The spleen lies within the peritoneal cavity in the left upper quadrant (LUQ), adjacent to ribs 9, 10, 11. Size correlates with a person's height and weight. ^[1]

• Normal size: Approximately 1 × 3 × 5 inches; weight ~7 oz (~150–200 g). Cranio-caudal length on ultrasound: upper limit of normal = 12 cm in HK Chinese (a local study recommendation cited in the lecture). ^[1]
• Why ribs 9–11 matter: the spleen is protected posterolaterally by the lower left rib cage. This is why you "can't get above it" on palpation — the superior pole hides behind the ribs.

Red pulp: microcirculatory structure of venous sinuses and splenic cords ("Cords of Billroth") ^[1]

White pulp: peri-arteriolar lymphoid sheath (PALS) contains mainly T-cells (CD4), and the primary follicles contain B-cells ^[1]

Why this matters for understanding splenomegaly mechanisms:

• Red pulp = the blood-filtering zone. When the spleen has to destroy more abnormal RBCs (e.g. in haemolytic anaemia), the red pulp expands → spleen enlarges.
• White pulp = the immune zone. When the immune system is activated (infections, autoimmune disease), B-cells proliferate in follicles and T-cells expand in PALS → spleen enlarges.
• The marginal zone between red and white pulp is where blood-borne antigens first encounter immune cells — critical for defence against encapsulated bacteria.

Mechanism 1 — Increased splenic function: ^[1]

Why this makes the spleen enlarge: The spleen is doing "overtime." More abnormal RBCs to filter → red pulp work overload → red pulp hypertrophy. More antigens to fight → white pulp B/T cell expansion.

Mechanism 2 — Vascular congestion: Blockage of blood flow and pooling of blood in red pulp ^[1]

Why this causes splenomegaly: The spleen drains via the splenic vein → portal vein → liver → hepatic veins → IVC. Any obstruction along this pathway causes back-pressure, venous engorgement, and blood pooling in the red pulp sinusoids. Think of it like a traffic jam — if the highway is blocked, cars pile up at the on-ramp (the spleen).

Mechanism 3 — Infiltration: ^[1]

Why this causes splenomegaly: Abnormal cells or storage material physically occupy space within the splenic parenchyma, expanding it from within. In myelofibrosis specifically, the fibrotic marrow pushes haematopoietic stem cells to the spleen (extramedullary haematopoiesis), which then massively enlarges.

• Abdominal fullness
• Early satiety (spleen pushes against stomach)
• Symptoms related to pancytopenia (from hypersplenism: anaemia → fatigue/pallor, leucopenia → infections, thrombocytopenia → bleeding)

Abnormal blood counts: anaemia, thrombocytopenia, leucopenia ^[1] Abnormal liver function tests: cirrhosis ^[1]

• M/60, heavy drinker, mother died of HBV-related HCC
• Jaundice, tea-colour urine, abdominal distension × 2 months
• Exam: dilated abdominal veins, splenomegaly 4cm, liver not palpable, shifting dullness
• Cause: Vascular congestion — cirrhosis → portal hypertension → congestive splenomegaly
• Clues: alcohol, HBV family history, stigmata of CLD (caput medusae, ascites, non-palpable shrunken liver)

• M/20, medical student, GPH
• Fever + cervical lymphadenopathy × 2 weeks
• Exam: hepatomegaly 2cm, splenomegaly 2cm
• Monospot +, EBV VCA IgM +
• Cause: Increased white pulp function — immune response to EBV
• Key point from supporting notes: splenomegaly in EBV occurs in 50–60% of patients. Risk of splenic rupture (0.1–2%) → avoid contact sports ^[3]

• F/30, travelled to Philippines, no prophylaxis
• Fever, dark colour urine
• Exam: pallor, jaundice, splenomegaly 3cm
• Blood film: Plasmodium falciparum
• Cause: Increased red and white pulp function — destruction of parasitized RBCs (haemolysis) + immune activation
• The dark urine = haemoglobinuria from intravascular haemolysis ("blackwater fever")

• F/60, GPH
• Weight loss, loss of appetite, no fever
• Exam: pallor, massive splenomegaly up to umbilicus
• CBP: pancytopenia, leukoerythroblastic blood picture, tear-drop cells
• Cause: Infiltration — marrow fibrosis drives extramedullary haematopoiesis in spleen
• Key blood film features: leukoerythroblastic picture = nucleated RBCs + immature granulocytes in peripheral blood (displaced from marrow). Tear-drop cells (dacrocytes) = RBCs squeezed through fibrotic marrow.

