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Phase 3 > Wk3 - Haematology > Flashcards

Wk3 - Haematology Flashcards

1
Q

Site of haemopoiesis in foetus, infants and adults

A

Foetus:
0-2 months - yolk sac
2-7 months - liver, spleen
5-9 months - bone marrow

Infants:
Bone marrow (all bones - not just axial skeleton)
Adults:
Bone marrow (vertebrae, ribs, sternum, skull, sacrum, pelvis, ends of femurs)
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2
Q

Pluripotent stem cell divides to

A

Myeloid stem cell and lymphoid stem cell

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3
Q

Haemopoietc stem cell characteristics

A

Self renewal capacity
Unspecialised
Ability to differentiate (mature)
Quiescent (i.e. not undergoing cell cycle, in in G0) - only undergoes occasional cell division

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4
Q

Where are haemopoietic stem cells found?

A

Bone marrow
Peripheral blood after treatment with G-CSF (stem cells can be obtained out of bone marrow by G-CSF)
Umbilical cord blood

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5
Q

Haemopoietic stem cells can underrgo one of 3 things,,,

A

Self-renewal (identical copy)
Apoptosis
Differentiation

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6
Q

Haemopoietic stem cells can undergo one of 3 types of differentiation

A

1) Symmetrical division, contraction of stem cell numbers
2) Asymmetrical division, maintenance of stem cell numbers
3) Symmetrical division, expansion of stem cell numbers

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7
Q

Stroma = ?

A

The bone marrow microenvironment that supports the developing haemopoietic cell
Rich environment for growth and development of stem cells.
Stromal cells supported by an extracellular matrix.

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8
Q

BOne marrow microenvironemnt contains a number of different cells…

A

e.g. macrophages, fibroblasts, endothelial cells, fat cells, reticulum cells
These produce e.g. collagen, fibronectin, laminin, proteoglycans

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9
Q

What site is bone marrow aspirate taken from?

A

Iliac crest

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10
Q

Hereditary conditions impairing bone marrow function?

A 
Thalassaemia, sickle cell anaemia, Fanconi anaemia, Schwachman-Diamond syndrome
Hereditary leukaemia (very rare)
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11
Q

Acquired conditions impairing bone marrow function

A

Aplastic anaemia, leukaemia, myelodysplasia, myeloproliferative disorders, lymphoproliferative disorders, metastatic malignancy e.g. breast, infections e.g. TB/HIV, drugs and toxins, chemotherapy, haematinic deficiency

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12
Q

Principles of leukaemogenesis

A

HSC–> LSC –> Clonogenic leukemia cells –> non-clonogenic leukaemia blast cells

A multistep process
Neoplastic cell is a haemopoietic stem cell or early myeloid or lymphoid cell.
Dysregulation of cell growth and differentiation (associated with mutations)
Proliferation of the leukaemic clone with differentiation blocked at an early stage.

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13
Q

Haematological malignancies and pre-malignant conditions are termed ___ if they arise from a single ancestral cell

A

‘clonal’

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14
Q

Chronic myelogenous leukemia

A

Increase in WBCs (from myeloid lineage)
CML is acuased by BCr gene on chromosome 22 translocating to Abl gene on chromosome 9 –> this creates a new type of chromosome - Philadelphia chromosome.
This leads to increased pleuripotent stem cell production from bone marrow –> increased WBC

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15
Q

Chronic myelogenous leukemia

A

Increase in WBCs (from myeloid lineage)
CML is caused by BCr gene on chromosome 22 translocating to Abl gene on chromosome 9 –> this creates a new type of chromosome - Philadelphia chromosome.
This leads to increased pleuripotent stem cell production from bone marrow –> increased WBC

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16
Q

Myeloproliferative disprders =

A

clonal disorders of haemopoiesis leading to increased numbers of one or more mature blood progency

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17
Q

Classical MPDs (myeloproliferative disorders) are…

A

Polycythaemia rubrae vera (inc. RBCs)
Essential thrombocytosis (inc. platelets)
Myelofibrosis (inc. fibrous tissue)

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18
Q

Myeloproliferative disorders are variably associated with what mutation

A

JAK2V617F (point mutation) and calreticulin mutation

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19
Q

Myeloproliferative disorders have potential t transform into

A

AML

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20
Q

Clinical features of essential thrombocytosis

A

50% cases carry JAK2v617F, 50% carry calreticulin mutation.

Continuum with PRV
Thrombotic complications
Haemorrhagic complications
Splenomegaly
Transformation to PRV or myelofibrosis
Leukaemic transmation in 3%
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21
Q

Treatment of essential thrombocytosis

A

Low risk (<40y with no high risk features e.g. diabetes) - aspirin or anti-platelet agent

Intermediate risk (40-60y with no high risk features) - aspirin +/- hydroxycarbamide)

High risk (>60y with thrombotic risk factors):
1st line = hydroxycarbamide + aspirin
2nd line = anagrelide + aspirin
IFN alpha -usefu with pregnancy
Busulphan (e.g. someone not independent)
JAK2 inhibitors e.g. ruxolitinib
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22
Q

Describe JAK2 inhibitors

A

JAK2 mutations result in continuous activation of JAK receptor regardless of ligand binding
Ruxolitinib - inhibits JAK1 and 2, reduces splenomegaly, main side effect is thrombocytopenia, results in jak2 pos and neg patients

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23
Q

Describe myelodysplastic syndromes (MDS)

A

Characterised by dysplasia and ineffective haemopoiesis
May be secondary to previous chemotherapy or radiotherapy.
May have increased myeloblasts.
Often associated with acquired cytogenic abnormalities e.g. monosomy 5, monosomy 7, trisomy 8.
Majority characterised by progressive bone marrow failure
Some progress to AML

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24
Q

MDS clinical features

A

Predominantly affects the elderly
Majority present with fatigue due to anaemia
Fewer present with infections or bleeding or FBC

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25
Q

MDS management

A

Supportive caare - blood and platelet .transfusion.
Growth factors - Erythropoietin +/- granulocyte colony stimulating factor (G-CSF).
Immunosupression - anti-thymocyte globulin (ATG).
Low dose chemotherapy - e.g hydroxycarbamide, low dose cytarabine.
Demethylating agents - e.g. azacytidine, an epigenetic therapy.
Intensive chemotherapy - AML type chemotherapy.
Allogenic stem cell transplantation - only in selected patients

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26
Q

Features of fanconi anaemia

How is aplastic anaemia diagnosed?

