis) [3]
- The spleen becomes massively enlarged as it attempts (ineffectively) to compensate
- But not just liver or spleen, could go anywhere → could go to spine, cause cord compression [3]
- EMH is ineffective — it does not meaningfully correct the cytopenias
- Leukoerythroblastic blood picture = nucleated RBCs + immature white cells (myelocytes, metamyelocytes) in peripheral blood → because immature cells are being "squeezed out" of the fibrotic marrow prematurely [5]
- Tear-drop RBCs (dacrocytes) = RBCs deformed by squeezing through the narrowed, fibrotic marrow sinusoids or through the splenic cords [5]
- Dry tap on bone marrow aspiration = because the marrow is so fibrotic that you cannot aspirate liquid marrow [2][3]
The Analogy
Think of the bone marrow like a garden. In PMF, the megakaryocytes (the "gardener gone rogue") over-fertilize the soil (release PDGF, TGF-β), causing the weeds (fibroblasts) to overgrow. The plants (haematopoietic cells) get choked out, so seeds (HSCs) blow away to other fields (spleen, liver) — but those fields are poor soil, so the crops that grow there are meagre and ineffective.
Classification
PMF is divided into two phases [5]:
| Phase | Bone Marrow Findings | Clinical Features |
|---|---|---|
| Prefibrotic/early PMF (pre-PMF) | Megakaryocyte atypia only without significant fibrosis (reticulin grade 0–1) | Anaemia only with ↑WBC and platelet counts; may mimic ET |
| Overt PMF (fibrotic phase) | Significant marrow fibrosis (reticulin grade 2–3) | Pancytopenia (marrow replacement) with hepatosplenomegaly (extramedullary haematopoiesis) |
Pre-PMF vs ET — A Common Exam Pitfall
Pre-PMF can present with thrombocytosis and may be misdiagnosed as ET. The distinction requires bone marrow biopsy showing megakaryocyte atypia (large, hyperlobated, clustered) and reticulin staining. This distinction matters because pre-PMF has a higher risk of fibrotic transformation and AML than ET.
| Grade | Description |
|---|---|
| MF-0 | Scattered linear reticulin, no intersections (normal) |
| MF-1 | Loose network of reticulin, ± focal collagen; no osteosclerosis |
| MF-2 | Diffuse, dense reticulin with extensive intersections; ± focal collagen and osteosclerosis |
| MF-3 | Diffuse, dense reticulin with coarse collagen bundles; often with significant osteosclerosis |
C. Risk Stratification (IPSS / DIPSS / DIPSS-Plus)
Risk stratification systems for primary myelofibrosis: IPSS (at diagnosis), DIPSS/DIPSS-Plus (at follow-up) [2].
IPSS & DIPSS use 5 parameters → classified into low, Int-1, Int-2, high risk [2]:
| Risk Factor | Score |
|---|---|
| Age > 65 | 1 |
| Constitutional symptoms (weight loss, fever, night sweats) | 1 |
| Hb < 10 g/dL | 1 |
| WBC > 25 × 10⁹/L | 1 |
| Peripheral blood blasts ≥ 1% | 1 |
| Risk Category | Score | Median Survival |
|---|---|---|
| Low | 0 | 11.3 years |
| Int-1 | 1 | 7.9 years |
| Int-2 | 2 | 4.0 years |
| High | ≥ 3 | 2.3 years |
- Same 5 variables as IPSS but Hb < 10 scores 2 points (weighted more heavily)
- Platelet count < 100 × 10⁹/L
- Transfusion dependence
- Unfavourable karyotype (complex karyotype, +8, -7/7q-, i(17q), -5/5q-, 12p-, inv(3), 11q23 rearrangement)
- Incorporates molecular data (absence of CALR type 1 mutation, presence of high-molecular-risk mutations: ASXL1, EZH2, SRSF2, IDH1/2)
- More refined prognostication for transplant-eligible patients (age ≤ 70)
- Used increasingly in 2024–2026 guidelines
Clinical Features
PMF has a clinical course divided into two phases: prefibrotic (cellular) phase and fibrotic (overt) phase [5]. The clinical features differ by phase but overlap considerably.
| Symptom | Pathophysiological Basis |
|---|---|
| Severe fatigue (most common presenting symptom) [2][5] | Multifactorial: anaemia (reduced oxygen-carrying capacity), cytokine excess (TNF-α, IL-6 causing systemic inflammation), and hypermetabolic/hypercatabolic state |
| Constitutional symptoms: weight loss, night sweats, low-grade fever [3] | Pro-inflammatory cytokine storm from abnormal megakaryocytes and clonal cells (IL-1, IL-6, TNF-α) → hypercatabolic state. Similar mechanism to B-symptoms in lymphoma. |
| Early satiety, abdominal discomfort/fullness | Massive splenomegaly → physical compression of stomach and bowel [3] |
| Left upper quadrant pain | Splenic infarction (due to outgrowth of blood supply to the enlarging spleen) or capsular stretching |
| Bone and joint pain | Osteosclerosis (new bone formation driven by cytokines such as OPG, PDGF) + secondary gout (high cell turnover → hyperuricaemia) [2] |
| Symptoms of anaemia: dyspnoea on exertion, palpitations, dizziness | Progressive marrow failure from fibrosis → reduced erythropoiesis; also splenic sequestration of RBCs; and ineffective erythropoiesis from EMH |
| Bleeding symptoms: bruising, petechiae, mucosal bleeding | Thrombocytopenia (marrow failure) or acquired platelet dysfunction; also acquired von Willebrand disease (AvWD) — extreme thrombocytosis can consume VWF [6] |
| Symptoms of gout (joint swelling, acute monoarthritis) | Hyperuricaemia from high cell turnover → urate crystal deposition |
| Symptoms of portal hypertension: abdominal distension (ascites), haematemesis/melaena (variceal bleed) | EMH in liver → hepatomegaly → sinusoidal infiltration → increased portal pressure; also increased splenic blood flow |
| Sign | Pathophysiological Basis |
|---|---|
| Massive splenomegaly (often crossing the midline, may reach into the pelvis) | Extramedullary haematopoiesis — the spleen becomes a site of (ineffective) blood cell production; also sequestration of blood cells. This is one of the hallmark physical findings [1][3] |
| Hepatomegaly | Extramedullary haematopoiesis in the liver; portal hypertension with congestion |
| Pallor | Anaemia from marrow failure, splenic sequestration, and ineffective erythropoiesis |
| Petechiae, ecchymoses | Thrombocytopenia or platelet dysfunction |
| Signs of portal hypertension: ascites, caput medusae, splenomegaly, variceal bleeding [3] | Hepatic sinusoidal infiltration by EMH, increased splenic blood flow through the portal system |
| Cachexia / wasting | Hypercatabolic state from cytokine excess |
| Peripheral oedema | Hypoalbuminaemia (liver dysfunction from EMH infiltration), portal hypertension |
| Lymphadenopathy (uncommon) | EMH in lymph nodes |
| Skin findings (rare): papules/nodules | Cutaneous EMH (dermal infiltration by haematopoietic precursors) |
| Finding | Explanation |
|---|---|
| Anaemia (↓ Hb) | Marrow failure + ineffective erythropoiesis + splenic sequestration |
| Variable WBC | Early: may be ↑ (released from EMH); Late: ↓ (marrow failure) |
| Variable platelets | Early/pre-PMF: may be ↑ (megakaryocyte hyperplasia); Late: ↓ (marrow failure) |
| Leukoerythroblastic blood picture | Immature myeloid precursors (myelocytes, metamyelocytes) + nucleated RBCs released from fibrotic marrow and EMH sites |
| Tear-drop RBCs (dacrocytes) | RBCs physically deformed by squeezing through fibrotic marrow sinusoids or splenic cords |
| Circulating blasts (≥1%) | Premature release from marrow; higher blast percentage = worse prognosis; ≥ 20% = transformation to AML |
Bone marrow:
- Aspirate: dry tap (unable to aspirate because of dense fibrosis) [2][3]
- Biopsy (trephine): megakaryocytic proliferation and atypia, with fibrosis (reticulin/collagen) [2]
'Dry Tap' = Think PMF
When a bone marrow aspirate yields a "dry tap" (no marrow obtained on aspiration), think of:
- Primary myelofibrosis — the most classic cause
- Hairy cell leukaemia — marrow fibrosis from reticulin deposition
- Metastatic carcinoma — desmoplastic reaction
- Aplastic anaemia (rarely) — hypocellular marrow packed with fat
A trephine biopsy is essential whenever a dry tap is obtained — it is the gold standard for diagnosing PMF.
Overview table of Philadelphia-negative MPNs [1][2]:
| Feature | PV | ET | PMF |
|---|---|---|---|
| Predominant lineage | Erythroid (Hb ↑↑) | Megakaryocytic (Plt ↑↑) | Megakaryocytic → fibrosis |
| Hb | ↑↑ | N | ↓ |
| WBC | ↑ | N | Variable |
| Plt | ↑ | ↑↑ (≥450) | Variable |
| Spleen | Moderate | Mild | Massive |
| PBS | May show erythrocytosis | Normal morphology | Leukoerythroblastic + tear-drop cells |
| BM aspirate | Hypercellular, panmyelosis | Megakaryocyte hyperplasia | Dry tap |
| Key mutations | JAK2 (97%) | JAK2 (50%), CALR (25%), MPL (3-5%) | JAK2 (60-65%), CALR (20-25%), MPL (7%) |
| Transformation to AML | 10% at 10y, 25% at 25y | < 5% | 6–18% (highest among MPNs) |
| Median survival | > 15 years | > 15 years | 3–5 years |
| Curative treatment | Venesection + aspirin + HU | Aspirin ± HU | Allogeneic HSCT |
PMF has the highest rate of leukaemic transformation (15%) and worst prognosis among the Ph-negative MPNs [3].
MPN increases risk of both arterial and venous thrombosis due to blood hyperviscosity from high cell counts [6].
JAK2 mutation-positive MPN is especially prone to thrombosis risk [6]. Key points:
- Thrombosis can occur in unusual sites — most commonly mesenteric vein [6]
- When seeing mesenteric vein thrombosis, screen for JAK2 mutations [6]
- Patients with JAK2 mutation can clot even before developing the cytosis — so even if CBC doesn't show MPN features, genetic screening is still indicated [6]
- Extreme thrombocytosis can cause acquired von Willebrand disease (AvWD) — excess platelets consume VWF → paradoxical bleeding tendency [6]
| Direction | Mechanism |
|---|---|
| Thrombosis | Hyperviscosity (high cell counts), JAK2-mediated endothelial activation, activated platelets, leukocyte-platelet interactions |
| Bleeding | Thrombocytopenia (marrow failure), platelet dysfunction (qualitative defect), AvWD (consumption of VWF by excessive platelets in early/pre-fibrotic phase) |
| Pathophysiological Process | Clinical Consequence |
|---|---|
| Marrow fibrosis → marrow failure | Anaemia, neutropenia, thrombocytopenia |
| Premature release from fibrotic marrow | Leukoerythroblastic picture, circulating blasts |
| Physical deformation of RBCs in fibrotic sinusoids | Tear-drop cells (dacrocytes) |
| Extramedullary haematopoiesis in spleen/liver | Massive splenomegaly, hepatomegaly, portal hypertension |
| Cytokine excess (TNF-α, IL-6, IL-1) | Constitutional symptoms, cachexia, fatigue |
| Osteoblast stimulation by PDGF/OPG | Osteosclerosis, bone pain |
| High cell turnover | Hyperuricaemia → gout |
| Hyperviscosity + JAK2 activation | Arterial and venous thrombosis (unusual sites) |
| Platelet dysfunction / AvWD | Bleeding tendency |
| Clonal evolution / genomic instability | Transformation to AML (6–18%) |
High Yield Summary
-
PMF is a chronic Ph-negative MPN characterised by bone marrow fibrosis (from reactive fibroblasts, NOT clonal fibroblasts), extramedullary haematopoiesis, and massive splenomegaly.
