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Haematology Flashcards

1
Q

Define haematopoesis

A

The process of blood cell production

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2
Q

Where does haematopoesis occur during different stages of foetal and human life?

A

Foetus: 0-2 months: yolk sac

2-7 months: liver, spleen

5-9 months: red bone marrow (becomes main site of haematopoesis)

All blood cells come from RED bone marrow in humans

Infant: red bone marrow

  • All bones are red/haematopoetic in infants
  • There is progressive replacement of marrow by fat (yellow BM) in long bones

Therefore..

Adult: red bone marrow

  • Red BM confined to the central skeleton and proximal ends of femurs
  • I.e. vertebrae, ribs, sternum, skull, sacrum, pelvis, ends of femurs
  • 30% BM still haematopoetically active
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3
Q

What are the characteristics of haematopoetic stem cells?

A
  • Unspecified
  • Self-renewal capacity
  • Ability to differentiate/mature
  • In the quiescent state (i.e. G0 in cell cycle): only undergo occasional cell division
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4
Q

Draw the hierarchy of haematopoetic stem cell differentiation

A

Pluripotent haeamtopoetic stem cell → myeloid stem cell or lymphoid stem cell or self-renewal (another pluripotent stem cell)

Myeloid stem cell can differentiate into:

  • Erythrocytes
  • Megakaryocytes → Platelets
  • Monocytes → Macrophages
  • Myeloblasts → Neutrophil, Eosinophils, Basophils (Granulocytes)

Lymphoid stem cell can differentiate into:

  • B- and T-Lymphocytes
  • NK (Natural Killer) cell (type of lymphocyte)
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5
Q

What are haematopoetic stem cells found?

A

Bone marrow, umbilical cord, peripheral blood after G-CSF treatment (used for chemotherapy)

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6
Q

What is the potential fate for a haematopoetic stem cell?

A
  • Self-renew and produce another stem cells
  • Differentiate into a different cell type

(HSCs have multipotent properties as they can produce several cell types)

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7
Q

What maintains and controls the fate of stem cells?

A

Different types of division:

  • Symmetrical differentiation division: contraction of stem cell numbers (cell divides into two differentiated cells)
  • Asymmetrical diversion: maintenance of stem cell numbers (one differentiated cell and one stem cell)
  • Symmetrical division: expansion of stem cell numbers (divides to produce two stem cells)

The balance between these influenced by multiple micro-environmental signals and internal cues

  • Under strict control
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8
Q

Describe the bone marrow micro-environment.

A
  • Bone marrow micro-environment = stroma
  • Supports the growth and development of haematopoetic cells
  • Rich environment composed of stromal cells and a microvascular network
  • Stromal cells display adhesion molecules to keep the developing cells in the bone marrow and are supported by an ECM
  • Stromal cells: macrophages, fibroblasts, endothelial cells, fat cells, reticulum cells
  • Macrophages, fibroblasts and fat cells secrete growth factors and adhesion molecules
  • Extra-cellular molecules secreted by stromal cells: collagen, adhesion molecules (fibronectin, haemonectin), proteoglycans inc. growth factors
  • Extra-cellular molecules needed for stem cell growth, division and differentiation into mature blood cells
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9
Q

What are the types of bone marrow?

A

Red: erythrocytes

Yellow: fat cells

There’s conversion from red to yellow but this can interconvert

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10
Q

What is the architecture of bone marrow?

A

The overall combination of the stromal layer, the glycoproteins and the extra-cellular matrix

  • Stromal cells: macrophages, fibroblasts, fat cells, reticulum cells, endothelial cells
  • Extra-cellular molecules: adhesion molecules, growth factors, collagen
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11
Q

Give three examples of hereditary haematopoetic stem cell disorders.

A
  • Thalassaemia
  • Sickle cell anaemia
  • Fanconi anaemia
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12
Q

Give 3 examples of acquired haematopoetic stem cell disorders

A

Any of:

  • Aplastic anaemia
  • Leukaemia
  • Myelodysplasia
  • Myeloproliferative disorders
  • Lymphoproliferative disorders
  • Myelofibrosis
  • Metastatic malignancy e.g. prostate, breast
  • Infeciton e.g. HIV/TB
  • Chemotherapy
  • Haematinic deficiency
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13
Q

Define leukemogenesis and leukaemia?

A
  • Leukemogenesis: The induction of leukaemia
  • Leukaemia: Malignant progressive disease (cancer) in which the BM and other blood-forming organs produce increased numbers of immature or abnormal leucocytes (called leukaemic cells). This suppresses formation of normal blood cells, leading to anaemia and other symptoms
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14
Q

How does leukemogenesis occur?

A
  • Haematopoeitc stem cells can self-renew
  • If hit by leukemogenetic event(s), the HSC becomes a leukaemic stem cell which also has the ability to self-renew and proliferate
  • The leukaemic cell will proliferate to form many clonogenic leukaemia cells (have the ability to proliferate indefinitely)
  • Differentiation will be blocked at an early stage by other leukemogenic events to form non-clonogenic leukaemia blast cells
  • Production of normal blood cells is suppressed, therefore individual is at risk of bleeding and infection
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15
Q

What is the term for haematological malignancies and pre-malignant conditions that arise from a single ancestral cell?

A

Clonal

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16
Q

What does it mean if haematological malignancies or pre-malignant conditions are termed ‘clonal’?

A

It means they arise from a single ancestral cell and can proliferate indefinitely

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17
Q

Compare and contrast lymphoid and myeloid stem cells

A

Myeloid SC: Give rise to erythrocytes, platelets, monocytes, eosinophils, basophils, neutrophils

Lymphoid SC: Give rise to T-lymphocytes, B-lymphocytes and natural killer (NK) cells

Myeloid SC: Related to bone marrow cells

Lymphoid: Related to the lymphatic system

Myeloid SC: AML and CML are the main types of malignancy

Lymphoid SC: ALL and CLL are the main types of malignancy

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18
Q

What are myeloproliferative disorders and give 3 types of chronic myeloproliferative disorders (CMD) ?

A

Clonal disorders of haematopoesis leading to cellular proliferation (over production) of one or more mature blood progeny from myeloid stem cells, being erythrocytes, granulocytes/monocytes or platelets

  • Over-production issue
  • (Slow-growing if chronic) Blood cancer in which the bone marrow makes too many abnormal RBCs, granulocytes or platelets

Examples of CMD (slow-growing cancer):

  • Essential thrombocytosis (platelet proliferation)
  • Polycythaemia rubra vera (erythrocyte prolif)
  • Myelofibrosis (over production of fibrotic tissue due to too many megakaryocytes)
  • CML
  • Chronic neutrophilic leukaemia
  • Chronic esoinophilic leukaemia
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19
Q

What is the complication of myeloproliferative disorders?

A

Can develop into acute myeloid leukaemia (AML)

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20
Q

What is essential thrombocytosis?

A

A chronic myeloproliferative disorder in which sustained megakaryocyte (platelet precursor) proliferation causes over-production of platelets

  • Defined as a platelet count greater than 600x109/L consistently
  • 50% cases carry JAK2 mutation
  • Can transform into PRV or myelofibrosis
  • Transformation to leukaemia in 3%
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21
Q

What are the signs and symptoms of myeloproliferative disorders?

A

Symptoms

  • Easily fatigued
  • Anorexia, weight loss
  • Splenomegaly: Abdominal discomfort and secondary satiety
  • Haemorrhagic complications: Easy brusing/bleeding
  • Thrombotic complications

Signs

  • Pallor (except polycythaemia rubra vera)
  • Plethora (redish complexion)
  • Petechiae (small purple spots)
  • Palpable spleen or liver (Splenomegaly and/or hepatomegaly)
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22
Q

How is essential thrombocytosis characterised?

A
  • Persistant platelet count greater than 600x109
  • Splenomegaly
  • Megakaryocyte hyperplasia
  • History of thrombotic and/or haemorrhagic episodes
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23
Q

What is the treatment for essential thrombocytosis?

A

Low risk:

  • <40yrs with no high-risk features
  • Aspirin or anti-platelet agent

Intermediate risk:

  • 40-60yrs with no high-risk features
  • Aspirin +/- Hydroxycarbamide

High risk:

  • >60yrs and/or
  • 1+ high-risk features e.g. high placelet count (>1500x109/l), previous thrombosis, thrombotic RFs e.g. HTN
  • 1st line: hydroxycabamide and aspirin
  • 2nd line: anagrelide (inhibits megakaryocyte differentiation) and aspirin
  • JAK2 inhibitors (DMARDs): reduces splenomegaly and cause funcational improvement in 70-80% patient

Main side effect of JAK2 inhibitors: thrombocytopenia

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24
Q

What is the class, action and indication for aspirin?

A

Class: Anti-platelet drug

Action:

  • Irreversible inactivation of cyclooxygenase (COX) enzyme
  • This reduces platelet thromboxane production and endothelial prostaglandin production
  • Reduced platelet thromboxane production: Reduces platelet aggregation and thrombus formation
  • Reduced prostaglandin production: Decreases nociceptive sensitisation and inflammation

Indications:

  • Secondary prevention of thrombotic events
  • Pain relief
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25
Q

What is the class, action and indication of Clopidogrel?

