Blood Cell Abnormalities

Question 1

What is anaemia and what are some features in the blood that indicate signs of anaemia?

Answer 1

Reduction in the amount of Hb in a given volume of blood, below what would be expected in comparison with a healthy subject of the same age and gender
Therefore, reduction in absolute amount of Hb in circulation
Lowered Hb concentration and RBC count

Question 2

Why might anaemia arise?

Answer 2

Low iron intake
Low B12 / folic acid
Bone marrow diseases e.g. cancer
Thalassaemia - inherited defect leading to the reduced synthesis of globin
Bleeding
Sickle Cell Anaemia
Increased plasma volume (rare) - general treatment is to increase urine output to reduce plasma volume

Question 3

Cause Vs Mechanism?

Answer 3

Cause = underlying condition, puts mechanism into operation
Mechanism = method
Multiple causes may lead to the same mechanism

Question 4

What are the 4 mechanisms of anaemia?

Answer 4

1. Reduced production of red cells / Hb in the bone marrow
2. Loss of blood from the body
3. Reduced survival of red cells in the circulation
4. Pooling of red cells in a very large spleen

Question 5

What can be used to determine the cause of anaemia?

Answer 5

Clinical history
Physical examination
Classification on the basis of cell size

Question 6

What are the names of the 3 sizes of red cell (small, normal, large)?

Answer 6

Microcyte - smaller
Normocyte - normal
Macrocyte - larger

Question 7

What is hypochromic?

Answer 7

RBC paler than usual due to reduced Hb (increased central palor)

Question 8

What is normochromic?

Answer 8

Hb concentration in RBCs is within the standard range, but there is an insufficient number of RBCs

Question 9

How are micro/normo/macrocytes linked to hypo/normochromic?

Answer 9

Microcyte - usually also hypochromic
Normocyte - usually also normochromic
Macrocyte - usually also normochromic

Question 10

What are some common causes of microcytic anaemia?

Answer 10

1. Defect in haem synthesis
   Iron deficiency
   Anaemia of chronic disease*
2. Defect in globin synthesis (thalassaemia)
   Defect in α chain synthesis (α thalassaemia)
   Defect in β chain synthesis (β thalassaemia)

Question 11

Causes of iron deficiency?

Answer 11

Commonest cause in adults: Increased blood loss (depletion of iron stores)
Menorrhagia
Commonest cause worldwide: Insufficient iron intake or uptake - diet or malabsorption e.g. celiac disease, a condition of the small bowel where iron is not absorbed; H. pylori gastritis, condition where reduced HCl results in malabsorption
Increased requirements e.g. infancy, pregnancy

Question 12

How does a macrocytic RBC develop?

Answer 12

Usually from abnormal haemopoiesis (the production of RBC in the bone marrow)
RBC precursors continue to synthesise Hb but fail to divide normally
RBC ends up larger than normal

Question 13

What are some common causes of macrocytic anaemia?

Answer 13

Megaloblastic erythropoiesis (Nucleus is not maturing normally whilst the cytoplasm continues to mature and the cell continues to grow, delay in nuclear maturation)
Deficiency in B12 or folic acid
Use of drugs interfering with DNA synthesis
Liver disease and ethanol toxicity
Recent major blood loss with adequate iron stores
Haemolytic anaemia

Question 14

Where are megaloblasts seen typically?

Answer 14

In the bone marrow, not in the typical blood film

Question 15

What does the megaloblast in the blood film from the bone marrow show?

Answer 15

Larger than normal
Shows nucleocytoplasmic dissociation -
A mature RBC with an immature nucleus
On a megaloplastic bone marrow blood film, the maturity can be known from the pink stain of the cytoplasm in the RBC, however, it also contains a nucleus (with chromosomes that are not condensed)

Question 16

Why are there more reticulocytes present in the blood after major blood loss in someone with adequate iron supply or someone with haemolytic anaemia?

Answer 16

Reticulocytes increased as the bone marrow tries to compensate for the haemolysis

Question 17

Why does the MCV (mean cell volume) increase when there are more reticulocytes in the blood?

