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

These are lecture-era categories, not automatic indications. Image-guided splenic biopsy can sometimes avoid diagnostic splenectomy. In ITP and AIHA, modern medical options and patient preference influence timing. In transfusion-dependent thalassaemia, splenectomy is now uncommon and reserved for carefully selected hypersplenism/high-transfusion-burden cases because lifelong infection and thrombosis risks may outweigh the reduction in transfusion need. ^[12]

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

These percentages are the lecture's historical estimates and vary by underlying disease, age, vaccination, prophylaxis and follow-up. The safe learning point is lifelong susceptibility with especially high risk early after splenectomy—not a universal 5% prediction for an individual.

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

The principle remains correct, but product schedules change. Current adult planning accounts for prior doses and includes age/risk-appropriate pneumococcal vaccination, both MenACWY and MenB schedules, Hib if indicated, and annual influenza vaccination. Give indicated pneumococcal, meningococcal and Hib vaccines at least 14 days before elective splenectomy when possible; after emergency surgery, vaccinate when clinically stable according to local protocol rather than delaying protection indefinitely. ^[9][10]

Fever in an asplenic or hyposplenic patient is a time-critical sepsis risk: the patient should use their agreed rescue-antibiotic plan if one has been supplied and seek urgent assessment for cultures and parenteral empirical antibiotics. Vaccination does not remove the risk. Daily antibiotic prophylaxis is individualised by age, time since splenectomy, immune status and local policy. ^[22]

Other post-splenectomy changes: ^[1]

• Leucocytosis (a real postoperative count rise, which must still be interpreted against the clinical possibility of infection)
• Increase in platelet counts (spleen normally stores 20–40% of platelets)

Reactive thrombocytosis alone is not an automatic indication for aspirin. Assess the trajectory, thrombotic and bleeding risks, cause of splenectomy and possible acquired von Willebrand syndrome; treat the patient rather than a single platelet threshold.

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.

The coloured-star figure is not a simple linear staircase. A founding driver mutation arises in a haematopoietic stem cell, then subclones can branch, coexist and acquire additional mutations in different orders. A blast-phase clone may therefore emerge from the dominant chronic-phase clone, from an earlier shared ancestor, or from a minor branch. Mutation order and clonal architecture help explain why patients with the same headline driver (JAK2, CALR or MPL) can have different phenotypes and progression risks. ^[1]

MPN Classification: ^[1]

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

Reading the receptor diagram: without EPO, receptor-associated JAK2 is quiet. EPO brings receptor subunits together, allowing JAK2 phosphorylation and downstream STAT, PI3K and RAS–MAPK signalling. JAK2 V617F releases normal autoinhibition, producing cytokine-independent or hypersensitive signalling, nuclear transcription and clonal myeloid expansion.

• PV: mutant JAK2 drives EPO-receptor-pathway signalling → erythroid expansion
• ET: JAK2, CALR or MPL drivers converge on MPL/JAK–STAT signalling → megakaryocyte/platelet expansion
• PMF: the same driver pathways plus additional clonal events produce atypical megakaryocytes → cytokine release → reactive fibroblast activation and 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]

The haemoglobin/haematocrit thresholds are entry criteria for evaluation, not a diagnosis by themselves. Current classification integrates persistent erythrocytosis, characteristic panmyelosis on marrow, a JAK2 V617F or exon 12 mutation, and subnormal serum EPO; secondary and relative erythrocytosis must be excluded. ^[11]

• JAK2 V617F is found in most PV; exon 12 mutations account for most JAK2 V617F-negative cases
• 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

The algorithm's platelet > 450 × 10⁹/L footnote should not be memorised as a stand-alone trigger: that value is common in PV and far below “extreme thrombocytosis.” For otherwise low-risk PV, ELN considers persistent/progressive leukocytosis, extreme thrombocytosis > 1500 × 10⁹/L, symptomatic progressive splenomegaly, inadequate haematocrit control or phlebotomy intolerance, persistently high cardiovascular risk, or high symptom burden as reasons to consider cytoreduction. ^[13]

When cytoreduction is required, treatment selection considers age, sex, fertility/conception, and comorbidities. Options include recombinant interferon-α or hydroxyurea ± anagrelide; ruxolitinib may be considered for resistance or intolerance. ^[1]

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 in suitable patients, but check contraindications and bleeding/acquired-vWD risk rather than treating it as universal.