A

Class: anti-platelet drug

Action:

  • Irreversibly blocks the ADP-receptor on platelet cell membrane
  • Therefore inhibits formation of GPIIb/IIIa complex, required for platelet aggregation
  • Decreased thrombus formation

Indication: Secondary prevention of thrombotic events

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26
Q

What is a potential genetic component of myeloproliferative disorders?

A
  • JAK2 mutation
  • These mutations result in continuous activation of JAK receptor regardless of ligand binding
  • JAK2 is normally activated to stimulate RBC production
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27
Q

What are the different cateogories for abnormal number or type of cells in haematopoetic stem cell disorders?

A

Over-production:

  • Myeloproliferative disorders (myeloid SC)
  • Lymphoproliferative disorders (lymphoid SC)

Abnormal production:

  • Myelodysplastic syndromes

Under-production:

  • Aplastic anaemia
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28
Q

What are the types of lymphoproliferative disorders?

A

Hodgkin’s disease

  • Nodular sclerosing
  • Mixed cellularity
  • Lymphocyte rich

Non Hodgkin’s lymphoma

  • Diffuse large B-cell lymphoma
  • Follicular cell lymphoma
  • MALT lymphoma
  • Lymphoblastic lymphoma
  • Mantle cell lymphoma

Chronic lymphocytic leukaemia

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29
Q

How do you define myelodysplastic syndromes and what causes them?

A

Definition: Production of immature cells from myeloid series from the bone marrow

  • A type of cancer
  • Characterised by dysplasia and ineffective haematopoesis in one or more of the myeloid series
  • Characterised by bone marrow failure (when there is insufficient production of normal RBC, granulocytes/monocytes or platelets)
  • Some progress to AML

Aetiology: secondary to chemotherapy or radiotherapy, or de novo (new)

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30
Q

What are the main types of myelodysplastic syndromes (MDS)?

A
  • MDS with single lineage dysplasia (aka refractory anaemia): under-production of normal erythrocytes
  • MDS with multilineage dysplasia (aka cytopenic anaemia): under-production of normal erythrocytes, WBCs or platelets
  • MDS with excess blasts (aka refractory anaemia with excess blasts): under-production of normal RBCs, WBCs or platelets and have a higher risk of developing AML
  • Sideroblastic anaemia (refractory anaemia with ringed sideroblasts)
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31
Q

What is the pathogensis of myelodysplastic syndrome (MDS)/myelodysplasia?

A
  • Stem cells (blasts) don’t mature properly and accumulate in the bone marrow, pushing out normal cells, and have shortened life-span
  • Increase in the number of immature cells (blasts)
  • Increase in abnormally developed cells (dysplastic cells)
  • Fewer mature blood cells in the circulation
  • Means there are fewer RBCs, WBCs and/or platelets
  • Bone marrow failure
  • This can develop indolently (slowly) or agressively (quickly)
  • Can develop into acute myeloid leukaemia (AML)
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32
Q

What is the hallmark feature of myelodysplasia?

A

Low blood cell counts (Pancytopenia)

  • Anaemia (low erythrocyte count)
  • Neutropenia (low white cell count)
  • Thrombocytopenia (low platelet count)
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33
Q

How do cell changes manifest (i.e. correlate to symptoms/signs) in myelodysplasia (MDS)?

A
  • Anaemia: Weakness, easily fatigued, SOB, pallor
  • Neutropenia: increased risk of infection e.g. UTI, skin infection. lung infection
  • Thrombocytopenia: bruising and easy bleeding (e.g. nosebleeds)
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34
Q

What is sideroblastic anaemia and how is it characterised?

A
  • A benign type of myelodysplasia
  • The body has enough iron but is unable to use it to make haemoglobin (therefore less haemaglobin in RBCs)
  • Therefore it accumulates in the mitochondria of erythroblasts, giving a ringed appearance
  • These cells are called ringed sideroblasts and are found in the bone marrow
  • Erythroblasts - precursor to erythrocytes, are nucleated and found in bone marrow

Characterised by:

  • Refractory anaemia (underproduction of RBCs)
  • Hypochromic cells in circulating blood
  • Ring sideroblasts in the bone marrow
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35
Q

How would someone with MDS present and what investigations would you do?

A
  • Usually elderly
  • 20%: incidental finding of FBC
  • 20%: present with infection or bleeding
  • Most present with fatigue due to anaemia

Investigations:

  • Complete blood count
  • Blood smear (% and morphology of cells)
  • Bone marrow aspirate and biopsy (% of each cell in the BM)
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36
Q

How is someone with myelodysplasia managed?

A

Supportive care: Blood and platelet transfusions

  • Growth factors (erythropoietin and G-CSF (granulocyte colony stimulating factor)) to prevent infection and improve QoL

High-blast counts: low-dose chemotherapy

High-risk of developing AML: intensive chemotherapy

Allogenic stem-cell transplant: for selected patients who are well enough to tolerate the procedure i.e. younger (50-70) and no other medical problems

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37
Q

What is the function of the spleen?

A

Red pulp

  • Removal of old, damaged and dead RBCs through phagocytosis by macrophages
  • Phagocytosis of opsonised bacteria
  • Sequesteration of platelets (storage of platelets)
  • Storage of RBCs

White pulp

  • Contains T- and B- lymphocytes and macrophages
  • Important in the normal immune response
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38
Q

Why is the spleen enlarged with myeloproliferative disorders?

A
  • Extramedullary haematopoiesis i.e. haematopoiesis occuring outside the bone marrow
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39
Q

Define aplastic anaemia and its pathophysiology

A

= Anaemia due to bone marrow failure

  • Defined as pancytopenia with hypocellularity (aplasia) of the bone marrow
  • Usually an aquired disease
  • It’s due to a reduction in the number of pluripotent stem cells together with a fault in those remaining meaning they cannot repopulate the bone marrow
  • This causes deficiencies in blood cells (one or more lineages)
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40
Q

Give 3 examples of causes of aplastic anaemia

A

Primary

  • Congenital e.g. Fanconi’s anaemia (10-20% cases)
  • Idiopathic aquired (50% cases)

Secondary

  • Drugs e.g. chemotherapy
  • Infections e.g. hepatitis, HIV
  • Pregnancy
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41
Q

How is aplastic anaemia characterised in a bone marrow aspirate?

A
  • Increased % of bone marrow occupied by fat spaces

Normally

  • At 30yrs, 30% of the bone narrow should be fat spaces
  • At 70yrs, 70% should be fat spaces etc.

In aplastic anaemia, can see around 90% taken up by fat spaces

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42
Q

What is the inheritance pattern for fanconi anaemia?

A

Autosomal recessibe inheritance

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43
Q

What are the characteristics of Fanconi anaemia and what is the gold standard for treatment?

A
  • Bone marrow failure (can be present from birth into adulthood)
  • Malignancy
  • Short telomeres (causing increased cell turnover)

Gold-standard for treatment: allogenic stem-cell transplant

  • Donors need screened for Fanconi anaemia as it’s autosomal recesive
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44
Q

What are the types of stem cell transplant?

A
  • Autologous: use patients own stem cells
  • Allogenic: use stem cells from a donor

Types of donor in an allogenic transplant:

  • Syngenic: transplant between identical twins
  • Allogenic sibling: HLA identical
  • Volunteer unrelated (VUD)
  • Umbilical cord blood
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45
Q

What are autologous stem cell transplants used for and how are the stem cells acquired?

A
  • Relapsed leukaemia, Hodgkin’s disease, non-Hodgkin’s lymphoma and myeloma
  • Patient given G-CSF +/- chemotherapy to force the stem cells to leave the bone marrow to be collected from the blood
  • Use mobilised peripheral blood stem cells
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46
Q

What are allogenic stem cell transplants used for, how are the stem cells collected and what is the benefit in malignancy?

A
  • Acute and chronic leukaemia, relapsed lymphoma, aplastic anaemia, hereditary disorders
  • Use peripheral blood stem cells, bone marrow or umbilical cord blood
  • In malignancy: benefit of graft-v-leukaemia effect but at the expense of graft-v-host disease
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47
Q

What is graft-v-host disease (GvHD) and how is it treated?

A
  • An immune condition that can occur in those who receive allogenic stem cell transplants
  • The donor’s immune system (immune cells) recognises the host’s tissues as foreign and starts to attack it
  • Manifestation: Skin rash, jaundice or diarrhoea

Two forms

  • Acute: occurs within first 100 days

Chronic: occurs after the first 100 days

Treated with immunosuppressive agents

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48
Q

What is graft-v-leukaemia (GvL)?

A
  • Hidden within GvHD
  • The immune cells from the donor (same cells causing GvHD) attack the remaining leukaemic cells
  • Very effective, especially in those who’ve had difficulty maintaining remission
  • Also works for lymphoma and myeloma
  • Minimising GvHD reduces GvL therefore higher risk of relapse
  • Challange: minimise GvHD and maximise GvL
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49
Q

What are some of the issues with stem cell transplants?

A
  • GvHD
  • Limited donor availability
  • Immunosuppression
  • Relapse
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50
Q

What is the drive for erythropoiesis?

What codes for erythropoiesis?

What substances are needed?

Where does erythropoiesis take place?

A

Drive: erythropoietin (kidneys)

Code: Globin genes

Substances: folate, B12, minerals, hormones (testosterone, thyroxine)

Location: functional bone marrow

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51
Q

What is the shape (and why) and role of RBCs?

