Haematology Flashcards
1
Q
Learning objectives
A
Answer
2
Q
Define anti-phospholipid syndrome
A
• Characterised by the presence of antiphospholipid antibodies (APL) in the plasma, venous and arterial thrombosis, recurrent foetal loss and thrombocytopaenia
3
Q
Explain the aetiology/risk factors of anti-phospholipid syndrome
A
- Antiphospholipid antibodies (APL) are directed against plasma proteins bound to phospholipids
- APL may develop in susceptible individuals following exposure to infectious agents
- Once APL are present, a second event is needed for the syndrome to develop
- APL has effects on a number of coagulation factors (e.g. protein C, annexin V, platelets, fibrinolysis)
- Complement activation by APL is critical for the complications
4
Q
Summarise the epidemiology of anti-phospholipid syndrome
A
- More common in YOUNG WOMEN
- Accounts for 20% of strokes in < 45 yrs
- Accounts for 27% of women with > 2 miscarriages
5
Q
Recognise the presenting symptoms of anti-phospholipid syndrome
A
• RECURRENT MISCARRIAGES • History of: o Arterial thromboses (stroke) o Venous thromboses (DVT, PE) • Headaches (migraine) • Chorea • Epilepsy
6
Q
Recognise the signs of anti-phospholipid syndrome on physical examination
A
• Livedo reticularis
o A skin finding consisting of a mottled reticulated vascular pattern that appears as a lace-like purplish discolouration of the skin
• Signs of SLE (e.g. malar rash, discoid lesions)
• Signs of valvular heart disease
7
Q
Identify appropriate investigations for anti-phospholipid syndrome
A
• FBC - low platelets
• ESR - usually normal
• U&Es - can get APL nephropathy
• Clotting screen - high APTT
• Presence of antiphospholipid antibodies may be demonstrated by:
o ELISA testing for anticardiolipin antibodies
o Lupus anticoagulant assays
8
Q
Define aplastic anaemia
A
• Characterised by diminished haematopoietic precursors in the bone marrow and deficiency of all blood cell elements (pancytopaenia)
9
Q
Explain the aetiology/risk factors of aplastic anaemia
A
• Idiopathic (> 40%)
o May be due to destruction or suppression of stem cells via autoimmune mechanisms
• Acquired
o Drugs (e.g. chloramphenicol, sulphonamides, methotrexate)
o Chemicals (e.g. benzene, DDT)
o Radiation
o Viral infection (e.g. parvovirus B19)
o Paroxysmal nocturnal haemoglobinuria
• Inherited
o Fanconi’s anaemia
o Dyskeratosis congenita (a rare, progressive bone marrow failure syndrome)
10
Q
Summarise the epidemiology of aplastic anaemia
A
- Annual incidence: 2-4/1,000,000
* Slightly more common in males
11
Q
Recognise the presenting symptoms of aplastic anaemia
A
• Can be both slow-onset (months) or rapid-onset (days) • Anaemia Symptoms: o Tiredness o Lethargy o Dyspnoea • Thrombocytopaenia Symptoms: o Easy bruising o Bleeding gums o Epistaxis • Leukopaenia Symptoms: o Increased frequency and severity of infections
12
Q
Recognise the signs of aplastic anaemia on physical examination
A
• Anaemia Signs: o Pallor • Thrombocytopaenia Signs: o Petechiae o Bruises • Leukopaenia Signs: o Multiple bacterial and fungal infections o No hepatomegaly, splenomegaly or lymphadenopathy
13
Q
Identify appropriate investigations for aplastic anaemia
A
• Bloods o FBC • Low Hb • Low platelets • Low WCC • Normal MCV • Low or absent reticulocytes • Blood Film o Exclude leukaemia (check for abnormal circulating white blood cells) • Bone Marrow Trephine Biopsy • Fanconi's Anaemia o Check for presence of increased chromosomal breakage in lymphocytes cultures in the presence of DNA cross-linking agents
14
Q
Define DIC
A
• A disorder of the clotting cascade that can complicate a serious illness.