A

Fanconi anaemia makes up 10-20 % of aplastic anaemia cases

Autosomal recessive inheritance
Characteristics:
Somatic abnormalitis e.g. skeletal deformities.
Bone marrow failure
Short telomeres
Malignancy
Chromosome instability
Features:
microphthalmia
GU malformations
GI malformations
Mental retardations
Mental retardation
Hearing loss
CNA e.g. hydrocephalus

Currently 7 genetic sub-types FANCA-G

Aplastic anaemia diagnosed - definitively diagnosed through bone marrow biopsy –> most stem cells are gone and replaced by fat

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27
Q

Treatment of fanconi anaemia

A

Main cause of mortality is premature bone marrow failure
Gold standard therapy is allogenic stem cell transplant

Corticosteroids
Androgens (oxymethalone) - to increase blood counts

Lifetime surveillance for secondary tumours
Possibility of gene therapy in future where faulty FANC gene is replaced

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28
Q

Types of stem cell transplant

A

Autologous - uses patients own stem cells
Allogenic - stem cells come from a donor. - 5 types:
1. Syndeneic - identical twins
2. Allogenic sibling - HLA identical
3. Haplotype identical - half matched family member. Usually a parent or half matched sibling
4. Volunteer unrelated (VU) - akak matched unrelated (MUD)
5. Umbilical cord blood

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29
Q

Main indications for autologous stem cell transplant

A

relapsed Hodgkin’s disease, non Hodgkins lymphoma and myeloma, chronic leukaemia

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30
Q

Preparation for autologous transplant

A

Patients receive growth factor (G-CSF) +/- chemotherapy to make the stem cells leave the bone marrow so they can be collected from the blood.
Mozobili has been used to collect stem cells in patients that have failed to mobilise

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31
Q

Features of umbilical cord blood transplant

A

Blood stem cells collected from umbilical cord and placenta.

Cells are tissue typed and frozen in liquid nitrogen in cord blood banks for future use

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32
Q

Advantages and disadvantages of umbilical cord transplant

A

Advan: more rapidly available in VUD, less rigorous matching to patient type of patient as immune system naive
Disadvan: if relapse, cannot go back for DLI

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33
Q

Describe graft versus host disease (GvHD)

A

Can happen in patients who have receieved an allogenic transplant. The new donor’s immune system recognises the host’s body as ‘foreign’ and start to attack it.
Most commonly manifests as a skin rash, jaundice or diarrhoea

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34
Q

What are the 2 types of GvHD

A

Acute GvHD - occurs within the first 100 days of the transplant
Chronic GvHD - occurs after first 100 days of transplant

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35
Q

GvHD is usually treated with …

A

immunosuppressive agents

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36
Q

GvL (graft vs leukaemia effect)

A

the same cells which cause GvHD also attack remaining leukaemic cells. GvL is very effective, especially in patients where a good remission has been difficult to maintain. Can also work in other blood cancers such as lymphoma and myeloma.
Minimising GvHD carries an increased risk of relapse.
In an autologous transplant there is no GvHD and therefore no GvL resulting in a greater risk of a relapse.
The challenge is to minimise GvHD and maximise GvL.

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37
Q 
Anaemia = ?
Polycythaemia = ?

Know about aplastic anaemia

A

Too little blood
Too much blood

Aplastic anameia - This is damage to haemopoietic stem cells, resulting in deficiency of all 3 blood cell types –> Pancytopenia (thrombocytopenia, leukopenia, anaemia)

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38
Q

1 molecules of Hb contains

Describe the requirements of normal red cell production

A

4 globin chains (2 alpha, 2 beta)
4 haem groups

Erythropoietin - drive for eryhtropoiesis
Genes for the process
Iron
Vitamin B12
Folate and other minerals
Functioning bone marrows
No inc loss or destruction of RBCs
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39
Q

Transferrin

A 
Involved in iron transport
is a glycoprotein
Synthesised in hepatocytes
Dec. iron = inc. Tf
Inc. iron = dec. Tf
2 iton binding sites.
30% saturated with Fe
Tf delivers iron to all tissues, erythroblasts, hepatocytes, muscle etc.
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40
Q

RES storage and recycling

A

Effete red blood cells are removed by the macrophages of the reticuloendothelial system (RES) (RBC lifespan 120d)
The RES stores 500mg of iron
RES iron is stored in ferritin/haemosiderin
RES releases iron to Tf in plasma
Tf-iron taken up via Tf receptors on erythroblasts, hepatocytes etc.

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41
Q

Hepcidin

A

Is the ‘low iron’ hormone - it reduces levels of iron in plasma. Hereditary haemochromotosis dt loss of Hepcidin.
Hepcidin binds ferroportin and degrades it - reducing iron absoprtion (enterocyte) and decreasing iron release from the RES.
Hepcidin is synthesised in the liver (requires expression of HFE)

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42
Q

4 causes of hypochromic microcytic RBCs

A

IDA (not enough haem)
Thalassaemia (not enough globin)
ACD
Sideroblastic anaemia (particularly congenital SA)

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43
Q

iron and transferrin saturation levels

A

Normal - 30%

IDA - <15%

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44
Q

Low serum ferritin always indicates …

A

low RES iron stores

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45
Q

How can IDA occur with normal serum ferritin levels

A

In presence of tissue inflamamtion (RA & IBD)

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46
Q

Signs of IDA

Diagnosis of IDA

A

Koilonychia
Atrophic Glossitis
Angular stromatitis
Oesophageal web (plumer vinson syndrome)

Hypochromic microcytic RBCs
<15% saturation transferrin
Low serum ferritin –> always indicates low RES iron stores

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47
Q

Causes of IDA

A

Dietary - premature neonates, adolescent females
Malabsorption
Blood loss

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48
Q

Levels of menorrhagia

A

> 80mls blood/period

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49
Q

Golden rule of IDA

A

IDA in males and post-menopausal females is due to F=GI blood loss until proven otherwise
Young women; menstrual blood loss +/- pregnancy

