Haematology Flashcards
(107 cards)
1
Q
Describe the volume and composition of blood
A
Blood:
- 5 L blood volume per adult (7% body weight)
- 40-50% increase in volume during pregnancy
- Composition of blood:
- Erythrocytes
- Thrombocytes
- Leukocytes: neutrophils, eosinophils, basophils, lymphocytes, monocyte
- Plasma: water, proteins, clotting factors, electrolytes, CO2, O2
- Haematocrit:
- Volume percentage of red blood cells (47% M; 42% F)
2
Q
Describe haematopoeisis
A
Haematopoiesis – production of blood cells in bone marrow (BM):
- Multipotent hematopoietic stem cells (HSCs) are able to differentiate into both myeloid and lymphoid cell lines.
- Dysregulation may lead to deficiencies (e.g. anaemia, leukopenia, thrombocytopaenia) or over-production (e.g. haematological malignancies)
3
Q
Describe the regulation of haematopoeisis
A
Regulation depends on glycoprotein growth factors, which drive the proliferation and differentiation of progenitor cells:
- Erythropoietin (EPO)
- Thrombopoietin (TPO)
- Interleukins (e.g. IL-3, IL-6, IL-7, IL-11)
- Colony-stimulating factors (e.g. M-CSF, G-GSF)
- Negative regulators (e.g. TNF-alpha, TGF-beta)
4
Q
Recall the haematopoetic cell lineages
A
5
Q
Describe the pre-natal and post-natal haematopoetic niches (2 points)
A
Two key hematopoietic niches:
- Prenatally: aorta-gonad-mesonephros (AGM) region and yolk sac, placenta, foetal liver, spleen, and bone marrow.
- Postnatally: primary site is bone marrow (BM) but can shift to extramedullary sites in response to haematopoietic stress.
Bone marrow niches:
- Local tissue microenvironments that maintain and regulate HSC
- Perivascular
- Most commonly located near trabecular bone.
6
Q
Describe the maturation process of red blood cells (4 points)
A
Erythropoiesis – synthesis and maturation of red blood cells (erythrocytes):
- HSCs differentiate into myeloid progenitor cell
- Nucleated erythroblasts are committed to becoming mature erythrocytes
- Extrusion of their nucleus (to increase space for Hb)
- Reticulocytes – immature red blood cells that contain organelle remnants (enter circulation)
7
Q
Recall the erythopoeisis mechanism of action (4 points)
A
Regulation – negative feedback mechanism (4 points):
- Low O2 level in the blood (2° to hypoxia, hypotension, hypovolaemia)
- Kidneys produce and secrete ertythropoetin (EPO)
- EPO acts on committed, undifferentiated cells to stimulate maturation
- Increased oxygen-carrying capacity of the blood results in return to original levels of EPO (negative feedback)
8
Q
Recall the breakdown of red blood cells in the recycling or iron and haem
A
9
Q
Recall the Schilling Test
A
Note:
IM injection of Vitamin B12 needed to fully saturate the transcobalamin proteins in blood. Once saturated, any remaing free (or later absorped vitamin B12) cannot be bound and so will just end up excreted in the urine – we want this to happen as part of the test.
The “later absorped” vitamin B12 in this case is the oral dose, and this is what is being tested to see if your GI tract can naturally absorb vitamin B12.
Any absorption of vitamin B12 into the blood (by either IM or p.o.) must result in excretion by the kidney.
To know if you are actually peeing out vitamin B12 which was taken orally and absorped via the terminal illeum, it is radiolabelled for detection.
Vitamin B12 in blood → “When it’s free, it will pee. When it’s bound, it is sound (i.e. cannot be peed out whilst still bound to transcobalomin protein).”
10
Q
Recall the metabolic pathway of vitamin B12 and folate
A
11
Q
Recall the lymphopoeisis pathway
A
12
Q
List 5 properties of an erythrocyte
A
Erythrocytes:
- Biconcave shape
- No nucleus
- Rich in haemoglobin (iron-containing protein)
- Primary function is gas exchange
- Lifespan of ~120 days
13
Q
Recall the exchange of gases (O2 and CO2) in alveolar capillaries of lungs
A
14
Q
Describe haemoglobin (4 points)
A
Haemoglobin (Hb):
- ~6 x 109 Hb molecules per erythrocyte (i.e. inside each RBC)
- Each Hb molecule made of 4 subunits:
- 2 alpha globin chains
- 2 beta globin chains
- Each Hb can carry 4 oxygen molecules
- Centre is ferric iron (Fe2+) – binding site for O2.
