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What are the requirements for erythropoiesis?
- Correct gene sequence
- Components - iron, b12, folate, minerals
- Functioning bone marrow
- No increased loss/destruction (for haemoglobin)
- Deficiency features
- B12 released by stomach. Parietal cells produce intrinsic factor = binds. Complex binds with cubulin (in ileum) then transported by transcobalamin
- Used in homocysteine methylation to methionine
- Found in meat, dairy. Microorganism synthesis.
- Stores last 3-4 yrs. 1-2µg lost daily. Periphery neuropathy, pyramidal tract demyelination
- Absorbed in small bowel with no carrier molecules
- Used in end product of DNA
- Green vegetables, destroyed by cooking
- Stores last days. Dysfunction of rapidly dividing tissues = reduced nuclear vs cytoplasm synthesis. Fetal tissue and bone marrow
- Blood markers are raised bilirubin an LDH.
- Define thalassaemia
- Define Sickle cell disease
- Inherited condition, with mutation affecting a globin protein. Presentation and severity depends on protein affected.
- Polymerisation of haemoglobin creating Hb S. This de and repolymerises frequently causing RBC morphology to change.
What are the clinical findings of haemolytic anaemia?
- Reduced Haemoglobin
- Increased reticulocytes
- Increased bilirubin
- Polychromatic, spherocytic cells if congenital.
Define haemolytic anaemia and outline the causes and treatment
- Anaemia related to a reduced RBC lifespan, with no blood loss or haematinic deficiency
- Abnormal RBC enzymes, e.g. pyruvate kinase or G6P
- Autoimmunity (warm IgG or cold IgM)
- Isoimmune (haemolytic disease of infant)
- Non immune (fragmentation, e.g. mechanical valve)
What are the clinical features and findings of iron deficiency anaemia?
- Clinical features:
- Gradual onset
- Clinical findings:
- Reduced haemoglobin
- Hypochromic and microcytic cells in blood smear
- Increased transferrin concentration, reduced saturation
- Low serum ferritin (acute phase protein = variable)
What are the findings in the anaemia of chronic disease?
- Mean corpuscular volume reduction - microcytic
- Mean corpuscular haemoglobin reduction - hypochromic
- ESR and ferritin raised
- Iron and transferrin (TIBC) lowered
- Rouleax seen in blood smear - 'stack' of RBCs
What are the causes of B12 and folate deficiency
- Pernicious anaemia
- Ileal disorders e.g. Crohns
- Dietary, e.g. extensive small bowel disease
- Increased cell turnover, e.g. haemolysis or skin disorders
Describe the approach to investigating anaemic patients
- IDA in males/post menopausal females is due to GI blood loss unless proven otherwise
- In young women, IDA caused by menstruation/pregnancy. GI investigated only if symptoms or FOB
Outline the pathogenesis of a stem cell clonal disorder
- A healthy haemopoietic stem cell is affected by a mutagen, becoming leukaemogenic.
- Pluriporten stem cell either becomes abnormal, or a primitive progenitor gains self renewing ability = clonal haemopoietic disorder
- Causes a raised number of abnormal blast cells in blood, either myeloid or lymphoid
- Leukemia is a clonal disorder of WBCs
Outline the pathogenesis of myeloproliferative disorders
- An over production of a single myeloid ancestral cell = one or more mature, functional blood progeny
- Associated with JAK receptor mutations, causing continuous activation and reduced apoptosis
- May transform into an acute leukemia
- Examples include polycythemia rubra vera, essential thrombocytosis and myelofibrosis
Define aplastic anaemia
When the bone marrow does not produce sufficient new cells to replenish destroyed cells. I.e. Bone marrow failure.