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50
Q

Iron replacement in IDA

A

Ferrous sulphate
Ferrous Gluconate
IV iron (when- intolerant to oral iron, complicance, renal anaemia & Epo replacement

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51
Q

Describe Anaemia of Chronic Disease (ACD)

A

Failure of iron utilisation
iron trapped in RES
Causes - infection, inflammation, neoplasia

Pathophysiology ACD = Iron is trapped in REs within macrophages, causing a reduced Epo response. This results in depressed marrow activity –> cytokine marrow depression

Anaemia of CRF = ACD + dec. Epo

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52
Q

Lab values in ACD

A 
MCV/MCH N/dec. - normochromic normocytic or hypochromic microcytic RBCs
ESR - inc. (RBC Rouleaux)
Ferritin - N/inc.
Iron - dec.
TIBC - dec.
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53
Q

Causes of ACD

A

RE Iron blockade; iron trapped in macrophages; raised levels of Hepcidin
Reduced Epo response
DEpressed marrow activity; cytokine marrow depression

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54
Q

Treatment of ACD

A

Treat underlying disorder

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55
Q

B12/folate is essential for…

A

DNA synthesis and nuclear maturation.

Required for all dividing cells, deficiency noted first in red cells

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56
Q

DEficiency in B12/folate

A

results in megaloblastic anaemia intitially, but will effect other organs

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57
Q

B12 (Cobalamin) is necessary for 2 processes -

A

Methylation of homocysteine to methionine

Methylmalonyl-CoA isomerisation

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58
Q

Dietary sources of B12

A

Meat (esp. iver and kidney), small amount in dairy products
Normal western diet 5-30ug/day
Daily requirement - 1ug/day

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59
Q

Describe B12 absorption

A

B12 ingested (in form of animal protein).
Gastric pariteall cells in fundus/body produce Intrinsic factor.
B12 released by enzymes/acid in sotmach and duodenum.
Intrinsic Factor binds to B12 in duodenum/jejunum.
IF-B12 complex binds to cubulin (specific receptor in ileum) - is absorbed in ileum.
B12 absorbed and binds to transcobalamin in the blood.

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60
Q

B12 stored for …

A

3-4 years

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61
Q

Folate - dietary stores, absorption, stores

A

Green veg (destroyed by cooking)
Absorption - mostly small bowel. No carrier molecule required.
Stored - few days only - quickly used up if increased demand (ie increased cell turnover)

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62
Q

Clinical B12 deficiency - blood abnormalities and neurological manifestations

A

Megaloblastic anaemia (leucopenia, thrombocytopenia)

Bilateral peripheral neuropathy or demyelination of the posterior and pyramidal tracts of spinal cord. (likely related to problem with homocysteine -> methionine

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63
Q

Clinical folate deficiency - blood abnormalities and growing fetus

A

Megaloblastic anaemia (leucopenia and thrombocytopenia)

1st 12 weeks - deficiency can cause neural tube defects

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64
Q

Signs and symptoms of B12/folate deficiency

A

Symptoms of anaemia/cytopenia:
Tired - macrocytic/megaloblastic anaemia (common); easy bruising - thrombocytopenia (rare)

Mild jaundice - haemolysis

Neurological problems - nerve disturbance as a result of B12 def - subacute combined degeneration of cord

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65
Q

Causes of folate deficiency

A

Dietary
Extensive small bowel disease - coeliac, sever Crohns
Increased cell turnover - haemolysis, severe skin disorders, pregnancy

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66
Q

Components of HbA and HbF

Develop a logical approach to the investigation of a patient with anaemia

A

HbA - 2alpha, 2 beta
HbF - 2alpha, 2gamma

Is the information new? - helps determine congenital or acquired
Any clues in the history? - blood loss, diet, chronic disease, family history, medication etc.
Examination findings - angular stromatitis, splenomegaly, lymphadenopathy, abdominal passes
Blood film
Coombs test - this is used to test for autoimmune haemolytic anaemia:
Direct Coombs test - This is used to detect antibody on RBC surface. Blood sample is taken and RBCs washed to removed own plasma, which they are then incubated with anti-human globulin. If this produces agglutination of RBCs, positive test –> shows AIHA or HDN
Indirect Coombs test - This is sued to detect RBS antibodies within the plasma during prenatal testing of pregnant women, and in testing blood prior to blood transfusion. Serum extracted from blood sample and incubated with RBCs of a known antigenicity. If agglutinaiton occurs, positive test

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67
Q

Provide examples of diseases causing anaemia

Thalassaemias =

A

Thalassaemias, Haemoglobin chain variants, Haemolytic anaemia (congenital and acquired (warm and cold type))

relative lack of normal globin chains due to absent genes

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68
Q

Clinical significance of alpha thalassaemia

A

Missing one gene - mild microcytosis
Missing 2 genes - micorcytosis, increased red cell count and sometimes very mild (asymptomatic) anaemia
Missing 3 genes - significant anaemia and bizarre shaped small red cells - Haemoglobin H (HbH) disease
Missing 4 genes - incompatible with life (need alpha chains for fetal haemoglobin) - alpha thalassaemia major

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69
Q

Featurs of Hbh disease

A

Missing 3 alpha genes
Lack og alpha chains -> excess beta chains
Beta chains end up joining together (HbH)
Blood transfusion require during periods of stress
Hb variable 65-75g/l

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70
Q

Features of beta thalassaemia major

A

missing both beta globin genes.
Autosomal recessive
Unable to make adult haemoglobin (HbA)
Significant dyserythropoiesis (poorly functioning RBCs)
Hypochromic, will have splenomegaly and CF
Maxillary prominence
Thicker skull

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71
Q

Presentation and treatment/management of beta thalassaemia major

A

Don’t feed well, falling off centile, smaller stature

Transfusion dependent from early life (first couple of years)
Ion overload has major effect on life expectancy

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72
Q

pathogenesis of sickle cell disease

A

Chromosome 11:
Single amino acid substitution on B globin gene at position 6
Glutamine>Valine = Hb S
(Glutamine>Lysine = HbC)

HbS = 2 alpha + 2 beta (sickle) = (a2bs2)