o DIC can occur in TWO forms:
• Acute overt form where there is bleeding and depletion of platelets and clotting factors
• Chronic non-overt form where thromboembolism is accompanied by generalised activation of the coagulation system
15
Q
Explain the aetiology/risk factors for DIC
A
• Infection - particularly GRAM-NEGATIVE sepsis
• Obstetric Complications
o Missed miscarriage (when the foetus dies but the body doesn’t realise it and the placenta continues to release hormones)
o Severe pre-eclampsia
o Placental abruption (separation of the placenta from the wall of the uterus during pregnancy)
o Amniotic emboli
• Malignancy
o Acute promyelocytic leukaemia - ACUTE DIC
o Lung, breast and GI malignancy - CHRONIC DIC
• Severe trauma or surgery
• Others: haemolytic transfusion reaction, burns, severe liver disease, aortic aneurysms, haemangiomas
• Pathophysiology
o Acute DIC
• Endothelial damage and the release of granulocyte/macrophage procoagulant substances (e.g. tissue factor) lead to activation of coagulation
• This leads to explosive thrombin generation, which depletes clotting factors and platelets, whilst also activating the fibrinolytic system
• This leads to bleeding in the subcutaneous tissues, skin and mucous membranes
• Occlusion of blood vessels by fibrin in the microcirculation leads to microangiopathic haemolytic anaemia and ischaemic organ damage
o Chronic DIC
• IDENTICAL process to acute DI
• Happens at a slower rate with time for compensatory responses
• The compensatory responses diminish the likelihood of bleeding but give rise to hypercoagulable states and thrombosis can occur
16
Q
Summarise the epidemiology of DIC
A
• Seen in any severely ill patient
17
Q
Recognise the presenting symptoms of DIC
A
- The patients will tend to be severely unwell with symptoms of the underlying disease
- Confusion
- Dyspnoea
- Evidence of bleeding
18
Q
Recognise the signs of DIC on physical examination
A
• Signs of underlying disease • Fever • Evidence of shock (hypotension, tachycardia) • Acute DIC o Petechiae, purpura, ecchymoses o Epistaxis o Mucosal bleeding o Overt haemorrhage o Signs of end organ damage o Respiratory distress o Oliguria due to renal failure • Chronic DIC o Signs of deep vein and arterial thrombosis or embolism o Superficial venous thrombosis
19
Q
Identify appropriate investigations for DIC
A
• Bloods o FBC • Low platelets • Low Hb • High APTT/PT • Low fibrinogen • High fibrin degradation products • High D-dimers • Peripheral Blood Film o Schistocytes
20
Q
Define haemolytic anaemia
A
• Premature erythrocyte breakdown causing shortened erythrocyte life span (< 120 days) with anaemia
21
Q
Explain the aetiology/risk factors of haemolytic anaemia
A
• Hereditary o Membrane Defects • Hereditary spherocytosis • Elliptocytosis o Metabolic Defects • G6PD deficiency • Pyruvate kinase deficiency o Haemoglobinopathies • Sickle cell disease • Thalassemia • Acquired o Autoimmune • Antibodies attach to erythrocytes causing intravascular and extravascular haemolysis o Isoimmune • Transfusion reaction • Haemolytic disease of the newborn o Drugs • Penicillin • Quinine • NOTE: this is caused by the formation of a drug-antibody-erythrocyte complex o Trauma • Microangiopathic haemolytic anaemia (caused by RBC fragmentation in abnormal microcirculation) E.g. haemolytic uraemic syndrome, DIC, malignant hypertension o Infection • Malaria • Sepsis o Paroxysmal nocturnal haemoglobinuria
22
Q
Summarise the epidemiology of haemolytic anaemia
A
- COMMON
- Genetic causes are prevalent if African, Mediterranean and Middle Eastern populations
- Hereditary spherocytosis is the most common inherited haemolytic anaemia in northern Europe
23
Q
Recognise the presenting symptoms of haemolytic anaemia
A
- Jaundice
- Haematuria
- Anaemia
24
Q
Recognise the signs of haemolytic anaemia on physical examination
A
- Pallor
- Jaundice
- Hepatosplenomegaly
25
Identify appropriate investigations for haemolytic anaemia
```
• Bloods
o FBC:
• Low Hb
• High reticulocytes
• High MCV
• High unconjugated bilirubin
• Low haptoglobin (a protein that binds to free Hb released by red blood cells)
o U&Es
o Folate
• Blood Film
o Leucoerythroblastic picture
o Macrocytosis
o Nucleated erythrocytes or reticulocytes
o Polychromasia
o May identify specific abnormal cells such as:
• Spherocytes
• Elliptocytes
• Sickle cells
• Schistocytes
• Malarial parasites
• Urine
o High urobilinogen