-
The megakaryocytes are the culprit — they release PDGF and TGF-β → stimulate fibroblast proliferation → reticulin/collagen deposition → marrow fibrosis.
-
Driver mutations: JAK2 V617F (60–65%), CALR (20–25%), MPL (7%). All converge on constitutive JAK-STAT activation. Triple-negative = worst prognosis.
-
Two phases: Pre-fibrotic (↑ WBC and Plt, minimal fibrosis) → Overt fibrotic (pancytopenia + massive splenomegaly).
-
Classic blood film: Leukoerythroblastic picture + tear-drop RBCs. BM aspirate = dry tap. Trephine biopsy is essential.
-
Most common symptom: Severe fatigue. Most apparent sign: Massive splenomegaly.
-
Least common MPN, worst prognosis (median survival 3–5 years). Highest rate of AML transformation (6–18%).
-
Risk stratification: IPSS (at diagnosis), DIPSS/DIPSS-Plus (dynamic). Parameters: age > 65, constitutional symptoms, Hb < 10, WBC > 25, blasts ≥ 1%.
-
Only curative treatment: Allogeneic HSCT (limited by age and comorbidities).
-
MPN thrombosis: JAK2+ MPNs prone to unusual-site thrombosis (e.g., mesenteric vein). Screen for JAK2 in unusual-site clots.
Active Recall - Primary Myelofibrosis
[1] Lecture slides: Block A - Splenomegaly: common causes of splenomegaly; myeloproliferative diseases.pdf (pp. 22, 30–31) [2] Senior notes: Maksim Medicine Notes.pdf (pp. 170–171) [3] Senior notes: Block A - Splenomegaly: common causes of splenomegaly; myeloproliferative diseases.pdf (pp. 30–31) [4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1450–1451) [5] Senior notes: Ryan Ho Haemtology.pdf (pp. 75, 78) [6] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p. 18)
Differential Diagnosis of Primary Myelofibrosis
The differential diagnosis of PMF is really about two clinical presentations that bring a patient to attention:
- The patient with massive splenomegaly — what else causes this?
- The patient with pancytopenia and a leukoerythroblastic blood film — what else causes this?
- The patient with bone marrow fibrosis on biopsy — what else causes fibrosis?
We need to systematically work through each of these because PMF sits at the intersection of all three.
PMF is not diagnosed in a vacuum. The WHO diagnostic criteria for PMF are partly criteria of exclusion — you must demonstrate that the clinical picture does not meet criteria for CML, PV, ET, or MDS before calling it PMF [5][7]. This means the differential diagnosis is baked into the diagnostic criteria themselves.
Let's organise the DDx by the clinical presentation that triggers the workup.
This is the most specific DDx. When a trephine biopsy shows fibrosis, you must ask: is this primary or secondary?
Myelofibrosis can be due to [5]:
| Category | Condition | Key Distinguishing Feature |
|---|---|---|
| Primary MPN | Primary myelofibrosis (PMF) | JAK2/CALR/MPL mutation; megakaryocyte atypia; no BCR-ABL1; no prior PV/ET |
| Secondary MPN-related | Post-PV myelofibrosis | Documented prior PV (elevated Hb/Hct, JAK2 97%); transformation to myelofibrosis occurs in ~10–12% of PV [8][9] |
| Post-ET myelofibrosis | Documented prior ET (sustained thrombocytosis ≥ 450); transformation to myelofibrosis < 5% of ET [3] | |
| Other chronic myeloid disorders | CML (BCR-ABL1+) | Defined by Philadelphia chromosome t(9;22) / BCR-ABL1 fusion gene; marked leukocytosis with bimodal myelocyte-neutrophil distribution; basophilia [10] |
| MDS with fibrosis | Dysplastic marrow cells (hypogranular neutrophils, Pelger abnormality, ring sideroblasts); should NOT have significant splenomegaly or characteristic MPN genetic changes (e.g., JAK2) [7] | |
| MDS/MPN overlap syndromes (e.g., CMML) | ↑ monocyte count > 1 × 10⁹/L (CMML); features of both dysplasia and proliferation [7] | |
| Other haematological malignancies | Hairy cell leukaemia | Pancytopenia + splenomegaly + dry tap; but PBS shows "hairy cells" (lymphocytes with cytoplasmic projections); CD25/CD103/Annexin A1 positive on flow |
| Lymphoma (marrow infiltration) | Lymphadenopathy usually prominent; tissue biopsy diagnostic | |
| Multiple myeloma | Bone pain + lytic lesions; paraprotein on SPEP; BM shows clonal plasma cells [11] | |
| Acute myelofibrosis | Very rare form of AML characterised by rapid onset of severe BM fibrosis with fever, pancytopenia, tear-drop RBCs and leukoerythroblastic picture but NO splenomegaly [5] — acute onset distinguishes it from chronic PMF | |
| Metastatic cancer | Breast cancer, prostate cancer | Known primary malignancy; desmoplastic reaction in marrow; imaging/biopsy confirmatory [4] |
| Non-haematological | Autoimmune disorders (e.g., SLE) | Multi-system autoimmune features; ANA/dsDNA positive [4] |
| Granulomatous disease (TB, sarcoidosis) | Granulomas on biopsy; AFB stain/culture for TB; ACE level/CXR for sarcoidosis [4] | |
| Secondary hyperparathyroidism | Renal osteodystrophy; elevated PTH with low calcium | |
| Primary pulmonary hypertension | Rare cause of marrow fibrosis |
The Critical First Step in DDx of Myelofibrosis
BM fibrosis may accompany virtually any chronic myeloid disorder → must rule out features of these disorders before making diagnosis of primary MF [5]. The most important exclusions are:
- CML — check BCR-ABL1 (if positive, it's CML, not PMF)
- PV — check for elevated RBC mass (if present, it's PV with fibrosis, not PMF)
- MDS — check for dysplastic features (if present, consider MDS with fibrosis)
- ET — note that ET by definition should NOT display prominent marrow fibrosis [5]
Massive splenomegaly (spleen crossing the midline or extending into the pelvis) has a limited differential. This is a high-yield exam topic.
Causes of massive splenomegaly [12]:
| Category | Conditions |
|---|---|
| Haematological malignancy | CML ★, Primary myelofibrosis ★, Lymphoma (esp. splenic marginal zone lymphoma), CLL, Hairy cell leukaemia |
| MPN | PV, ET (usually moderate, not massive) |
| Infection | Malaria (tropical splenomegaly), Visceral leishmaniasis (kala-azar), Schistosomiasis |
| Infiltrative | Gaucher disease (lysosomal storage disease — glucocerebrosidase deficiency), Amyloidosis |
| Congestive | Portal hypertension (cirrhosis), Splenic/portal/hepatic vein thrombosis (Budd-Chiari) |
| Haemolytic anaemia | Thalassaemia major (chronic extravascular haemolysis → work hypertrophy) |
★ = Classic causes of massive splenomegaly to remember for exams
A useful mnemonic for causes of massive splenomegaly is "CML Makes Kala-azar Patients Groan":
- CML
- Myelofibrosis (PMF)
- Kala-azar (visceral leishmaniasis)
- Polycythaemia vera (moderate-massive)
- Gaucher disease
In Hong Kong, the most relevant causes of massive splenomegaly are CML, PMF, lymphoma, and portal hypertension from chronic liver disease (HBV-related cirrhosis) — tropical infections like malaria and kala-azar are uncommon locally but important for returned travellers.
PMF in its overt fibrotic phase presents with pancytopenia. The DDx of pancytopenia is broad [13]:
| Mechanism | Conditions | Key Distinguishing Features |
|---|---|---|
| Bone marrow failure | Aplastic anaemia | Hypocellular marrow with fat replacement; NO fibrosis, NO infiltration; NO hepatosplenomegaly, NO lymphadenopathy [14][15] |
| Bone marrow infiltration — malignant | AML, ALL, CML blast crisis, Lymphoma, Multiple myeloma, MDS | Blasts on PBS/BM; specific immunophenotype/cytogenetics |
| Bone marrow infiltration — non-malignant | PMF, TB, Metastatic cancer | PMF: dry tap + megakaryocyte atypia + fibrosis; TB: granulomas |
| Bone marrow suppression | HIV, EBV, Drug-induced (e.g., cytotoxic agents) | Viral serology; drug history |
| Nutritional deficiency | Vitamin B12 deficiency, Folate deficiency, Copper deficiency | Megaloblastic anaemia (↑ MCV); hypersegmented neutrophils; low B12/folate levels [7] |
| Peripheral destruction/sequestration | Hypersplenism (e.g., portal hypertension) | Underlying liver disease; splenomegaly; proportional reduction in all lines |
| Alcoholism | Direct marrow suppression + nutritional deficiency + hypersplenism | Social history; macrocytosis; liver disease |
Aplastic Anaemia vs PMF — A Critical Distinction
Both present with pancytopenia. But:
- Aplastic anaemia: NO hepatosplenomegaly (the spleen has nothing to filter — no abnormal cells being produced) [14][15]
- PMF: MASSIVE splenomegaly (extramedullary haematopoiesis)
- Aplastic anaemia: hypocellular marrow with fat replacement [14]
- PMF: fibrotic marrow with megakaryocyte atypia (dry tap on aspiration)
- Aplastic anaemia: NO leukoerythroblastic picture on PBS [14]
- PMF: leukoerythroblastic picture + tear-drop cells
This distinction is straightforward at the bedside — feel for the spleen!
A leukoerythroblastic picture (left shift in granulocyte series + nucleated RBCs ± tear-drop RBCs) indicates marrow infiltration [16]. This is not exclusive to PMF.
| Cause | Explanation |
|---|---|
| Primary myelofibrosis | The prototype — fibrotic marrow squeezes out immature cells |
| Metastatic cancer to bone marrow | Breast, prostate, lung cancer — desmoplastic reaction |
| Haematological malignancies | Leukaemia, lymphoma, myeloma — marrow replacement by malignant cells |
| Severe sepsis / haemorrhage / haemolysis | Stress response → marrow "over-drives" and releases immature cells |
| Megaloblastic anaemia (severe) | Ineffective erythropoiesis → nucleated RBCs released |
| Post-PV or post-ET myelofibrosis | Secondary marrow fibrosis after long-standing PV/ET [5] |
This is one of the most commonly tested distinctions because pre-PMF can mimic ET clinically (both present with thrombocytosis).
| Feature | Pre-fibrotic PMF | ET |
|---|---|---|
| Platelet count | ↑ (may be ≥ 450) | ↑↑ (≥ 450, often higher) |
| Anaemia | Often present | Usually absent |
| WBC | Often mildly ↑ | Usually normal |
| LDH | Often elevated | Usually normal |
| Splenomegaly | May be present | Usually mild or absent |
| BM megakaryocytes | Atypical: large, hyperlobated, clustered, with cloud-like nuclei | Large, mature, deeply lobated ("staghorn" nuclei) |
| BM reticulin | Grade 0–1 (but atypia present) | Grade 0–1 (no atypia) |
| BM cellularity | Hypercellular with granulocytic proliferation | Not significantly hypercellular; megakaryocyte predominance only |
| Risk of fibrotic transformation | Higher (~15%) | Lower (< 5%) [3] |
| Risk of AML transformation | Higher | Lower |
Why This Matters
Pre-fibrotic PMF has a significantly worse prognosis than ET, with higher rates of fibrotic progression, AML transformation, and overall mortality. The distinction requires careful bone marrow biopsy interpretation by an experienced haematopathologist. A patient labelled as "ET" who actually has pre-PMF will be under-managed and under-monitored.