A

Shape: Biconcave

  • Inc. SA for O2 transfer
  • Smaller to fit through small vessels

Role: Gas transfer

  • Transport oxygen from lungs to tissues
  • Remove CO2 as a waste product
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52
Q

What is the structure of haemoglobin?

A
  • 1 Haemoglobin molecule has 4 haem groups and 4 globin chains (2a and 2b chains)
  • Each haem can bind to one oxygen
  • Therefore each Hb molecule can bind to 4 oxygen molecules
  • Hb can bind reversibily to O2 without being oxidised or reduced
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53
Q

How much iron is in the body and where is it stored?

A

Total body iron: 4g

Bone marrow and RBCs: 3g

RES (Macrophage store): 200-500mg

Myoglobin: 200-300mg

Enzymes containing iron): 100mg

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54
Q

What molecule transports iron in plasma?

What type of molecule is it and how does it bind to iron?

Where is it synthesised?

How do the amounts of this molecule correspond to iron levels?

A

Transferrin (Tf)

  • Glycoprotein
  • Two iron binding domains on one Tf molecule
  • 30% saturated with iron
  • Synthesised in hepatocytes in relation to iron levels
  • High iron stores: Tf levels drop
  • Low iron stores: hepatocytes produce more Tf
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55
Q

What is the role of Transferrin (Tf)?

A
  • Transports iron in plasma to cells with Tf-receptors on their surface i.e. all tissues e.g. erythroblasts (in BM), hepatocytes, muscles etc.
  • Most Tf-receptors are found on erythroblasts
  • Each transferrin molecule has two iron binding sites
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56
Q

What happens when Transferrin bound to iron reaches erythroblasts?

A
  • Iron is bound to Tf and transported to tissues with Tf-receptors e.g. erythroblasts
  • Iron is then released into the erythroblast
  • Most is taken into the mitochondria to make haem
  • The rest is stored as erythroblast ferritin
  • Most Tf-receptors are found on erythroblasts
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57
Q

What is the role of macrophages in RES in the RBC lifespan and storage of iron?

A
  • RBCs remain in circulation for 120 days then are degraded by macrophages in the reticuloendothelial system (RES)

Haemoglobin → Haem and Globin

  • Globin broken down into amino acids
  • Haem → Iron and bilirubin
  • Iron can be stored in macrophages as ferratin or haemosiderin
  • Usually stored as ferritin but if there’s a lot of ferritin, iron is stored as haemosiderin (insoluble ferritin aggregates)
  • From here it can be transported to BM to produce more RBCs
  • Macrophages found in CT, lymphoid organs, BM, bone, liver, lung
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58
Q

What can you use to determine iron deficiency?

A

Serum ferritin

  • A small amount of ferritin is found in serum
  • Levels of serum ferritin are proportional to RES iron stores
  • However, serum ferritin is also an acute phase protein, so a serum ferritin could be normal with underlying iron deficiency in the context of inflammation
  • Low serum ferritin = always low RES iron
  • Normal serum ferritin doesn’t always mean normal iron store levels
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59
Q

Describe iron homeostasis/pathway

A
  • There is no excretory pathway for iron
  • Daily iron requirements: 1-2mg/day (more in women to compensate for pregnancy and menstruation)

Hepcidin: the iron absorption regulator

  • Regulates iron absorption, which would then bind to Tf and taken to tissues expressing Tf receptor
  • Hepcidin reduces the amount of iron in plasma by binding to and degrading ferroportin (a transmembrane protein that transports iron from inside to outside the cell)
  • It reduces iron absorption at enterocyte and decreases iron release from RES
  • Once iron absorbed, bound to Tf and taken to tissues expresing Tf-receptor
  • RBCs circulate for 120 days, broken down by macrophages (RES) and stored ferritin/haemosiderin
  • This can be released when needed and bound to Tf
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60
Q

What molecule controls levels of iron in the body?

Where is this molecule synthesised?

A
  • Hepcidin: regulates iron absorption
  • ‘Low iron’ hormone: it reduces amount of absorbed iron at the enterocyte by binding to and degrading ferroportin (transmembrane protein transporting iron from inside to outside the cell)
  • Hepcidin also reduces iron release from RES

Synthesis: liver (requires HFE expression)

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61
Q

What condition occurs when there is a loss of Hepcidin?

A

Hereditary haemochromatosis

  • All the iron from the intestines is absorbed
  • Due to altered HFE expression
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62
Q

What is the role of Hepcidin?

A

Regulates iron absorption at the enterocyte

  • Binds to and degrade ferroportin to reduce iron absorption (‘low iron’ hormone)
  • Reduces iron release from RES
  • Synthesised in hepatocytes, which requires HFE expression
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63
Q

What types of anaemia are characterised by hypochromic and microcytic erythrocytes?

A
  • Iron deficiency anaemia (IDA): not enough haem
  • Thalassaemia: not enough globin
  • Anaemia of chronic disease
  • Sideroblastic anaemia
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64
Q

What is iron deficiency anaemia (IDA)?

What is the aetiology of IDA?

A

Definition

  • The body doesn’t produce enough erythrocytes and haem (made on iron) because there is not enough iron
  • Gradual onset

Aetiology

  • Dietary (rare): usually premature neonates adolescent females
  • Malabsorption (usually due to small bowel disease)
  • Blood loss
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65
Q

What would be the laboratory findings for IDA?

A
  • Blood smear: Hypochromic and microcytic erythrocytes
  • Tf saturation: <15% (liver senses less iron so produces more Tf so saturations fall

Low MCV and MCH levels on FBC

  • MCV: Mean Corpuscle Volume (ave. size of RBC) - would correspond to microcytic RBC on blood smear
  • MHC: Mean Cell Haemoglobin - would correspond to hypochromic RBC on blood smear

Low or normal serum ferritin

  • Low serum ferritin will confirm an IDA diagnosis
  • Low serum ferritin always means low RES iron stores
  • Serum ferritin could be normal with low RES iron stores in context of tissue inflammation (or rheumatoid arthritis / IBD) as it’s an acute phase protein and will be abnormally high for RES iron stores
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66
Q

What are the signs and symptoms of anaemia?

A

Symptoms

  • Fatigue, SOB, Palpitations, Pallor

Signs

  • Pallor
  • Koilonychia: spoon-shaped nails
  • Atrophic glossitis: smooth, pale, painless tongue

Angular stomatitis: small cracks ay the side of the mouth

  • Oesophageal web: leads to trouble swallowing
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67
Q

What is the golden rule for determining likely cause of IDA?

A
  • IDA in males and post-menopausal women: GI blood loss until proven otherwise
  • Young women: menstrual blood loss +/- pregnancy (only undergo GI investigations if presence of GI symptoms or blood in stool)
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68
Q

70 yr old man who is tired and pale comes to the GP.

He is not on any medication and has no GI upset.

FBC comes back:

  • Hb 90g/l (130-170)
  • MCV 60fl (80-100)
  • MCH 20pg (27-32)
  • WBCs, platelets normal

What is the likely diagnosis, how would this be confirmed and what is the most likely cause? Explain your answer

A

Blood: microcytic, hypochromic RBCs

Likely diagnosis: Iron deficiency anaemia (IDA)

Confirm diagnosis: serum ferritin

Likely cause: GI blood loss

  • Golden rule: GI blood loss until proven otherwise
  • Duodenal ulcer: usually causes gastric symptoms
  • Diverticulosis: usually associated with rapid pellet stool (upsets bowel habit)
  • Stricture in right sigmoid junction: would be painful and cause constipation/diarrhoea
  • Caecal carcinoma: asymptomatic, faeces is fluid so no disruption of bowel habit
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69
Q

What is the management for IDA?

A
  • Iron replacement

Oral Replacement

Ferrous sulfate or ferrous gluconate

IV Replacement

  • IV iron: 1g over 2-3 hours
  • Only used as a last resort and can have serious consequences
  • Used if intolerant to oral iron, poor compliance, renal anaemia and erythropoeitin (Epo) replacement
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70
Q

Where is erythropoeitin produced and what is it’s role?

A

Produced in kidneys

  • Produced in response to low blood oxygen levels (hypoxaemia)
  • It’s taken to the bone marrow to stimulate stem cells to differentiate into erythrocytes
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71
Q

Define Anaemia of Chronic Disease (ACD)

What is the aetiology of ACD?

A

Def: Anaemia due to an inflammation-mediated reduction in erythrocyte production and sometimes survival (i.e. shortened life-span)

  • Failure of iron utilisation
  • Commonly found in acute and chronic infections, autoimmune disorders, after major trauma and surgery
  • Inflammation
  • Infection
  • Neoplasia
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72
Q

What is the pathogenesis of anaemia of chronic disease (ACD)?

What would be the laboratory findings?

What is the treatment?

A

Pathogenesis

  • RES iron blockade: iron trapped in macrophages and raised Hepcidin
  • Reduced Epo repsonse
  • Depressed marrow activity

Laboratory Findings

  • MCV/MCH: normal/low

(Therefore either normocytic/normochromic or microcytic/hypochromic blood smear)

  • ESR (inflammation marker): High
  • Ferritin: Normal/high (i.e. high RES stores)
  • Serum Iron: low
  • TIBC (Tf measurement): low
  • Tf saturation: normal/low
  • Blood smear: RBC rouleaux (looks like a stack of coins) due to ESR
  • Low absolute reticuocyte count

Treatment

  • Treat the underlying disorder
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73
Q

What is the role of folate and B12 in erythrocytes?