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73
Q

Describe how sickle cell anaemia is described as a multisystem disease

A

Brain - stroke
Lungs - acute chest syndrome, pulmonary hypertension
Bones - Dactilytis, osteonecrosis
Spleen - hyposlenic
Kidneys - loss of ocncentration, infartion
Urogenital - priapism - chronic, acute
Eyes - vascular retinopathy\Placenta - IUGR/fetal loss

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74
Q

Treatment of sickle cell anaemia

A

Prevent crissi - hydration, analgesia, early intervention, prophylactic vaccination and antibiotics, folic acid

Prompt manageemnt of crises - oxygen, fluids, analgesia, antibioticis, transfusion/red cell exchange

Bone marrow transplantation

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75
Q

Definition of haemolytic anaemia

A

Anaemia related to reduced RBC lifespan
No blood span
No haematinic deficiency

76
Q

3 reasons for congenital haemolytic anaemia

A
  1. Abnormalities of RBC membrane - hereditary spherocytosis - autosomal dominant, jaundice, splenomegaly, give supply of folic acid
  2. Haemoblobinopathies
  3. Abnormalities of RBC enzymes e.g. pyruvate kinase deficiency anaemia (autosomal recessive), glucose 6 phosphate dehydrogenase deficiency (x-linked)
77
Q

3 reasons fro acquired haemolytic anaemia

A
  1. Autoimmune - warm type (IgG), cold type (IgM)
  2. Isoimmune - ahemolytic disease of newborn (HDN) (antibodies arise in mother & cross the placenta)
  3. Non-immune - fragmentation haemolysis (can be seen with Ecoli)
78
Q

Treatment of Cold AIHA and warm AIHA

A

Cold - self limiting mycoplasma
Idiopathic - keep warm

Warm - stop and drugs, steroids, immunosuppression, splenectomy

79
Q

What is leukaemia?

Difference between chronic and acute

A

Accumulation of abnormal leucocytes in marrow +/- blood +/- other tissues

Chronic - symptoms from accumulation of cells
Acute - symptoms from bone marrow

80
Q

What are the 2 pre leukaemic conditions

A

MDS - myelo-dysplastic syndrome
MPD - myleo-proliferative disorders

Both clonal blood disorders

81
Q

Features of MDS

A

Failure of effective haemopoiesis (low blood count)
Most common in elderly
‘Dysplastic’ blood and marrow appearances
Approx 25% rate of transformation to AML
Consequences of marrow failure

Low and high risk established by proportion of blast cells in marrow and cytogenic profile (MDS vs AML)

82
Q

Features of MPDs

A

JAK2 mutation is prevalent
Effective haemopoiesis - too many platelets (essential thrombocythaemia) or too many red cells (&plts and WC) (polycythaemia Vera or primary polycythaemia) or too much fibrous tissue (&plts & WC) (Myelofibrosis)

83
Q

Treatment of MPDs

A

Et & PRV - risk of vascular events (aspirin), cytoreduction (hydroxycarbamide, venesection or interferon)

Myelofibrosis - large spleen, systemic cymptoms, blood counts high or low, incurabel other than with SCT.
New class of drugs - JAK2 inhibitors
84
Q

Diagnosing acute leukaemia

A

Do blood count then blood film
- anaemia, neutropenia, thrombocytopenia, blasts

Bone marrow - Blast cells>20%

Flow cytometry

Karyotyping:
Standard cytogenics
t(15:17) M3 AML
t(8:21) M2 AML

85
Q

What are the 3 choices for managing AML

A
  1. Intensive chemotherapy +/- SCT (<60-65 y/o)
    Most young patients entered into trails
    Bleeding, infection, hair loss, sterility, mucositis, psychological element.
    Anthracycline and cytarabine based. Some only curable using allogenic transplant.
  2. Low dose chemotherapy (>60-65)
  3. Supportive care only (older patients, major comorbidities, median survival 3-6 months)
86
Q

Clinical presentation of ALL

A

The limping child
Purpuric rash
Unexplained, sometimes severe, bone pains

87
Q

Management of ALL

A

Chemotherapy:
Anthracycline, Prednisolone, vincristine, cytarabine etc.
Initial aggressive therapy, then oral maintenance (1-2 years)

88
Q

Management of acute leukaemia - supportive

A

Blood transfusion
Fresh frozen plasma - for coagulopathy/DIC
Platelet transfusion - purpura and bleeding, during fveer, sepsis, DIC
Antibiotics
Growht factors (G-CSF)
Granulocytes - refractory infections

89
Q

Transplant procedures for acute leukaemia mostly for

A

Relapsed patients, refractory patients, poor risk disease in first CR
Age less than 60 yrs

Allogenic transplant done

90
Q

Presenting features of chronic lymphocytic leukaemia (CLL)

A 
More present in older patients
Commonest leukaemia
Most cases - patients are asymptomatic
Lethargy, night sweats, weight loss (B symptoms)
Symptoms of anaemia
Lymphadenopathy
Infection (as often quite immunosuppressed)
Is often an incidental diagnosis

(CLL is reduction in B lymphocytes)

91
Q

Clinical staging of CLL

A

A - <3 involved nodes - 10yrs survival
B - >3 involved nodes, liver, spleen - 7 yrs
C - Anaemia or thrombocytopenia - 2 yrs

92
Q

Cytogenetics for CLL

A

Interphase FISH is useful

93
Q

CLL with 17p deletion

A

Aggressive disease
Refractory to chemoherapy
Deletion 17p results in loss of p53
Patients may respond to steroids and antibiotics
B-cell tyrosine kinase inhibitors - new oral drugs - can kill p53 mutated cells

94
Q

CLL - immune complications

A

Autoimmune haemolytic anaemia
Autoimmune thrombocytopenia
Treat with steroids

95
Q

What is seen on blood film with AIHA (autoimmune haemoltic anaemia0

A

Spherocytes

Polychramasia

96
Q

CML clinical presentation

A

May be asymptomatic

Fatigue, weight loss, night sweats, abdominal discomfort, splenomegaly (seen in most patients)

97
Q

CML natural history

A

Chronic phase –> accelerated phase –> myeloid blast phase

98
Q

What trasnlocation is a cause of CML

A

Translocation between chromosome 9 and 22 - creating BCrABl

–> Philadelphia chromosome

99
Q

Diagnosis of CML

A

Blood film and clinical features
Molecular test on blood (BCR-ABL PCR/FISH)
Cytogenetic analysis (‘karyotype’) - to look for Philadelphia chromosome

If BCR-ABL negative - not CML!

