— 1. MYELODYSPLASTIC SYNDROME (MDS) Definition: Clonal disorder of haemopoietic stem cells characterized by ineffective haematopoiesis → pancytopenia despi
--- 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