• 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)

The slide gives the older two-tier framework. A more useful current scheme incorporates thrombosis history, age and JAK2 status: very low (≤60, no thrombosis, JAK2-wild type), low (≤60, no thrombosis, JAK2-mutated), intermediate (> 60, no thrombosis, JAK2-wild type) and high (prior thrombosis or age > 60 with JAK2 mutation). Cytoreduction is advised for high-risk disease and considered individually in intermediate risk. ^[14]

Before aspirin in ET, assess bleeding and acquired von Willebrand syndrome, particularly with very high platelet counts. Aspirin is not automatic in a very-low-risk asymptomatic patient and can worsen bleeding when acquired vWD is present. ^[14][15]

Cytoreductive choices include recombinant interferon-α or hydroxyurea ± anagrelide. Treatment selection considers age, sex, fertility/conception, and comorbidities; resistance or intolerance should prompt a treatment switch or consideration of a clinical trial. ^[1]

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

• Platelet ≥ 1000 (in general)
• Vasomotor symptoms

Again, 1000 × 10⁹/L is a prompt to assess, not an isolated universal treatment threshold. Consider symptoms, acquired vWD/bleeding, progressive extreme thrombocytosis, pregnancy plans and the patient's total thrombotic risk.

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 boxed statement is too absolute. The enlarged spleen is a major site of pathological extramedullary haematopoiesis and sequestration. Splenectomy can improve pressure symptoms and selected cytopenias, but it can also cause bleeding, infection, thrombosis and accelerated hepatic extramedullary haematopoiesis; published series report substantial peri-operative morbidity and mortality. It is therefore a specialist, last-line option for carefully selected drug-refractory patients, not a harmless removal of a non-functional organ. ^[16]

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]

The image is a compressed study table. In the 2022 ICC framework, diagnosis requires all three major criteria plus at least one minor criterion, with the minor abnormality confirmed on two consecutive determinations. “Another clonal marker” can support a triple-negative case, and reactive fibrosis must be excluded. ^[11]

Risk assessment helps estimate prognosis and identify patients who may benefit from transplantation. DIPSS adverse features are:

• Age > 65 years
• WCC > 25 × 10⁹/L
• Hb < 10 g/dL
• Peripheral blood blasts ≥1%
• Constitutional symptoms ^[1]

DIPSS-plus adds unfavourable karyotype, platelet count < 100 × 10⁹/L, and transfusion dependency. Molecularly informed systems include GIPSS and MIPSS70+, which incorporate karyotype, CALR status, and high-molecular-risk mutations. ^[1]

The lecture quotes leukaemic transformation around 15% and median survival 3–5 years. ^[1] Allogeneic stem cell transplantation is the only potentially curative procedure — feasibility limited by age and comorbidities ^[1]

Those fixed prognosis figures are historical population summaries. The survival plots on the next slide show why they cannot be applied to an individual: primary versus secondary MF and DIPSS/DIPSS-plus/GIPSS/MIPSS70+ strata have widely separated curves. Current counselling should use the applicable clinical, cytogenetic and molecular risk model. ^[17]

Treatment shown in the lecture: ^[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

Luspatercept is an activin-receptor ligand trap, but its licensed uses are anaemia in beta-thalassaemia and selected MDS settings—not routine approved MF therapy—so the mechanistic slide should be read as an emerging/off-label or trial strategy. Conversely, momelotinib, shown as “in development” in the 2023 deck, was FDA-approved in September 2023 for intermediate/high-risk primary or secondary MF in adults with anaemia. ^[18][19]

In intermediate-2/high-risk MF, assess eligibility for allogeneic HSCT; eligible patients may receive a JAK inhibitor before transplantation. Patients who are not eligible are managed with symptom-directed therapy, a JAK inhibitor, or a clinical trial. ^[1]

For symptomatic MF, JAK-inhibitor choice is influenced by platelet count, anaemia, previous JAK-inhibitor exposure and local licensing. The deck lists ruxolitinib/fedratinib for platelets ≥50 × 10⁹/L and pacritinib for severe thrombocytopenia; momelotinib is now an option in MF with anaemia where approved. ^[18][20]

Ruxolitinib inhibits JAK1 and JAK2 and dampens dysregulated cytokine signalling. The COMFORT-II waterfall plot shows substantially more spleen-volume reductions than best available therapy, and the quality-of-life bars favour ruxolitinib. These establish spleen and symptom benefit; the later pooled survival plot is affected by crossover and is not proof that the drug eradicates the clone. ^[21]

Clinically it:

• 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)
• Usually does not eradicate the driver clone and is not curative
• Is not prescribed as a direct antifibrotic replacement for transplant

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

Reading the diagram: TGF-β-superfamily ligands activate an activin receptor and phosphorylate SMAD2/3, which complexes with SMAD4 and changes nuclear gene expression, restraining late erythroid maturation. Luspatercept is a soluble activin-receptor fusion protein that traps selected ligands upstream, reducing SMAD2/3 signalling. This explains the erythroid-maturation rationale, but does not by itself establish an approved MF indication. ^[19]

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

Interferon-alpha can reduce JAK2 V617F allele burden in some patients and is useful when long-term disease control, younger age or pregnancy potential favours it. Call this a molecular response, not guaranteed molecular remission; treatment choice and monitoring remain specialist decisions.