Both PMF and CML can present with splenomegaly, leukocytosis, and marrow fibrosis.
| Feature | PMF | CML |
|---|---|---|
| Defining mutation | JAK2/CALR/MPL | BCR-ABL1 (Philadelphia chromosome) — no t(9;22), not CML [10] |
| PBS | Leukoerythroblastic + tear-drop cells | Marked leukocytosis with bimodal distribution of myelocytes and neutrophils; basophilia [10] |
| Anaemia | Present (↓ Hb) | Present (↓ Hb) but less prominent early |
| Platelets | Variable | Usually ↑ |
| Splenomegaly | Massive | Massive (most apparent physical exam finding in CML) [10] |
| BM | Dry tap; fibrosis + megakaryocyte atypia | Hypercellular; full maturation; megakaryopoiesis markedly increased with small hypolobated forms [10] |
| Treatment | Ruxolitinib / HSCT | TKI (Imatinib, Nilotinib, Dasatinib, Ponatinib, Asciminib) [10] |
| AML risk (untreated) | 6–18% | > 90% if untreated [5] |
Take-home: The gold standard diagnosis of CML is cytogenetics — defined by the presence of the Philadelphia chromosome t(9;22)(q34.1;q11.2) [10]. If BCR-ABL1 is negative, CML is excluded and you can proceed to consider PMF.
| Condition | Spleen | PBS | BM Aspirate | BM Biopsy | Key Mutation/Test |
|---|---|---|---|---|---|
| PMF | Massive | Leukoerythroblastic + dacrocytes | Dry tap | Megakaryocyte atypia + fibrosis | JAK2/CALR/MPL |
| CML | Massive | Leukocytosis, basophilia, bimodal peak | Hypercellular | Granulocytic hyperplasia | BCR-ABL1 |
| PV | Moderate | Erythrocytosis | Panmyelosis | Trilineage growth | JAK2 (97%) + low EPO |
| ET | Mild/absent | Thrombocytosis | Megakaryocyte hyperplasia | Large mature megakaryocytes | JAK2/CALR/MPL |
| MDS | Usually absent | Dysplastic cells, macrocytosis | Dysplasia ± ring sideroblasts | Hypercellular with dysplasia | del(5q), -7, complex |
| Aplastic anaemia | Absent | Pancytopenia, NO abnormal cells | Hypocellular (fat) | Profoundly hypocellular, NO fibrosis | — |
| Hairy cell leukaemia | Moderate-massive | "Hairy" lymphocytes | Dry tap | Diffuse infiltration | BRAF V600E |
| Metastatic cancer | Variable | Leukoerythroblastic possible | Tumour cells | Desmoplastic fibrosis + tumour | Tissue-specific markers |
High Yield Summary — DDx of PMF
-
Before diagnosing PMF, you MUST exclude: CML (BCR-ABL1), PV (elevated RBC mass), ET (megakaryocyte-predominant without fibrosis/atypia), and MDS (dysplastic features).
-
Massive splenomegaly DDx (exam favourite): CML, PMF, Gaucher disease, Kala-azar, Malaria, Thalassaemia major.
-
Pancytopenia DDx: Aplastic anaemia (hypocellular marrow, NO splenomegaly) vs PMF (fibrotic marrow, MASSIVE splenomegaly) — feel for the spleen!
-
Leukoerythroblastic picture = marrow infiltration until proven otherwise. Causes: PMF, metastatic cancer, leukaemia/lymphoma, severe sepsis/haemolysis.
-
Pre-PMF vs ET: Both can present with thrombocytosis. Pre-PMF has megakaryocyte atypia, higher LDH, higher risk of progression. BM biopsy is the only way to distinguish.
-
Dry tap on BM aspirate: Think PMF, hairy cell leukaemia, metastatic cancer. Always proceed to trephine biopsy.
-
Acute myelofibrosis (rare AML variant): rapid onset, pancytopenia, NO splenomegaly — unlike chronic PMF.
Active Recall - Differential Diagnosis of PMF
References
[1] Lecture slides: Block A - Splenomegaly: common causes of splenomegaly; myeloproliferative diseases.pdf (pp. 22, 27, 29–31) [2] Senior notes: Maksim Medicine Notes.pdf (pp. 170–171) [3] Senior notes: Block A - Splenomegaly: common causes of splenomegaly; myeloproliferative diseases.pdf (pp. 29–31) [4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1450–1451) [5] Senior notes: Ryan Ho Haemtology.pdf (pp. 75, 77–78) [7] Senior notes: Ryan Ho Haemtology.pdf (pp. 83) [8] Lecture slides: GC 086. Splenomegaly.pdf (p. 38) [9] Senior notes: Block A - Splenomegaly: common causes of splenomegaly; myeloproliferative diseases.pdf (p. 27) [10] Senior notes: Block A - High white cell count: acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p. 22) [11] Senior notes: Block A - An old man with bone pain and anaemia: multiple myeloma; monoclonal gammopathy.pdf (p. 12) [12] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (p. 130) [13] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 772) [14] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 369) [15] Senior notes: Block A - Family history of anaemia: inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (pp. 7–8) [16] Senior notes: Ryan Ho Fundamentals.pdf (pp. 390, 398)
Preamble: Why the Diagnosis of PMF Is Criteria-Based
PMF cannot be diagnosed on a single test. There is no pathognomonic single marker — JAK2 is shared with PV and ET, CALR with ET, and marrow fibrosis occurs in dozens of conditions. The diagnosis therefore requires a combination of histopathological, molecular, and exclusionary criteria. The WHO framework demands that you prove:
- The marrow looks right (megakaryocyte atypia ± fibrosis)
- It is not something else (exclude CML, PV, ET, MDS)
- There is a clonal marker (JAK2/CALR/MPL or alternative) OR no identifiable reactive cause
WHO 2016 (Revised 4th Edition) Diagnostic Criteria
Requires ALL 3 major criteria AND at least 1 minor criterion [4][5]:
| Criterion | Explanation | |
|---|---|---|
| Major 1 | Megakaryocytic proliferation and atypia, without reticulin fibrosis > grade 1, accompanied by increased age-adjusted bone marrow cellularity, granulocyte proliferation and often decreased erythropoiesis [4] | The marrow is hypercellular with atypical megakaryocytes (hyperchromatic, irregularly folded nuclei, clustering) but has NOT yet developed dense fibrosis. Grade 1 myelofibrosis is a loose network of reticulin with many intersections especially in perivascular areas [4] — this is the upper limit allowed for pre-PMF. |
| Major 2 | WHO criteria for PV, ET, CML, MDS or other myeloid neoplasm are NOT met [4][5] | This is the exclusion criterion. You must actively demonstrate that BCR-ABL1 is negative (excludes CML), there is no erythrocytosis meeting PV criteria, no isolated megakaryocyte hyperplasia without atypia (which would suggest ET), and no dysplasia (which would suggest MDS). |
| Major 3 | Demonstration of JAK2, CALR, MPL mutation or another clonal marker (ASXL1/EZH2/TET2/IDH1/IDH2/SRSF2/SR3B1) OR no identifiable cause of reactive myelofibrosis [4][5] | If one of the three driver mutations is present, this criterion is satisfied. If all three are negative (triple-negative), you must demonstrate that there is no reactive cause of fibrosis (e.g., infection, autoimmune, metastatic cancer). |
| Minor Criterion | Explanation | |
|---|---|---|
| Minor 1 | Anaemia not attributable to a comorbid condition | Anaemia from marrow dysfunction, not from iron deficiency or chronic disease |
| Minor 2 | Leukocytosis ≥ 11 × 10⁹/L | Reflects myeloproliferation |
| Minor 3 | Palpable splenomegaly | From early extramedullary haematopoiesis |
| Minor 4 | LDH above upper limit of normal | Reflects high cell turnover and ineffective haematopoiesis |
Minor criteria must be confirmed in 2 consecutive measurements [4][5].
Note on Pre-PMF
Pre-PMF does NOT include leukoerythroblastosis as a minor criterion — that feature is reserved for overt PMF, because in pre-PMF the marrow is not yet fibrotic enough to squeeze out immature cells.
Requires ALL 3 major criteria AND at least 1 minor criterion [4][5]:
| Criterion | Explanation | |
|---|---|---|
| Major 1 | Megakaryocytic proliferation and atypia with either reticulin and/or collagen fibrosis grades 2 or 3 [4][5] | This is the key difference from pre-PMF: the fibrosis is now significant (grade 2 = diffuse dense reticulin with extensive intersections ± focal collagen; grade 3 = dense reticulin with coarse collagen bundles ± osteosclerosis) |
| Major 2 | WHO criteria for PV, ET, CML, MDS or other myeloid neoplasm are NOT met [4][5] | Same exclusion criterion as pre-PMF |
| Major 3 | Demonstration of JAK2, CALR, MPL mutation or another clonal marker OR no identifiable cause of reactive myelofibrosis [4][5] | Same as pre-PMF |
| Minor Criterion | Explanation | |
|---|---|---|
| Minor 1 | Anaemia not attributable to a comorbid condition | |
| Minor 2 | Leukocytosis ≥ 11 × 10⁹/L | |
| Minor 3 | Palpable splenomegaly | |
| Minor 4 | LDH above upper limit of normal | |
| Minor 5 | Leukoerythroblastosis [4][5] | This additional minor criterion for overt PMF reflects the consequence of significant marrow fibrosis — immature cells (nucleated RBCs + myelocytes) are squeezed out into peripheral blood |
Minor criteria must be confirmed in 2 consecutive measurements [4][5].
High Yield: The difference between pre-PMF and overt PMF in the major criteria is purely the grade of fibrosis: pre-PMF = grade ≤ 1; overt PMF = grade 2–3. In the minor criteria, overt PMF adds leukoerythroblastosis as a 5th minor criterion.
The WHO 2022 classification and the International Consensus Classification (ICC 2022) largely retain the 2016 framework but emphasise:
- Integration of molecular data for prognostication (MIPSS70, GIPSS)
- Greater emphasis on distinguishing pre-PMF from ET (a common diagnostic pitfall)
- Recognition that ASXL1, SRSF2, EZH2, IDH1/2 mutations can serve as clonal markers in triple-negative cases
- The overall diagnostic structure (3 major + ≥1 minor) remains unchanged
For HKUMed exam purposes, the 2016 WHO criteria as presented above remain the standard tested framework [4][5].