100
Q

Treatment for CML

A

Imatinib - a targeted therapy

2nd line - TKI inhibitors

101
Q

What is the most common type of lymphoma?

A

Non-Hodgkins (85%)

Hodgkins (15%)

102
Q

Presentation of lymphoma

A

Lymphadenopathy - painless, rubbery
Splenomegaly
B symptoms - night sweats, weight loss, unexplained fever
Anaemia

103
Q

The site bone marrow biopsies are taken from - to aid diagnosis of lymphoma

Investigations of lymphoma

A

Posterior superior iliac spine

Investigations:
History - symptoms, duration of symptos, B symptoms
Clinical examination - lymph nodes, splenomegaly
Blood tests - FBC, U&Es, LFTs, Ca, ESR, LDH
Imaging tests - CT scan, PET/CT scan
Bone marrow biopsy - aspirate and trephine
Additional tests (may be required pre treatment) - echocardiogram, pulmonary function tests

104
Q

Staging of lymphoma

A

I: single lymph node group
II: more than one lymph node group SAME side of diaphragm
III: lymph node groups BOTH sides of the diaphragm (includes spleen)
IV: extranodal involvement e.g. liver, bone marrow
A or B added to signify absence or presence of B symptoms

Early stage - 1 or 2A
Advanced stage - 2B or 3 or 4

Most HL diagnosed at early stage
Most NHL diagnosed at advanced stage

105
Q

Non-hodgkins lymphoma - when T or B cell affected

A 
B cell (>90%)
T cell (10%)

CD20 - antigen expressed on B-lymphocytes
Target for treatment with the monoclonal antibody Rituximab

106
Q

Features of follicular lymphoma

A

Low grade lymphoma
Resemblance to normal germinal centres
Characterised by transloations involving BCL2 gene (upregulation of BCL2 - an anti-apoptotic protein)
Slow growth but reduced cell death (apoptosis)
Is a B cell lymphoma
Usually incurable
Predominantly affects adult

107
Q

Treatment of follicular lymphoma

A 
Treatment aimed at alleviating symptoms
Early stage (1A, some 2A) -> localised radiotherapy

Advanced stage:
Asymptomic, no end organ compromise -> watch and wait
Symptomatic and/or organ compromise -> immunochemotherapy - Rituximab and chemo
Followed by maintenance Rituximab every 2 months for 2 years

108
Q

Features of diffuse large B-cell lymphoma

A

high grade lymphoma
Resemblance to activated B-cells
Associated with various translocations and geentic abnormalities; complex karyotype.
High proliferation fraction, variable rate of cell death
Commonest subtype of NHL
Most cases BCL-6 positive but variable CD10 and BCL2 expression.
Mostly adults but wide age range and can occur in children
Aggressive but curable in >50%

109
Q

Presentation of diffuse large B cell lymphoma

A

Lymphadopathy - usually rapidly enlarging LN mass
Extra-nodal presentation also common - GI tract, skin, bon, CNS etc.
Night sweats and weight loss

110
Q

Treatment of DLBCL

A

Aggressive chemotherapy

Early stage (1A) - R-CHOP x 3

All other stages - R-CHOP x 6

R-CHOP chemotherapy =
Rituximab, cyclophosphamide, Adriamycin, Vincristine, Prednisolone

111
Q

Burkitt lymphoma - features

A

High grade lymphoma
Resemblence to proliferating centre cells
Characterised by translocations involving MYC gene and IG gene (but simple karyotype)
MYC gene drives proliferation but is alsoo linked to apoptosis - rapid proliferation of neoplastic cell and high rate of apoptosis.
Very high rate of proliferation
High rate of cell death (apoptosis) - Tumour Lysis Syndrome is an issue

112
Q

Presentation of Burkitt lymphoma

A

Short history, marked B symptoms, rapidly growing tumours.

Most cases present with extranodal disease - jaw and facial bone, ovaries, kidneys, breast, lymph nodes and bone marrow

113
Q

Describe features of classic Hodgkin lymphoma

A

Lymphoid neoplasms affecting lymph nodes (unlike NHL do not present at extranodal sites).
High grade lymphoma with prominent component of reactive cells.
Neoplastic cell resembles atypical activated B-cell as seen in some viral infections (e.g. EBV).
Characterised by strong expression of CD30 and loss of some B-cell antigens.
2 main subtypes:
Nodular lymphocyte predominant Hodgkin lymphoma (6% of HL)
Classic Hodgkin lymphoma (94% of all HL)

114
Q

Presentation of Hodgkins lymphoma

A

Bimodal age incidence.
Usually presents with painless lymphadenopathy - neck lump, cough, shortness of breath.
May have B symptoms
Itch may precede diagnosis for many months

115
Q

Treatment of HL

A

Very effective - high cure rates
Early stage -> usually combined modality Rx ie chemotherapy followed by radiotherapy.
Advanced stage -> chemotherapy

ABVD - adriamycin, bleomycin, vinblastine, dacarbazine

116
Q

Describe features of plasma cell myeloma

A

Neoplasm of mature plasma cells.
Express plasma cell markers e.g. CD138.
show aberrant phenotype e.g. CD19 negative, CD56 positive, Cyclin D1 positive, light chain restriction

117
Q

Presentation of plasma cell myeloma

A

Non-specific symptoms - backache, fatigue, symptoms from hypercalcaemia, recurrent infections, renal impairment

118
Q

In most myeloma patients, abnormal plasma cells produce an abnormal ‘monoclonal protein; called a

A

paraprotein or ‘M’ protein

  • 5 different types (IgG, A, M, D, E)
  • IgE very rare
  • IgM rare (more commonly associated with lymphoma
119
Q

What is the classic triad of myeloma

A

Increased plasma cells in bone marrow
Clonal imunoglobulin or paraprotein
Lytic bone lesions

120
Q

Diagnosing myeloma

A

Blood tests - FBC, ESR, U&Es, Ca++, SFLC
Urine tests - to look for light chains in urine - Bence-Jones protein
Bone marrow aspirate
imaging