o Haemoglobinuria
o Haemosiderinuria
• Direct Coombs' Test
o Tests for autoimmune haemolytic anaemia
o Identifies erythrocytes coated with antibodies
• Osmotic fragility test or Spectrin mutation analysis
o Identifies membrane abnormalities
• Ham's Test
o Lysis of erythrocytes in acidified serum in paroxysmal nocturnal haemoglobinuria
• Hb Electrophoresis or Enzyme Assays
o To exclude other causes
• Bone Marrow Biopsy (rarely performed)
```
26
Define HUS and TTP
```
• DEFINITION: triad of:
o Microangiopathic haemolytic anaemia (MAHA)
o Acute renal failure
o Thrombocytopaenia
• There are TWO forms of HUS:
o D+ = diarrhoea-associated form
o D- = no prodromal illness identified
• HUS overlaps with TTP, which has additional features of:
o Fever
o Fluctuating CNS signs
```
27
Explain the aetiology/risk factors for HUS and TTP
```
• Endothelial injury results in platelet aggregation and the release of unusually large vWF multimers and activation of platelets and the clotting cascade
• This leads to small vessel thrombosis
• The glomerular-afferent arteriole and capillaries are particularly vulnerable - they undergo fibrinoid necrosis
• This leads to renal ischaemia and acute renal failure
• The thrombi also promote intravascular haemolysis
• CAUSES:
o Infection
• Escherichia coli O157
• Shigella
• Neuraminidase-producing infections
• HIV
o Drugs
• COCP
• Ciclosporin
• Mitomicin
• 5-fluorouracil
o Others:
• Malignant hypertension
• Malignancy
• Pregnancy
• SLE
• Scleroderma
```
28
Summarise the epidemiology of HUS and TTP
* UNCOMMON
* D+ HUS often affects YOUNG CHILDREN
* It is the most common cause of acute renal failure in children
* TTP mainly affects ADULT FEMALES
29
Recognise the presenting symptoms of HUS and TTP
```
• GI
o Severe abdominal colic
o Watery diarrhoea that becomes bloodstained
• General
o Malaise
o Fatigue
o Nausea
o Fever < 38 degrees (D+)
• Renal
o Oliguria or anuria
o Haematuria
```
30
Recognise the signs of HUS and TTP on physical examination
```
• General
o Pallor
o Slight jaundice (due to haemolysis)
o Bruising
o Generalise oedema
o Hypertension
o Retinopathy
• GI
o Abdominal tenderness
• CNS Signs
o Occurs in TTP
o Weakness
o Reduced vision
o Fits
o Reduced consciousness
```
31
Identify appropriate investigations for HUS and TTP
```
• FBC
o Normocytic anaemia
o High neutrophils
o Very low platelets
• U&Es
o High urea
o High creatinine
o High K+
o Low Na+
• Clotting
o Normal APTT and fibrinogen levels (abnormality may indicate DIC)
• LFTs
o High unconjugated bilirubin
o High LDH from haemolysis
• Blood cultures
• ABG
o Low pH
o Low bicarbonate
o Low PaCO2
o Normal anion gap
• Blood Film
o Schistocytes
o High reticulocytes and spherocytes
• Urine
o 1+ g protein/24 hrs
o Haematuria
• Stool Samples
o MC&S
• Renal Biopsy
o Can distinguish between D+ and D- HUS
```
32
Define haemophilia
• Bleeding diatheses resulting from an inherited deficiency of a clotting factor
o THREE subtypes:
• Haemophilia A: MOST COMMON - deficiency in factor 8
• Haemophilia B: deficiency in factor 9
• Haemophilia C: RARE - deficiency in factor 11
33
Explain the aetiology/risk factors of haemophilia
* Haemophilia A and B have X-linked recessive inheritance
* 30% of cases are new mutations
* Due to its inheritance pattern, Haemophilia is mainly seen in MALES
34
Summarise the epidemiology of haemophilia
* Haemophilia A incidence: 1/10,000 males
* Haemophilia B incidence: 1/25,000 males
* Haemophilia C is more common in Ashkenazi Jews
35
Recognise the presenting symptoms of haemophilia
* Symptoms usually begin in early childhood
* Swollen painful joints occurring spontaneously or with minimal trauma (haemarthroses)
* Painful bleeding into muscles
* Haematuria
* Excessive bruising or bleeding after surgery or trauma
* FEMALE carriers are usually asymptomatic, but may experience excessive bleeding after trauma
* Generally speaking, bleeding in haemophilia is DEEP (into muscles and joints)
36
Recognise the signs of haemophilia on physical examination
* Multiple bruises
* Muscle haematomas
* Haemarthroses
* Joint deformity
* Nerve palsies (due to nerve compression by haematomas)
* Signs of iron deficiency anaemia
37
Identify appropriate investigations for haemophilia
* Clotting screen (high APTT)
* Coagulation factor assays (low factor 8, 9 or 11 (depending on type of haemophilia))
* Other investigations may be performed if there are complications (e.g. arthroscopy)
38