Understanding the grading system is essential because it defines pre-PMF vs overt PMF:
| Grade | Description | Clinical Significance |
|---|---|---|
| MF-0 | Scattered linear reticulin with no intersections (corresponds to normal marrow) | Normal |
| MF-1 | Loose network of reticulin with many intersections, especially in perivascular areas [4] | Upper limit for pre-PMF |
| MF-2 | Diffuse, dense increase in reticulin with extensive intersections, occasionally with focal bundles of collagen ± focal osteosclerosis | Overt PMF |
| MF-3 | Diffuse, dense reticulin with coarse bundles of collagen, often associated with significant osteosclerosis | Overt PMF (advanced) |
The stains used:
- Reticulin is visualised with silver stain (reticulin fibres are argyrophilic — they bind silver) [3][4]
- Collagen is visualised with trichrome stain (Masson's trichrome stains collagen blue/green) [4]
Investigation Modalities with Key Findings and Interpretations
| Parameter | Typical Finding in PMF | Interpretation |
|---|---|---|
| Haemoglobin | ↓ (anaemia) | Marrow failure from fibrosis + ineffective erythropoiesis from EMH + splenic sequestration. In pre-PMF, Hb may be near-normal. |
| WBC | Variable — may be ↑ in early/pre-fibrotic phase, ↓ in late fibrotic phase | Early: myeloproliferation still active. Late: marrow failure predominates. |
| Platelets | Variable — may be ↑ in pre-PMF (mimicking ET), ↓ in overt PMF | Pre-PMF: megakaryocyte hyperplasia drives thrombocytosis. Overt: marrow failure → thrombocytopenia. |
| MCV | Usually normocytic | Unlike megaloblastic anaemia or MDS |
Characteristic CBC in PMF: ↓ Hb, variable WBC & Plt [2]. In overt PMF, pancytopenia is the rule.
High Yield: If a patient has pancytopenia + massive splenomegaly, think PMF. If a patient has pancytopenia + NO splenomegaly, think aplastic anaemia [14][15].
This is the single most informative non-invasive test. The workup framework is MCICM = Morphology (PBS, BM), Cytochemistry, Immunophenotype, Cytogenetics, Molecular genetics [16].
| Finding | Significance | Why It Occurs |
|---|---|---|
| Tear-drop RBCs (dacrocytes) | Pathognomonic for marrow infiltration | RBCs are physically deformed as they squeeze through the narrowed, fibrotic marrow sinusoids [3][5] |
| Leukoerythroblastic picture | Left shift in granulocyte series + nucleated RBCs ± tear-drop RBCs → indicates marrow infiltration (by primary MF or any metastatic cancer) [16] | Premature release of immature cells from the fibrotic marrow and from ineffective EMH sites |
| Circulating blasts | If ≥ 1%, is a minor criterion/prognostic factor (IPSS); if ≥ 20%, diagnostic of AML transformation [16] | Reflects clonal evolution and loss of maturation control |
| Large/giant platelets, platelet fragments | Abnormal megakaryopoiesis | Atypical megakaryocytes produce abnormal-sized platelets |
| Nucleated RBCs (NRBCs) | Component of leukoerythroblastic picture | Released from EMH and fibrotic marrow |
PBS in PMF: leucoerythroblastic picture, tear-drop cell [2].
Leukoerythroblastic Picture — What Exactly Is It?
Leukoerythroblastic picture = left shift in granulocyte series (band cells, metamyelocytes, myelocytes) + nucleated RBCs ± tear-drop RBCs [16]. It indicates marrow infiltration — whether by fibrosis (PMF), metastatic cancer, or leukaemia. When you see this on a PBS, you MUST investigate the bone marrow.
3. Bone Marrow Examination
Bone marrow examination is necessary to demonstrate marrow fibrosis [5] and is mandatory for the diagnosis of PMF. It consists of two components:
The aspirate permits cytology examination, flow cytometry, and genetic studies [16].
| Finding | Significance |
|---|---|
| Dry tap (classically) | BM in PMF is often difficult to aspirate yielding a "dry tap" and is not diagnostic even if successful [4]. The marrow is so fibrotic that liquid marrow cannot be withdrawn. |
| If successful: megakaryocytic and neutrophilic hyperplasia | Most common findings would be megakaryocytic and neutrophilic hyperplasia [4] |
| Megakaryocytes often morphologically abnormal with both micro- and macro-megakaryocytes [4] | Atypical megakaryocytes with hyperchromatic, irregularly folded nuclei — the hallmark histological feature |
Investigations performed on bone marrow aspirate [17]:
- Morphology
- Iron storage (Perl's Prussian Blue stain) — to assess iron stores
- Flow cytometry — to assess immunophenotype (helps exclude lymphoproliferative disorders)
- Cytogenetics — conventional karyotyping
- FISH for recurrent cytogenetic abnormalities
- IgH or TCR PCR — to assess clonality of lymphoid populations if suspected
- NGS (Next-Generation Sequencing) — the "silver bullet" for complex cases [17], identifies sub-clonal mutations (ASXL1, EZH2, etc.) with prognostic value
- Microbiological cultures — if infection (e.g., TB) is in the differential
The trephine permits histological examination (marrow cellularity, architectural details, marrow fibrosis, bone structure) and immunohistochemistry [16].
Investigations performed on trephine biopsy [17]:
- Cellularity
- Degree of fibrosis — this is the critical assessment
- Abnormal infiltration
- Immunohistochemistry
| Finding | Significance |
|---|---|
| Increased age-adjusted bone marrow cellularity [4] | Reflects myeloproliferation |
| Megakaryocytic proliferation and atypia | The defining histological feature — megakaryocytes are large, clustered, with hyperlobated/cloud-like nuclei (different from the mature "staghorn" megakaryocytes of ET) |
| Severe extensive reticulin or collagen fibrosis [4] | Reticulin visualised with silver stain; collagen visualised with trichrome stain [4] |
| Decreased erythropoiesis [4] | Erythroid precursors are progressively replaced by fibrosis |
| Granulocyte proliferation [4] | Part of the myeloproliferative process |
| Osteosclerosis | New bone formation, especially in advanced disease (grade 3 fibrosis); driven by cytokines (OPG, PDGF) |
| Trephine biopsy showing dense reticulin with silver stain [3] | The confirmatory finding |
Why Aspirate Gives 'Dry Tap' But Trephine Works
The aspirate uses suction to pull liquid marrow — this fails when the marrow is replaced by dense fibrous tissue (like trying to suck honey through a straw filled with cotton). The trephine biopsy physically cores out a solid cylinder of bone + marrow → the architecture is preserved, allowing direct visualisation of fibrosis, cellularity, and megakaryocyte morphology. This is why trephine biopsy is essential whenever a dry tap is obtained [3][4].
From a technician perspective, the major limitation of the trephine biopsy over the bone marrow aspirate is that the trephine takes a long time → requires decalcification of the specimen, which takes a week [17].
This is Major Criterion 3 and is critical for diagnosis.
| Test | Target | Frequency in PMF | Method | Interpretation |
|---|---|---|---|---|
| JAK2 V617F | Exon 14 of JAK2 | 60–65% [5] (45–50% per some sources [4]) | PCR on peripheral blood (no need for marrow) | Gain-of-function → constitutive JAK-STAT activation |
| JAK2 exon 12 | Exon 12 of JAK2 | Rare in PMF (more relevant for PV) | PCR | |
| CALR exon 9 | Calreticulin | 20–30% [2][4][5] | PCR | Mutant CALR activates MPL → JAK-STAT |
| MPL | Thrombopoietin receptor | 7–10% [4][5] | PCR | Gain-of-function (W515L/K) |
| BCR-ABL1 | Philadelphia chromosome | Must be negative for PMF diagnosis | FISH / RT-PCR / Karyotype | If positive → CML, not PMF |
| ASXL1, EZH2, TET2, IDH1/2, SRSF2, SR3B1 | Sub-clonal / epigenetic mutations | Variable | NGS panel | Can serve as clonal markers in triple-negative cases; also important for prognosis (ASXL1 = adverse) |
Genetic testing: JAK2 (60–65%), CALR (20–25%), MPL (5%), triple-negative (8–10%) [5].
Mutations of MPN serve as clonal markers and diagnostic tools [4]:
- JAK2 V617F: PV = 95%; ET = 50%; PMF = 50% [4]
- CALR exon 9: ET = 25%; PMF = 35% [4]
- BCR-ABL1 fusion: ALL cases of CML [4]
High Yield: JAK2 mutation testing can be done on peripheral blood — no marrow needed. This makes it the first-line genetic test when MPN is suspected.
| Test | Typical Finding | Why |
|---|---|---|
| LDH (↑) [5] | Elevated | High cell turnover + ineffective haematopoiesis + tissue damage; also a minor diagnostic criterion |
| ALP (↑) [5] | Elevated alkaline phosphatase | Osteosclerosis (new bone formation) |
| Serum urate (↑) [5] | Hyperuricaemia | High cell turnover → purine catabolism → uric acid; risk of gout |
| Serum ferritin | May be ↑ or ↓ | ↑ if transfusion-dependent (iron overload); ↓ if concurrent iron deficiency |
| Serum EPO | Usually normal or ↑ | Unlike PV where EPO is suppressed. In PMF, EPO is appropriately elevated in response to anaemia. |
| LFT | May be deranged | Hepatic EMH infiltration, portal hypertension |
| Coagulation profile | Requested when patient has extreme thrombocytosis with bleeding tendency → to exclude acquired von Willebrand disease (AvWD) [6] | Excess platelets consume VWF → AvWD → paradoxical bleeding |
Performed on marrow aspirate or peripheral blood.
| Finding | Significance |
|---|---|
| Normal karyotype | Seen in ~50% of PMF; does not exclude diagnosis |
| Abnormal karyotype (del(13q), del(20q), +8, +9, del(1p)) | Common non-specific abnormalities; some have prognostic significance |
| Unfavourable karyotype (complex karyotype, +8, -7/7q-, i(17q), -5/5q-, 12p-, inv(3), 11q23 rearrangement) | Used in DIPSS-Plus for risk stratification [2] |
| t(9;22) / BCR-ABL1 | If present → diagnosis is CML, NOT PMF |
| Modality | Findings | Purpose |
|---|---|---|
| Ultrasound abdomen | Splenomegaly (may be massive, > 20 cm), hepatomegaly | Non-invasive assessment of organomegaly; baseline measurement for monitoring |
| CT abdomen | Splenomegaly, hepatomegaly, portal hypertension features (varices, ascites), EMH masses | More detailed assessment; identify EMH at unusual sites |
| MRI spine | Diffuse marrow signal changes (loss of normal fatty marrow signal); paravertebral EMH masses | Useful if suspected cord compression from EMH [3] |
| X-ray / CT bone | Osteosclerosis (increased bone density), especially in axial skeleton | Reflects cytokine-driven new bone formation |
| PET-CT | Generally not first-line; may show metabolically active EMH sites | Used mainly to exclude lymphoma or metastatic disease in the DDx |
8. Prognostic Risk Stratification Tools
These are not diagnostic tests but are integral to the workup because they guide management (especially the decision for allogeneic HSCT).
Risk stratification systems for primary myelofibrosis: IPSS (at diagnosis), DIPSS/DIPSS-Plus (at follow-up) [2].