What would be affected in folate or B12 deficiencies?

A
  • They’re required for DNA synthesis
  • Folate or B12 deficiencies would affect all rapidly growing, DNA synthesising cells (bone marrow, spithelial surfaces e.g. stomach, mouth, SI, female GUT)
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74
Q

Describe the storage and absorption of B12 and folate.

A

B12

  • Well stored: ast 3/4 years, so takes a long time for deficiencies to occur
  • B12 only absorbed in the terminal ileum
  • To be absorbed, it is bound to intrinsic factor (from parietal cells)
  • Daily intake of normal western diet (15-30ug/day) outweighs requirement (1ug/day) - small daily requirements

Folate

  • Absorption occurs in the small bowel (200-400ug/day)
  • No carrier molecule required
  • Poorly stored: only lasts a few weeks and used quickly, therefore lhigh daily requirements
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75
Q

What causes B12 deficiency?

A

Pernicious anaemia

  • Autoimmune disease with antibodies directed at intrinsic factor found in parietal cells
  • Therefore, loss of transporter molecule

Low B12 in plasma

  • Pregnancy
  • Hormone contraceptives
  • Metformin and PPIs
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76
Q

What causes folate deficiency?

A

Dietary

  • Extensive small bowel disease (where folate is absorbed) e.g. severe Crohn’s or coeliac disease

Increased cell turnover

  • Haemolysis
  • Pregnancy
  • Severe skin disorders
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77
Q

What blood abnormalities would be seen in clinical B12 OR folate deficiency?

A

Anaemia

- with macrocytic RBCs and megaloblastic bone marrow

  • caused by insufficient erythropoeisis
  • Hypercellular bone marrow so the WBC count will eventually fall

Bone marrow: megaloblastic anaemia

  • I.e. very large, abnormal immature red blood cells
  • Resulting from inhibition of DNA synthesis during RBC production, therefore cell cycle cannot progress from G2 to mitosis
  • This leads to continuing cell growth without division (macrocytic)
  • Leucopenia: reduced number of WBCs
  • Thrombocytopenia: reduced number of platelets

Macrocytic RBCs

  • Raised MCV
  • Macrocytic: larger cells therefore insufficient concentration of haemoglobin (low MCH)
  • Anisopoiklocytosis: variance in shape and size of RBCs
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78
Q

What are the signs and symptoms of B12 and folate deficiencies?

A

Symptoms of anaemia: fatigue and easy bruising

Mild jaundice: ineffective erythropoeisis in marrow (RBCs are being broken more therefore more bilirubin being produced)

With B12 only

Neurological problems: nerve disturbance

  • Bilateral peripheral neuropathy or demyelination of posterior and pyramidal tracts of the spinal cord
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79
Q

What is the only difference between B12 and folate deficiences?

A

B12 deficiencies cause neurological problems

  • Demyelination of posterior and pyramidal tracts of the spinal cord or bilateral peripheral neuropathy
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80
Q

What is macrocytosis and what causes it?

A

Definition: RBCs that are larger than normal

Causes:

  • B12 and folate deficiencies
  • Reticulocytosis
  • Cell wall abnormalities e.g. alcohol, liver disease
  • Bone marrow failure syndromes i.e. myelodysplastic syndromes
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81
Q

What are haemoglobinopathies and what are the two types?

A
  • Inherited conditions involving an abnormality in the structure of haemoglobin
  • Thalassaemia: relative lack of normal globin chains due to absent genes
  • Sickle cell disease: production of abnormal globin chains
82
Q

What chromosomes contain the coding/genes for globin chains?

A

Chromosome 11

  • 2 Beta globin genes (one on each chromosome)
  • Produces gamma globin for foetal haemoglobin and beta globin (adult haemolgobin)

Chromosome 16

  • 4 Alpha globin genes (two on each chromosome)

There are 2 copies of each chromosome so two beta globin genes and two alpha globin genes

83
Q

What are the different haemoglobins produced in foetal and adult life and what do they consist of?

A

Foetal haemoglobin:

  • F haemoglobin: 2y and 2a globin molecules

After birth (Adult haemoglobin):

  • y production switched off and b production switched on
  • A haemoglobin: 2a and 2b globin molecules
84
Q

Define thalassaemia and discuss the different types

A

Definition: Haemoglobinopathies due to lack of normal globin production due to lack of globin genes

Alpha Thalassaemia

  • Normal: inherit 4 alpha genes (2 from each parent)
  • Mutation: missing alpha genes e.g. could inherit 2 genes from mother and 1 from mother so missing one alpha gene

Beta Thalassaemia

  • Normal: inherit 2 beta genes (1 from each parent)
  • Mutation: Missing beta genes and is more of an issue as we only have 2 beta genes
85
Q

What is the clinical significance of alpha thalassaemia?

A

Missing one alpha gene

  • Mild microcytosis (small RBC therefore low MCV vaule)

Missing 2 genes

  • Microcytosis, decreased RBC count, mild asymptomatic anaemia

Missing 3 genes: Haemoglobin H Diseases (HbH disease)

  • Lack of alpha chains = relative excess beta chains which bind together (rather than with alpha globin) to produce H haemoglobin
  • RBCs: severely hypochromic, microcytic and mis-shapen
  • Splenomegaly, anaemia and fatigue
  • Blood transfusion independent condition unless periods of stress e.g. infection, as Hb levels drop

Missing 4 genes: Hydrops foetalis

  • Incompatible with life
86
Q

What is the clinical signficance of beta thalassaemia?

A

Missing 1 beta gene: Beta Thalassaemia Triat

  • Mild microcytosis

Missing 2 genes: Beta Thalassaemia Major

  • Autosomal recessive
  • Unable to make HbA (adult haemoglobin)
  • Microcytic, mis-shapen RBCs
  • Significant dyserythropoiesis (defective RBC development): BM works hard to produce RBCs (fails to do so) so get expansion of both the bone marrow and bone: cellular but ineffective BM = get frontal bossing
  • Transfusion dependent anaemia from 2yrs (problem: will develop iron overload and toxicity so need iron chelators to remove iron in urine)
87
Q

Define Sickle Cell Disease and the types

A

Sickle cell disease: haemoglobinopathy caused by production of abnormal globin chains due to abnormal globin genes

Two types:

  • Hb SS: more severe with two copies of sickle cell haemoglobin
  • Hb SC: less severe
88
Q

What is the pathogenesis of sickle cell disease?

A
  • A mutation in the B-globin gene on Chromosome 11

resulting in HbS (sickle haemoglobin) production

  • Sickle haemoglobin (HbS) = 2 alpha and 2 beta (sickle) chains
  • Problem: in low oxygen states, Hbs polymerises and with continual polymerisation the RBCs will sickle (become moon shaped)
  • Rate of of polymerisation depends on: deoxygenation rate and Hb concentration
89
Q

What is the clinical result of sickle cell disease?

A
  • Reduced RBC survival: haemolysis (haemolytic anaemia)
  • Episodes of pain (sickle crises) which can occur in many places (pain usually in hands, feet or breastbone/ribs), and are caused by occlusion of small blood vessels when RBCs sickle (in low oxygen states)
  • Occlusion of vessels can also lead to infarction

Infarction can occur in many systems:

  • Brain (stroke), lungs (pulmonary HTN), bones (dactylitis - swelling of a digit), spleen (hyposplenic), eyes (vascular retinopathy)
90
Q

How do you diagnose and treat sickle cell disease?

A

Diagnosis: blood spot test for newborns

Treatment:

  1. Prevent crisis
    - Hydration, analgesia, early intervention
    - Prophylactic vaccines and Abx: spleen is removed once sickle RBCs occlude the vessels and it starts to enlarge, therefore the patient has a reduced immune function
    - Folic acid: bone marrow is more active therefore higher folic acid requirements
  2. Management of Crises
    - Oxygen, fluids, analgesia, Abx
    - Transfusion/Red cell exchange: reduce the amount of HbS
  3. Bone marrow tranplantation: rarely
91
Q

Define haemolytic anaemia and it’s types

A

Definition: anaemia related to reduced RBC lifespan

Congenital haemolytic anaemia

  • Abnormalities of RBC membrane: Hereditary spherocytosis
  • Haemoglobinopathies: Thalassaemia and sickle cell disease
  • Abnormalities of RBC enzymes: pyruvate kinase deficiency anaemia or G6P dehydrogenase deficiency anaemia

(Structural abnormalities: Autosomal dominant, Enzymatic abnormalities: AR or X-linked)

Acquired haemolytic anaemia

  • Autoimmune: warm type (IgG) and cold type (IgM)
  • Iso-immune: haemolytic disease of new born (HDN)
  • Non-immune: fragmentation haemolysis
92
Q

Describe the relationship between progression of haemolytic anaemia and haematological results

A
  • Normally: bone marrow can compensate for a reduction in RBC lifespan down to 20days
  • RBC lifespan <20days: BM can no longer accomodate and anaemia develops

RBC lifespan = 120d

  • Normal Hb

RBC lifespan = 20-100d

  • Normal Hb, increased reticulocyte number, increased unconj. bilirubin
  • BM is pushing out more reticulocytes to compensate for reduced life span and patient won’t be anaemic: compensated haemolytic state