15
Q
Recall the oxygen-haemoglobin dissociation curve
A
16
Q
List 4 key erythrocyte (red blood cell) diseases
A
Key erythrocyte diseases (4 points):
- Anaemia
- Polycythaemia
- Haemochromatosis
- Haemolysis
17
Q
Define anaemia
A
Anaemia – decreased number of RBCs, haemoglobin or ability to carry oxygen in blood
Basic causes of anaemia (3 points):
- Blood loss
- Impaired RBC production
- Increased RBC destruction
Classified by size (MCV):
- Hb < 130 g/L (M); < 120 g/L (F)
18
Q
List 3 key basic causes of anaemia
A
Basic causes of anaemia (3 points):
- Blood loss
- Impaired RBC production
- Increased RBC destruction
19
Q
List the 3 classifications of anaemia
A
Classifcations of anaemia:
- Microcyitc anaemia (MCV < 80 fL)
- Normocyctic anaemia (MCV 80–100 fL)
- Macrocytic anaemia (MCV > 100 fL)
Reference Hb levels by gender:
- Hb < 130 g/L (M)
- Hb < 120 g/L (F)
20
Q
Describe 2 key underlying causes of normocytic anaemia
A
Anaemia (MCV 80–100 fL) – normocytic anaemia:
- Total Hb and haematocrit reduced, RBC size remains normal.
Reticulocyte (immature RBC) count low – hypoproliferative (< 2%):
- Anaemia of chronic disease (e.g. cancer, autoimmunity) related to infalmmation-mediated reduction in RBC count
- Aplastic anaemia (bone marrow failure – haematopoietic stem cells damaged → pancytopenia)
21
Q
Recall anaemia of chronic disease with respect to inflammation-mediated reduction in RBC count
A
22
Q
Define microcytic anaemia and list 2 main types
A
Anaemia (MCV < 80) – microcytic anaemia:
- Main types (2 points):
- Iron deficiency anaemia
- Thalassaemia (haemoglobin deficiency)
23
Q
Describe the aetiology of iron deficiency anaemia and list 8 risk factors
A
Main causes of iron deficiency anaemia (3 key points):
- Blood loss – principal cause, GI bleed (e.g. NSAID-associated peptic ulceration), menorrhagia
- Decreased dietary intake – inadequate diet/impaired absorption of iron
- Increased demand – pregnancy, lactation, growth
Prevalence of iron deficiency aneamia – 3% (M); 8% (F) in UK:
More common in premenopausal and third trimester women (i.e. menstruation/postpartum hemorrhage)
Infants and adolescents increased risk during growth spurt
Prevalence decreasing due to fortification of foods (e.g. cereals)
Risk factors for iron deficiency anaemia:
- Black women
- Pregnancy
- Vegan diet
- Menorrhagia
- Haemodialysis
- Gastrectomy
- NSAID use
- Obesity
24
Q
List 5 key signs and symptoms of iron-deficiency anaemia
A
Signs and symptoms:
- Fatigue
- Koilonychia (‘spoon nail’ convexity)
- Alopecia
- Glossitis
- Angular stomatitis
25
**Describe the treatment options for iron-deficiency anaemia**
Treatment of iron deficiency anaemia – where dietary changes insufficient:
* Oral supplementation – ferrous sulfate 2-3 mg/kg/day divided doses
* Red cell transplantation – symptomatic at rest with dyspnoea, chest pain or pre-syncope
26
**Describe the aetiology of thalassaemia (4 points)**
Thalassaemia aetiology:
1. _Inherited_ erythropoiesis disorder – _abnormal Hb production_
2. Type depends on which _globin chain_ is abnormal:
* Alpha
* Beta
3. Inherited in _recessive_ fashion
* Parents diagnosed with thalassaemia minor have a 50% of passing on the disorder to their offspring
4. Most common in Italian, Greek, Middle Eastern, South Asian, and African ethnicity
27
**Describe thalassaemia pathophysiology (5 points)**
Thalassaemia pathophysiology:
1. _Globin chain_ production is _deficient/absent_
2. _Imbalance_ between alpha and beta chains
3. _Precipitation of excess chains_ in erythroid precursors and maturing red cells
4. Results in _membrane damage and cell destruction_ → anaemia
5. _Extramedullary haematopoiesis_ in the liver and spleen, resulting in _organomegaly_.