Define ITP
• Syndrome characterised by immune destruction of platelets resulting in bruising or a bleeding tendency
39
Explain the aetiology/risk factors of ITP
• Often IDIOPATHIC
• Acute ITP is often seen after viral infection in children
• Chronic ITP is more common in adults
• ITP may be associated with:
o Infections (e.g. malaria, EBV, HIV)
o Autoimmune diseases (e.g. SLE, thyroid disease)
o Malignancies
o Drugs (e.g. quinine)
• Autoantibodies are generated, which bind to platelet membrane proteins (e.g. GlpIIb/IIIa) resulting in thrombocytopaenia
40
Summarise the epidemiology of ITP
• Acute ITP presenting CHILDREN aged 2-7 yrs
• Chronic ITP is seen in ADULTS
o 4 x more common in WOMEN
41
Recognise the presenting symptoms of ITP
* Easy bruising
* Mucosal bleeding
* Menorrhagia
* Epistaxis
42
Recognise the signs of ITP on physical examination
* Visible petechiae and bruises
| * Signs of other illness (e.g. infections, wasting, splenomegaly) would suggest that other causes
43
Identify appropriate investigations for ITP
```
• Diagnosis of exclusion - exclude:
o Myelodysplasia
o Acute leukaemia
o Marrow infiltration
• Bloods
o FBC - low platelets
o Clotting screen - normal PT, APTT and fibrinogen
o Autoantibodies (e.g. antiplatelet antibody)
• Blood Film
o To rule out pseudothrombocytopaenia (which is caused by platelets clumping together and giving falsely low counts)
• Bone Marrow
o To exclude other pathology
```
44
Define ALL
• Malignancy of the bone marrow and blood characterised by the proliferation of lymphoblasts (primitive lymphoid cells)
45
Explain the aetiology / risk factors of ALL
* Lymphoblasts undergo malignancy transformation and proliferation
* This leads to the replacement of normal marrow elements, leading to bone marrow failure and infiltration into other tissues
```
Risk Factors:
o Environmental (radiation, viruses)
o Genetic (Down's syndrome, Neurofibromatosis type 1, Fanconi's anaemia, xeroderma pigmentosum)
```
46
Summarise the epidemiology of ALL
* MOST COMMON malignancy of CHILDHOOD
* Peak incidence: 2-5 yrs old
* There is a second peak in incidence in the elderly
* Annual UK incidence: 1/70,000
47
Recognise the presenting symptoms of ALL
Symptoms of Bone Marrow Failure:
o Anaemia (fatigue, dyspnoea)
o Bleeding (spontaneous bruising, bleeding gums, menorrhagia)
o Opportunistic infections
```
Symptoms of Organ Infiltration:
o Tender bones
o Enlarged lymph nodes
o Mediastinal compression
o Meningeal involvement (headache, visual disturbances, nausea)
```
48
Recognise the signs of ALL on physical examination
```
Signs of Bone Marrow Failure:
o Pallor
o Bruising
o Bleeding
o Infection
```
```
Signs of Organ Infiltration:
o Lymphadenopathy
o Hepatosplenomegaly
o Cranial nerve palsies
o Retinal haemorrhage
o Papilloedema on fundoscopy
o Leukaemic infiltration of the anterior chamber of the eye
o Testicular swelling
```
49
Identify appropriate investigations for ALL and interpret the results
```
Bloods
o FBC - normochromic normocytic anaemia, low platelets, variable WCC
o High uric acid
o High LDH
o Clotting screen
```
Blood Film
o Abundant lymphoblasts
Bone Marrow Aspirate or Trephine Biopsy
o Hypercellular with > 20% lymphoblasts
Immunophenotyping - using antibodies to recognise cell surface antigens
Cytogenetic - karyotyping to look for chromosomal abnormalities or translocations
Cytochemistry
Lumbar Puncture - check for CNS involvement
CXR - may show mediastinal lymphadenopathy, lytic bone lesions
Bone Radiographs - mottled appearance with punched out lesions due to leukaemic infiltration
50
Define AML
• Malignancy of primitive myeloid lineage white blood cells (myeloblasts) with proliferation in the bone marrow and blood
o Classified using the FAB (French-American-British) System into EIGHT morphological variants
51
Explain the aetiology / risk factors of AML
* Myeloblasts undergo malignant transformation and proliferation
* This leads to replacement of normal marrow and bone marrow failure
52
Summarise the epidemiology of AML
* MOST COMMON acute leukaemia in ADULTS
| * Incidence INCREASES with age
53
Recognise the presenting symptoms of AML
Symptoms of Bone Marrow Failure:
o Anaemia (lethargy, dyspnoea)
o Bleeding (due to thrombocytopaenia or DIC)
o Opportunistic or recurrent infections
Symptoms of Tissue Infiltration:
o Gum swelling or bleeding
o CNS involvement (headaches, nausea, diplopia)
54
Recognise the signs of AML on physical examination