Indications for splenectomy: ^[1]

1. Diagnostic: Suspected splenic lymphoma
2. Therapeutic:
   • Symptomatic relief in massive splenomegaly e.g. myelofibrosis (less common now)
   • Refractory ITP or AIHA (less common now)
   • Decrease transfusion requirement in thalassaemia major

Risk of INFECTION — life-threatening infection from encapsulated bacteria ^[1]

Pre-operative vaccination: ^[1]

1. Pneumococcus
2. H. influenzae
3. Meningococcus

Post-operative: Antibiotic prophylaxis, Patient education — immediate referral to hospital for treatment of febrile episodes

OPSI is a rare but life-threatening complication in post-splenectomy patients ^[1]

• > 50% of infections are due to Streptococcus pneumoniae
• Lifetime risk of OPSI is estimated to be 5%, but most (50%) occur within the first two years of splenectomy
• Prevention of OPSI includes vaccination and early empirical antibiotics for febrile episodes

Vaccinations are recommended against S. pneumoniae, N. meningitidis, H. influenzae type b and influenza virus ^[1]

• For elective splenectomy: first vaccine at least 2 weeks before surgery
• For emergency splenectomy: vaccines can be administered 2 weeks after surgery

Other post-splenectomy changes: ^[1]

• Spurious leucocytosis (WBC marginating pool released)
• Increase in platelet counts (spleen normally stores 20–40% of platelets)
• Prophylactic aspirin if platelets > 1000 post-splenectomy ^[4]

MPN are clonal haematopoietic stem cell disorders characterized by the overproduction of mature cells of myeloid lineages. ^[1]

All MPNs share the potential to PROGRESS to: ^[1]

1. Myelofibrosis (post-PV MF, post-ET MF)
2. Blastic transformation (acute leukaemia)

Key concept: Unlike acute leukaemias (where the problem is immature blasts), MPNs produce mature or near-mature cells in excess. The cells are functional but there are too many of them, causing hyperviscosity, thrombosis, and organ infiltration.

MPN Classification: ^[1]

JAK2 mutation leads to a constitutively active tyrosine kinase → translocates to nucleus → activates transcription of target genes ^[1]

From first principles: JAK2 is a Janus kinase that normally sits on cytokine receptors (EPO receptor, TPO receptor, G-CSF receptor). When a cytokine binds, JAK2 phosphorylates itself and downstream STAT proteins, which enter the nucleus and turn on genes for cell proliferation and survival. A JAK2 V617F mutation means the kinase is always on — no cytokine signal needed. The result: uncontrolled proliferation of the myeloid lineage.

• PV: JAK2 mutation on EPO receptor → erythrocytosis
• ET: JAK2/CALR/MPL mutation on TPO receptor → thrombocytosis
• PMF: JAK2/CALR/MPL mutation → megakaryocyte proliferation → cytokine release → fibroblast activation → fibrosis

Must exclude secondary causes: ^[1]

1. Absolute polycythaemia (increased red cell mass)
   • a) Primary: Polycythaemia vera
   • b) Secondary (EPO mediated):
     • i. Hypoxia: COPD, cyanotic heart disease
     • ii. Abnormal EPO secretion: hepatoma
2. Apparent polycythaemia (normal red cell mass)
   • Normal red cell mass / low plasma volume → elevated HCT

Why this matters: An elevated haematocrit doesn't automatically mean PV. You must exclude dehydration (apparent polycythaemia — the red cell mass is normal but concentrated due to low plasma volume) and secondary causes (the body is appropriately making more EPO because of hypoxia, or a tumour is secreting EPO ectopically).