RBC lifespan < 20d

  • Low Hb, increased reticulocyte number, inc. uncong. bilirubin (product of haem breakdown), splenomegaly
  • In chronic haemolytic states, raised bilirubin can cause pigment gall stones
  • Haemolytic anaemia
93
Q

Give 3 examples of congenital and acquired haemolytic anaemias

A

Congenital

  • Hereditary spherocytosis: abnormality of RBC membrane
  • Thalassaemia: reduced normal globin production
  • Sickle cell disease: production of abnormal globin

Acquired

  • autoimmune haemolytic anaemia (warm and cold types)
  • Haemolytic disease of the newborn (HDN)
  • Fragmentation haemolysis
94
Q

Describe hereditary spherocytosis along with the cell changes (blood film), presentation and treatment

A

Hereditary spherocytosis: autosomal dominant (congenital) form of haemolytic anaemia involving abnormalities of the RBC membrane

Cell changes/Blood film

  • RBCs = spherocytic (spherical rather than biconcave) and polychromatic (reticulocyte count has increased)
  • Reticulocytes are immature RBCs still containing RNA therefore stain blue

Presentation

  • Jaundice
  • Splenomegaly
  • Pigment gallstones

Treatment

  • Splenectomy and hyposplenic prophylaxis: Hyposplenic state can lead to serious infection therefore try to avoid
95
Q

What enzymes, if abnormal or deficient, can cause haemolytic anaemia

A
  • Congenital haemolytic anaemia (autosomal recessive)

Kinase pyruvate: needed for ATP production

  • Deficiency causes chronic haemolytic anaemia

Glucose-6-Phosphate (G6P) dehydrogenase: helps protect against oxidative damage

  • Deficiency causes acute haemolytic anaemia
96
Q

Compare and contrast Cold and Warm type autoimmune haemolytic anaemia

A

Cold AIHA v Warm AIHA

Cold: Autoantibody IgM with complement

Warm: Autoantibody IgG with/without complement

Cold: IgM is a giant molecule with 10 binding sites, therefore causes red cells to agglutinate (stick together): seen on blood film

Warm: IgG binds to RBCs and damages membranes: become spherocytic (Autoantibodies opsonise the RBCs for phagocytosis by macrophages in the reticuolendothelial system (RES))

Cold: Usually idiopathic

Warm: Causes include idiopathic, other autoimmune disease, lymphoproliferative disorder, drug induced

Cold: Intravascular haemolysis i.e. RBCs lyse in the circulation releasing haemoglobin into the plasma

Warm: Extravascular haemolysis i.e. RBCs opsonised by Ab and phagocytosed by RBCs in the liver and spleen

97
Q

What does the blood film look like for cold AIHA, how do you diagnose it and what’s the treatment?

A

Blood film: RBCs are stuck together (agglutinated) due to IgM autoantibody

Diagnosis with a blood film: presence of agglutinates (RBCs stuck together)

Treat: harder to treat than warm AIHA. If idiopathic, keep the patient warm (hatm gloves, warm shoes)

98
Q

What does the blood film look like for warm AIHA, how do you diagnose it and how is it treated?

A

Blood film: identical to hereditary spherocytosis

  • RBCs are spherocytic and polychromatic (reticulocytes look blue due to presence of RNA in cytoplasm)

Diagnosis: Direct Coombs Test

  • Detects IgG autoantibody on the surface of RBCs

Treatment:

  • Stop any medication
  • Start steroids (this is an AI disorder)
  • Immunosuppression
  • Splenectomy: last resort. RBCs are coated with warm autoimmune autoantibodies (IgG). The RBCs are opsonised and destroyed by macrophages of the RES, most of which are found in the spleen
99
Q

What causes polychromatic RBCs on a blood film and how?

A

An increased number of reticulocytes (RBC precursors) as they still contain RNA in the cytoplasm. RNA stains blue which causes difficult colours on a blood film

100
Q

How to you diagnose warm AIHA?

A

The Direct Coombs Test

  • Detects the presence of IgG autoantibody on the surface of RBCs

How does it work?

  • Antibodies are added to a blood sample
  • These antibodies will react to the IgG on RBC surface, forming immunological lattices
  • The red cells will stick together: red cell agglutination

A +ve result will occur with:

  • AIHA
  • HDN (Haemolytic Disease of the Newborn)
  • Patients with antibody on the surface of RBCs
101
Q

What is the purpose, procedure and use for Direct Coombs Test?

A

Purpose: Detects IgG on the surface of RBCs

How it works: Add antibodies to a blood sample. The antibodies will react to IgG on the surface of RBCs and form immunological lattices.

  • This will cause RBCs to stick together: RBC agglutination

+ve test with:

  • AIHA
  • Haemolytic Disease of the Newborn (HDN)
  • A patient with antibodies on the surface of their RBCs (not necessarily AIHA)
102
Q

What is the use for the Indirect Coombs Test?

A

Purpose: To detect RBC antibodies in plasma

  • Used to crossmatch a patient with a unit of blood
  • Testing for immune antibodies
  • Mix a sample from the unit of blood intended for transfusion with a sample of the patient’s plasma
  • If there are immune antibodies: they will stick the the red cells from the blood sample of donor
  • Then add antibodies to detect the immune antibodies on the RBCs (i.e. Direct Coombs Test)
103
Q

What is haemolytic disease of the newborn (HDN)?

A
  • An iso-immune haemolytic anaemia
  • Occurs when there is a Rhesus -ve mother, RhD+ partner and a RhD+ baby
  • The foetal and maternal circulations mix
  • RhD+ red cells of the baby escape into maternal circulation and the mother makes antobodies against RhD+ antigens
  • These antibodies cross the placenta and attack RBCs of the baby§
104
Q

What’s a systematic approach when looking at haematological results?

A

Size of RBCs:

  • Hypochromic, microcytic: IDA usually
  • Macrocytic: megaloblastic bone marrow (B12/folate deficiency)

Are WBCs/platelets affected?

  • Anaemia with abnormal WBCs/platelets: likely to be a bone marrow problem

Haematinic results:

  • Haematinic: nutritents required for normal erythropoiesis i.e. folate/B12/ferritin

What does the blood film look like?

  • Rouleaux: ACD
  • Agglutinated RBCs: Cold AIHA
  • Polychromatic: inc. reticulocytes e.g. hereditary spherocytosis or Warm AIHA
  • Ringed sideroblasts
105
Q

Differentiate between lymphoma, myeloma and leukaemia

A

Lymphoma: cells tend to aggregate and form massess/tumours in lymphatic tissue

Myeloma: tumour of the bone marrow and involves plasma cells that produce antibodies

Leukaemia: cancerous cells circulate in the blood and bone marrow

106
Q

What are the two classifications of lymphoma?

A

Hodgkin’s lymphoma (15%)

Non-Hodgkin’s lymphoma (85%)

107
Q

What is the epidemiology of lymphoma?

A
  • Commonest blood cancer
  • Occurs at any age
  • Commonest cancer in the <30yrs
108
Q

What is the clinical presentation of lymphoma?

A
  • Lymphadenopathy: painless, rubbery
  • Splenomegaly
  • B symptoms: systemic symptoms of unexplained fever, drenching night sweats and weight loss
  • Anaemia
109
Q

What investigations are needed with a patient with suspected lymphoma?

A
  • History: symptoms, duration, B symptoms
  • Clinical Exam: lymph nodes, splenomegaly
  • Blood tests: FBC etc, ESR (raised in Hodgkin’s lymphoma), LDH (turnover rate, raised in aggressive lymphoma), could be normal
  • Imaging: CT, PETCT
  • BM Biopsy: taken from iliac crest
110
Q

How is lymphoma staged ie what are the stages

A

Stage I: single lymph nodes group involved above or below the diaphragm

Stage II: more than 1 lymph node group involved on the same side of the diaphragm

Stage III: lymph node group involvement on both sides of the diaphragm (inc. spleen)

Stage IV: Extranodal involvement eg. liver, bone marrow

A or B

  • A: no B symptoms, B: B symptoms present
111
Q

What factors affect lymphoma treatment?

A
  • Type and stage of lymphoma
  • Age, performance status
  • Co-morbidities
  • Patient preference
112
Q

What are the types of non-Hodgkin’s lymphoma?

A

B Cell (>90%):

  • Follicular lymphoma (indolent)
  • Diffuse Large B cell lymphoma (aggressive)

T Cell:

  • Aggressive or indolent
113
Q

What are the features of follicular lymphoma?

A
  • Indolent (low-grade) B-cell lymphoma
  • CD20 antigen expressed on B-lymphcytes (target for the monoclonal antibody Rituximab)
  • Resembles normal germinal centres (where B cells proliferate)
  • Characterised by translocations involving BCL2 gene
  • Slow growth but reduced apoptosis
114
Q

How does follicular lymphoma usually present?

A
  • Usually presents with stage 4 (advanced) disease as they are slow growing and don’t cause many symptoms
  • Median age: 65yrs
  • B symptoms less common
  • Indolent: causing little/no pain
  • Usually incurable as diagnosed at such a late stage
115
Q

What is the treatment for follicular lymphoma?

How does it respond to treatment?