```
Signs of Bone Marrow Failure:
o Pallor
o Cardiac flow murmur
o Ecchymosis
o Bleeding
o Opportunistic or recurrent infections (e.g. fever, mouth ulcers, skin infections)
```
Signs of Tissue Infiltration:
o Skin rashes
o Gum hypertrophy
o Deposit of leukaemic blasts in the eye, tongue and bone (RARE)
55
Identify appropriate investigations for AML and interpret the results
Bloods
o FBC - low Hb, low platelets, variable WCC
o High uric acid
o High LDH
o Clotting studies, fibrinogen and D-dimers (to check for DIC)
Blood Film
o Myeloblasts
Bone Marrow Aspirate or Biopsy
o Hypercellular with > 20% blasts
Immunophenotyping
o Antibodies against surface antigens used to classify the lineage of the abnormal clones
Cytogenetics
Immunocytochemistry
56
Define CLL
• Characterised by progressive accumulation of functionally incompetent lymphocytes, which are monoclonal in origin. There is an overlap between CLL and non-Hodgkin's lymphoma
57
Explain the aetiology / risk factors of CLL
• Malignant cells may accumulate as a result of their inability to undergo apoptosis
The most common chromosomal changes include:
o Trisomy 12
o 11q and 13q deletions
58
Summarise the epidemiology of CLL
* 90% are > 50 yrs
* More common in MALES
* Rare in Asians
59
Recognise the presenting symptoms of CLL
Asymptomatic - 40-50% of cases are diagnosed following routine blood tests
Systemic Symptoms:
o Lethargy
o Malaise
o Night sweats
Symptoms of Bone Marrow Failure:
o Recurrent infections
o Herpes zoster infection
o Easy bruising or bleeding
60
Recognise the signs of CLL on physical examination
* Non-tender lymphadenopathy
* Hepatomegaly
* Splenomegaly
LATE STAGE signs of bone marrow failure:
o Pallor
o Cardiac flow murmur
o Purpura/ecchymosis
61
Identify appropriate investigations for CLL and interpret the results
• NOTE: CLL may be associated with autoimmune phenomena such as haemolytic anaemia (warm agglutinins) or thrombocytopaenia
```
Bloods
o FBC
• Lymphocytosis
• Low Hb - Could be due to bone marrow infiltration, hypersplenism or autoimmune haemolysis
• Low platelets
• Low serum Ig
```
Blood Film
o Small lymphocytes with thin rims of cytoplasm
o Smudge cells
Bone Marrow Aspirate or Biopsy
o Lymphocytic replacement of normal marrow
Cytogenetics
62
Define CML
• Chronic myeloblastic leukaemia is a malignant clonal disease characterised by proliferation of granulocyte precursors in the bone marrow and blood, distinguished from AML by its slower progression
63
Explain the aetiology / risk factors of CML
Malignant proliferation of stem cells
95% of cases have a chromosomal translocation between chromosomes 9 and 22 to form the Philadelphia chromosome
Variants of CML include:
o Ph-negative CML
o Chronic neutrophilic leukaemia
o Eosinophilic leukaemia
Pathogenesis
o The Philadelphia chromosome results in the formation of the BCR-ABL fusion gene
o The product of this gene enhances tyrosine kinase activity and drives cell replication
THREE phases of CML
o Relatively stable chronic phase (4-6 yr duration)
o Accelerated phase (3-9 months)
o Acute leukaemia phase - blast transformation
64
Summarise the epidemiology of CML
* Incidence increases with age
* Mean age of diagnosis: 40-60 yrs
* 4 x more common in MALES
65
Recognise the presenting symptoms of CML
ASYMPTOMATIC in 40-50% of cases - diagnosed on routine blood count
Hypermetabolic Symptoms:
o Weight loss
o Malaise
o Sweating
```
Bone Marrow Failure Symptoms:
o Lethargy
o Dyspnoea
o Easy bruising
o Epistaxis
o Abdominal discomfort and early satiety
o Rare symptoms:
• Gout
• Hyperviscosity symptoms (visual disturbance, headaches, priapism)
o May present during a blast crisis with symptoms of AML and ALL
```
66
Recognise the signs of CML on physical examination
```
• SPLENOMEGALY - most common physical finding (90% of cases)
• Signs of bone marrow failure:
o Pallor
o Bleeding
o Ecchymosis
```
67
Identify appropriate investigations for CML and interpret the results
```
Bloods
o FBC
• High WCC
• Low Hb
• High basophils/neutrophils/eosinophils
• High/normal/low platelets
• High uric acid
• High B12 and transcobalamin I
```
Blood Film
o Immature granulocytes
Bone Marrow Aspirate or Biopsy
o Hypercellular with raised myeloid-erythroid ratio
Cytogenetics
o Show the Philadelphia chromosome
68
Define lymphoma (Hodgkin’s)