Bony changes in the skull due to the marked erythroid hyperplasia:
28
**Outline the thalassaemia history and examination**
Thalassaemia Hx and examination:
1. Lethargy
2. _Hepatosplenomegaly_
3. Jaundice
4. Spinal deformity
5. _Large head_
6. _Chipmunk facies_
7. _Misaligned teeth_
8. Failure to thrive
29
**List the treatment options for thalassaemia and the disease complications**
Thalassaemia treatment options:
* Genetic counselling
* Transfusion if symptomatic
* Iron chelation
* Splenectomy
* Stem cell transplant is only cure
Thalassaemia complications:
* _Thrombotic complications_
* Arthropathy (Fe2+ related)
* Osteopaenia
* Skin pigmentation
* Anterior pituitary dysfunction
* Transfusion complication
* Cord compression
* CVS complications
30
**Define macrocytic anaemia and describe 2 main types**
Anaemia (MCV \> 100) – macrocytic anaemia:
* _Inhibition of DNA synthesis_ during erythropoiesis → cell therefore has _prolonged growth phase of cell cycle_ → large (macro-) cell (-cyte)
Main types of macrocytic anaemia (2 points):
1. Megaloblastic
2. Non-megaloblastic
31
**List three basic causes of macrocytic anaemia (3 points)**
Main causes of macrocytic anaemia:
1. Vitamin B12/folate deficiency (resulting in _megaloblastic_ anaemia)
2. Alcoholism (resulting in _non-megaloblastic_ anaemia)
3. Hypothyroidism (resulting in _non-megaloblastic_ anaemia)
32
**Define megaloblastic anaemia and list 2 main causes**
Megaloblastic anaemia – results from _inhibition of DNA synthesis:_
* _Megalocytes_ and _hypersegmented neutrophils_ are present on peripheral smear.
Main causes of inhibition of DNA synthesis (which leads to megaloblastic anaemia):
1. _Vitamin B12 deficiency_ (e.g. pernicious anaemia due to lack of intrinsic factor produced by stomach)
2. _Folate deficiency_ (e.g. dietary insufficiency; absorption insufficiency
_Both_ vitamin B12 and folate mutually depend on each other for metabolism:
33
**Define non-megaloblastic anaemia and list 4 main causes**
Non-megaloblastic anaemia – megalocytes and segmented neutrophils are _not present_ on peripheral smear.
Therefore, _unlikely_ to be due to inhibition of DNA synthesis.
Main causes of non-megaloblastic anaemia
* Alcohol abuse (resulting in _liver disease_)
* _Hypothyroidism_
* Reticulocytosis (i.e. BM is highly active in an attempt to replace RBC loss in haemolytic anaemia)
* Myelodysplastic syndrome
34
**Describe the aetiology of sickle cell anaemia (4 points)**
Sickle cell anaemia is caused by an _autosomal-recessive_ gene defect in the _beta chain of Hb_ (_HbA – 'adult'_) which results in production of sickle cell haemoglobin (_HbS – 'sickle'_).
HbS causes the red blood cell to assume a sickle cell shape which is _more easily destroyed_ (resulting in anaemia)
35
**Describe the epidemiology of sicle cell anaemia (5 points)**
Sickle cell anaemia epidemiology:
1. SCA – 1 in 2000 live births in UK
2. 8% of black people carry the sickle cell gene
3. 10% - 30% in sub-Saharan Africa
4. Associated with African, Arab, Indian subcontinent, SE Asia and Mediterranean ethnicities
5. _Gives some resistance to Malaria_
36
**Describe the pathophysiology of sickle cell anaemia (6 points)**
SCA pathophysiology:
1. Deformed cells cause _vaso-occlusion_ in the _small vessels_ or adhere to vascular endothelium, resulting in _intimal hyperplasia_ in larger vessels and slowing blood flow
2. _Inflammatory state_
3. Precipitating factors: acidosis, dehydration, cold temperatures, extreme exercise, stress and infection
4. High blood cardiac output to compensate for anemia may result in _cardiomegaly_.
5. _Splenic sequestration_ or _temporary bone marrow aplasia_ can cause _circulatory failure_ and become life-threatening in children
6. Splenic dysfunction increases _vulnerability to serious infections_
37
**List 9 history and examination findings of SCA**
SCA Hx and examination:
1. _Painful crises_
2. _Maxillary hypertrophy with overbite_
3. Dactylitis
4. Fever
5. Pneumonia-like symptom
6. Bone pain
7. Visual floaters
8. Failure to thrive
9. Pallor
10. Jaundice
11. Tachycardia
38
**List the treatment options for sickle cell anaemia (SCA) and the disease complications**
SCA treatment:
* Analgesia
* Antihistamine
* Correction of trigger
* Hydration
* Antibiotics
* Blood transfusion
* Hydroxyurea
* Bone marrow transplant
39
**Define haemostasis ( 2 points)**
Haemostasis is the physiological process that _stops bleeding at the site of an injury_ while _maintaining normal blood flow elsewhere in the circulation_
40
**List 3 basic components of haemostasis (3 points)**
Components of haemostasis:
1. Vascular reaction
2. Platelet aggregation – primary haemostasis
3. Coagulation cascade – secondary haemostasis
41
**Describe the vascular reaction of haemostasis**
Vascular reaction:
1. Vascular endothelial cells produce both _pro-_ and _anti-coagulating factors_
2. In the absence of injury _anti-coagulation_ factors are _released_
3. Pro-coagulant factors are contained in _subendothelial_ tissue and so are _only exposed during vessel injury_ (e.g. von Willebrand factor, vWF)
42
**Recall the basic components of endothelial cells and subendothelial connective tissue in relation to blood**
43
**List 4 properties of a thromboyctes (platelets)**
Thrombocytes (4 points):
1. _Anuclear_
2. Derived from _megakaryocytes_ of _myloid cell lineage_ (fragments of cytoplasm)
3. Circulating _lifespan ~10 days_
4. _Without injury_ – _do not adhere_ to each other or to endothelium
44
**Recall the platelete adhesion and aggregation pathway of primary haemostasis**
Platelet adhesion and aggregation pathway:
1. Vessel _injury_
2. _Platelets adhere_ to exposed subendothelial materials e.g. _collagen_ and _von Willebrand factor_ (vWF)
3. vWF in endothelium binds to platelet glycoprotein GP Ib
4. vWF binding _exposes GPIIb/IIIa sites_ (activation of GP IIb/IIIa)
5. GP IIb and GP IIIa link with counterparts on other platelets via vWF
6. Primary haemostatic plug → stable haemostatic plug
45
**Recall the primary haemostasis pathway**
46
**List the stages of primary haemostasis**
Primary haemostasis mechanism – primary haemostatic plug formation:
1. _Platelets adhere_ to exposed vWF and collagen, and _partially activate_
* __Full activation of platelets via paralell secondary haemostasis pathway
2. _Platelets degranulate_ releasing _adenosine diphosphate_ (ADP), _serotonin_ and _thromboxane A2_.
