Blood Cell Abnormalities (14) Flashcards
What is anaemia?
- a reduction in the amount of Hb in a given volume of blood below what would be expected w/ a healthy subject of same age and gender
- Hb conc. reduced
- RBC and Hct/PCV usually also reduced
What are the 4 mechanisms of anaemia?
- reduced production of RBCs/Hb in bone marrow
- blood loss
- reduced survival of RBCs in circulation
- pooling of RBCs in v. large spleen
How do we distinguish between the mechanism and cause of anaemia?
- mechanism might be reduced synthesis of Hb in bone marrow
- cause could be a condition causing reduced synthesis of haem or globin
What is the relationship between RBC size and haemoglobinisation?
microcytic- usually also hypochromic
normocytic- usually also normochromic
macrocytic- usually also normochromic
What are common causes of microcytic anaemia?
- defect in haem synthesis: iron deficiency or anaemia of chronic disease
- defect in globin synthesis: alpha thalassaemia (defect in alpha chain synthesis) or beta thalassaemia (defect in beta chain synthesis)
What are causes of iron deficiency?
- insufficient intake: dietary or malabsorption (coeliac disease, H.pylori gastritis)
- increased blood loss: due to hookworm or menorrhagia
- increased requirements: pregnancy or infancy
What do macrocytic anaemias usually result from?
abnormal haemopoiesis–> so that RBC precursors continue to synthesise Hb and other cellular proteins, but fail to divide normally, so cells end up larger than normal
What is megaloblastic erythropoiesis?
- a delay in maturation of the nucleus in RBC (bc impaired DNA synthesis) while cytoplasm continues to mature and cell continues to grow
- megaloblasts generally seen in bone marrow, not blood film
What are common causes of macrocytic anaemia?
- lack of vitamin B12 or folic acid (megaloblastic anaemia)
- drugs that interfere w/ DNA synthesis
- liver disease and excess alcohol intake
- recent major blood loss w/ adequate iron stores (inc. reticulocytes, inc. MCV bc young RBC 20% larger than mature)
- haemolytic anaemia (inc. reticulocytes)
What is the difference between polychromasia and reticulocytosis?
- polychromasia= presence of RBCs w/ a blue tinge to cytoplasm on a routinely stained blood film; indicates young cells, newly released from bone marrow
- reticulocytosis= cells exposed to specific stain; indicates inc. numbers of young RBCs bc lots of ribosomes
What are the mechanisms and causes of normocytic anaemia?
- recent blood loss due to GI haemorrhage, or trauma
- failure of RBC production due to early stages of iron deficiency, or bone marrow failure/suppression (e.g. chemo), or bone marrow infiltration (e.g. leukaemia) where normal HSCs are crowded out
- pooling of RBCs in spleen due to hypersplenism (e.g. liver cirrhosis), or splenic sequestration in sickle cell
What is polycythaemia?
- too many RBCs in circulation
- Hb, RBC and Hct all increased compared to normal subjects of same age and gender
What can cause pseudo polycythaemia?
- result of reduced plasma volume
- acute or chronic
- severe dehydration or shock
What are the mechanisms of true polycythaemia?
- blood doping or overtransfusion
- appropriately increased erythropoietin (as a result of hypoxia)
- inappropriate erythropoietin synthesis or use (e.g. kidney tumour)
- independent of erythropoietin (myeloproliferative neoplasm- polycythaemia vera)
What is hyperviscosity and how can we treat it?
polycythaemia can lead to thick blood–> high haematocrit can lead to vascular obstruction, thrombosis and heart attacks etc..–> blood can be removed by venesection to reduce viscosity and can give drugs to reduce bone marrow production of RBCs
What is leukaemia?
- ‘white blood’–> cancer of the blood
- 5% of all cancers are blood cancers
- bone marrow disease (not all patients have abnormal cells in the blood)
What is the mechanism of leukaemia?
- results from a series of mutations in a single lymphoid/myeloid stem cell, HSC, or a B/T lymphocyte
- these mutations lead the progeny of that cell to show abnormalities in proliferation, differentiation, or cell survival leading to steady expansion of leukaemic clone
Why is leukaemia different from other cancers?