A

As most present at advanced disease, treatment aimed at alleviating symptoms rather than cure

Early stage: 1A/2A: localised radiotherapy, curable

Advanced stage:

  • Asymptomatic, no bulk, no end organ damage: watch and wait
  • Symptomatic +/or organ compromise: immunochemotherapy
  • Rituximab (anti CD20 monoclonal Ab) and chemo

Very responsive to tratment but there’s a tendancy to relapse

116
Q

What are the features of Diffuse large B-cell lymphoma?

A
  • Agressive/High grade B-cell lymphoma
  • Resembles activated B-cells: large, multinucleated cells
  • CD20 antigen expressed on B-lymphocytes (Rituximab target)
  • High proliferation fraction, variable rate of cell death
  • Most common NHL subtype
117
Q

How does diffuse large b cell lymphoma normally present?

A
  • Lymphadenopathy: usually rapidly enarging LN mass
  • B symptoms
  • Extra-nodal presentation: Waldeyer’s ring, GI tract, skin, bone, CNS
  • Agressive but curable in >50%
118
Q

What is the treatment for diffuse large b-cell lymphoma?

A
  • Agressive chemotherapy with intention to cure
  • Variable response

Early (Stage 1A): R-CHOP (chemo) x3 and radiotherapy

  • All other stages: R-CHOP x6

R-CHOP Chemotherapy

  • Rituximab
  • Cyclophosphamide
  • H: Adriamycin
  • O: Vincristine
  • Prednisolone

Given on day 1 of 21 day cycle

119
Q

What is Burkitt Lymphoma?

What are the characteristic clinical features?

How is it treated?

A
  • Very high-grade B-cell lymphoma
  • Resembles proliferating germinal centre cells
  • Very high proliferation rate and high rates of apoptosis
  • Marked B symptoms, massive tumour bulk and extra-nodal disease
  • Treat with intensive chemotherapy
120
Q

What are the main subtypes of Hodgkin’s lymphoma?

A

Classical (>90%)

  • Nodular sclerosing
  • Mixed cellularity
  • Lymphocyte rich
  • Lymphocyte depleted

Nodular lymphocyte predominant

121
Q

What is the peak incidence of Hodgkin’s lymphoma?

What is the other RF for Hodgkin’s lymphoma?

What are the most common subtypes?

A

Peak incidence: 20-24yr olds, second peak in 70-79yr olds

Other RF: male

Most common: nodular sclerosing and mixed cellularity

122
Q

Describe the pathology of classical Hodgkin’s lymphoma

A
  • High grade lymphoma with prominent component of reactive cells
  • Neoplastic cells resemble atypical activated B-cells
  • Characterised by strong CD30 expression and loss of some B-cell antigens

Malignant cell: Reed-Sternberg cell

  • Giant cells, mono-/binucleated
  • This is the differentiating cell between Hodgkin’s and non-Hodgkin’s lymphoma (ie. no Reed-Sternberg cell: classified as non-Hodgkin’s)
  • These are mixed with neutrophils, lymphocytes, macrophages
123
Q

What is the differentiating feature between Hodgkin’s and non-Hodgkin’s lymphoma?

A

Presence of the Reed-Sternberg cell in Hodgkin’s lymphoma

124
Q

What is the clinical presentation of classical Hodgkin’s lymphoma?

How would it spread?

A
  • Painless lymphadenopathy: usually a neck lump with associated cough and SOB
  • Spreads to adjacent lymph nodes than haematogenous spread to liver, lungs and bone marrow
  • May have B symptoms
  • Itch
  • Alcohol related pain
  • May present with CXR mass (usually neck)
125
Q

How is classical Hodgkin’s lymphoma diagosed?

A

A core biopsy or excision node biopsy

126
Q

What is the treatment for classical Hodgkin’s lymphoma?

A
  • High cure rate (>90%)

Early stage: chemotherapy followed by radiotherapy

Advanced: intensive chemotherapy

Chemotherapy: ABVD

Adriamycin

Bleomycin

Vinblastine

Dacarbazine

127
Q

Define myeloma

A

A tumour of plasma cells in the bone marrow which are part of the immune function and release antibodies

128
Q

What are some features of myelomas?

A
  • Neoplastic cells resemble normal plasma cells
  • Typically the nucleus is to one side and basophilic cytoplasm

Abnormal plasma cells will produce abnormal antibodies called paraproteins

  • Usually see IgG and IgA
  • Light chain myeloma: only part of the immunoglobulin is produced
  • Non-secretory myeloma: no Ig produced
129
Q

What is the clinical presentation of a myeloma?

A

Majority of cases have non-specific symptoms

  • Backache, rib pain
  • Fatigue
  • symptoms from hypercalaemia (due to bony erosion)
  • recurrent infection
  • renal impairment
130
Q

What typifies myeloma?

A

Classical triad

  1. Increased plasma cells in bone marrow
  2. Clonal immunoglobulin or paraprotein
  3. Lytic bone lesions (bone damage caused by build up of cancerous plasma cells)
131
Q

What investigations would be indicated in a suspected myeloma?

A

Blood tests

  • ESR: >100
  • FBC, Ca, U&Es
  • SFLC (serum free light chain) quantity

Blood film

  • Rouleaux: coin stacking of red cells
  • Blue-ish background due to rise in protein

Urine Tests: look for light chains in urine

Bone marrow aspirate: excess plasma cells

Imaging: MRI goos for identifying lytic lesions

  • Numerous lytic lesions scattered throughout skull: pepperpot skull
132
Q

What would a blood film look like in myeloma?

A

Rouleaux RBCs (stacking)

Blue-ish background due to increased protein (immunoglobulins)

133
Q

How is myeloma diagnosed?

A

Neoplastic plasma cells in BM >10% of total cells with one of the following

  • Evidence of end-organ damage attributable to plasma cell prolif (CRAB): hypercalaemia, renal insufficiency, anaemia, bone lesion
  • Biomarker of malignancy: clonal plasma cell % >=60%, serum free light chain ratio >=100, >1 focal lesion on MRI
134
Q

How is myeloma treated?

A

Only treat the symptomatic

  • Bone marrow transplant
135
Q

Define leukaemia

A

Blood cancer resulting in the accumulation of abnormal leucocytes (WBCs) in bone marrow +/- blood +/- other tissues

136
Q

Outline the classification of leukaemia

A

Acute

  • Acute myeloid leukaemia (AML)
  • Acute lymphoid leukaemia (ALL)

Chronic

  • Chronic myeloid leukaemia (CML): can turn into acute leukaemia (AML or ALL)
  • Chronic lymphoid leukaemia (CLL): can transform into a high-grade lymphoma
137
Q

What is the main consequent of leukaemia?

A

Bone marrow failure

138
Q

Compare acute and chronic leukaemia

A

Acute: symptoms due to bone marrow failure

Chronic: symptoms due to accumulation of cells

Acute: presents with florrid marrow failure, taking over the marrow quickly causing bruising, fatigue, pancytopenia

Chronic: don’t get marrow failure to same degree with non-specific symptoms eg. weight loss, night sweats. High WBC counts in the blood

Acute: Arises over a couple of weeks and will probably kill you quickly

Chronic: Presents over a couple of months and may kill you slowly

139
Q

Compare lymphoid and myeloid leukaemia

A

Lymphoid: tumour of T and B lymphocytes (related to the lymphatic system)

Myeloid: everything else ie. neutrophils, basophils, monocytes, eosinophils etc. (related to the bone marrow)

140
Q

What is secondary acute leukaemia?

A

When it arises from a pre-existing bone marrow condition:

  • myeloproliferative disorders (MPD)
  • myodysplastic syndromes (MDS)
141
Q

Outline the pathology of acute leukaemia

How quickly does it progress?

A

Clonal disorders: neoplastic malignant cells derived from a single ancestor

Blastic proliferation in bone marrow: maturation arrest ie. blast cells look primative and not maturing so expand and encroach on the bone marrow

Rapid onset

Serious compromise of normal marrow

Death within days-weeks if untreated

142
Q

List 3 aetiologies of acute leukaemia

A

Usually idiopathic

Chemical

Chemotherapy

Radiotherapy

Genetics eg. Down’s syndrome, Fanconi syndrome

MDS

MPD

143
Q

List 5 clinical features seen with acute leukaemia

A

Rapid onset of symptoms

Lymphadenopathy (accumulation of WBCs in the lymph nodes)

Legarthy (anaemia)

infection (neutropenia)

bleeding and bruising inc. purpuric rash (thrombocytopenia)

bone pain

gum swelling, mouth ulcers

144
Q

What is seen on a blood film of a patient with acute leukaemia?

A

anaemia

neutropenia

thrombocytopenia

blast cells present (as well as excess blast cells seen in BM)

145
Q

What is seen in a bone marrow sample in a patient with acute leukaemia?

A

Blast cells >20% of the bone marrow

146
Q

What is the role of flow cytology in diagnosing acute leukaemia?

A
  • Can look for CD20 antigens
  • can type leukaemias quickly and accurately
  • essential to determine prognosis
  • allows decisions to be made on management
147
Q

List 3 associations with a poorer outcome with acute myeloid leukaemia (AML)

A

secondary AML (to MDS/MPD)

relapsed AML

Elderly patients

Refractor to induction ie. no response to first line chemo

148
Q

What are the management options for acute myeloid leukaemia (AML)?

A
  1. Intensive chemotherapy +/- stem cell transplant
    - Used for patients <60
    - 5yr survival: 50%
  2. Low dose chemotherapy
    - For patients 60-65
    - 5yr survival: <10%
  3. Supportive care only
    - Older patients with major co-morbidities and a median survival 4-6 months
149
Q

What in the aim of chemotherapy in acute leukaemia?