* ADP recruits more platelets
* Serotonin is a vasoconstrictor
* Thromboxane A2 stimulates platelet aggregation and further activation
3. Platelet plug generated at site of vessel injury (needs to be stabilized)
Stabilization of haemostatic plug → via secondary haemostasis pathway
47
**Recall the secondary haemostasis pathway**
48
**List the secondary haemostasis mechanism**
Secondary haemostasis mechanism – cogulation cascade
Coagulation cascade overview:
1. Three pathways:
* _Intrinsic pathway_ and _extrinsic pathway_ result in a _common pathway_
2. _Stepwise progression_
3. Most components are _serine proteases_ (about 30 proteins involved overall)
4. Activated components act as _enzyme_ for next step (i.e. cascade)
5. Results in _generation of fibrin clot (i.e. stable haemostatic plug)_
49
**Describe the intrinsic pathway of the coagulation cascade (5 points)**
Intrinsic pathway:
1. Activated by _endothelial injury_ (exposure to subendothelial connective tissue)
2. Takes _minutes to activate_
3. Otherwise known as _“contact pathway”_
4. Cascade: (XII→XIIa) ⇒ (XI→XIa) ⇒ (IX→IXa) ⇒ (VIII→VIIIa)
5. Results in formation of factor Xa
* Factor XIIIa and Ca2+ converts factor X to Xa
50
**Describe the extrinsic pathway of the coagulation cascade (5 points)**
Extrinsic pathway (5 points):
1. Activated by _endothelial injury_ (exposure to subendothelial connective tissue)
2. _Immediate_ activation
3. Otherwise known as _"tissue factor pathway"_
4. _Tissue factors_ released converts factor _VII to VIIa_
5. Results in formation of factor _Xa_
* Factor VIIa and Ca2+ converts factor X to Xa
51
**Describe the common pathway of the coagulation cogaulation cascade (3 points)**
Common pathway:
1. Factor Xa converts _prothrombin_ to _thrombin_
2. Thrombin converts _soluble fibrinogen_ to _insoluble_ fibrin
3. Factor XIIIa helps _crosslinking of fibrin to stabilize clot_ (form stable haemostatic plug)
52
**List 2 clotting co-factors essential for normal haemostasis**
Clotting co-factors (2 points):
1. Calcium – binds to the phospholipids of endothelial cells to _provide a surface for local assembly of coagulation factors_
2. Vitamin K – required for _carboxylation_ of _factors II, VII, IV, and X_ in the liver:
* Vitamin K is given to newborns to prevent neonatal haemorrhagic disease.