121
Q

tion of featuresDiagnosis of plasma cell myeloma is based on a combina

A

Neoplastic plasma cells in bone marrow >=10% of total cells plus at least one of the following:

End-organ dmaage attributable to the plasma cell proliferation (CRAB criteria) - hyperclacaemia, renal insufficiency, anaemia, bone lesions: >=1 lytic lesion on skeletal x-ray, CT or PET/CT
Biomarkers of malignancy

122
Q

Treatment of plasma cell myeloma

A 
Asymptomatic myeloma (smouldering) -> watch and wait
Symptomatic (determined by CRAB) criteria) -> requires treatment

Chemotherapy usually including a steroid and thalidomide
Radiotherapy -> e.g. severe bone pain
Supportive therapy - bisphosphonates - reduce pain, hypercalcaemia and reduces need for radiotherapy; Blood transfusion/EPO; surgery; interventional radiology

123
Q

Prognosis of myeloma

A

incurable

Variable - median 5.5 years

124
Q

Lymphoma is malignancy derived fro…

A

lymphocytes, either from B-lymphocytes, T-lymphocytes or natural killer cells.

Unlike leukaemia it generally presents with a tumour mass

125
Q

Risk factors for lymphoma

A

Immunosuppressive disorders/treatments - organ trasnplant, HIV
Infections - EBV, h.pylori (MALT lymphoma od stomach)
Age - increased chance of genetic change
Having a close relative with lymphoma

126
Q

Lymphoma arises as a consequence of ___ damage

A

DNA damage
Altered expression subverts normal regulation of growth:
Cell birth/division (proliferation) - usually increased and autonomous
Cell death (apoptosis) - often reduced

127
Q

Difference between leukaemia and lymphoma

A

Leukaemia - widespread involvement of bone marrow and peripheral blood
Lymphoma - discrete tissue masses

128
Q

There are 4 broad categories of lymphoid neoplasms based on cell lineage and stage of development at which neoplasms arise i.e.

A

Precursor B-cell and T-cell neoplasms (mostly leukaemias)

Mature B cell and T-cell neoplasms (mostly lymphomas)

129
Q

Where is the malignancy in plasma cell myeloma based on?

What type of immunoglobulin is it associated with?

A

Bone marrow

Cloncal immunoglobulin production (usually IgG)

130
Q

General categories of lymphoma

A

Non-Hodgkins (75%) - Nodal (60%), extranodal (40%)

Hodgkins (25%)

131
Q

How can u differentiate between low grade and high grade lymphoma on immunohistochemistry

A

Ki67 is a protein expressed by cells in cell cycle (S-phase) i.e dividing or proliferating cells express this protein.
High grade - lot stained

132
Q

What do activated platelets express on their surface membrane

A

Phospholipids

133
Q

Describe primary and secondary haemostasis (briefly)

A

Primary - recruitment of platelets (platelet plug)
Secondary - activation of coagulation factors (initiation, propagation, thrombin generation, fibrin clot)

Occurs simultaneously

134
Q

How to assess primary and secondary haemostasis

A

Primary - invivo - bleeding time; ex vivo - FBC, platelet function

Secondary - PT (stimulates activation via the extrinsic pathway), APTT (stimulates activation via the intrinsic pathway (activated through collagen)), TCT (measurement of conversion of fibrinogen to fibrin clot), individual coagulation factor assays

135
Q

What are the 3 types of antithrombotic agents

A

Anticoagulants (inhibit one or several components of cascade to inhibit formation of fibrin clot) e.g. heparin, warfarin
Fibrinolytic agents (enhance lysis of fibrin clot)
Anti-platelet agent - inhibit platelet activation or aggregation

136
Q

What factors does Warfarin act on

A

IIa, VIIIa, IXa, Xa

137
Q

Mechanism of action of heparin

A 
Mixture of glycosaminoglycans of differing polysaccharide chain length.
Particularly acts on IIa and Xa
Heparin does not cross placenta
Short half life
Administered parenterally
138
Q

Side effects of heparin

A

HIT (heparin induced thrombocytopenia)
Osteoporosis
Hyperkalaemia

The effects are less with LMWH than with UFH

139
Q

LMWH vs UFH

A

LMWH have superior pharmacokinetic profile
LMWH have safer side effects.
LMWH have higher drug costs but lower consumable costs and do not require monitoring
LMWH can be used in out-patients

140
Q

What is inhibited by warfarn

A

VKOR - Vitamin K Oxide Reductase

Is an oral vitamin K antagonist –> dysfunction factors II, VII, IX, X

141
Q

What is haematinic?

A

folic acid

142
Q

Hyposplenism does not cause increased risk of?

a) Meningococcus
b) Pneumococcus
c) Haemophilus
d) E Coli
e) Malaria

A

e.coli

143
Q

Diagnosis of baby anaemia
a. Alloimmune anaemia of the foetus

b. Rhesus haemolytic disease of the newborn
c. α-thalassaemia minor
d. β-thalassaemia major
e. Vitamin K deficiency

A

Rhesus haemolytic disease of the newborn

144
Q

Management of acquired warm type haemolytic anaemia

A
  1. Corticosteroids - Prednisolone (60-100mg per day, subsequenlty reducing). Haemolysis should be dramatically reduced in 80% of patients within 3 weeks
  2. Blood transfusion - transfusion of packed red cells may be required depended on the patients symptoms
  3. Folic acid - such may be the demands for red cell production that folic acid stores may be compromised and supplementation may be required in sever cases
  4. Splenectomy - - in patients whose anaemia is refractory to prednisolone, or in those who require long term high dose therapy to suppress the haemolytic state. Such patients are liable to develop the serious complications of steroid therapy
145
Q

Risks of splenectomy

A

The spleen is an important organ in sieving out micro-organsims including streptococcus pneumoniae, Haemophilus influenzae and neisseria meningitis
Such organisms can cause overwhelming post splenectomy infections (OPSI).
Patients must be vaccinated against these organisms pre-operatively. In addition life long antibiotic prophylaxis (penicillin V) is recommended.
Patients must be informed of this risk, understand they require antibiotic in the event of an infection and carry a ‘splenectomy’ card with them at all times.