• Lymphomas are neoplasms of lymphoid cells, originating in the lymph nodes or other lymphoid tissues. Hodgkin's lymphoma (15% of all lymphomas) is diagnosed histopathologically by the presence of Reed-Sternberg Cells (binucleate lymphocytes)
69
Explain the aetiology / risk factors of lymphoma (Hodgkin’s)
* UNKNOWN
* Likely to be an environmental trigger in a genetically susceptible individual
* EBV genome has been detected in 50% of Hodgkin's lymphomas
70
Summarise the epidemiology of lymphoma (Hodgkin’s)
* Bimodal age distribution with peaks at 20-30 yrs and > 50 yrs
* More common in MALES
71
Recognise the presenting symptoms of lymphoma (Hodgkin’s)
Painless enlarging mass
o Most commonly in the neck
o Can also be in the axilla or groin
The mass may become painful after alcohol ingestion
B symptoms of Lymphoma
o Fever > 38 degrees
• If this is cyclical it is referred to as Pel-Ebstein fever
o Night sweats
o Weight loss > 10% body weight in the past 6 months
Other symptoms
o Pruritis
o Cough
o Dyspnoea
72
Recognise the signs of lymphoma (Hodgkin’s) on physical examination
* Non-tender firm rubbery lymphadenopathy (may be cervical, axillary or inguinal)
* Splenomegaly (or sometimes, hepatosplenomegaly)
* Skin excoriations
* Signs of intrathoracic disease (e.g. pleural effusion, superior vena cava obstruction)
73
Identify appropriate investigations for lymphoma (Hodgkin’s) and interpret the results
```
Bloods
o FBC
• Anaemia of chronic disease
• Leucocytosis
• High neutrophils
• High eosinophils
• Lymphopaenia in advanced disease
o High ESR and CRP
```
Lymph Node Biopsy
Bone Marrow Aspirate and Trephine Biopsy
Imaging - CXR, CT, PET
```
Ann Arbor Staging
o I = single lymph node region
o II = 2+ lymph node regions on one side of the diaphragm
o III = lymph node regions on both sides of the diaphragm
o IV = extranodal involvement
o A = absence of B symptoms
o B = presence of B symptoms
o E = localised extranodal extension
o S = involvement of spleen
```
74
Define lymphoma (non-Hodgkin’s)
• Lymphomas are malignancies of lymphoid cells originating in lymph nodes or other lymphoid tissues. Non-Hodgkin's lymphomas are a diverse group consisting of:
o 85% B cell
o 15% T cell and NK cell forms
• It can range from stable, indolent disease to aggressive disease
75
Explain the aetiology / risk factors of lymphoma (non-Hodgkin’s)
```
• Complex process involving the accumulation of multiple genetic lesions
• The changes in the genome in certain lymphoma subtypes have been associated with the introduction of foreign genes via oncogenic viruses (e.g. EBV and Burkitt's lymphoma)
• Other risk factors:
o Radiotherapy
o Immunosuppressive agents
o Chemotherapy
o HIV, HBV, HCV
o Connective tissue disease (e.g. SLE)
```
76
Summarise the epidemiology of lymphoma (non-Hodgkin’s)
* Incidence increases with age
* More common in MALES
* More common in the WESTERN WORLD
77
Recognise the presenting symptoms of lymphoma (non-Hodgkin’s)
Painless enlarging mass (in neck, axilla or groin)
```
Systemic Symptoms (occurs less frequently than in Hodkin's):
o Fever
o Night sweats
o Weight loss > 10% body weight
o Symptoms of hypercalcaemia
```
```
Symptoms related to organ involvement
o Extranodal disease is MORE COMMON in NHL than in Hodgkin's lymphoma
o Skin rashes
o Headache
o Sore throat
o Abdominal discomfort
o Testicular swelling
```
78
Recognise the signs of lymphoma (non-Hodgkin’s) on physical examination
```
• Painless firm rubbery lymphadenopathy
Skin rashes
o Mycosis fungoides - looks like a fungal infection but is in fact a cutaneous T-cell lymphoma)
• Abdominal mass
• Hepatosplenomegaly
```
Signs of bone marrow involvement:
o Anaemia
o Infections
o Purpura
79
Identify appropriate investigations for lymphoma (non-Hodgkin’s) and interpret the results
```
Bloods
o FBC
• Anaemia
• Neutropaenia
• Thrombocytopaenia
o High ESR and CRP
o Calcium may be raised
o HIV, HBV and HCV serology
Blood Film
o Lymphoma cells may be visible in some patients
Bone Marrow Aspiration and Biopsy
Imaging - CXR, CT, PET
Lymph Node Biopsy - allows histopathological evaluation, immunophenotyping and cytogenetics
Staging - Ann-Arbor
```
80
Define macrocytic anaemia
• Anaemia associated with a high MCV of erythrocytes (> 100 fl in adults)
81
Explain the aetiology/risk factors of macrocytic anaemia
• Megaloblastic - when the bone marrow produces unusually large, structurally abnormal, immature red cells
o Caused by deficiency of B12 or folate required for the conversion of deoxyuridate to thymidylate, DNA synthesis and nuclear maturation