IPSS & DIPSS use 5 parameters → classified into low, Int-1, Int-2, high risk [2]:
| Risk Factor | Points |
|---|---|
| Age > 65 | 1 |
| Constitutional symptoms | 1 |
| Hb < 10 g/dL | 1 |
| WBC > 25 × 10⁹/L | 1 |
| Peripheral blood blasts ≥ 1% | 1 |
| Category | Score | Median Survival |
|---|---|---|
| Low | 0 | 11.3 years |
| Int-1 | 1 | 7.9 years |
| Int-2 | 2 | 4.0 years |
| High | ≥ 3 | 2.3 years |
- Same 5 parameters; Hb < 10 weighted as 2 points (instead of 1)
- "Dynamic" because it can be recalculated at any follow-up visit
- Platelet count < 100 × 10⁹/L
- Transfusion dependence
- Unfavourable karyotype
- Incorporates molecular data: absence of CALR type 1 mutation, presence of high-molecular-risk mutations (ASXL1, EZH2, SRSF2, IDH1/2)
- Used for patients ≤ 70 years to guide transplant decisions
- Increasingly adopted in 2024–2026 guidelines
| Step | Investigation | What You're Looking For |
|---|---|---|
| 1 | CBC + differential | Anaemia, variable WBC/Plt, cytopenias |
| 2 | PBS | Leukoerythroblastic picture, tear-drop cells, circulating blasts |
| 3 | LDH, urate, ALP, LFT, RFT | Elevated LDH (minor criterion), hyperuricaemia, liver/renal function |
| 4 | BCR-ABL1 (peripheral blood) | Must be negative to proceed to PMF diagnosis |
| 5 | JAK2 V617F (peripheral blood) | Present in 60–65% |
| 6 | If JAK2 negative → CALR, MPL | CALR 20–25%, MPL 7% |
| 7 | Bone marrow aspirate + trephine biopsy | Dry tap (aspirate); fibrosis grading + megakaryocyte atypia (trephine) |
| 8 | Reticulin (silver stain) + Collagen (trichrome stain) on trephine | Fibrosis grade determines pre-PMF vs overt PMF |
| 9 | Cytogenetics / Karyotype | Prognostic; exclude CML (t(9;22)); identify unfavourable karyotype |
| 10 | NGS panel (if triple-negative or for prognostication) | ASXL1, EZH2, SRSF2, IDH1/2, TET2 |
| 11 | Imaging (US abdomen ± CT/MRI) | Splenomegaly, hepatomegaly, EMH sites |
| 12 | Risk stratification (IPSS/DIPSS/DIPSS-Plus) | Guide management decisions, especially HSCT eligibility |
High Yield Summary — Diagnosis of PMF
-
WHO 2016 criteria: ALL 3 major + ≥ 1 minor for both pre-PMF and overt PMF. The key difference is fibrosis grade (≤ 1 for pre-PMF; ≥ 2 for overt PMF).
-
Major criteria: (1) Megakaryocyte atypia ± fibrosis, (2) Exclusion of CML/PV/ET/MDS, (3) Clonal marker or no reactive cause.
-
Minor criteria: Anaemia, WBC ≥ 11, splenomegaly, ↑LDH, ± leukoerythroblastosis (overt PMF only). Must be confirmed on 2 consecutive measurements.
-
PBS hallmarks: Leukoerythroblastic picture + tear-drop RBCs — indicates marrow infiltration.
-
BM aspirate = dry tap (classic). Trephine biopsy is mandatory — shows megakaryocyte atypia + fibrosis. Reticulin = silver stain; Collagen = trichrome stain.
-
Molecular testing: JAK2 V617F (60–65%), CALR (20–25%), MPL (7%). BCR-ABL1 must be negative. Can be done on peripheral blood.
-
Exclusion of CML is the first molecular step — if BCR-ABL1 positive, it is CML by definition.
-
Risk stratification: IPSS at diagnosis, DIPSS/DIPSS-Plus dynamically. 5 parameters: age > 65, constitutional symptoms, Hb < 10, WBC > 25, blasts ≥ 1%.
Active Recall - Diagnosis of PMF
[2] Senior notes: Maksim Medicine Notes.pdf (pp. 170–171) [3] Senior notes: Block A - Splenomegaly: common causes of splenomegaly; myeloproliferative diseases.pdf (pp. 30–31) [4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1450, 1453, 1455) [5] Senior notes: Ryan Ho Haemtology.pdf (pp. 75–76, 78–79) [6] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p. 18) [14] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 369) [15] Senior notes: Block A - Family history of anaemia: inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (pp. 7–8) [16] Senior notes: Ryan Ho Fundamentals.pdf (pp. 390–391) [17] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (pp. 3, 15)
Guiding Principles
The management of PMF is fundamentally guided by two questions:
- What is the patient's risk category? (IPSS/DIPSS/DIPSS-Plus/MIPSS70)
- Is the patient eligible for allogeneic haematopoietic stem cell transplantation (HSCT)?
PMF is a heterogeneous disease — some may have good prognosis with more than 10 years of survival; others have worse, die within 1–2 years [3]. This heterogeneity drives a risk-stratified approach.
The key reality to accept: the management of PMF is predominantly palliative if not suitable/eligible for allogeneic HSCT [5]. The only potentially curative treatment is allogeneic HSCT, but most patients are elderly and unfit for it [3].
Treatment Modalities in Detail
1. Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) — The Only Cure
Allogeneic stem cell transplantation is the only potentially curative procedure for PMF [3].
- Allogeneic HSCT replaces the patient's clonal, mutated haematopoietic stem cells with healthy donor stem cells
- There is also a graft-versus-tumour (GvT) effect — the donor's immune cells recognise and attack residual malignant clones
- It can reverse marrow fibrosis over time (months to years) as the donor-derived haematopoiesis gradually replaces the fibrotic environment
Indications for allogeneic HSCT in PMF [18]:
- High-risk + eligible patients [2]
- Int-2 and High risk by IPSS/DIPSS/DIPSS-Plus
- Int-1 with adverse features: transfusion dependence, unfavourable karyotype, high-molecular-risk mutations (ASXL1, EZH2, SRSF2, IDH1/2)
- Transformed MPN (blast phase / AML transformation) [18]
- NCCN/ELN guidelines (2024–2026): consider HSCT for patients with MIPSS70 intermediate or higher risk, age ≤ 70, adequate performance status
Feasibility limited by age and comorbidities [3]:
- Median age at diagnosis = 67 years → most patients are too old for myeloablative conditioning
- Reduced-intensity conditioning (RIC) has expanded eligibility to patients up to age ~70–75 in selected centres
- Requires a matched donor (sibling or unrelated) — HLA matching is critical
- Surgical risks: 6.3% 30-day operative mortality for splenectomy (relevant if splenectomy is done pre-HSCT) [16]
- Transplant-related mortality (TRM): 20–30% at 1 year, depending on conditioning intensity and patient fitness
- Graft-versus-host disease (GvHD) — acute and chronic
- Splenectomy before HSCT — debated; may improve engraftment but carries perioperative risks. Not routinely recommended unless massive splenomegaly is causing mechanical problems
- JAK inhibitor bridging therapy (ruxolitinib) — increasingly used to reduce spleen size and improve performance status before transplant, but should be tapered gradually (risk of withdrawal syndrome with cytokine rebound)
Why Not Transplant Everyone?
HSCT has a 20–30% transplant-related mortality. For low/Int-1 risk patients with a median survival of 8–11 years, the risk of the transplant outweighs the benefit. HSCT is reserved for patients whose disease prognosis is worse than the expected transplant mortality.
2. JAK Inhibitors — Disease-Modifying Symptom Control
Targeted JAK2 inhibitors decrease spleen size and constitutional symptoms [3].
Treatment of primary cause, e.g., JAK2 inhibitor in primary myelofibrosis [16].
The name tells you the mechanism: JAK = Janus Activated Kinase inhibitor — blocks the constitutively active JAK-STAT signalling pathway that drives the disease.
Important Concept
JAK inhibitors are NOT curative. They do not significantly reduce the mutant allele burden or reverse marrow fibrosis. They work primarily by suppressing the cytokine storm (reducing spleen size, improving constitutional symptoms, and improving quality of life). They are given regardless of JAK2 mutation status because the JAK-STAT pathway is activated in all PMF subtypes (JAK2, CALR, and MPL mutations all converge on this pathway) [2].
- Mechanism: JAK1/JAK2 inhibitor (non-selective)
- Indication: Symptomatic splenomegaly and/or constitutional symptoms, regardless of JAK2 status [2][3]
- Benefits (COMFORT-I and COMFORT-II trials):
- ≥ 35% reduction in spleen volume in ~40–50% of patients
- Significant improvement in constitutional symptoms and quality of life
- Possible overall survival benefit compared to placebo/best available therapy
- Key Side Effects:
- On-target risk of worsening anaemia and thrombocytopenia [3] — because JAK2 is essential for normal erythropoiesis (EPO-R signalling) and thrombopoiesis (TPO-R signalling). Blocking JAK2 non-selectively therefore suppresses all three lineages
- Dose-dependent cytopenias — dose adjustments or transfusion support may be needed
- Infections (immunosuppression): herpes zoster reactivation, TB reactivation, opportunistic infections
- Weight gain
- Withdrawal syndrome: if discontinued abruptly → cytokine rebound with fever, respiratory distress, splenic enlargement, shock — must taper gradually
- Contraindication / Caution: Severe thrombocytopenia (platelets < 50 × 10⁹/L) — dose reduction required; historically contraindicated below 50
- Mechanism: JAK2-selective inhibitor (also inhibits FLT3)
- Indication: PMF patients who are refractory to or intolerant of ruxolitinib
- Benefits: Significant spleen volume reduction and symptom improvement in ruxolitinib-refractory patients
- Key Side Effects:
- Worsening anaemia and thrombocytopenia (same on-target mechanism) [3]
- Gastrointestinal toxicity (diarrhoea, nausea, vomiting) — more pronounced than ruxolitinib
- Wernicke encephalopathy (thiamine deficiency) — FDA black box warning; monitor thiamine levels before and during treatment
- Contraindication: Thiamine deficiency; severe hepatic impairment
- Mechanism: Selective JAK2 inhibitor (also inhibits IRAK1 and FLT3) [3]
- Pacritinib, a selective JAK2 inhibitor, was approved in 2022 [3]
- Indication: PMF patients with severe thrombocytopenia (platelets < 50 × 10⁹/L) — the population where ruxolitinib and fedratinib cannot be safely used
- Why it's special: Compared to the older non-selective JAK inhibitors ruxolitinib and fedratinib that carry on-target risks of worsening anaemia and thrombocytopenia [3], pacritinib's selectivity for JAK2 (sparing JAK1) means less myelosuppression — allowing use in severely cytopenic patients
- Key Side Effects: GI toxicity (diarrhoea), bleeding events, cardiac events
- Contraindication: Concomitant use of strong CYP3A4 inhibitors/inducers
- Mechanism: JAK1/JAK2 inhibitor + ACVR1 (activin receptor) inhibitor
- Unique feature: ACVR1 inhibition reduces hepcidin levels → improves iron availability → reduces transfusion dependence. This addresses the anaemia problem that other JAK inhibitors worsen
- Indication: PMF with anaemia, especially transfusion-dependent patients
- Key Side Effects: Peripheral neuropathy, diarrhoea, thrombocytopenia (less than ruxolitinib)
- Approved: FDA 2023, NCCN-recommended for anaemic PMF patients
| JAK Inhibitor | JAK Selectivity | Key Advantage | Key Limitation |
|---|---|---|---|
| Ruxolitinib | JAK1/2 | First-line; best evidence | Worsens anaemia/thrombocytopenia |
| Fedratinib | JAK2 > JAK1 | Second-line post-ruxolitinib | GI toxicity; Wernicke encephalopathy risk |
| Pacritinib | Selective JAK2 | Safe in Plt < 50 | GI, cardiac, bleeding |
| Momelotinib | JAK1/2 + ACVR1 | Reduces anaemia/transfusion need | Peripheral neuropathy |
3. Supportive Care for Cytopenias
Supportive for cytopenia [3]:
| Modality | Mechanism / Rationale | Details |
|---|---|---|
| Long-term transfusion ± iron chelation to prevent haemosiderosis [3] | Packed RBC transfusions to maintain Hb and functional capacity; chronic transfusion leads to iron overload (each unit deposits ~250 mg iron) → requires chelation | Iron chelation: deferasirox (oral) or deferoxamine (SC/IV) |
| EPO (erythropoietin) [2][3] | Stimulates residual erythroid precursors in the marrow; works best when baseline EPO < 500 mU/mL | Recombinant EPO (darbepoetin alfa or epoetin alfa); response rate ~30–50% in those with low baseline EPO |
| Luspatercept (TGF-β inhibitor) [3] | Inhibits TGF-β superfamily signalling → promotes late-stage erythroid maturation → reduces ineffective erythropoiesis | Originally approved for MDS with ring sideroblasts; increasingly used in PMF; reduces transfusion burden |
| Danazol | Attenuated androgen → stimulates erythropoiesis (possibly via increasing EPO production and direct marrow stimulation) | Dose: 200 mg TDS; response rate ~30%; monitor LFTs (hepatotoxicity risk) |
| Immunomodulatory drugs (IMiDs) | Thalidomide ± prednisone, lenalidomide | Low-dose thalidomide (50 mg) + prednisone can improve anaemia and thrombocytopenia in ~20–30% of patients; risk of peripheral neuropathy (thalidomide), teratogenicity |
Why Is Anaemia in PMF So Difficult to Treat?