146
Q

The mechanism of destruction of RBCs in haemolytic anaemia is of 2 main types:

A

Intravascular - the destruction fo red cells occuring directly in the circulation
Extravascular - occurring within the reticuloendothelial system of the spleen, liver and bone marrow

147
Q

Features of intravascular anaemia

A

can occur by mechanical trauma to the red cell - so called red cell fragmentation.
Intravascular haemolysis can also follow ABOincompatible blood transfusion (anti-A and Anti-B and IgM antibodies).
Other causes include malaria and Cold (IgM) autoantibodies. Cold autoantibodies cause the RBCs to agglutinate on the blood film. Cold antibody is difficult to treat. The patient must be advised to keep warm as the antibody only fixes to the RBCs in colder parts of the body i.e. cold hands etc.

148
Q

Causes of cold autoimmune haemolytic anaemia (usually IgM antibodies)

A

a. Primary (idiopahtic)
b. Secondary including:
Infection-Mycoplasma pneumoniae
Infectious mononucleosis (Glandular fever)
Lymphoproliferative disorders

149
Q

Main laboratory findings in intravascular haemolysis are

A
  1. Anaemia, reticulocytosis and raised unconjugated bilirubin
  2. Haemoglobinaemia and haemoglobinuria
  3. Haemosiderinuria
150
Q

Features of extravascular haemolysis

A

Extravascualr is more common than intravascualr and occurs in the reticuloendothelial system, particularly the spleen. This type of haemolysis is often related to the production of ‘warm’ (incomplete) antibodies, usually IgG
The IgG attaches to the red cell antigen and damages the RBC membrane. The damaged RBCs become spherocytic and are phagocytosed by the RES, particularly the spleen. As a result the spleen enlarges. A positivedirect antiglobulin test indicates the presence of antibodies (or complement) on the RBC surface. Serum bilirubin is usually elevated and is of the unconjugated variety (hence alcoholic jaundice)

151
Q

Causes of warm type AIHA

A

Primary (idiopathic) - 55-60%
Secondary causes include lymphoproliferative disorders such as chronic lymphocytic leukaemia and non-Hodgkins lymphoma, other neoplasms, SLE, other connective tissue disorders and drugs

152
Q

B cell development

A

B cells are produced in bone marrow from commited stem cell progenitor
Mature B-cells circulate in peripheral blood and populate lymphoid and other organs
Interaction with antigen results in production of:
- Memory B cells
- Plasma cells

153
Q

T cell development

A

T-cells originate in bone marrow from committed stem cell progenitor
Precursor T-cells migrate to thymus where they develop into mature T-cells
Mature T-cells circulate in peripheral blood and populate lymphoid and other organs

154
Q

Mechanism of normal red cell destruction

A

Senescent red cells (100 + days are old) are destroyed by the cells of the reticuloendothelial system particularly in the spleen. Intravascular haemolysis (break down of red cells in the general circulation) plays a little or no part in red cell destruction under normal circumstances.

155
Q

Mechanism of abnormal RBC destruction

A

Haemolysis may be defined as an increase in red cell destruction. The bone marrow has the ability to increase red cell production some six to eight fold. Thus the red cell span would have to be <15-20 days before anaemia develops.
The mechanism of destruction in the haemolytic anaemias is of 2 main types:
Intravascular - that is destruction of red cells occurring directly in the circulation
Extravascular - occurring within the reticuloendothelial system of the spleen, liver and bone marrow

156
Q

Causes of intravascular haemolysis

A

Intravascular haemolysis can occur by mechanical trauma to the red cell - so called red cell fragmentation syndrome i.e. RBC breakdown by defective mechanical heart valves (RBC fragmentation also seen in HUS and MAHA).
Can also follow ABO compatible blood transfusion (anti-A and anti-B are IgM antibodies).
Other causes include malaria and cold (IgM) autoantibodies. Cold autoantibodies cause the RBCs to agglutinate on the blood film. Cold antibody haemolysis is difficult to treat. The patient must be advised to keep warm as the antibody only fixes to the RBCs in colder parts of the body i/e/ cold hands.

157
Q

Explain the term ‘pancytopenia’

A

Reduce WBCs, Hb and platelets

Caused by variety of bone marrow disease. Can also be caused by hypersplenism and peripheral consumption of blood cells

158
Q

Treatment of immune thrombocytopenia

A

Steroids - Prenisolone. Possibly splenectomy

No splenomegaly with ITP though

159
Q

MOA of warfarin

A

Warfarin is a Vitamin K Antagonist.

  • Inhibits Vitamin K epoxide reductase
  • Prevents recycling of Vitamin K to reduced form after carboxylation of coagulation factors II, VII, IX, X.
  • Prevents thrombus formation
160
Q

MOA of heparin

A

Enhances activity of antithrombin III.
Antithrombin III inhibits thrombin
Heparins also inhibit multiple other factors of the coagulation cascade (particularly II and X)
This produces its anticoagulant effect.

161
Q

Examples of Direct Oral Anti-Coagulants (DOACs)

A

Factors IIa inhibitor - Dabigatran etexilate

Factors Xa inhibitors - Rivaroxaban, Apixaban, Edoxaban

162
Q

Pros and Cons of DOACs v Warfarin

A 
Warfarin:
Slow onset slow offset: results in smooth coagulation
Requires very individualised dosing
Required INR monitoring
Many drug, food and alcohol interactions
Renal impairment may increase bleed risk
Rare s/e other than bleeding
Rapid reversal with PCC and Vitamin K

DOACs:
Rapid onset and offset: anti-coagulated within 3h of 1st dose.
May require dose adjustment based on CrClRequires annual review
Few drugs and no food or alcohol interactions
Renal impairment may be a contra-indication
More minor s/e
Currently no rapid reversing agent

163
Q

Causes of intravascular haemolysis

A

Can occur by mechanical trauma to the red cell - so called red cell fragmentation syndrome.
Can also follow ABO incompatible blood transfusion (anti-A and anti-B are IgM antibodies.)
Other causes include malaria and cold (IgM) autoantibodies. cOld autoantibodies cause the RBCs to aglgutinate on the blood film. Cold antibody haemolysis is difficult to treat - stay warm.

164
Q

How is purpura caused?