- Clinical features
- Autosomal recessive inheritance, onset till adulthood
- Short stature, limb abnormalities, skin hypo/hyperpigmentation, mental retardation, hearing loss, GU/GI/CNS abnormalities
- Loss of telomere maintenance + increased TNF + oxidative stress = chromosomal instability = BM failure and malignancy
Outline the treatment of Fanconi's anaemia
- Allogeneic stem cell transplant
- Lifetime surveillance for secondary tumours
Define a myelodysplastic syndrome
- Disease characterised by dysplasia and ineffective haemopoiesis in more than one myeloid series
- Can be spontaneous or secondary to radio/chemo
- Aggressiveness = increased myeloblasts
Describe the pathophysiology of myelodysplastic syndromes
- Often associated with acquired cytogenetic abnormalities, e.g. monosomy 5 or 7, trisomy 8
- Characterised by progressive bone marrow failure: reduced haemopoiesis and haematocrit
- Some progress to more aggressive conditions e.g. AML
- The incidence increases with age, but usually an incidental finding investigating fatigue and anaemia
Outline the prognosis and treatment of myelodysplastic syndromes
- Prognosis: depends on the % of bone marrow which is blasts, karyotype and cytopenias
- Treatment: Iron chelation, growth factors or immunosuppresion if very aggressive
Describe methods for taking a bone marrow biopsy
- Aspirate: 'Liquid blood' showing a mixture of cells
- Trephine: 'A solid core of bone, with bone and fat spaces. Allows architecture to be investigated
What are the indications for a bone marrow transplant?
- In malignancy, to utilise graft vs leukemia effect
- Acute and chronic leukemias
- Relapsed lymphoma
- Aplastic anaemia
- Hereditary disorders
How is an apheresis bone marrow transplant taken?
- Patient given G-CSF and chemotherapy to mobilise cells
- Cells removed by a needle
- Blood spun in the machine
- Stem cells removed and frozen
- Chemotherapy and radiotherapy given to recipient and stemm cells reperfused
What is the difference between a 'mini' and a 'myeloblative' bone marrow transplant
- Mini: Patient given immunosuppressive treatment and transplant given. Used for older, weaker patients
- Myeloblative: chemotherapy or total body irradiation given and immune system destroyed. Marrow transplant given and system replaced.
A cancer of lymphoid cells, commonly found in lymph nodes, with a wide bariation in clinical behaviour and prognosis depending on sub-type
Outline the difference between Hodgkins and non-Hodgkins
- Hodgkins: Characteristic spread to adjacent nodes, with no hepatosplenomegaly. Usually presents in teens-middle age.
- Non-hodgkins: A wide variety of lymphomas, either localised or general. Only usually presents in 60+
Describe the pathology of Hodgkins
- Malignant cell is the 'reed-sternberg' cell: giant cells
- Majority of cells are reactive in a Hodgkins lymphoma node
- Painless lymphadenopathy spreading to adjacent nodes
- In later stages, haemogenous spread to liver, lungs and marrow.
What are the clinical features of Hodgkins lymphoma
- Fever, with no infection
- Night sweats
- Weight loss; more than 10% of body in 6 months
- Generalised pruritis
- Alcohol induced lymph node pain; rare but very specific
Outline the investigations for Hodgkins lymphoma
- Bloods: anaemia, WBC [raised or low] and platelets [high]. ESR
- Biochemistry: LFTs + renal, LDH
- Imaging: CT and PET for lymphadenopathy
- Biopsy: Aspirate/trephine for staging + infiltration
What is the Ann Arbor staging system?
- Stage 1: Single lymph node region
- Stage 2: 2 or more nodes on same side of diaphragm
- Stage 3: Nodes on both side of diaphragm
- Stage 4: Disseminated disease, in marrow, liver etc.
- A/B: Presence or absence of B symptoms: fever, night sweats, weight loss.
How are different stages of lymphoma treated?
- Early (1a-2a): 3 courses ABVD and radiotherapy of involved node/field
- Advanced (>2b): 6 courses ABVD and/or radiotherapy
- Follow ups important due to effects of radio/chemo, e.g. cardiac, pulmonary, endocrine and malignancy
High grade lymphoma
- Clinical features
- Aggressive non-hodkins lymphoma type, e.g. diffuse large b cell
- Localised with rapid growth and earlier presentation.