o Causes of Vitamin B12 Deficiency:
• Reduced absorption (e.g. post-gastrectomy, pernicious anaemia, terminal ileal resection or disease)
• Reduced intake (vegans)
• Abnormal metabolism (congenital transcobalamin II deficiency)
o Causes of Folate Deficiency:
• Reduced intake (alcoholics, elderly, anorexia)
• Increased demand (pregnancy, lactation, malignancy, chronic inflammation)
• Reduced absorption
• Jejunal disease (e.g. coeliac disease)
• Drugs (e.g. phenytoin)
o Drugs
• Methotrexate (dihydrofolate reductase inhibitor)
• Hydroxyurea
• Azathioprine
• Zidovudine
• Non-Megaloblastic
o Alcohol excess
o Liver disease
o Myelodysplasia
o Multiple myeloma
o Hypothyroidism
o Haemolysis (shift to immature red cell form - reticulocytosis)
o Drugs (e.g. tyrosine kinase inhibitor)
82
Summarise the epidemiology of macrocytic anaemia
* More common in ELDERLY FEMALES
| * Pernicious anaemia is the MOST COMMON cause of B12 deficiency in the West
83
Recognise the presenting symptoms of macrocytic anaemia
```
• Non-specific symptoms of anaemia:
o Tiredness
o Lethargy
o Dyspnoea
• Family history of autoimmune disease
• Previous GI surgery
• Symptoms of the CAUSE (e.g. weight loss, diarrhoea)
```
84
Recognise the signs of macrocytic anaemia on physical examination
```
• Signs of Anaemia
o Pallor
o Tachycardia
o Breathlessness
• Signs of Pernicious Anaemia
o Mild jaundice
o Glossitis
o Angular stomatitis
o Weight loss
• Signs of B12 Deficiency
o Peripheral neuropathy
o Ataxia
o Subacute combined degeneration of the spinal cord
o Optic atrophy
o Dementia
```
85
Identify appropriate investigations for macrocytic anaemia
• Bloods
o FBC
• High MCV
• Pancytopaenia in megaloblastic anaemia
• Different degrees of cytopaenia in myelodysplasia
• Exclude reticulocytosis
o LFT
• High bilirubin (due to ineffective erythropoiesis or haemolysis)
o ESR
o TFT
o Serum vitamin B12
o Red cell folate
o Anti-parietal cell and anti-intrinsic factor antibodies
o Serum protein electrophoresis - looking for a dense band in myeloma
• Blood Film
o Large erythrocytes
o In megaloblastic anaemia:
• Megaloblasts
• Hypersegmented neutrophil nuclei
• Schilling Test
o Method of testing for pernicious anaemia
o B12 will only be absorbed when given with intrinsic factor
• Bone Marrow Biopsy (rarely needed)
• Investigations for the cause
86
Generate a management plan for macrocytic anaemia
```
• Pernicious Anaemia
o IM hydroxycobalamin for life
• Folate Deficiency
o Oral folic acid
o If B12 deficiency is present, it must be treated before the folic acid deficiency
```
87
Identify possible complications of macrocytic anaemia
* Pernicious anaemia --> increased risk of gastric cancer
| * Pregnancy - folate deficiency increases the risk of neural tube defects
88
Summarise the prognosis for patients with macrocytic anaemia
• Majority are treatable if there are no complications
89
Define microcytic anaemia
• Anaemia associated with a low MCV (< 80 fl)
90
Explain the aetiology/risk factors of microcytic anaemia
• Iron Deficiency - MOST COMMON
o Iron deficiency can be caused by:
• Blood loss (e.g. GI)
• Reduced absorption (e.g. small bowel disease)
• Increased demands (e.g. growth, pregnancy)
• Reduced intake (e.g. vegans)
• Anaemia of Chronic Disease
o Microcytic anaemia in a patient with chronic disease
• Thalassemia
• Sideroblastic Anaemia
o Abnormality of haem synthesis
o It can be inherited or it can be secondary (e.g. to alcohol, drugs)
91
Summarise the epidemiology of microcytic anaemia
• Iron deficiency anaemia is the MOST COMMON form of anaemia worldwide
92
Recognise the presenting symptoms of microcytic anaemia
```
• Non-Specific
o Tiredness
o Lethargy
o Malaise
o Dyspnoea
o Pallor
o Exacerbation of ischaemic conditions (e.g. angina, intermittent claudication)
• Lead Poisoning - can cause microcytic anaemia
Symptoms of lead poisoning
o Anorexia
o Nausea/Vomiting
o Abdominal pain
o Constipation
o Peripheral nerve lesions
```
93
Recognise the signs of microcytic anaemia on physical examination
```
• Signs of anaemia
o Pallor
o Brittle nails and hair
o Koilonychia (if severe)
• Glossitis
```
• Angular stomatitis
• Signs of thalassemia
• Lead poisoning signs:
o Blue gumline
o Peripheral nerve lesions (causing wrist or foot drop)
o Encephalopathy
o Convulsions
o Reduced consciousness
94
Identify appropriate investigations for microcytic anaemia
```
• Bloods
o FBC
• Low Hb