A

Either due to platelet problem (usually thrombocytopenia) or vasculitis (i.e. Henoch Schonlein)

Purpura is seen in ALL
(Petechiae in AML)
Purpura can also be seen in immune thrombocytopenia (ITP)

165
Q

What is DIC?

A

An acquired syndrome characterised by activation of coagulation pathways, resulting in formation of intravascular pathways, resulting in formation of intravascular thrombi and depletion of platelets and coagulation factors

166
Q

Clinical history and examination consistent with DIC

A

Clinical history can include haematuria, oliguria, cough, dyspnoea, epistaxis, fever, delirium and coma.
Physical examination may reveal petechiae, ecchymosis, gangrene, mental disorientation, hypoxia, hypotension and GI bleeding

167
Q

Diagnosis + Investigations for DIC

A

Diagnosis is based on presence of >=1 known underlying conditions causing DIC plus abnormal coagulation tests: decreased platelet count, increased prothrombin time, elevated fibrin-related marker (D-dimer/fibrin degradation products), and decreased fibrinogen level

Investigations - Lumbar puncture and blood culture

168
Q

What is the bacteria responsible for meningococcal septicaemia (than can cause DIC - presenting with nuchal rigidity)

A

Neisseria meningitides

169
Q

Treatment of meningococcal septicaemia causing DIC

A

IV antibiotics

170
Q

Young female presents with exudation tonsillitis, cervical lymphadenopathy, slightly enlarged spleen and fever.
WBC shows atypical mononuclear cells.

What is the diagnosis?
What is the causative organism?
Describe the tests used to diagnose this condition.

Should she be given Amoxicillin while awaiting confirmation of diagnosis?

A

Infectious mononucleosis
EBV
Tests - Monospot test (Non-specific for Epstein Barr virus (EBV) infection. IgM antibodies agglutinate red cells from other species (sheep, horse, goat, bovine).
Commonly used Monospot test is a rapid qualitative slide agglutination test using horse or bovine red cells.)
- EBV titres

No amoxicillin will cause a rash in IM patients. If diagnosis is not clear the patient could be given simple Penicillin V to cover against potential Strep throat.

171
Q

What is meant by the term heterophile antibodies?

A

They are agglutinins that appear in blood during IM (infectious mononucleosis) infection that react with sheep RBCs ie. they react across species barriers

172
Q

A young male presents with a facial rash (butterfly distribution) and polyarthritis.
What is the likely diagnosis?
What is the likely cause of her prolonged PTT?

A

SLE
(systemic lupus erythematous)
Prolonged PTT - due to Lupus anticoagulant (LA) - an antiphospholipid antibody found in many people with lupus. LA increases your body’s ability to clot. DRBVT - to test for LA

173
Q

Signs of Haemolytic Uraemic Syndrome

A 
Bloody diarrhoea following travel.
Anaemic
Thrombocytopenic
Uraemic
Jaundices
174
Q

Likely causative organism of haemolytic urease syndrome (following travel)

A

E. Coli 0157

175
Q

What is the expected RBC appearance with HUS?

A

RBC fragmentation

176
Q

Describe the Reed Sternerg (RS) cells

A

Large cels, abundant cytoplasm, 2 nuclear lobes each with prominent nucleolus, Owl’s eye appearance.

Found in Hodgkins lymphoma.

177
Q

What are the different stages of lymphoma?

A

Stage I - single lymph node group
Stage II - more than one lymph node group on SAME side of diaphragm
Stage III - lymph node groups on BOTH sides of the diaphragm (includes spleen)
Stage IV - extranodal involvement e.g. liver, bone marrow.

A or B added after to signify absence or presence of B symptoms:

  • Night sweats
  • Weight loss
  • Unexplained fever

Early stage = 1 or 2A
Advanced stage = 2B, 3, 4

178
Q

What type of lymphoma is usually seen in older patients?

A

Non-Hodgkins lymphoma

179
Q

An elderly woman is found to have painless cervical lymphadenopathy. She is otherwise well. She has rubbery nodes (1-2cm) in all areas and splenomegaly of 2 fingerbreadths.
High WBC, high haemoglobin, N platelets.
What is the likely diagnosis?

A

CLL

- Has monoclonal B cells

180
Q

Hoes does CLL differ from CML

A

CLL does not change to acute leukaemia. It can progress but stays as CLL.
CML on the other hand has a tendency to change to acute leukaemia. Oddly CML can change to AML or aLL as well.

181
Q

Staging of CLL

A

A <3 involved nodes (10yr survival)
B > 3 involved nodes, liver, spleen (7yr)
C - Anaemia or thrombocytopenia

182
Q

Elderly man presents with sudden onset severe low back pain.
He has 3 months history of fatigue, but most recently developed polyuria and polydipsia.
Neurological examination normal.
What is the likely diagnosis?
What cells will be present in the bone marrow?
Why does the patient have raised calcium and back pain?

A

Multiple myeloma

Cells present in the bone marrow:
Abnormal plasma cells - derived from B lymphocytes.
>10 abnormal plasma cells = myeloma.

Back pain and inc. Calcium:
Myeloma causes lytic bone lesions with calcium release. Patient is likely to have had acute collapse of a vertebral body. Normal neurology would indicate that the spinal cord is intact. Patients are at risk of spinal cord compression.

183
Q

Typical presenting complaints of a patient with multiple myeloma

A

CRAB:
C - Calcium elevation
R - Renal disturbance e.g. polydipsia, polyuria
A - Anaemia - fatigue, recurrent infections
B - Bone disease - back or rib pain

184
Q

Why are urea and creatinine elevated in a patient with multiple myeloma?

A

Myeloma kidney - can result from hypercalcaemia, infection or damage to the kidneys by the paraprotein (monoclonal antibody).
Hypercalcaemia requires urgent IV rehydration

185
Q

Why is the globulin level elevated in a patient with multiple myeloma?

What protein might you find in the urine?

A

The abnormal plasma cells release their immunoglobulins, producing an abnormal monoclonal antibody called the paraprotein (or M protein).

Protein in the urine - Bence Jones i.e. light chains

186
Q

What cancers (non-haematological cancers) metastasise to bone?

A

LP Thomas Knows Best:

Lung
Prostate
Thyroid
Kidney
Breast

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