- If 1a - 3 courses combined mod. If >1a - 6 courses
Low grade lymphoma
- Clinical features
- Non-hodgkins, indolent lymphoma
- Usually between 60-65yoa male. Asymptomatic, diffuse lymphadenopathy, B symptoms. Late presentation
- Conservative. If progressing, rituximab and chemo.
How is a non-hodgkins lymphoma diagnosed?
- Clinical features
- Fine needle aspirate
- Trephine biopsy
- Flow cytometry: cell markers (e.g. CD20)
- Cytogenetics/molecular studies
- Clinical features
- Neoplastic proliferation of plasma cells in bone marrow
- Lytic lesions in bones. Anaemia. Renal failure. Hypercalcaemia. Infection (low Ig and neutropenia)
- Thalidomide, but usually incurable.
What investigations are performed for multiple myeloma? What can be expected?
- FBC: Anaemia
- Biochemistry: Increased Ig or hypercalcaemia
- Ig electrophoresis: Monoclonal band
- BM aspirate: basophilic cytoplasm, monomorphic infiltration, eccentric nuclei
- Imaging: Bone lesions
Outline the pathogenesis of acute leukemias
- An acquired clonal disorder; cells descended from a mutated bone marrow cell
- Mutations = no maturation and increased proliferation
- Blastic proliferation in bone marrow = failure
How do acute leukemias commonly present?
- Age groups
- ALL most common in children (80-90% of cases), AML most common in adults
- Rapid onset. Infection (pancytopenia). Mucosal swelling. Bleeding/bruising. Liver/lymph swelling. Retinal haemorrhage.
- Bone pain. Lethargy (anaemia)
What blood abnormalities are normally found in acute leukemias?
- Blood count: Anaemia, neutropenia, thrombocytopenia
- Blood smear: Monoblasts and myeloblasts
- Flow cytometry: Cell markers = subtype + chronicity
- Immunohisto: Cell marker predominance
What chromosomal abnormalities can be found in acute leukemias?
- AML: 15-17 or 8-21 translocation.
- Philadelphia chromosome (95% of CML but also ALL)
Outline supportive care for acute leukemias
- BM removal with replacement transfusions
- Palliative transfusions; platelet, granulocyte, RBC
- Antibiotics; prophylaxis and treatments
Outline different treatments for acute leukemias, and their problems
- BM transplant: Selectively used due to toxicity. Higher mortality but reduced relapse
- Chemotherapy: Steroids, monoclonal Ig. High morbidity; sterility, mucositis, bleeding, infection.
Outline the clinical presentation of chronic leukemias
- Usually asymptomatic, with 50% of cases incidental
- Classic B symptoms and increased infection risk
- Genetics the main factor affecting aggression and presentation
- In CLL, presentation usually when BM fails = anaemia
- In CML, presentation can include abdominal pain from splenomegaly
What are the typical investigative abnormalities found in chronic lymphoid leukemia?
- LN biopsy: Lymphocytosis - clonal b cells
- Flow cytometry: T cell antigen overexpression
- Blood smear: small lymphoid cells, with condense chromatin (mature cells)
- BM biopsy: Nodular/diffuse infiltration
- Ctyogenetics: Chromosomal abnormalities
What are the typical investigative abnormalities found in chronic myeloid leukemia?
- Neutrophilia, with sometimes other lineages proliferating
- Shift towards immature cells - may become acute "blast crisis"
- Philadelphia gene the ONLY cause of CML
Outline management of the chronic leukemias
- CLL: Watch for infection, autoimmune haemolytic anaemia, pure red cell aplasia and treat if present
- CML: Imatinib most commonly used - tyrosine kinase blocks proliferation. Correct cytogenetics and normalise blood count main goals.