Hb > 16.5 g/dL / Hct > 49% (males); Hb > 16 g/dL / Hct > 48% (females) ^[1]

Diagnosis requires BM biopsy + JAK2 mutation testing:

• JAK2 V617F found in > 95% of PV cases (the most sensitive molecular marker of any MPN)
• JAK2 exon 12 mutations account for most of the remaining ~3–4%
• Low serum EPO level is a minor criterion — if the marrow is autonomously producing RBCs, EPO is suppressed by negative feedback

Clinical features of PV: ^[1]

• Hyperviscosity symptoms: dizziness, headaches
• Pruritus particularly after a hot bath (aquagenic pruritus — due to mast cell degranulation from basophilia/histamine release)
• Risk of arterial and venous thrombosis
• Microvascular symptoms (erythromelalgia — burning pain/redness of hands/feet)

Why thrombosis? The blood is thicker (more RBCs → higher viscosity), platelets are often elevated and dysfunctional, and there's endothelial activation. The combination creates a pro-thrombotic state. PV patients can present with stroke (as in past paper Q4, 2018), DVT/PE, portal vein thrombosis, or Budd-Chiari syndrome.

Treatment: Venesection, Cytoreductive (hydroxyurea, Interferon), Aspirin ^[1]

Treatment algorithm based on risk: ^[1]

• High risk = Age ≥ 60 years OR history of vascular events

Transformation to myelofibrosis (10%), acute leukaemia (5%) ^[1]

Venesection rationale: Removing blood physically reduces haematocrit and viscosity. Target Hct < 45% has been shown to reduce thrombotic events.

Aspirin rationale: Low-dose aspirin reduces microvascular symptoms and thrombotic risk without significantly increasing bleeding.

• Usually asymptomatic
• Microvascular symptoms: headache, dizziness, erythromelalgia
• Thrombosis: Arterial > Venous
• Paradoxical bleeding in very high platelet count (acquired von Willebrand disease) — when platelets are extremely high (> 1000–1500 × 10⁹/L), they adsorb and deplete VWF multimers
• Risk of transformation to myelofibrosis and AML (< 5%)

Diagnosis by exclusion: ^[1]

• Exclude reactive causes: infections, inflammations, malignancy, iron deficiency
• Bone marrow to exclude CML and other MPN/MDS
• JAK2 V617F mutation in ~50%, CALR, MPL
• Platelet persistently > 450 × 10⁹/L

Why diagnosis by exclusion? Reactive thrombocytosis (from infection, iron deficiency, inflammation, post-splenectomy) is far more common than ET. You must exclude all reactive causes before diagnosing a clonal disorder. Iron deficiency is particularly tricky — it causes both anaemia and reactive thrombocytosis, and treating the iron deficiency may normalize the platelets.

Management is based on thrombosis risk: ^[1]

• High risk: Age > 60 years OR history of thromboembolic disease → hydroxyurea + aspirin
• Interferon for pregnancy
• Cardiovascular risk modification (HT, smoking, CHF, WBC)

Indications for cytoreduction in very low/low/intermediate-risk ET: ^[1]

• Platelet ≥ 1000 (in general)
• Vasomotor symptoms

PMF fibroblasts are NOT clonal ^[1] Abnormal megakaryocytes release cytokines (PDGF and TGF-β) which stimulate fibroblast proliferation and collagen deposition ^[1] Fibrotic BM unable to function → HSC move to spleen and liver (extramedullary haematopoiesis) ^[1]

From first principles: The clonal abnormality is in the haematopoietic stem cell (JAK2/CALR/MPL mutations), NOT in the fibroblasts. The abnormal megakaryocytes produce excessive cytokines → reactive fibroblast proliferation → marrow fibrosis. This is a critical distinction — the fibrosis is a reactive process driven by the abnormal clone, not a primary fibroblast neoplasm.

When the marrow fills with collagen and reticulin, it can no longer produce blood cells effectively. The body compensates by reverting to fetal haematopoiesis — the spleen and liver take over blood production (extramedullary haematopoiesis). This causes massive splenomegaly.

No significant or functional haematopoiesis occurs even in this situation, and removal of the spleen will not impair the blood production capability. ^[1]

This is a crucial clinical point: Even though the spleen is performing extramedullary haematopoiesis, it's ineffective. So splenectomy for symptomatic relief doesn't significantly worsen cytopenias.

Patients present with fatigue, weight loss (hypercatabolic), massive splenomegaly, portal hypertension ^[1]

Pancytopenia with leukoerythroblastic blood picture ^[1] Bone marrow dry tap, trephine showing dense reticulin ^[1] JAK2 mutation 50%, other mutations ^[1]

Leukoerythroblastic blood picture = nucleated RBCs + immature myeloid cells (myelocytes, metamyelocytes) in the peripheral blood. This happens because the marrow fibrosis physically displaces haematopoietic precursors into the circulation before they mature. Tear-drop cells (dacrocytes) = RBCs squeezed and distorted as they pass through the fibrotic marrow or the splenic sinusoids. ^[5]

Dry tap = inability to aspirate liquid marrow because it's replaced by fibrosis. The trephine biopsy (a core of tissue) is essential — it shows reticulin and collagen fibrosis.