Anaemia in PMF is multifactorial: marrow fibrosis → reduced erythropoietic space; ineffective erythropoiesis from EMH; splenic sequestration; cytokine-mediated suppression (TNF-α, IL-6); and JAK inhibitor therapy itself worsens anaemia. No single agent addresses all these mechanisms, which is why treatment often combines multiple modalities.
- Platelet transfusions for active bleeding or before procedures
- Avoid antiplatelet agents if platelets < 50 × 10⁹/L
- Pacritinib is preferred over ruxolitinib if Plt < 50
- Allopurinol [2] — xanthine oxidase inhibitor; prevents uric acid formation from high cell turnover
- Indicated when serum urate is elevated or patient has symptomatic gout
- Folic acid [2] — compensates for increased folate consumption from high cell turnover and ineffective erythropoiesis
Hydroxyurea [2]:
- Mechanism: Ribonucleotide reductase inhibitor → inhibits DNA synthesis → reduces proliferation of all haematopoietic lineages
- Indications in PMF:
- Symptomatic leukocytosis or thrombocytosis
- Symptomatic splenomegaly (if JAK inhibitor unavailable or contraindicated)
- Cytoreduction before splenectomy or HSCT
- Side effects of hydroxyurea: myelosuppression, mucocutaneous ulcer, peripheral neuropathy, teratogenicity [2]
- Monitoring: Regular CBC to titrate dose and avoid excessive cytopenias
- Hydroxyurea does NOT reverse fibrosis and is NOT disease-modifying in the way JAK inhibitors are
5. Splenectomy — Surgical Intervention
Splenectomy → sometimes performed to relieve pressure symptoms and decrease transfusion requirements [3].
Surgical treatment if splenomegaly causes problems, e.g., ↑ transfusion requirement [16].
- Refractory symptomatic splenomegaly not responding to JAK inhibitors or hydroxyurea
- Refractory transfusion-dependent anaemia (where splenic sequestration is contributing significantly)
- Symptomatic portal hypertension from splenic blood flow
- Diagnostic splenectomy if cause of splenomegaly cannot be ascertained [16]
- 6.3% 30-day operative mortality [16] — this is high because PMF patients are often elderly, cytopenic, and may have portal hypertension with collateral vessels
- Post-operative thrombocytosis (rebound) → risk of thrombosis
- Post-operative hepatomegaly (compensatory expansion of hepatic EMH)
- Infection risk:
- Post-splenectomy overwhelming sepsis [16]
- Spleen is critical for producing antibodies against polysaccharide antigens on encapsulated bacteria [16]
- 2–3× risk of infection, sepsis, and sepsis-related mortality [16]
- Must vaccinate pre-splenectomy against: Pneumococcus, Meningococcus, Haemophilus influenzae type b (the encapsulated organisms)
- Post-splenectomy antibiotic prophylaxis: phenoxymethylpenicillin (Penicillin V)
Splenectomy Does NOT Worsen Haematopoiesis
Remember from the pathophysiology section: even if you remove the spleen, it will not impair the blood production capability [3] because the extramedullary haematopoiesis in the spleen is ineffective — it does not contribute meaningful blood cell production. This is why splenectomy can be offered for symptom relief without fear of worsening the cytopenias (though in practice, other complications limit its use).
- Mechanism: Targeted radiation to the spleen → reduces spleen size by destroying EMH tissue
- Indication: Patients with symptomatic splenomegaly who are not surgical candidates (too frail for splenectomy)
- Limitation: Effect is temporary (weeks to months); repeated courses needed; risk of prolonged and severe cytopenias (because radiation also damages the small amount of effective haematopoiesis occurring in the irradiation field)
- Generally a palliative, last-resort measure
| Agent | Mechanism | Status |
|---|---|---|
| Navitoclax + Ruxolitinib | BCL-xL/BCL-2 inhibitor (promotes apoptosis of fibrotic clone) + JAK inhibitor | Phase III (TRANSFORM trials); shows improved fibrosis reduction and spleen response vs ruxolitinib alone |
| Pelabresib + Ruxolitinib | BET inhibitor (epigenetic modifier) + JAK inhibitor | Phase III (MANIFEST-2); shows improved spleen and symptom responses, and importantly reduction in marrow fibrosis |
| Imetelstat | Telomerase inhibitor | Phase III (IMbark); targets telomere maintenance in clonal cells |
| Selinexor | XPO1 inhibitor | Early phase trials |
| IDH1/2 inhibitors (ivosidenib, enasidenib) | For IDH-mutant PMF | Used in AML; emerging data in PMF |
| Risk | IPSS Score | Median Survival | Approach |
|---|---|---|---|
| Low | 0 | 11.3 years | Watch and wait; treat symptoms only (anaemia support, gout prophylaxis) |
| Int-1 | 1 | 7.9 years | Symptom management; consider HSCT if adverse molecular features present |
| Int-2 | 2 | 4.0 years | Allogeneic HSCT if eligible; JAK inhibitor if not transplant-eligible |
| High | ≥ 3 | 2.3 years | Allogeneic HSCT if eligible; JAK inhibitor + supportive care if not |
| Clinical Problem | Treatment | Rationale |
|---|---|---|
| Constitutional symptoms (fatigue, weight loss, sweats) | Ruxolitinib (regardless of JAK2 status) [2] | JAK-STAT-driven cytokine storm suppression |
| Symptomatic splenomegaly | Ruxolitinib first-line → Hydroxyurea → Splenectomy → Splenic irradiation [2][3] | Stepwise escalation |
| Anaemia (symptomatic) | Transfusion, folic acid, EPO [2]; Luspatercept; Danazol; Momelotinib | Multifactorial anaemia management |
| Transfusion-dependent anaemia | Iron chelation (deferasirox); consider momelotinib | Prevent haemosiderosis |
| Severe thrombocytopenia with symptoms | Pacritinib [3] | Safe in Plt < 50 |
| Hyperuricaemia / gout | Allopurinol [2] | Xanthine oxidase inhibition |
| Thrombosis | Anticoagulation (as per standard VTE/arterial guidelines); address underlying MPN | JAK2+ MPN = high thrombotic risk [6] |
| Acquired vWD with bleeding | Exclude by checking VWF levels when extreme thrombocytosis with bleeding [6]; avoid aspirin; consider DDAVP or VWF concentrate | Paradoxical bleeding from VWF consumption |
| AML transformation | Induction chemotherapy ± allogeneic HSCT | PMF has highest AML transformation rate (6–18%) |
| Cord compression from EMH | Radiation therapy to EMH mass ± dexamethasone | EMH could go to spine, cause cord compression [3] |
High Yield Summary — Management of PMF
-
Only curative treatment: Allogeneic HSCT — reserved for Int-2/High risk patients who are fit and have a donor. Feasibility limited by age (median 67) and comorbidities.
-
Management is predominantly palliative if not eligible for HSCT.
-
JAK inhibitors (ruxolitinib first-line): reduce spleen size and constitutional symptoms; work regardless of JAK2 mutation status (all driver mutations converge on JAK-STAT). NOT curative. Worsen anaemia and thrombocytopenia (on-target effect).
-
Pacritinib (selective JAK2 inhibitor, approved 2022): specifically for patients with Plt < 50 where ruxolitinib is too myelosuppressive.
-
Supportive care: Transfusion ± iron chelation, EPO, folic acid, allopurinol (gout prophylaxis), luspatercept (TGF-β inhibitor for anaemia).
-
Hydroxyurea: Cytoreductive agent for leukocytosis/thrombocytosis/splenomegaly; S/E include myelosuppression, mucocutaneous ulcers, peripheral neuropathy, teratogenicity.
-
Splenectomy: For refractory symptomatic splenomegaly; high perioperative mortality (6.3%); requires pre-splenectomy vaccination (Pneumococcus, Meningococcus, Hib). Does NOT impair haematopoiesis because EMH in spleen is ineffective.
-
Risk stratification guides management: IPSS at diagnosis; DIPSS/DIPSS-Plus dynamically; MIPSS70 for transplant decisions.
Active Recall - Management of PMF
[2] Senior notes: Maksim Medicine Notes.pdf (pp. 170–171) [3] Senior notes: Block A - Splenomegaly: common causes of splenomegaly; myeloproliferative diseases.pdf (pp. 18, 30–32) [5] Senior notes: Ryan Ho Haemtology.pdf (pp. 77–79) [6] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p. 18) [16] Senior notes: Ryan Ho Fundamentals.pdf (pp. 390, 398) [18] Senior notes: Block A - High white cell count: acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (pp. 23, 28)
Complications of Primary Myelofibrosis
PMF is a progressive disease whose complications arise from three fundamental processes: (1) progressive marrow failure from fibrosis, (2) extramedullary haematopoiesis and its consequences, and (3) clonal evolution of the malignant stem cell. Additionally, complications can arise from the treatments themselves. Let's work through each systematically.
1. Leukaemic Transformation (Blast Phase / AML)
This is the most feared complication.
PMF has the highest rate of leukaemic transformation among the Ph-negative MPNs — 15% [3]. Other sources report 6–18% [5] or 8% per year [4].
For comparison across MPNs [3][5][8]:
- PMF: 6–18% (highest)
- PV: 10% at 10 years, 25% at 25 years (2nd highest) [5]; transformation to acute leukaemia 5% [8]
- ET: < 5% (15-year cumulative risk) (lowest) [19]
All forms of MPN share the potential to progress to myelofibrosis and blastic transformation [8].
The clonal haematopoietic stem cells in PMF accumulate additional somatic mutations over time (clonal evolution). Key "high-molecular-risk" mutations that accelerate transformation include:
- TP53 — loss of tumour suppression → genomic instability
- RUNX1 — disrupts normal haematopoietic differentiation
- IDH1/IDH2 — altered cellular metabolism (2-hydroxyglutarate accumulation → epigenetic derangement)
- SRSF2, EZH2, ASXL1 — epigenetic dysregulation
These mutations destabilise the genome, push cells toward a blast phenotype (loss of differentiation), and ultimately lead to AML when blasts reach ≥ 20% in peripheral blood or bone marrow.