List 3 complications of chemotherapy

A
  • Aims to eradicate the abnormal clone

Complications:

  • Bleeding and infection worsens with treatment
  • Hair loss, sterility, mucositis
  • Prolonged inpatient stays
  • Psychological element
150
Q

Which age group is mostly affected by acute lymphoid leukaemia?

List 3 symptoms/signs of ALL

A

Age group: mostly seen in kids

Clinical Presentation

  • limping child: bone pain
  • purpuric rash (thrombocytopenic rash)
  • unexplained, severe bone pains
151
Q

What is the mainstay of treatment for ALL?

A

Chemotherapy

  • CNS directed treatment is essential to prevent relapse
152
Q

Outline the supportive care provided for acute leukaemia

A

Blood transfusions: symptomatic patients, improves quality of life

Fresh frozen plasma (FFP):

  • For coagulopathy/disseminated intravascular coagulation (DIC: blood clots form throughout the body)

Platelet transfusion:

  • Purpura and bleeding

Abx

Growth factors (prevent risk of infection)

153
Q

List 3 patients with acute leukaemia who would benefit from stem cell transplants

Outline the type of transplant used

A

Patients:

  • younger, healthier patients
  • relapsed patients
  • refractory patients
  • age <60

Transplant used: allogenic

  • HLA matched stem cells
  • NB GvHD and GvL: donor immune system is what cures the patient but will also attack patient’s normal cells and so need a balance
154
Q

Outline the epidemiology and aetiology of chronic lymphoid leukaemia (CLL)

A

Epidemiology:

  • incidence rises with age (median is 67yrs)
  • male

Aetiology: idiopathic

155
Q

How does CLL present and how is it diagnosed?

A

Presentation:

  • None (75% incidental findings)
  • B symptoms (night sweats, weight loss, legarthy)
  • Anaemia symptoms
  • Lymphadenopathy (excess WBCs accumulate in lymph nodes)
  • Infection (neutropenia)

Diagnosis:

  • Incidental finding
  • FBC shows isolated lymphocytosis (elevated lymphocyte numbers): seeing this in an older, fit person is almost always CLL until proven otherwise

- Diagnosed by flow cytology: clonal B-lymphocyte population >5x109/L

156
Q

List 3 infective complications of CLL

A

Hypogammaglobinaemia: may need globin replacement

Cell mediated immunity impaired

  • T-lymphopenia
  • Neutropenia
  • Defects in complement activation

Pulmonary infection is common

157
Q

What determines the need for treatment with CLL?

A

Symptoms:

  • B symptoms, symptomatic nodes

Bone marrow failure:

  • anaemia, thrombocytopenia, neutropenia
  • Do not treat the asymptomatic*
158
Q

What is the clinical presentation of chronic myeloid leukaemia (CML)?

A
  • Asymptomatic (20-50%)
  • B symptoms
  • Abdominal discomfort
  • Splenomegaly in 50-70%
159
Q

What genetics are involved in CLL and CML

A

CLL: 17p deletions resulting in loss of p53

CML: gene translocation of Bcr-Abl gene (the bcr-abl protein produced changes the behaviour of the cell)

160
Q

How is chronic myeloid leukaemia (CML) diagnosed and treated?

A

Diagnosis;

  • blood film and clinical features
  • molecular testing: bcr-abl on PCR or FISH
  • if Bcr-abl negative: not CML

Treatment;

  • imatinib: blocks bcr-abl phosphorylation of these targets
161
Q

What blood type is the universal donor and which is the universal recipient?

A

O- : universal donor

AB+ : universal recipient

162
Q

Outline the primary assessment for a patient with a major bleed

A

ABCDE

Resuscitation

  • Access
  • Fluids (replace what’s being lost)
  • Blood products
  • Transexamic acid: a fibrinolysis inhibitor (helps clots that form to remain establisted)

If still in shock due to blood loss:

- Major haemorrhage protocol: RBCs, FFP, platelets and cryoll (rich source of fibrinogen)

163
Q

Outline the major bleed protocol

A
  1. Take baseline blood samples before transfusion for
    - FBC, U&Es, LFTs, Ca, group and save, clotting screen including fibrinogen
  2. If trauma and <3hr from injury, give transexamic acid
  3. Gain IV access, do ABC and give oxygen
  4. Use O- until patient group is known and use group-specific blood as soon as possible. Also give FFP and platelets

If bleeding continues:

  • If no lab results available: give further FFP, cryoll and platelets
  • If lab results known: red cells if falling Hb, FFP if PT ratio >1.5, cyroll if low fibrinogen and platelets if low platelets
164
Q

Define a major haemorrhage

A
  • Loss of more than one blood volume within 24hours (around 70ml/kg, >5l in a 70kg adult)
  • 50% of total blood volume lost in less than 3 hours
  • Bleeding in excess of 150ml/min
165
Q

List 3 complications of a major bleed

How can these be avoided

A

Haemorrhagic shock:

  • more bleeding, less circulating volume, lower CO, less oxygen delivery, less tissue perfusion
  • hypothermia: use warmer blood, keep patint warm, foil hat, monitor temp
  • acidosis: monitor with blood gases
  • coagulopathy: Give platelets, FFP, cryoll
  • hypocalcaemia: replace if low levels on blood gas
166
Q

What 3 things are required for effective coagulation and what would imbalance of coagulant and anticoagulant facots cause?

A

Required:

  • Functioning platelets
  • Functioning endothelium
  • Coagulation factors

Imbalance:

  • Thrombosis or bleeding
167
Q

Outline the process from a laceration to the skin to activation of coagulation factors

A

Laceration damages the blood vessels and disrupts endothelium

Exposure of:

  • tissue factor and collagen
  • Von Willebrand Factor (VWF - promotes platelet aggregation) binds to collagen when it’s exposed
    1. Stimulates primary haemostasis:
  • Recruitment and adhesion of platelets (bind to VWF)
  • The binding activates the platelets and they release granular contents, attracting more platelets, activating them etc.
  • Activation of platelets also leads to exposure of phospholipids
  • this forms a platelet plug
    2. Stimulates secondary haemostasis:
  • activation of coagulation factors
  • Primary and secondary haemostasis occur simultaneously*
168
Q

Draw the coagulation cascade and clotting factors

169
Q

Outline the events that occur in the coagulation cascade

A

Initiation: extrinsic pathway

  • Produces small amounts of thrombin (IIa) from prothrombin (II)
  • Thrombin also activated F VIII, which cross-links fibrin and strengthens it

Propagation: intrinsic pathway

  • Comes from the small amount of thrombin produced in initiation and propagates the whole system
  • Thrombin with F IX activates XIII
  • XIIIa and IXa propagate prothrombinase complex

Thrombin generation and fibrin production

Regulation:

  • Need balance between coagulation and anticoagulation factors
  • Initiation and propagation need regulated
  • Anti-thrombin III: down-regulates prothrombin and almost all coag factors
  • When thrombin is made, it binds to a thrombomodulin receptor which is an important feedback mechanism

Fibrinolysis

  • Need to be able to breakdown the fibrin clot when wound is healing
  • Plasminogen is converted to plasmin
  • Plasmin degrades cross-linked fibrin into fibrin degradation products
  • Self-regulation: fibrin stimulates production of plasminogen activators
170
Q

What laboratory tests can be used to assess primary haemostasis?

A
  • FBC (platelet count)
  • Platelet functionality: light transmission aggregometry
171
Q

What laboratory tests can be used to assess secondary haemostasis?

A

Prothrombin Time (PT): extrinsic pathway

  • Extrinsic: Factors VII
  • Common: X, V, II and fibrinogen

Activated Partial Thromboplastin Time (APTT): intrinsic pathway

  • Intrinsic: XIII, IX, XI, XII
  • Common: X, V, II and fibrinogen

Thrombin clotting time (TCT)

  • Measurement of how much fibrinogen is in the blood to be comverted into the fibrin clot
  • Dependent on levels of fibrinogen and how well the fibrinogen functions
172
Q

What are the three classes of antithrombin agents?

A

Anticoagulants: inhibit one or several components of the coagulation cascade

  • Warfarin, rivaroxaban, apixaban, dabigatran, Heparin

Fibrinolytic agents: enhance lysis of fibrin clot

Anti-platelet agents: inhibit platelet activation or aggregation

  • Aspirin, Clopidogrel
173
Q

Where do the following act in the coagulation cascade:

Warfarin

Heparin

Dabigatran

Apixaban

Rivaroxaban

A

Warfarin: Vit K antagonist, so factors II, VII, IX, X

Heparin: stimulates anti-thrombin III that directly inhibits activation of prothrombin

Dabigatran: thrombin

Apixaban and rivaroxaban: Xa

174
Q

What is the indication and action of Heparin?