53
**Recall the pathways for clot stabilzation and clot breakdown (fibrinolysis)**
54
**List 2 antiplatelet drugs and describe their role in treatment and prevent of blood clots**
Antiplatelet drugs:
1. Aspirin
2. Clopidogrel
Role in treatment and prevention of blood clots:
* Decrease platelet aggregation (_inhibit thrombus formation_)
* Effective in _arterial circulation_
* Used in prevention (and management) of _small vessel disease_
* Indications: secondary prevention of stroke/MI
55
**List 2 key anticoagulant drugs**
Anticoagulant drugs:
1. Warfarin
2. Heparin (and low molecular weight heparin, LMWH)
Other drugs include directly acting oral anticoagulants (DOACs) and fondaparinux
Role in the treatment and prevention of blood clots:
* Inhibit the coagulation cascade (targets clotting factors)
* Prevent and treat thrombus e.g. in DVT/PE/AF
56
**Recall the mechanism of action of warfarin**
Warfarin – Vitamin K antagonist (inhibits vitamin K reductase, VKORC1):
* Reduces availability of functional factor II, VII, IX, X → inhibits coagulation cascade
57
**Recall the mechanism of action of heparin**
Heparin:
* Binds to and activates _antithrombin_ → inactivates thrombin and factor Xa → prevents formation of fibrin → destabilizes blood clot
58
**Describe 3 pro-coagluant drugs**
Pro-coagulant drugs (3 points):
1. Tranexamic acid – antifibrinolytic:
* Stabilization of fibrin clot (commonly used in trauma, XLA, PPH)
2. Prothrombin complex
* Contains factors II, VII, IV and X (reverses effects of warfarin)
3. Vitamin K (e.g. phytomenadione)
* Inhibits action of warfarin by replacing vitamin K
59
**List 5 key blood clotting disorders**
Bleeding disorders – coagulopathies:
"**_V_**ampires **_D_**o **_H_**ave **_L_**ong **_T_**eeth"
1. **_V_**on Willebrand disease (most common hereditary coagulopathy):
* Autosomal dominant
* Deficiency in vWF
* Easy bruising, nosebleeds and bleeding gums
* Tx with desmopressin prior to dental procedure.
2. **_D_**isseminated intravascular coagulation:
* Widespread clotting throughout body
* Occlusion of small vessels
* Clotting factors and platelets “used up”
* Widespread bleeding and organ failure – high mortality
* Key causes of disseminated intravascular coagulation (3 points):
* Cancers
* Massive tissue injury
* Sepsis.
3. **_H_**aemophilia A and B:
* X-linked recessive inheritance
* Type A – reduced factor VIII; type B – reduced factor IX
* Spontaneous bleeding (commonly intra-articular)
* Heavy bleeding in dental treatment/surgery.
4. **_L_**iver failure:
* Impaired clotting factor synthesis – jaundice, ascites, bleeding gums
5. **_T_**hrombocytopaenia:
* Low levels of platelets
* Inherited or acquired condition (e.g. heparin-induced thrombocytopaenia)
* Purpura of arms and petechiae in feet, legs, and mucous membranes.
60
**Recall the triad of death**
Trauma and severe blood loss → triad of death:
"**_C_**uts **_A_**re **_H_**azardous"
1. **_C_**oagulopathy (decreased coagulation)
2. **_A_**cidosis (incrased acid in blood)
3. **_H_**ypothermia (decreased heart performance)
61
**Define leukaemia**
Leukaemia (‘leuk-’ – white; ‘-aemia’ – blood):
* Uncontrolled proliferation of partially developed white blood cells (i.e. blast cells) – build up in blood
* Although leukaemia specifically means cancer of white blood cells, it may refer to cancer of _any_ of the blood cells (including erythrocytes, thrombocytes, and lymphocytes)
62
**Describe 4 key haematological malginancias**
Hamatological malignancies (4 points):
1. Acute myeloid leukaemia (AML)
2. Chronic myeloid leukaemia (CML)
3. Acute lymphoid leukaemia (ALL)
4. Chronic lymphoid leukaemia (CLL)
Both _myeloid_ and _lymphoid_ progrenitors are susceptiple to haematological malgnancy
63
**Recall the genetic aetiology of leaukamia with reference to clonal expansion (5 points)**
Genetic factors – clonal expansion:
"**_S_**omatic **_M_**utation **_A_**llows **_L_**eukaemia **_C_**ommencement"
1. **_S_**ingle cell somatic mutation – alteration of DNA that happens _after_ conception
2. **_M_**utation can occur at _stem cell_ or _progenitor cell_ stages during development
3. **_A_**cquisition of _growth advantage_
4. **_L_**eukaemic stem cells (LSCs) then undergo _clonal expansion_ → _bulk leukaemia_
5. **_C_**lonal expansion exhibits _pre-clinical_ and eventually _clinical manifestations_
64
**List 4 environmental factors associated with leukamogenesis**
Environmental factors (4 points):
"**_C_**arcinogens **_D_**o **_I_**ncrease **_R_**isk"
1. **_C_**arcinogens (e.g. alkylating agents, oxidising agents, DNA)
2. **_D_**rugs (e.g. nitrosourea)
3. **_I_**nfections (e.g. EBV, H pylori)
4. **_R_**adiation (e.g. X-ray, UV)
65
**Describe the pathophysiology of acute myeloid leukaemia (5 points)**
AML pathophysiology:
1. _Differentiation “freeze”_ occurs in myeloid progenitor cell (_myeloblast_)
2. Myeloblasts do not mature/differentiate
3. Disruption in control of proliferation leads to uncontrolled clone of immature myeloid cells
4. Immature myeloblasts secrete _inhibitory substances_ into BM
5. Development of healthy blood cells in marrow disrupted → "_ANT_":
* **_A_**naemia
* **_N_**eutropenia
* **_T_**hrombocytopenia.