The lecture presents WHO/ICC 2022 criteria for Pre-PMF and Overt PMF: ^[1]

Leukaemic transformation in 15% ^[1] Median survival 3–5 years ^[1] Allogeneic stem cell transplantation is the only potentially curative procedure — feasibility limited by age and comorbidities ^[1]

Treatment: ^[1]

• Supportive for cytopenia: Transfusion (± iron chelation), EPO
• TGF-β inhibitor e.g. luspatercept
• Ruxolitinib (JAK1/2 kinase inhibitor) — decreases size of spleen and constitutional symptoms
• Splenectomy sometimes performed to relieve pressure symptoms and decrease transfusion requirement

Ruxolitinib inhibits JAK1 and JAK2, blocking the constitutively activated signalling pathway. This:

• Reduces spleen size (by decreasing the cytokine-driven splenic infiltration)
• Improves constitutional symptoms (by reducing the inflammatory cytokine storm that causes weight loss, night sweats, fatigue)
• Does NOT significantly reduce the allele burden or cure the disease
• Does NOT directly reduce marrow fibrosis

Luspatercept is a specific activin receptor fusion protein that acts as a ligand trap to neutralize negative regulators of late-stage erythropoiesis ^[1]

From first principles: In myelofibrosis (and MDS), the SMAD2/3 signalling pathway (part of the TGF-β superfamily) is constitutively activated, which blocks terminal red cell maturation → anaemia. Luspatercept traps the ligands (activins, GDF11/GDF15) that activate SMAD2/3, releasing the brake on erythropoiesis → improved Hb → reduced transfusion burden.

IFN has anti-angiogenic, anti-proliferative, pro-apoptotic, and immunomodulatory effects ^[1]

Specific mechanisms in MPNs: ^[1]

1. Suppression of megakaryopoiesis — inhibits CFU-Mk, inhibits TPO signalling
2. Inhibition of erythroid colony-forming cells — inhibits ECFCs, stimulates erythroblast apoptosis
3. Decrease in bone marrow fibroblasts — IFN-γ modulates cytokines via STAT pathway, reducing collagen production
4. Immunomodulatory — enhances T-cell, NK cell, monocyte activity against neoplastic clone

IFN-alpha can achieve molecular remissions (reduction in JAK2 V617F allele burden), unlike ruxolitinib. It is particularly used in younger patients and during pregnancy (hydroxyurea is teratogenic).

Q4: 45M, stroke with left hemiparesis. Hb 20.5, WCC 11.2, Plt 510. → Answer: Polycythaemia Vera (H)

• Discriminators: Markedly elevated Hb/Hct + thrombocytosis + thrombotic event (stroke) = PV. Not secondary polycythaemia because WCC and Plt are also elevated (pan-myeloid proliferation). ^[6]

Q6: 52F, incidental WCC 150 × 10⁹/L, predominance of myelocytes and neutrophils, Hb 10, Plt 510, splenomegaly 4cm. → Answer: CML (D)

• Discriminators: Massive leukocytosis with bimodal distribution (myelocytes + neutrophils), splenomegaly, thrombocytosis. Must confirm with BCR-ABL/Philadelphia chromosome. ^[6]

Q9: 52M, pallor, splenomegaly 10cm, occasional nucleated RBCs and myelocytes, tear-drop RBCs, no blasts, BM dry tap. → Answer: Primary Myelofibrosis (I)

• Discriminators: Massive splenomegaly + leukoerythroblastic picture + tear-drop cells + dry tap = classic PMF triad. ^[7]

Q52: 19M, fever, malaise, enlarged tonsils, generalised lymphadenopathy, mild splenomegaly, atypical lymphocytes, red cell agglutination. → Answer: Infectious mononucleosis (D)

• Discriminators: Young + fever + pharyngitis + LAP + splenomegaly + atypical lymphocytes = EBV. Red cell agglutination = cold agglutinins (IgM anti-i, a known complication of EBV). Not ALL because no blasts; not Hodgkin because atypical lymphocytes are reactive T cells, not Reed-Sternberg cells. ^[8]