A

Indication:

  • Treatment and prophylaxis for thromboembolic events: immediate anticoag effect for acute DVT/PE and prophylaxis against VTE
  • Renal dialysis
  • Acute coronary syndrome treatment

Action:

  • Enhances the activity of antithrombin III
  • Antithrombin III inhibits thrombin
  • Heparin also inhibits other factors in the coagulation cascade inc. factor Xa
  • Produces an anticoagulant effect
175
Q

List 3 pharmacokinetics with Warfarin

A
  • Delayed onset and onset: 3-4 days before any level of coagulation, 4-5 more days to reach steady state, and 3 days for anti-coagulant effect to wear off
  • Effective T 1/2 (36hours)
  • Narrow therapeutic window: low INR means it’s ineffective, too high means high bleeding risk
  • Many drug and food interactions
  • Not for immediate anticoagulation or short-term thromboprophylaxis
176
Q

Compare Warfarin and DOACs

A

Warfarin: slow onset, slow offset resulting in smooth anticoagulation

DOACs: Rapid onset and offset

Warfarin: requires INR monitoring

DOACs: requires annual review

Warfarin: Many drug and food (inc. alcohol) interactions

DOACs: few drug and no food/alcohol interactions

Warfarin: renal impairment may inc. bleed risk

DOACs: renal impairment may be a contra-indication

Warfarin: rapid reversal with vit. K

DOACs: no rapid reversal agent

177
Q

What are the two major classes of fibrinolytics?

A

Kinases

  • Streptokinase, urokinase

Tissue plasminogen activators (tPA)

  • Alteplase, tenecteplase
178
Q

What is the class, indication and action of alteplase/tenecteplase?

A

Class: tissue plasminogen activators (tPA)

Indication:

  • acute ischaemic stroke within 4.5 hours of onset
  • myocardial infarction within 12 hours of onset
  • massive pulmonary embolism

Action:

  • recombinant form of tissue plasminogen activator
  • catalyses the conversion of plasminogen to plasmin
  • promotes fibrin clot lysis
179
Q

What drugs are used for catheter directed thrombolysis?

List 2 pros and 2 uses of catheter directed thrombolysis

A

Drugs:

  • tissue plasminogen activators (tPA): alteplase and tenecteplase
  • kinases: urokinase and streptokinase

Pros:

  • Smaller doses- Administered directly into the vessel containing thrombosis

Uses:

  • Acute limb ischaemia
  • Massive DVT
  • Blocked CVC (central venous catheters)
180
Q

What is the class, indication and action of clopidogrel?

A

Class: anti-platelet drug

Indication:

  • secondary prevention of thromboembolic events

Action:

  • Irreversibly blocks the ADP receptor on the platelet cell membrane
  • This inhibits the formation of GPIIb/IIIa complexes, needed for platelet aggregation
  • Reduced platelet aggregation and thrombus formation
181
Q

What is the class, indication and action of aspirin?

A

Class: anti-platelet drug

Indication:

  • secondary prevention of thrombotic events
  • Pain relief

Action:

  • Irreversible inactivation of the cyclo-oxygenase enzyme (COX-2)
  • This reduces platelet thromboxane production and endothelial prostaglandin production:
  • Reduced thromboxane production: reduced platelet aggregation and thrombus formation
  • Reduced prostaglandin production: reduced nociceptive sensitisation and inflammation
182
Q

List 3 indications for anti-platelet drugs

A
  • CV disease
  • Acute MI
  • Secondary prevention of CVD
  • Acute stroke/TIA/secondary prevention
  • Peripheral vascular disease
183
Q

Define disseminated intravascular coagulation (DIC)

What is the pathophysiology?

A

DIC is a acquired, consumptive process characterised by systemic activation of coagulation, resulting in the generation and deposition of fibrin, leading to microvascular thrombi formation in various organs

Pathophysiology:

  • Haemostasis is out of control with over-activation of the coag cascade
  • This leads to the formation of many micrsovascular thrombi
  • Eventually, there is exhaustion of the coag cascade due to consumption of coag factors and platelets
  • This leads to bleeding even with slight blood vessel damage
  • Can result in life-threatening haemorrhage

Patients have both thrombi and haemorrhage

184
Q

List 3 causes of disseminated intravascular coagulation

A

DIC due to the release of pro-coagulants eg. TF and bacterial components

Sepsis

Malignancy

Massive haemorrhage

Severe trauma

Pregnancy complications eg. pre-eclampsia

185
Q

How would disseminated intravascular coagulation (DIC) present?

A

Bleeding: bruising, mucous bleeding (eg. gums), needle placement

Blood in urine and stool

Chest pain, SOB

Confusion

Headache

Low BP

186
Q

What would the results be in the following for a patient with DIC?

Platelets

Fibrinogen

PT

APTT

D-dimer

A

Platelets: low

Fibrinogen: low

PT: prolonged

APTT: prolonged

D-Dimer: marker of clotting

187
Q

How is DIC managed?

A
  • Treat underlying cause
  • FFP +/- platelets in bleeding or high-risk of bleeding
  • Organ support: ventilator, haemodynamic, transfusions
188
Q

Confused 80yr old lady in A&E after being found behind the food of sheltered housing

GCS: 9

Right sided weakness with dysphasia

  • Irregular pulse
  • Sent for CT: intracranial bleed
  • FBC is normal
  • Coag: prolonged PT and APTT

What is the likely diagnosis?

A
  • Haemorrhage
  • Longer clotting time affecting both intrinsic and extrinsic pathways or common pathway

Over-coagulationg with warfarin

  • Warfain affects F II, VII, IX, X therefore mainly affects prothrombin time
189
Q

How is a patient with an elevated INR with Warfarin managed?

A
  1. Stop warfarin or reduce dose
  2. Give Vit K (oral or IV): rapid reversal
  3. Give coag factors (II, VII, IX, X): reverses warfarin effect within 30mins
190
Q

List 3 associations with coagulopathy in liver disease

A
  • poor coagulation for synthesis in the liver
  • disseminated intravascular coagulation
  • hypersplenism
  • reduced thrombopoietin synthesis
191
Q

35yr old man attends A&E following an altercation in the pub

  • Receives punches to the face and kicks to right leg, no bruising or bleeding and no fractrues on X-Ray
  • Tells staff he has an inherited bleeding disorder

Investigations:

  • PT: normal
  • APTT: 75 (range 26-38)
  • TCT: normal
  • Platelets: normal

What would explain the APTT value?

What is the likely diagnosis?

A

APTT = prolonged

  • Isolated prolonged APTT means defect in the intrinsic pathway (F VIII, IV, XI)
  • Factors VIII and IX deficiencies are more serious and associated with Haemophilia

Likely diagnosis: Haemophilia A

192
Q

Outline the pathology of haemophilia A

List 3 clinical features

What lab finding would you see?

A

Pathology:

  • Factor VIII deficiency: impairs the body’s ability to make blood clots
  • X-linked recessive (men affected, women are carriers)

Clinical features:

  • bleeding for a prolonged time after injury
  • easy brusiing
  • bleding inside joints (haemarthroses)
  • delayed bleeding

Lab: isolated prolonged APTT

193
Q

What is the management for coagulation factor deficiencies?

A
  • Education: remember to tell doctors
  • Desmopressin: boost’s body’s own factor VIII, but won’t work if patient cannot make any factor VIII
  • Replacement therapy in severe Haemophilia
194
Q

25yr old female referred to haematology

  • Heavy menstrual bleeding since menarche
  • Frequent nose bleeds
  • Easy bruising but no petechiae

Lab results:

  • elevated APTT, low Hb, low MCV
  • low F VIII

Comment on relevent factos from the history and results

What are the differential diagnoses?

A
  • Mucosal bleeding: uterus and nasal mucosa
  • No petechaie: petechaie suggest problem with primary haemostasis ie. platelets
  • Factor VIII is low

Differetials:

  • Haemophilia A
  • Von Willebrand Disease
195
Q

What is the role of Von Willebrand Factor?

A
  • facilitates platelet aggregation and adhesion in primary haemostasis
  • binds factor VIII and prolongs it’s T 1/2 in plasma (influences secondary haemostasis)
196
Q

What is Von Willebrand Disease?

What is the inheritance of WVD?

How is it characterised?

A

= A genetic disorder caused by lack of or defective Von Willebrand Factor

  • Mild bleeding disorder

Inheritance: autosomal dominant with variable penetrance

Characterisation:

  • Mucosal bleeding
  • Reduced VWF with/without reduced platelet aggregation (prolonged PT) with/without reduced F VIII (prolonged APTT)
197
Q

45yr old male with recurrent DVT

  • 1st DVT: 25yrs following a football injury, 2nd at 30yrs (unprovoked)
  • Both mother and sister have suffered from pulmoanry embolisms

What is the likely diagnosis?

A

Inherited thrombophilia (the tendancy to form thromboses)

198
Q

Define thrombophilia

Outline the potential causes

A

= Tendancy to form thromboses

Causes: deficiencies of natural anticoagulants (regulators of the coagulation cascade)

  • Antithrombin
  • Protein C
  • Protein S
199
Q

If a lab result shows prolonged APTT, what can you do to help determine the underlying cause of the abnormal result?

A

mix equal amounts of the patient’s plasma with normal plasma

  • If deficiency of a factor from extrinsic pathway: VIII, IX, XI, XII, mixing with normal plasma should fix the problem
  • If it is still prolonged: suggests the presence of an inhibitor causing the prolonged APTT
200
Q

What inhibitors could be present in a patient’s plasma to cause a prolonged APTT?

A
  • Lupus anticoagulant = phospholipid dependent antibody
  • interferes with phospholipid dependent tests ie. APTT
  • if persistent, may be associated with prothrombotic state

Phase 3 (12 decks)

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