66
**List the genetic changes which lead to AML**
Genetic changes which lead to AML (3 points):
1. Reciprocal chromosomal translocations:
* Rearrangement of chromosomes leads to gene fusion – most commonly _(t8;21)(q22;q22)_
2. Point mutations of the _p53 tumour suppressor gene_
3. Specific genetic mutations:
* _Class I mutations_ spontaneous mutations:
* _JAK2_, FLT3, cFMS, cKIT, or downstream signalling pathways (KRAS, NRAS/BRAF, or PTPN11)
* _Class II mutations_ – DNA damage
* In genes encoding for transcription factors important in haematopoietic differentiation
Normal karyotype:
* 23 pairs of autsomal chromosomes and 1 pair of sex chromosomes
67
**Recall the French-American-British (FAB) classification of AML**
68
**List 8 clinical presentations of AML**
AML clinical presentations:
1. _Mucosal bleeding_
2. _Bruising/petechiae_
3. _Gingival enlargement_
4. _Recurrent infections (dental, nasopharyngeal, chest, perianal)_
5. Hepatosplenomegaly
6. Sweet’s syndrome (neutrophilic infiltrates in skin)
7. Bone pain
8. Non-specific signs and symptoms:
* pallor, fatigue, fever, dyspnoea, lymphadenopathy, abdominal pain, palpitations
69
**List the diagnostic investigations for AML (5 points)**
AML diagnosis and investigations:
1. Full blood count – neutropaenia, thrombocytopaenia, anaemia
2. Peripheral blood smear – immature blast cells, Auer rods
3. Coagulation screen
4. Electrolytes – increased uric acid, hypercalcaemia
5. _Bone marrow biopsy_ – provides definitive diagnosis (blast cells in ≥ 20%)
70
**List 3 treatment options for AML and 5 disease complications**
AML treatment options (3 points):
1. Supportive care
* Hydroxycarbamide (i.e. hydroxyurea) to increase Hb
* Hydration therapy
* Blood transfusions
* Anti-infectives
2. _Chemotherapy_
3. Stem cell transplant
AML complications and prognosis (5 points):
1. Tumour lysis syndrome
2. Pancytopenia
3. Disseminated intravascular coagulation (DIC)
4. Neutropenic sepsis
5. Leukostasis (extremely elevated blast cell count and symptoms of decreased tissue perfusion)
Prognosis – 5-year survival rate 25%; poorer prognosis in patients aged \> 60 years.
71
**Describe the pathophysiology of chronic myeloid leukaemia (CML)**
CML pathophysiology:
1. _Reciprocal chromosomal translocation_ between _chromosomes 9 and 22_
* Results in an _abnormal chromosome 22_ → _Philadelphia chromosome_
2. _BCR gene on Ch 22_ is _fused_ to _ABL gene on Ch 9_,
* Results in a _BCR-ABL fusion oncogene_ → _p210 BCR-ABL protein_
3. p210 BCR-ABL protein is an _active tyrosine kinase_ that alters activity of downstream signal transduction proteins (via phosphorylation of a tyrosine residue of the target substrate) → transforming normal haematopoietic stem cells into _malignant cells_.
72
**Recall the genetic changes which lead to CML**
73
**List the 3 clinical presentation phases of chronic myeloid leukaemia (CML)**
CML clinical presentation phases (3 points):
1. _Chronic_ phase (\< 5% blasts)
2. _Accelerated_ phase (10–30% blasts)
3. _Blast crisis_ (\> 30% blasts)
74
**List 2 treatment options for CML**
Treatment options for CML:
1. Imatinib – tyrosine kinase inhibitor
2. Stem cell transplant plus high dose chemotherapy
75
**Define myeoloproliferative disorders**
Myeloproliferative disorders – group of disorders characterised by _overproduction of myeloid cells lines in BM_
76
**List the 5 WHO classified myeloproliferative disorders**
Myeloproliferative disorders – group of disorders characterised by _overproduction of myeloid cells lines in BM_
WHO classified myeloproliferative disorders (5 points):
"**_C_**hronic **_C_**ell **_P_**roliferation **_P_**rovokes **_E_**mergencies"
1. **_C_**hronic neutrophilic leukaemia
2. **_C_**hronic eosinophilic leukaemia
3. **_P_**rimary myelofibrosis
4. **_P_**olycythaemia vera
5. **_E_**ssential thrombocythemia
Includes also chronic myelogenous leukaemia and mastocytosis
77