- Rising blast count on PBS (≥ 20% = diagnostic of AML)
- Worsening cytopenias (especially sudden drops)
- New-onset fever, bone pain, rapidly enlarging spleen
- Increasing LDH
- AML arising from PMF (secondary AML / sAML) has a very poor prognosis compared to de novo AML
- Resistant to standard AML chemotherapy regimens — median survival only 2–5 months without HSCT
- Allogeneic HSCT is the only option with any chance of long-term survival, but TRM is high
Transformation into AML is generally lower than MDS, and is associated with disease type (e.g., CALR mutation confers lower risk) and treatment factors (use of alkylating agents or radioactive phosphorus increases risk) [5].
High Yield — AML Transformation Rates Across MPNs
| MPN | AML Transformation Rate |
|---|---|
| PMF | 6–18% (highest) |
| PV | 10% at 10y, 25% at 25y |
| ET | < 5% (15-year cumulative risk) |
| CML (untreated) | > 90% |
PMF is the worst among Ph-negative MPNs. CML untreated is the worst overall MPN for transformation.
2. Thrombotic Complications
MPN increases risk of both arterial and venous thrombosis because blood is more viscous due to the high cell counts [6].
The JAK2 mutation-positive subtype is especially prone to increasing thrombosis risk [6].
Multiple factors converge:
- Hyperviscosity from elevated cell counts (even if variable in PMF, early/pre-fibrotic phase may have leukocytosis and thrombocytosis)
- JAK2-mediated endothelial activation — mutant JAK2 is expressed in endothelial cells, increasing adhesion molecule expression and prothrombotic surface
- Activated platelets and leukocytes — increased platelet–leukocyte aggregate formation
- Increased circulating tissue factor from activated monocytes
- Reduced protein C/S activity in some patients
| Type | Examples |
|---|---|
| Arterial | Stroke, MI, peripheral arterial disease, splenic infarction |
| Venous | DVT, PE, unusual-site thrombosis |
Thrombosis occurs in peculiar locations → mesenteric vein [6]. Other unusual sites include:
- Hepatic veins → Budd-Chiari syndrome
- Portal vein → portal vein thrombosis → worsening portal hypertension
- Splenic vein → splenic infarction, worsening splenomegaly
- Cerebral venous sinuses → headache, seizures, raised ICP
When seeing mesenteric vein thrombosis, screen for JAK2 mutations [6]. Patients with JAK2 mutation can clot even before developing the cytosis [6].
High Yield for exams: An unusual-site venous thrombosis (mesenteric, hepatic, portal, cerebral) in a young or middle-aged patient should trigger a JAK2 mutation screen, even if the CBC is normal.
Bleeding in PMF is paradoxical and multifactorial:
| Mechanism | Explanation |
|---|---|
| Thrombocytopenia (overt PMF) | Progressive marrow failure → reduced platelet production |
| Platelet dysfunction | Platelets produced by atypical megakaryocytes are functionally abnormal (defective aggregation, storage pool deficiency) |
| Acquired von Willebrand disease (AvWD) | Excess platelets (in pre-fibrotic/early phase) consume VWF → deficient platelet adhesion → mucocutaneous bleeding [6]. When the patient has extreme thrombocytosis with bleeding tendency → exclude AvWD [6] |
| DIC (rare, in transformation) | Blast crisis / AML transformation can trigger DIC |
This means that excess platelets can also result in excess bleeding — not just thrombocytopenia [6].
- AvWD typically occurs when platelet count > 1000 × 10⁹/L [19] — more common in pre-PMF or ET than overt PMF
- Diagnosed by checking VWF:Ag, VWF:RCo (ristocetin cofactor activity), and factor VIII levels
EMH is a defining feature of PMF. While the spleen and liver are the primary EMH sites, haematopoietic precursors can seed any tissue, leading to a variety of complications:
| Site of EMH | Complication | Clinical Presentation |
|---|---|---|
| Spleen | Massive splenomegaly | Early satiety, LUQ pain/fullness, splenic infarction (acute LUQ pain, fever), hypersplenism (worsening cytopenias from sequestration) |
| Liver | Hepatomegaly, portal hypertension | Ascites, variceal bleeding, hepatic encephalopathy (late) |
| Spine / Paravertebral | Cord compression [3] | Back pain, lower limb weakness, sensory level, sphincter dysfunction — a neurological emergency requiring urgent radiation ± dexamethasone |
| Pleura | Pleural effusion (haemothorax if EMH bleeds) | Dyspnoea |
| Peritoneum | Ascites (from peritoneal EMH or portal hypertension or both) | Abdominal distension |
| Skin | Cutaneous EMH | Papules, nodules (uncommon) |
| Lymph nodes | Lymphadenopathy | Usually mild |
| Lung parenchyma | Pulmonary hypertension | Dyspnoea, right heart failure |
EMH could go anywhere → could go to spine, cause cord compression [3].
Portal Hypertension in PMF
Portal hypertension deserves special attention because it is a major source of morbidity:
Why does PMF cause portal hypertension?
- Hepatic sinusoidal infiltration by EMH → increased intrahepatic resistance (sinusoidal portal hypertension)
- Massively increased splenic blood flow → increased portal venous inflow
- Portal/splenic vein thrombosis → post-hepatic contribution (MPN thrombophilia)
Consequences: Ascites, oesophageal/gastric variceal bleeding, hypersplenism worsening cytopenias, hepatorenal syndrome (late)
Patients present with fatigue, weight loss (hypercatabolic), massive splenomegaly, portal hypertension [3].
As fibrosis advances, the marrow's ability to produce blood cells progressively declines:
| Cytopenia | Clinical Consequence | Management |
|---|---|---|
| Anaemia | Fatigue, dyspnoea, angina, high-output cardiac failure (chronic severe anaemia) | Transfusion, EPO, luspatercept, danazol |
| Neutropenia | Recurrent/severe infections (bacterial > fungal) | Antibiotics; G-CSF in selected cases (use cautiously — may stimulate myeloproliferation) |
| Thrombocytopenia | Bleeding (mucocutaneous, GI, intracranial) | Platelet transfusion, pacritinib |
Many PMF patients become transfusion-dependent. Chronic transfusion brings its own complications:
Transfusion haemosiderosis [20]:
- 200 mg iron per unit of blood [20]; body can only excrete 1 mg iron per day [20]
- Iron accumulates in:
- Prevention: iron chelation therapy (deferasirox oral, deferoxamine SC/IV) when ferritin persistently > 1000 μg/L or after ~20 units transfused
- Regular monitoring of serum ferritin, cardiac MRI T2* (for cardiac iron loading), liver iron concentration
Other transfusion complications include:
- Alloimmunisation (formation of red cell antibodies → difficulty cross-matching)
- Transfusion reactions (febrile non-haemolytic, allergic, haemolytic)
- Infection risk (screened blood, but residual risk)
7. Complications of Treatment
| Side Effect | Mechanism | Clinical Significance |
|---|---|---|
| Worsening anaemia and thrombocytopenia [3] | On-target effect: JAK2 inhibition suppresses normal erythropoiesis (EPO-R) and thrombopoiesis (MPL/TPO-R) | May require dose reduction, transfusion support, or switch to pacritinib |
| Infections (herpes zoster, TB, opportunistic) | JAK1 inhibition suppresses innate and adaptive immunity | Screen for latent TB pre-treatment; monitor; prophylactic antivirals in some centres |
| Withdrawal syndrome | Abrupt cessation → cytokine rebound (release of sequestered inflammatory cytokines) → acute systemic inflammation | Fever, respiratory distress, DIC-like picture, haemodynamic collapse, rapid splenic re-enlargement. Always taper gradually |
| Weight gain | Unclear; possibly JAK-mediated metabolic effects | |
| Non-melanoma skin cancers | Immune surveillance impairment | Regular dermatological screening |
Side effects of hydroxyurea (ribonucleotide reductase inhibitor): myelosuppression, mucocutaneous ulcer, peripheral neuropathy, teratogenicity [2].
| Timing | Complication |
|---|---|
| Immediate | Bleeding (slipped ligature, haematemesis from gastric mucosal damage); Injury to surrounding structures (pleural effusion, left basal atelectasis, stomach, pancreatic injury → abscess/fistula) [21] |
| Early | Post-operative thrombocytosis (rebound) → prophylactic aspirin if platelet > 1000 [21]; Post-splenectomy septicaemia [21]; Compensatory hepatomegaly (hepatic EMH expansion) |
| Late | Overwhelming post-splenectomy infection (OPSI) — asplenic patients unable to mount immunological response against encapsulated organisms [21] |
Encapsulated organisms at risk (mnemonic: "Some Nasty Killers Have Some Capsule Protection") [21]:
- Streptococcus pneumoniae (most common cause of OPSI)
- Neisseria meningitidis
- Klebsiella pneumoniae
- Haemophilus influenzae
- Salmonella typhi
- Cryptococcus neoformans
- Pseudomonas aeruginosa
Prevention of OPSI [21]:
- Vaccination: PCV13 + PPSV23 (repeat every 5 years), Hib vaccine, Meningococcal ACWY vaccine, Influenza vaccine
- Penicillin V prophylaxis (lifelong in some guidelines, especially for children)
- 2–3× risk of infection, sepsis, and sepsis-related mortality after splenectomy [16]
- Splenectomy carries 6.3% 30-day operative mortality [16]
Complications of HSCT [18]:
| Category | Complications |
|---|---|
| Complications related to high-dose chemotherapy | Infection, haemorrhage, veno-occlusive disease of liver (VOD) → chemo toxicity on liver vessels [18] |
| Complications related to allogeneic HSCT | Graft-versus-host disease (GVHD), acute or chronic; Graft rejection (host-versus-graft) [18] |
| Late / long-term effects | Cataract (mainly due to total body irradiation), immunodeficiency, endocrine dysfunction and infertility, secondary malignancy [18] |
| Relapse of disease | Not always a silver bullet — in some diseases can be up to 30–40% [18] |
Early HSCT complications [22]: Cytopenia-related (anaemia, bleeding — 26% in first year, 9% life-threatening; neutropenic infections); Oral mucositis; Non-oral mucositis; VOD (painful hepatomegaly, ascites, jaundice); Graft rejection; Acute GVHD
Late HSCT complications [22]: Cardiovascular disease (5% at 5y, 9% at 15y — most common cause of non-relapse mortality); Endocrine dysfunction (T2DM, hypothyroidism, hypogonadism, infertility); Osteoporosis/AVN (from steroid use); Second malignancy (PTLD, MDS/AML, solid organ tumours); Cataract; Chronic GVHD
Gouty arthritis from ↑ uric acid due to increased cellular turnover [4].
