--- 1. MYELODYSPLASTIC SYNDROME (MDS) Definition: Clonal disorder of haemopoietic stem cells characterized by ineffective haematopoiesis → pancytopenia despite
--- 1. MYELODYSPLASTIC SYNDROME (MDS) Definition: Clonal disorder of haemopoietic stem cells characterized by ineffective haematopoiesis → pancytopenia despite a cellular (not hypoplastic) marrow + risk of transformation to AML. Pathogenesis: - Acquired mutations in stem cells → abnormal clonal proliferation - Cells proliferate but die in the marrow before reaching blood (ineffective haematopoiesis) - Common mutations: SF3B1, TET2, ASXL1, TP53, RUNX1 - Risk factors: age ( 60 years), prior chemotherapy/radiotherapy, benzene exposure Key distinguishing features from aplastic anaemia: - MDS → marrow is cellular (hypercellular or normocellular) - Aplastic anaemia → marrow is hypocellular (replaced by fat) - MDS → dysplastic (abnormal-looking) cells in marrow - MDS → clonal cytogenetic abnormalities (e.g. del 5q, del 7q, trisomy 8) - Both can present with pancytopenia Morphology: - Dysplastic red cell precursors → ringed sideroblasts (iron deposits around nucleus) - Hypersegmented or hyposegmented neutrophils (pseudo-Pelger-Huët) - Abnormal megakaryocytes - Blast cells may be increased ( 20% = AML) Classification (WHO): - MDS with single lineage dysplasia - MDS with ring sideroblasts - MDS with excess blasts (MDS-EB1: 5–9% blasts; EB2: 10–19% blasts) - MDS with del(5q) - Hypoplastic MDS → mimics aplastic anaemia Clinical features: - Anaemia → most common presentation (fatigue, pallor) - Infections → neutropenia - Bleeding → thrombocytopenia - Splenomegaly in some cases Prognosis: - Variable — IPSS-R score used (cytogenetics, blast %, cytopenias) - 30% transform to AML - Median survival ranges from months to years depending on subtype Treatment: - Low risk → supportive (transfusions, EPO, G-CSF) - del(5q) → lenalidomide (very effective) - Ring sideroblasts → luspatercept - High risk → azacitidine (hypomethylating agent) or SCT (only curative option) --- 2. MYELOFIBROSIS Definition: Clonal myeloproliferative neoplasm characterized by progressive fibrosis of the bone marrow → extramedullary haematopoiesis + pancytopenia. Pathogenesis: - Mutations in JAK2 V617F (~50%), CALR, or MPL → abnormal megakaryocyte proliferation - Megakaryocytes release TGF-β, PDGF, FGF → stimulate fibroblasts → marrow fibrosis - Fibrotic marrow cannot produce cells → blood cell production shifts to liver and spleen ( extramedullary haematopoiesis ) Morphology: - Bone marrow → fibrosis replacing normal haematopoietic tissue (reticulin/collagen) - Peripheral blood → leucoerythroblastic picture (nucleated red cells + immature white cells in blood) - Teardrop red cells (dacrocytes) → pathognomonic — red cells squeezed through fibrotic marrow - Dry tap on bone marrow aspiration → needle goes in but nothing comes out (marrow too fibrotic) Clinical features: - Massive splenomegaly → most prominent feature - Hepatomegaly - Anaemia, fatigue - Constitutional symptoms → fever, night sweats, weight loss - Pancytopenia in advanced disease Prognosis: - Median survival ~5 years - Can transform to AML Treatment: - JAK2 inhibitors → ruxolitinib (reduces spleen size, improves symptoms) - SCT → only curative option - Supportive → transfusions, splenectomy in selected cases --- 3. HAEMOPHAGOCYTIC SYNDROME (HLH) Definition: Life-threatening syndrome of excessive immune activation → macrophages engulf (phagocytose) blood cells → pancytopenia + hyperinflammation. Pathogenesis: - Normal: cytotoxic T cells and NK cells kill infected/abnormal cells then shut off - In HLH: this shutdown fails → uncontrolled activation → macrophages activated by cytokines (IFN-γ, TNF-α, IL-6) → phagocytose red cells, white cells, platelets in marrow, liver, spleen - Primary HLH → inherited mutations in perforin (PRF1), UNC13D, STX11 → cytotoxic cells can't kill target cells → can't shut off immune response - Secondary HLH → triggered by infection (EBV most common), malignancy (lymphoma), autoimmune disease (SLE) — called MAS (macrophage activation syndrome) in autoimmune context Diagnostic criteria (HLH-2004) — 5 of 8: - Fever - Splenomegaly - Pancytopenia (≥2 cell lines) - Hypertriglyceridaemia and/or hypofibrinogenaemia - Haemophagocytosis on bone marrow/spleen/lymph node biopsy - Low/absent NK cell activity - Elevated ferritin (often 500; 10,000 strongly suggestive) - Elevated soluble CD25 (IL-2 receptor) Key feature: Very high ferritin → hallmark; ferritin 10,000 μg/L is highly specific Treatment: - HLH-94/2004 protocol → dexamethasone + etoposide ± ciclosporin - Treat underlying trigger (antivirals for EBV, chemotherapy for lymphoma) - SCT → for primary HLH and refractory cases --- 4. MEGALOBLASTIC ANAEMIA CAUSING PANCYTOPENIA Definition: Deficiency of B12 or folate → impaired DNA synthesis → ineffective haematopoiesis → pancytopenia (all three cell lines affected in severe cases). Pathogenesis: - B12/folate essential for thymidine synthesis → DNA replication - Deficiency → cells can make RNA and protein but can't replicate DNA properly - Cells grow large but can't divide → megaloblasts in marrow - Most die in marrow before reaching blood → ineffective haematopoiesis → pancytopenia - Affects fastest-dividing cells most → marrow, GI epithelium Morphology: - Hypersegmented neutrophils ( 5 lobes) → earliest peripheral blood finding - Macro-ovalocytes → large oval red cells - Megaloblasts in bone marrow → large cells with immature nucleus (open chromatin) but mature cytoplasm → nuclear-cytoplasmic dissociation - Marrow is hypercellular — cells proliferating but dying → ineffective Key distinguishing feature from aplastic anaemia: - Megaloblastic anaemia → hypercellular marrow with megaloblasts - Aplastic anaemia → hypocellular marrow replaced by fat - Both → pancytopenia Causes: - B12 deficiency → pernicious anaemia (anti-intrinsic factor antibodies), gastrectomy, veganism, terminal ileal disease - Folate deficiency → poor diet, pregnancy, malabsorption, methotrexate, trimethoprim Treatment: - B12 → IM hydroxocobalamin - Folate → oral folic acid - Never give folate alone without B12 → can precipitate or worsen subacute combined degeneration of the spinal cord --- 5. HYPERSPLENISM Definition: Splenomegaly of any cause → excessive sequestration and destruction of blood cells in the spleen → pancytopenia despite a normal or hypercellular marrow . Pathogenesis: - Normal spleen removes old/abnormal blood cells - Enlarged spleen → removes normal cells excessively → all three cell lines reduced - Marrow responds by increasing production → marrow becomes hypercellular - Key point: destruction is peripheral , marrow is reactive and compensating Causes of splenomegaly leading to hypersplenism: - Portal hypertension → liver cirrhosis, portal vein thrombosis - Haematological → lymphoma, leukaemia, myelofibrosis, haemolytic anaemias - Infections → malaria, schistosomiasis, leishmaniasis (kala-azar) - Storage disorders → Gaucher disease Key distinguishing feature from aplastic anaemia: - Hypersplenism → hypercellular marrow + splenomegaly present - Aplastic anaemia → hypocellular marrow + spleen NOT enlarged Treatment: - Treat underlying cause - Splenectomy → in selected cases; risks post-splenectomy sepsis (encapsulated organisms — pneumococcus, meningococcus, Haemophilus) - Post-splenectomy → vaccinate + lifelong penicillin prophylaxis ---