**Describe chronic neutrophilic leukaemia**
Chronic neutrophilic leukaemia:
* Rare
* Hepatosplenomegaly (accumulation in liver and spleen)
* _Progressive neutrophilia (≥ 25×109/L)_
* _Absence of Philadelphia chromosome_ is diagnostic criteria
* _Transformation to AML_ (median time 21 months)
* Survival 6 m – 20 yrs
78
**Describe polycythaemia vera**
Polycythaemia vera:
* Primarily erythrocytosis; often thrombocytosis and leukocytosis
* JAK2 V617F somatic mutation → activates EPO receptor signalling
* Increased RBC mass and/or haematocrit → hyperviscosity → increased clotting risk
* Increased risk of thrombosis (arterial and venous)
* 'Red face' due to excess blood volume
* Tx – phlebotomy (bloodletting) and aspirin (to prevent clotting)
79
**Describe primary myelofibrosis**
Primary myelofibrosis:
* Abnormal HSC clone proliferation results in fibrosis/scarring/replacement of BM
* Unknown aetiology – associated with JAK2 mutation
* Abnormalities in RBC, WBC, and platelet production (cytopenias)
* Leukoerythroblastosis and splenomegaly are the clinical hallmarks
80
**Describe essential thrombocythemia**
Essential thrombocythemia:
* Dysregulated megakaryocyte proliferation → increased platelet no./size
* Thrombosis and bleeding
* Half of patients are asymptomatic
* Diagnosis of exclusion
* High-risk patients treat with aspirin and hydroxycarbamide
81
**Describe chronic eosinophilic leukaemia**
Chronic eosinophilic leukaemia:
* Very rare myeloproliferative disease
* Overproduction of eosinophils
* Chronic disease that may progress to AML
* Overactivation of the oncogene or translocation
* Can be treated with Imatinib
82
**Describe the pathophysiology of acute lymphoid leukaemia (ALL)**
ALL pathophysiology:
* Genetic alteration of _lymphoid progenitor_ through somatic changes → _uncontrolled proliferation and clonal expansion_
* Leukaemic blasts infiltrate the BM and other organs
* Leukaemic blast cells duplicate most normal lymphoid progenitor cells
* Genetic abnormalities:
* Chromosomal translocations or aneuploidy are found in 75% of ALL cases
* _Philadelphia chromosome_
* Philadelphia-like ALL (poor prognostic factor)
83
**List the ALL classification (2 points)**
ALL classification:
1. B-lymphocytic leukaemia
2. T-lymphocytic anaemia
84
**List 9 clinical presentations of ALL**
ALL clinical presentations:
1. Hepatosplenomegaly
2. Bruising/petechiae
3. Epistaxis
4. Menorrhagia
5. CNS infiltration – papilledema (optic disc swelling due to ↑ICP), meningism, focal neurological signs
6. Unilateral testicular enlargement
7. Renal enlargement
8. Skin infiltration
9. Non-specific – fever, lymphadenopathy, symptoms of anaemia, body pain
85
**List the diagnostic investigations for ALL (6 points)**
ALL diagnosis and investigations:
1. FBC – normocytic normochromic anaemia, leukocytosis (WBC \>50 x 10^9), thrombocytopaenia, neutropaenia
2. Blood smear – lymphoblasts
3. Bone marrow biopsy – lymphoblasts, hypercellularity
4. Lumbar puncture – if evidence of CNS infiltration
5. CT/MRI brain
6. CT thorax/abo/pelvis
86
**List 5 treatment options for ALL and 8 disease complications**
ALL treatment (5 points):
1. Chemotherapy
2. Tyrosine kinase inhibitor
3. Prophylactic antibiotics +/- antifungals
4. Blood transfusions
5. _Stem cell transplant_
ALL complications (8 points):
1. Opportunistic infections
2. Febrile neutropenia
3. Tumour lysis syndrome
4. Tx-related alopecia
5. Tx-related coagulopathy
6. Multiorgan failure
7. CNS toxicity
8. Infertility
87
**Describe the pathophysiology of chronic lymphoid leukaemia (3 points)**
CLL pathophysiology:
1. Accumulation of multiple genetic events affecting oncogenes and tumour suppressor genes of lymphocytes
2. CLL _cells infiltrate lymphatic system_ and _haematopoietic organs_ such as liver, spleen, and BM
3. CLL cells also involved in _initiating autoantibody production by normal B cells_, leading to autoimmune reactions such as _autoimmune haemolytic anaemia_.