- The high cell turnover in PMF (both production and destruction of haematopoietic cells) → increased purine catabolism → hyperuricaemia → urate crystal deposition in joints
- Clinical: acute monoarthritis (classically 1st MTP joint), tophi in chronic disease
- Prevention: allopurinol (gout prophylaxis) [2]
- Also risk of urate nephropathy (acute or chronic kidney injury from urate crystal deposition in renal tubules)
- Cytokines released by abnormal megakaryocytes (PDGF, OPG, TGF-β) stimulate osteoblast activity → new bone formation
- Results in diffuse osteosclerosis, particularly in the axial skeleton
- Clinical: bone pain, pathological fractures (uncommon), characteristic "ground-glass" or dense appearance on X-ray/CT
- Not the same as osteolytic lesions seen in multiple myeloma — PMF causes osteosclerosis (too much bone), myeloma causes osteolysis (too little bone)
- Mechanism: multifactorial — EMH in pulmonary vasculature, chronic thromboembolic disease, high cardiac output from chronic anaemia, cytokine-mediated vascular remodelling
- Prevalence: reported in up to 30% of PMF patients on echocardiographic screening
- Clinical: progressive dyspnoea, right heart failure
- Poor prognostic sign
| Complication | Mechanism | Key Detail |
|---|---|---|
| AML transformation | Clonal evolution, additional mutations | Highest among Ph-negative MPNs (6–18%); poor prognosis |
| Thrombosis | Hyperviscosity, JAK2-mediated endothelial activation | Unusual sites (mesenteric, hepatic, portal vein); screen JAK2 |
| Haemorrhage | Thrombocytopenia, platelet dysfunction, AvWD | Paradoxical — excess platelets can also bleed (AvWD) |
| Massive splenomegaly | EMH + sequestration | Early satiety, splenic infarction, hypersplenism |
| Portal hypertension | Hepatic EMH, ↑ splenic flow, portal vein thrombosis | Ascites, variceal bleeding |
| Cord compression | Spinal EMH | Neurological emergency — radiation + steroids |
| Transfusion haemosiderosis | Chronic RBC transfusion, 200 mg Fe/unit | Liver fibrosis/HCC, DM, heart failure |
| Infections | Neutropenia, immunosuppression from treatment | Bacterial > fungal |
| Gout | Hyperuricaemia from cell turnover | Prevent with allopurinol |
| Osteosclerosis | Cytokine-driven osteoblast activation | Bone pain; dense bone on imaging |
| Pulmonary hypertension | Pulmonary EMH, chronic thromboembolic, anaemia | Progressive dyspnoea, RHF |
| Treatment-related | JAK inhibitor (cytopenias, infections, withdrawal); Hydroxyurea (ulcers, neuropathy); Splenectomy (OPSI); HSCT (GVHD, VOD, relapse, 2° malignancy) | See detailed subsections above |
High Yield Summary — Complications of PMF
-
AML transformation: PMF has the highest blast transformation rate (6–18%) among Ph-negative MPNs. Secondary AML from PMF has a dismal prognosis — resistant to standard chemotherapy.
-
Thrombohaemorrhagic complications: JAK2-positive MPN causes thrombosis in unusual sites (mesenteric, portal, hepatic veins — Budd-Chiari). Paradoxically, extreme thrombocytosis can cause acquired vWD → bleeding.
-
Portal hypertension: From hepatic EMH infiltration + increased splenic blood flow + portal vein thrombosis. Leads to ascites, variceal bleeding.
-
Cord compression: EMH can occur at any site, including spine → neurological emergency.
-
Transfusion haemosiderosis: 200 mg iron per unit of blood, only 1 mg/day excreted → iron overload in liver (fibrosis, HCC), heart (failure), endocrine organs (DM, hypogonadism).
-
Post-splenectomy OPSI: Encapsulated organisms (Pneumococcus, Meningococcus, Hib). Vaccinate pre-splenectomy + prophylactic penicillin. Mnemonic: "Some Nasty Killers Have Some Capsule Protection."
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HSCT complications: GVHD (acute/chronic), VOD, graft rejection, infections, secondary malignancy, endocrine dysfunction, infertility, cataract. HSCT is not always a silver bullet — relapse can be 30–40%.
Active Recall - Complications of PMF
References
[2] Senior notes: Maksim Medicine Notes.pdf (pp. 170–171) [3] Senior notes: Block A - Splenomegaly: common causes of splenomegaly; myeloproliferative diseases.pdf (pp. 28–32) [4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p. 1457) [5] Senior notes: Ryan Ho Haemtology.pdf (pp. 75, 77–78) [6] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p. 18) [8] Lecture slides: GC 086. Splenomegaly.pdf (pp. 32, 38) [16] Senior notes: Ryan Ho Fundamentals.pdf (pp. 397–398) [18] Senior notes: Block A - High white cell count: acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p. 34) [19] Senior notes: Block A - Splenomegaly: common causes of splenomegaly; myeloproliferative diseases.pdf (p. 29); MBBS Final MB (Medicine) (Felix PY Lai).pdf (p. 1449) [20] Senior notes: Block A - Fever after a blood transfusion: transfusion and related problems.pdf (p. 27) [21] Senior notes: Maksim Surgery Notes.pdf (p. 153) [22] Senior notes: Ryan Ho Haemtology.pdf (p. 156)
High Yield Summary
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PMF is a chronic Ph-negative MPN characterised by bone marrow fibrosis (from reactive fibroblasts, NOT clonal fibroblasts), extramedullary haematopoiesis, and massive splenomegaly.
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The megakaryocytes are the culprit — they release PDGF and TGF-β → stimulate fibroblast proliferation → reticulin/collagen deposition → marrow fibrosis.
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Driver mutations: JAK2 V617F (60–65%), CALR (20–25%), MPL (7%). All converge on constitutive JAK-STAT activation. Triple-negative = worst prognosis.
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Two phases: Pre-fibrotic (↑ WBC and Plt, minimal fibrosis) → Overt fibrotic (pancytopenia + massive splenomegaly).
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Classic blood film: Leukoerythroblastic picture + tear-drop RBCs. BM aspirate = dry tap. Trephine biopsy is essential.
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Most common symptom: Severe fatigue. Most apparent sign: Massive splenomegaly.
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Least common MPN, worst prognosis (median survival 3–5 years). Highest rate of AML transformation (6–18%).
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Risk stratification: IPSS (at diagnosis), DIPSS/DIPSS-Plus (dynamic). Parameters: age > 65, constitutional symptoms, Hb < 10, WBC > 25, blasts ≥ 1%.
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Only curative treatment: Allogeneic HSCT (limited by age and comorbidities).
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MPN thrombosis: JAK2+ MPNs prone to unusual-site thrombosis (e.g., mesenteric vein). Screen for JAK2 in unusual-site clots.
High Yield Summary — DDx of PMF
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Before diagnosing PMF, you MUST exclude: CML (BCR-ABL1), PV (elevated RBC mass), ET (megakaryocyte-predominant without fibrosis/atypia), and MDS (dysplastic features).
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Massive splenomegaly DDx (exam favourite): CML, PMF, Gaucher disease, Kala-azar, Malaria, Thalassaemia major.
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Pancytopenia DDx: Aplastic anaemia (hypocellular marrow, NO splenomegaly) vs PMF (fibrotic marrow, MASSIVE splenomegaly) — feel for the spleen!
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Leukoerythroblastic picture = marrow infiltration until proven otherwise. Causes: PMF, metastatic cancer, leukaemia/lymphoma, severe sepsis/haemolysis.
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Pre-PMF vs ET: Both can present with thrombocytosis. Pre-PMF has megakaryocyte atypia, higher LDH, higher risk of progression. BM biopsy is the only way to distinguish.
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Dry tap on BM aspirate: Think PMF, hairy cell leukaemia, metastatic cancer. Always proceed to trephine biopsy.
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Acute myelofibrosis (rare AML variant): rapid onset, pancytopenia, NO splenomegaly — unlike chronic PMF.
High Yield Summary — Diagnosis of PMF
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WHO 2016 criteria: ALL 3 major + ≥ 1 minor for both pre-PMF and overt PMF. The key difference is fibrosis grade (≤ 1 for pre-PMF; ≥ 2 for overt PMF).
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Major criteria: (1) Megakaryocyte atypia ± fibrosis, (2) Exclusion of CML/PV/ET/MDS, (3) Clonal marker or no reactive cause.
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Minor criteria: Anaemia, WBC ≥ 11, splenomegaly, ↑LDH, ± leukoerythroblastosis (overt PMF only). Must be confirmed on 2 consecutive measurements.
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PBS hallmarks: Leukoerythroblastic picture + tear-drop RBCs — indicates marrow infiltration.
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BM aspirate = dry tap (classic). Trephine biopsy is mandatory — shows megakaryocyte atypia + fibrosis. Reticulin = silver stain; Collagen = trichrome stain.
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Molecular testing: JAK2 V617F (60–65%), CALR (20–25%), MPL (7%). BCR-ABL1 must be negative. Can be done on peripheral blood.
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Exclusion of CML is the first molecular step — if BCR-ABL1 positive, it is CML by definition.
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Risk stratification: IPSS at diagnosis, DIPSS/DIPSS-Plus dynamically. 5 parameters: age > 65, constitutional symptoms, Hb < 10, WBC > 25, blasts ≥ 1%.
High Yield Summary — Management of PMF
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Only curative treatment: Allogeneic HSCT — reserved for Int-2/High risk patients who are fit and have a donor. Feasibility limited by age (median 67) and comorbidities.
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Management is predominantly palliative if not eligible for HSCT.
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JAK inhibitors (ruxolitinib first-line): reduce spleen size and constitutional symptoms; work regardless of JAK2 mutation status (all driver mutations converge on JAK-STAT). NOT curative. Worsen anaemia and thrombocytopenia (on-target effect).
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Pacritinib (selective JAK2 inhibitor, approved 2022): specifically for patients with Plt < 50 where ruxolitinib is too myelosuppressive.
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Supportive care: Transfusion ± iron chelation, EPO, folic acid, allopurinol (gout prophylaxis), luspatercept (TGF-β inhibitor for anaemia).
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Hydroxyurea: Cytoreductive agent for leukocytosis/thrombocytosis/splenomegaly; S/E include myelosuppression, mucocutaneous ulcers, peripheral neuropathy, teratogenicity.
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Splenectomy: For refractory symptomatic splenomegaly; high perioperative mortality (6.3%); requires pre-splenectomy vaccination (Pneumococcus, Meningococcus, Hib). Does NOT impair haematopoiesis because EMH in spleen is ineffective.
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Risk stratification guides management: IPSS at diagnosis; DIPSS/DIPSS-Plus dynamically; MIPSS70 for transplant decisions.
High Yield Summary — Complications of PMF
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AML transformation: PMF has the highest blast transformation rate (6–18%) among Ph-negative MPNs. Secondary AML from PMF has a dismal prognosis — resistant to standard chemotherapy.
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Thrombohaemorrhagic complications: JAK2-positive MPN causes thrombosis in unusual sites (mesenteric, portal, hepatic veins — Budd-Chiari). Paradoxically, extreme thrombocytosis can cause acquired vWD → bleeding.
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Portal hypertension: From hepatic EMH infiltration + increased splenic blood flow + portal vein thrombosis. Leads to ascites, variceal bleeding.
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Cord compression: EMH can occur at any site, including spine → neurological emergency.
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Transfusion haemosiderosis: 200 mg iron per unit of blood, only 1 mg/day excreted → iron overload in liver (fibrosis, HCC), heart (failure), endocrine organs (DM, hypogonadism).
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Post-splenectomy OPSI: Encapsulated organisms (Pneumococcus, Meningococcus, Hib). Vaccinate pre-splenectomy + prophylactic penicillin. Mnemonic: "Some Nasty Killers Have Some Capsule Protection."
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HSCT complications: GVHD (acute/chronic), VOD, graft rejection, infections, secondary malignancy, endocrine dysfunction, infertility, cataract. HSCT is not always a silver bullet — relapse can be 30–40%.
Polycythemia Vera
Polycythemia vera is a chronic myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells, predominantly erythrocytes, typically driven by a JAK2 mutation, leading to increased red blood cell mass and hyperviscosity.
Essential Thrombocythaemia
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.