Answer 17

Reticulocytes are larger than mature RBCs

Question 18

What is reticulocytosis?

Answer 18

Increased number of young red cells in the blood (reticulocytes)

Question 19

What is polychromasia?

Answer 19

Young red cells newly released from the bone marrow, have a slight blue tinge in the staining of their cytoplasm in the blood film

Question 20

What are some common mechanisms and causes for normocytic anaemia?

Answer 20

Recent blood loss i.e. due to trauma, haemorrhage etc.
Failure of production of red cells e.g. early stages of iron deficiency (later progresses to microcytic), bone marrow failure or suppression (e.g. chemotherapy), bone marrow infiltration (e.g. leukaemia)
Pooling of red cells in the spleen i.e. due to hypersplenism, e.g. liver cirrhosis, splenic sequestration in sickle cell anaemia

Question 21

What is polycythaemia?

Answer 21

Too many red cells in circulation
Usually Hb, RBC and Hct (hematocrit - the ratio of the volume of red blood cells to the total volume of blood) are all increased compared to normal subjects of the same age and gender

Question 22

In which two ways can polycythaemia present and potential causes behind the two ways?

Answer 22

Pseudo - reduced plasma volume e.g. passing more urine
True - Increase in total volume of red cells in circulation due to: blood doping / over transfusion, appropriately increased erythropoietin (e.g. result of hypoxia); inappropriate erythropoietin synthesis or use (e.g. renal tumour); or independent of erythropoietin (e.g.polycythaemia vera - bone marrow disorder where mutation in a hematopoietic stem cell enables it to divide without signalling from erythropoietin called a myeloproliferative neoplasm)

Question 23

What is the term to describe thick blood?

Answer 23

Hyperviscosity

Question 24

What are some negative effects of hyperviscosity?

Answer 24

Vascular obstruction - cause thrombosis

Question 25

What is leukemia and how does it arise?

Answer 25

A bone marrow disease
Neoplasm arising as a result of mutation in a precursor of myeloid or lymphoid cells
Descendants of mutated stem cell have abnormalities in their proliferation, differentiation or cell survival
Can result in overspill of the abnormal cells into the blood, although in some patients the bone marrow is replaced by leukemic cells (so not present in the blood)

Question 26

Why is it more difficult to describe leukemia as benign or malignant in the traditional way (e.g. invasiveness, metastases)?

Answer 26

Haemopoietic and lymphoid cells normally travel around the body, recirculating between tissues and blood
Therefore, difficult to apply the terms ‘invasion’ and ‘metastasise’ to these cells

Question 27

What is another way to determine benign Vs malignant leukemia?

Answer 27

‘Benign’ corresponds to chronic leukemia - chronic - the disease goes on for a long time
‘Malignant ’corresponds to acute - if not treated, the disease is very aggressive and the patient dies quite rapidly

Question 28

Overall what are the two ways to classify leukemia?

Answer 28

Lymphoid or myeloid
chronic or acute
(i.e. acute myeloid, acute lymphoblastic, chronic myeloid, chronic lymphocytic)

Question 29

What are some further classifications of leukemia?

Answer 29

Lineage : B, T or NK cells

Myeloid can be any combination of granulocytes, monocytes, erythrocytes or megakaryocytes

Question 30

What do the suffixes mean?

Answer 30

'blastic' = acute
'cytic' = chronic

Question 31

Why do people get leukemia?

Answer 31

Series of mutations in a single stem cell e.g. in the proto-oncogenes
Can occur due to oncogenic influences e.g. radiation, anti-cancer drugs, cigarette smoking, chemicals; or accumulation of random errors
Upregulated proto-oncogene (turning it into an oncogene) or downregulated tumour suppressor gene
Genetics / heritage makes some more susceptible e.g. if their chromosomes are more likely to break and re-attach

Question 32

What are some important leukemogenic mutations that have been recognized? (3 points)

Answer 32

Mutation in a known proto-oncogene
Creation of a novel gene, e.g. a chimaeric or fusion gene, composed of parts of 2 different genes
Dysregulation of a gene when translocation (gene’s location is moved from its original area to another) brings it under the influence of the promoter or enhancer of another gene

Question 33

What are features of acute myeloid leukemia?