88
**Describe the genetic changes which lead to CML**
CLL genetics:
1. Exact cause unclear → accumulation of multiple genetic events affecting oncogenes and tumour suppressor genes (e.g. TP53, NOTCH1, SF3B1, ATM, and BIRC3), leading to increased cell survival and resistance to apoptosis
2. Molecular markers e.g. mutated immunoglobulin heavy chain (_IgHV_)
89
**Recall the clinical presentation of CLL**
CLL clinical presentation:
1. Non-specific: fever, chills, night sweats, symptoms of anaemia, lymphadenopathy, brusing
2. Splenomegaly
3. Recurrent infections
90
**List 3 treatment options for chronic lymphoid leukaemia (CLL) and 5 disease complications**
CLL treatment options:
1. Observation only in early stages
2. Chemoimmunotherapy
3. Stem cell transplant
CLL complications:
1. Hypogammaglobulinaemia – deficient in IgG, IgA or IgM
2. Autoimmune haemolytic anaemia
3. Immune thrombocytopaenic purpura
4. Secondary malignancy
5. Richter transformation (15%)
91
**Define lymphoma**
Lymphoma – malignant neoplasms of lymphatic tissue
92
**List the two main types of lymphoma**
Two main types of lymphoma – Hodgkin’s lymphoma and Non-Hodgkin’s lymphoma:
* Hodgkin’s lymphoma:
* 15% of all lymphomas
* Presence of _Reed-Sternberg cells_
* Non-Hodgkin’s lymphoma:
* 85% of all lymphomas (i.e. the remaining percentage that is not Hodgkin’s)
93
**Describe Hodgkin's lymphoma (6 points)**
Hodgkin’s Lymphoma (HL):
1. Uncommon haematological malignancy arising from mature B cells → _Ig expression absent_
2. Presence of Hodgkin's cells and _Reed-Sternberg_ cells
3. Can be _EBV-related_
4. PET-CT, essential to determine extent of disease
5. Biopsy necessary to confirm diagnosis
6. Treatment: chemotherapy plus radiotherapy
94
**Recall the clinical presentation of HL**
HL clinical presentation:
* Most commonly presents with _painless cervical and/or supraclavicular lymphadenopathy_ in a young adult
* Fevers, night sweats, and weight loss occur in 30%
95
**Recall the lymph nodes of the head and neck**
96
**Describe Non-Hodgkin's lymphoma (5 points)**
Non-Hodgkin’s lymphoma (NHL):
1. NHL’s are a _heterogeneous group_ (\> 30) of solid malignancies of the lymphoid system
2. Malignant lymphoid cells _retain qualities of normal counterparts_ (B cells to produce immunoglobulins; T cells to travel to extra-nodal sites such as skin and CNS)
3. Incidence increases with age
4. M \> F
5. More common in Caucasians
97
**List the 4 stages of NHL progression**
Stages of NHL progression (4 points):
1. Stage I – localized disease; single lymph node region or single organ
2. Stage II – two or more lymph node regions on same side of diaphragm
3. Stage III – two or more lymph node regions above and below diaphragm
4. Stage IV – widespread disease; multiple organs with or without lymph node involvement
98
**List 8 clinical presentations of NHL**
NHL clinical presentation:
1. Non-specific – fever, fatigue/malaise, night sweats, lymphadenopathy, SOB, weight loss
2. Splenomegaly
3. Hepatomegaly
4. Focal neurological signs
5. Bone pain/back pain
6. Jaundice
7. Bruising
8. Skin lesions
99
**List 9 risk factors for NHL**
NHL risk factors:
1. Age \> 50 yrs
2. M \> F
3. Immunocompromised host
4. EBV
5. Human T lymphocyte virus
6. Human herpes virus
7. H pylori
8. HIV
9. Organ transplantation
100
List 8 diagnostic investigations for NHL
NHL diagnosis and investigations:
1. FBC
2. Blood smear
3. _Lymph node biopsy_
4. Skin biopsy
5. Bone marrow biopsy
6. HIV/hep virus
7. PET scan
8. Lumbar puncture
101
**What is the pharmacological treatment for NHL?**
NHL treatment – ‘R-CHOP-21’
* R – rituximab
* C – cyclophosphamide
* H – doxorubicin (hydroxydaunomycin)
* O – vincristine (oncovin)
* P – prednisolone
Given for 21 days (tratment may require several 21-day cycles)
102
**Describe multiple myeloma (MM)**
Multiple myeloma (MM):
Characterised by terminally differentiated plasma cells, infiltration of the bone marrow by plasma cells and the presence of a monoclonal Ig or Ig fragment in the serum/urine
Usually associated with osteolytic bone disease, anaemia and renal failure
103
**Recall the clinical presentation of MM (4 points)**
104
**List the diagnostic investigations for MM (4 points)**
MM diagnosis and investigations:
1. Serum/urine electrophoresis:
* Paraprotein spike (IgG \>35 g/L or IgA \> 20 g/L and _Bence-Jones proteins in urine_)
2. Skeletal survey
3. Bone marrow aspirate
4. Full blood count.
105
**List 3 treatment options for MM and 2 disease complications**
MM treatment:
1. Autologous HSC transplant if eligible
2. Bisphosphonates
3. Hydration therapy
MM complications:
* Death by infection
* Rrenal failure
Median survival ~3 years (remains incurable)
106
**Recall the oral manifestations of haematopoietic malignancies**
107
**List 6 causes of localized and generalized lymphadenopathy**
Localised and generalized causes of lymphadenopathy:
1. Infection (acute and chronic) e.g. HIV
2. Cancers
3. Benign tumours
4. Lymph obstruction
5. Trauma
6. Congenital defects
