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Haematopoietic stem cells (HSC, CD34 positive) self-renew and give myeloid progenitors (red cells, platelets, granulocytes, monocytes) and lymphoid progenitors (B, T and NK cells). Adult haematopoiesis is in the marrow of the axial skeleton; in fetal life in the liver and spleen. Regulation: stromal niche, erythropoietin (kidney; red cells), thrombopoietin (liver; platelets), G-CSF (neutrophils) and others. Marrow examination: aspirate and trephine biopsy.

Anaemia is haemoglobin below 13 g/dL in men and 12 g/dL in women. Classify by MCV: microcytic, normocytic, macrocytic; check reticulocytes (production versus destruction or loss). Iron deficiency: causes are blood loss (gastrointestinal, menstrual), increased demand (pregnancy, growth), poor intake and malabsorption (coeliac disease). Findings: low ferritin, low serum iron, high transferrin, microcytic hypochromic cells, koilonychia, angular stomatitis. In adults always look for a source of gastrointestinal blood loss. Treatment: oral iron, intravenous iron if not tolerated or absorbed.

Adult haemoglobin HbA has two alpha and two beta chains (alpha2 beta2). Alpha thalassaemia: deletion of alpha genes (four genes; one to four deleted: silent carrier to hydrops fetalis with Hb Bart; HbH disease with three deleted). Beta thalassaemia: reduced beta chain production: minor (trait; asymptomatic microcytosis, raised HbA2), intermedia and major (transfusion-dependent anaemia from infancy, hepatosplenomegaly, bone changes, iron overload needing chelation). Distinguish from iron deficiency by normal or high ferritin and a high red cell count with low MCV.

Features: anaemia, reticulocytosis, raised LDH and indirect bilirubin, low haptoglobin, jaundice, splenomegaly. - G6PD deficiency (X-linked): red cells cannot protect themselves from oxidant stress; haemolysis after infection, fava beans or drugs (primaquine, dapsone); Heinz bodies and bite cells. - Autoimmune haemolytic anaemia: warm (IgG; direct antiglobulin test positive; steroids) and cold (IgM; cold agglutinins). - Sickle cell disease: HbS (Glu6Val in beta globin) polymerises when deoxygenated; vaso-occlusive crises, chronic haemolysis, acute chest syndrome, splenic sequestration, stroke; treatment includes hydroxycarbamide, hydration, analgesia and transfusion. - Others: hereditary spherocytosis (membrane defect), microangiopathic haemolysis.

1. Which findings distinguish iron deficiency from thalassaemia trait? 2. What is the genetic defect in beta thalassaemia major? 3. Which tests support haemolysis? 4. What triggers haemolysis in G6PD deficiency?

1. Iron deficiency: low ferritin, high transferrin. Thalassaemia trait: normal or high ferritin, high red cell count, raised HbA2. 2. Severely reduced or absent beta globin chain synthesis. 3. Reticulocytosis, raised LDH and indirect bilirubin, low haptoglobin, direct antiglobulin test when autoimmune. 4. Oxidant stress: infections, fava beans and drugs such as primaquine and dapsone.

Presentation: anaemia, infections from neutropenia, bleeding from thrombocytopenia. Diagnosis: 20 percent or more blasts in blood or marrow, with immunophenotyping, cytogenetics and molecular tests (FLT3, NPM1, CEBPA, TP53). Treatment: intensive chemotherapy (cytarabine plus anthracycline) then consolidation or allogeneic stem cell transplantation in fit patients, with targeted agents (FLT3 inhibitors). Measurable residual disease (MRD) after therapy predicts relapse. Acute promyelocytic leukaemia (APL): t(15;17) PML-RARA; disseminated intravascular coagulation with severe bleeding is the emergency; treated with all-trans retinoic acid and arsenic trioxide, with very high cure rates.