- haemopoietic and lymphoid cells behave differently from other body cells
- HSCs and cells derived circulate in the blood and can enter tissues, and normal lymphoid stem cells recirculate between tissues and blood
- so we cannot use the concepts of invasion and metastasis
- chronic = benign… disease goes on for a long time
- acute = malignant… if not treated, disease is very aggressive and patient dies rapidly
How is leukaemia classified?
- acute or chronic
- lymphoid (B, T or NK lineage) or myeloid (granulocytic, monocytic, erythroid, or megakaryocytic)
acute lymphoblastic leukaemia (resemble precursors)
chronic lymphocytic leukaemia (resemble mature lymphocytes)
acute myeloid leukaemia
chronic myeloid leukaemia
Why do people get leukaemia?
- some mutations result from identifiable or unidentifiable oncogenic influences (e.g. radiation)
- others occur due to random errors that accumulate in individual cells
- important leukaemogenic mutations: mutation in oncogene, creation of novel gene, or dysregulation of a gene due to translocation making it susceptible to a promoter/enhancer
- loss of function of tumour suppressor gene (deletion or mutation)
- inherited tendency to inc. chromosomal breaks
- DNA repair inhibited, so error persists
What are some identifiable causes of leukaemogenic mutations?
- irradiation (therapeutic)
- anti-cancer drugs
- cigarette smoking
- chemicals e.g. benzene
What is the difference between acute and chronic myeloid leukaemia?
- in AML: buildup of immature cells (myeloblasts) in bone marrow w/ spread to blood, as they continue to proliferate but not mature and cell behaviour= profoundly disturbed, as product of oncogene prevents normal function of protein
- in CML: inc. production of end cells instead of failure, reduced apoptosis so that cells survive longer and leukaemic clone expands…cell function not as seriously affected as in AML
What is the difference between acute and chronic lymphoid leukaemia?
- in ALL: inc. in immature cells (lymphoblasts)- frozen at this stage of development, so don’t mature
- in CLL: leukaemic cells are mature, but abnormal and clonal (T, B or NK cells)
How does leukaemia cause the disease characteristics?
- accumulation of abnormal cells in bone marrow leads to bone pain (acute), leucocytosis, hepatomegaly, splenomegaly, lymphadenopathy (if lymphoid), thymic enlargement (if T lymphoid), skin infiltration
- lack of production of normal cells leads to anaemia, leucopenia, thrombocytopenia
How does chronic myeloid leukaemia arise genetically?
results from translocation between chromosomes 9 and 22 in an HSC, leading to a chimeric gene, BCR-ABL1–> protein encoded by this new gene gives cell a growth and survival advantage over normal cells, so expands into leukaemic clone
How does chronic myeloid leukaemia present?
- inc. in all granulocytes: neutrophils, basophils and eosinophils (and their precursors)
- anaemia (due to replacement of normal bone marrow cells by lymphoblasts)
- splenomegaly
How do we potentially cure chronic myeloid leukaemia?
BCR-ABL1 protein signals between cell surface and nucleus–> can be inhibited by specific tyrosine kinase inhibitor, leading to remission
What are the haematological features of acute lymphoblastic leukaemia?
- leucocytosis w/ lymphoblasts in blood
- anaemia (normocytic+ normochromic)
- neutropenia
- thrombocytopenia
^due to replacement of normal bone marrow cells by lymphoblasts
Why do we do cytogenetic and molecular genetic analysis for leukaemia patients?
- useful for managing the individual patient bc it gives us info about prognosis: hyperdiploidy- good prognosis, whereas reciprocal translocation- poor prognosis
- advances knowledge of leukaemia bc discovers mechanisms and targeted treatments
What are the leukaemogenic mechanisms of acute lymphoblastic leukaemia?
- formation of a fusion gene
- dysregulation of a proto-oncogene by juxtaposition of it to promoter of another gene e.g. T cell receptor gene
- point mutation of a proto-oncogene
What treatments are there for acute lymphoblastic leukaemia?
- supportive: red cells for anaemia, platelets to prevent haemorrhage, ABs for infection due to neutropenia
- systemic chemotherapy: IV and oral
- intrathecal chemotherapy: bc leukaemic cells can get into CSF