Answer 33

Cells continue to proliferate but no longer mature

Build up of myeloblasts (immature cells) - eventually spill into blood

Question 34

What is an impact of myeloid leukemia?

Answer 34

Failure to produce normal functioning end cells e.g. neutrophils, monocytes, erythrocytes, platelets

Question 35

What does the oncogene (in acute) generally affect?

Answer 35

Transcription factors
Consequently, the transcription of multiple other genes is also affected
So normal function of the protein is inhibited anyway - cell behaviour is disturbed

Question 36

What are features of chronic myeloid leukemia?

Answer 36

Affect a gene encoding a protein in the signalling pathway between a cell surface receptor and the nucleus e.g. membrane receptor or cytoplasmic protein
Cell function less severely affected (than in AML)
Cells become independent of external signals
Alterations in interactions with the stroma
Reduced apoptosis, cells survive longer, leukemia clone expands slowly over time
Hence results in increased production of end cells

Question 37

What are the major differences between acute and chronic myeloid leukemia?

Answer 37

Acute - Accumulation of blast cells

Chronic - Accumulation of mature cells e.g. mature neutrophils, eosinophils and basophils (too many of them)

Question 38

What is the difference between acute and chronic lymphoid leukemia?

Answer 38

Acute lymphoblastic leukaemia - increase in very immature cells / lymphoblasts, with a failure of these to develop into mature lymphocytes

Chronic lymphoid leukaemia - the leukaemic cells are mature, although abnormal, T, B or NK cells; clonal, all derived from a single cell

Question 39

How does leukemia causes disease characteristics?

Answer 39

Accumulation of abnormal cells leading to:
Leucocytosis (increase in number of white blood cells); bone pain (if leukaemia is acute); if lymphoid - englarged lymph nodes, and enlarged liver and spleen from leukemic cells proliferating in them (hepatomegaly, splenomegaly lymphadenopathy); if T lymphoid - thymic enlargement, skin infiltration

Lack of production of normal cells leading to: Anaemia, leucopenia (reduction in number of white blood cells), thrombocytopenia (low platelet count)

Question 40

What causes chronic myeloid leukemia?

Answer 40

Translocation (change in location of the genes) of chromosomes 9 and 22 in a haemopoietic stem cell
Causes formation of chimaeric gene, BCR-ABL1
gene product gives the cell a growth and survival advantage and gives rise to a leukaemic clone which expands and replaces the normal cells

Question 41

What are consequences of chronic myeloid leukemia?

Answer 41

Increase in granulocytes, neutrophils, eosinophils, and basophils and their precursors
Enlarged spleen
Anaemia

Question 42

How could you potentially cure chronic myeloid leukemia?

Answer 42

BCR-ABL1 protein signals between the cell surface and the nucleus
Can be inhibited by specific tyrosine kinase inhibitors, leading to remission (cancellation) and perhaps even cure of the disease

Question 43

What are some features of acute lymphoblastic leukemia?

Answer 43

Leucocytosis (increase in number of white blood cells) with lymphoblasts in the blood
Anaemia (normocytic, normochromic)
Neutropenia (low number of neutrophils)
Thrombocytopenia (low platelet count)
Replacement of normal bone marrow cells by lymphoblasts

Question 44

What are clinical features of acute lymphoblastic leukemia? (for a child)

Answer 44

Enlarged spleen and liver
Enlarged lymph nodes
Enlarged testes - caused by leukemic lymphoblasts migrating to testes in boys
Pale - due to anaemia
Bruises - from thrombocytopenia (low blood platelet count)

Question 45

What is the blood film of acute lymphoblastic leukemia?

Answer 45

Leukemic lymphoblasts:
Larger than normal (esp. compared to RBCs)
Cells with high nucleoplasmic ratio
Delicate chromatin pattern

Question 46

What are some features of chronic myeloid leukemia?

Answer 46

Anaemia (normocytic, normochromic)