Acute lymphoblastic leukaemia (B or T lineage): lymphoblasts; more frequent in children; may involve the central nervous system and testes; adverse features include Philadelphia chromosome positivity (treated with a tyrosine kinase inhibitor). Treatment: multiphase chemotherapy including CNS prophylaxis, blinatumomab or CAR-T in relapse. Myelodysplastic syndromes (MDS): clonal stem cell disorders with dysplasia, cytopenias and risk of transformation to AML. Related states: clonal haematopoiesis of indeterminate potential (CHIP: mutations without cytopenia) and clonal cytopenia of undetermined significance (CCUS). Treatment: supportive care, hypomethylating agents, transplantation for high-risk disease.

CML: t(9;22) (Philadelphia chromosome) produces BCR-ABL1, a constitutively active tyrosine kinase. Presentation: splenomegaly, marked leukocytosis with all stages of granulocyte maturation, basophilia. Phases: chronic, accelerated and blast crisis. Treatment: tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib for T315I mutation); monitoring by quantitative PCR for BCR-ABL.

CLL: clonal mature B cells (CD5, CD19, CD23 positive), smudge cells on the blood film, lymphocytosis above 5 x 10^9/L. SLL is the same disease with lymph node involvement without lymphocytosis; monoclonal B-cell lymphocytosis (MBL) has fewer than 5 x 10^9/L cells. Complications: hypogammaglobulinaemia and infections, autoimmune haemolytic anaemia and thrombocytopenia, Richter transformation. Many patients need no treatment for years (Binet or Rai staging); treatment indications: symptomatic marrow failure, bulky disease; drugs: BTK inhibitors (ibrutinib), venetoclax, anti-CD20 antibodies.

1. Which translocation defines APL and how is it treated? 2. Define CHIP. 3. What is the molecular abnormality in CML? 4. Which cells are seen on a CLL blood film? 5. Name the treatment of Philadelphia-positive ALL.

1. t(15;17) PML-RARA; ATRA plus arsenic trioxide. 2. Clonal haematopoiesis with somatic mutations in blood cells without cytopenia or dysplasia. 3. BCR-ABL1 fusion (Philadelphia chromosome). 4. Small mature lymphocytes and smudge cells. 5. Chemotherapy combined with a tyrosine kinase inhibitor.

Hodgkin lymphoma: Reed-Sternberg cells in an inflammatory background; young adults; contiguous spread; B symptoms (fever, night sweats, weight loss); highly curable with ABVD chemotherapy with or without radiotherapy or PD-1 antibodies. Non-Hodgkin lymphoma: aggressive types (diffuse large B-cell lymphoma, Burkitt) and indolent types (follicular lymphoma t(14;18), marginal zone, mantle cell). Diagnosis: excisional lymph node biopsy, imaging (PET-CT) for Ann Arbor staging. Treatment: R-CHOP (rituximab plus chemotherapy) for DLBCL; watchful waiting or rituximab for indolent disease.

Thrombocytopenia (platelets below 150 x 10^9/L): decreased production (marrow failure), increased destruction (ITP, DIC, TTP, drugs, hypersplenism) or dilution. ITP: isolated thrombocytopenia with a normal marrow and no other cause; mucocutaneous bleeding (petechiae, epistaxis). Treatment when needed (platelets below 30 or bleeding): corticosteroids, IVIG, thrombopoietin receptor agonists (eltrombopag, romiplostim), rituximab, splenectomy. Always exclude pseudothrombocytopenia (clumping) and check for TTP.

Patients with blood cancers often experience anxiety, depression and fatigue related to diagnosis, prolonged treatment, isolation during neutropenia and uncertainty about the future. Management: screening, communication and shared decision making, psychological support, treating anaemia and other causes of fatigue, physical activity and palliative care when appropriate.

1. Which cell characterises Hodgkin lymphoma? 2. What is the standard chemotherapy for DLBCL? 3. Give the treatments of ITP. 4. Name common psychological problems in haematological cancer.

1. The Reed-Sternberg cell. 2. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone). 3. Corticosteroids, IVIG, thrombopoietin receptor agonists, rituximab, splenectomy. 4. Anxiety, depression and fatigue.