• Low MCV
• Reticulocytes
o Serum iron (low in iron deficiency)
o Total iron binding capacity (high in iron deficiency)
o Serum ferritin (low in iron deficiency)
o Serum lead
• Blood Film
o Iron deficiency anaemia:
• Microcytic
• Hypochromic
• Anisocytosis
• Poikilocytosis
o Sideroblastic anaemia:
• Dimorphic blood film
• Hypochromic microcytic cells
o Lead poisoning:
• Basophilic stippling
```
• Hb Electrophoresis
o Checking for haemoglobin variants and thalassemia
• Sideroblastic Anaemia
o Ring sideroblasts in the bone marrow
• Special investigations for iron deficiency anaemia if > 40 yrs and post-menopausal women
These are considered if no obvious cause of blood loss is identified
o Upper GI endoscopy
o Colonoscopy
o Haematuria
95
Generate a management plan for microcytic anaemia
```
• Iron Deficiency - oral iron supplements
• Sideroblastic Anaemia
o Treat the cause
o Pyridoxine used in inherited forms
o Blood transfusion and iron chelation can be considered if there is no response to other treatments
• Lead Poisoning
o Remove the source
o Dimercaprol
o D-penicillinamine
```
96
Identify possible complications of microcytic anaemia
* High-output cardiac failure
| * Complications related to the CAUSE
97
Summarise the prognosis for patients with microcytic anaemia
• Depends on the CAUSE
98
Define multiple myeloma
• Haematological malignancy characterised by proliferation of plasma cells resulting in bone lesions and the production of a monoclonal immunoglobulin (paraprotein, usually IgG or IgA)
99
Explain the aetiology / risk factors of multiple myeloma
* UNKNOWN
* Possible viral trigger
* Chromosomal aberrations are frequent
* Associated with ionising radiation, agricultural work or occupational chemical exposures
100
Summarise the epidemiology of multiple myeloma
* Annual incidence: 4/100,000
* Peak incidence: 70 yrs
* Afro-Caribbean > White People > Asians
101
Recognise the presenting symptoms of multiple myeloma
• May be an INCIDENTAL finding on routine blood tests
Bone Pain
o Usually in the back and ribs
o Sudden and severe bone pain may be caused by a pathological fracture
Infections - often recurrent
```
General
o Tiredness
o Thirst
o Polyuria
o Nausea
o Constipation
o Mental change (due to hypercalcaemia)
```
Hyperviscosity
o Bleeding
o Headaches
o Visual disturbance
102
Recognise the signs of multiple myeloma on physical examination
* Pallor
* Tachycardia
* Flow murmur
* Signs of heart failure
* Dehydration
* Purpura
* Hepatosplenomegaly
* Macroglossia
* Carpal tunnel syndrome
* Peripheral neuropathies
103
Identify appropriate investigations for multiple myeloma and interpret the results
```
Bloods
o FBC - low Hb, normochromic normocytic
o High ESR (and possible high CRP)
o U&Es - high creatinine, high Ca2+
o Normal ALP
```
Blood Film
o Rouleaux formation with bluish background (suggests high protein)
Serum or Urine Electrophoresis
o Serum paraprotein
o Bence-Jones protein (monoclonal immunoglobulin light chain that's found in the urine and suggests multiple myeloma)
Bone Marrow Aspirate and Trephine
o High plasma cells (usually > 20%)
Chest, Pelvic or Vertebral X-Ray
o Osteolytic lesions without surrounding sclerosis
o Pathological fractures
104
Define myelodysplasia
• A series of haematological conditions characterised by chronic cytopaenia (anaemia, neutropaenia, thrombocytopaenia) and abnormal cellular maturation
• There are FIVE subgroups:
o Refractory anaemia (RA)
o RA with ringed sideroblasts (RARS)
o RA with excess blasts (RAEB)
o Chronic myelomonocytic leukaemia (CMML)
o RAEB in transformation (RAEB-t)
105
Explain the aetiology of myelodysplasia
* It may be PRIMARY (intrinsic bone marrow problem)
* It may arise in patients who have received chemotherapy or radiotherapy for previous malignancies
* Patients may have chromosomal abnormalities
106
Summarise the epidemiology of myelodysplasia
* Mean age of diagnosis: 65-75 yrs
* More common in MALES
* 2 x as common as AML
107
Recognise the presenting symptoms of myelodysplasia
• May be ASYMPTOMATIC and diagnosed on routine blood counts
• Symptoms of Bone Marrow Failure
o Anaemia (fatigue, dizziness)
o Neutropaenia (recurrent infections)
o Thrombocytopaenia (easy bruising, epistaxis)
• Check risk factors:
o Occupational exposure to toxic chemicals
o Prior chemotherapy or radiotherapy
108
Recognise the signs of myelodysplasia on physical examination
```
• Signs of bone marrow failure
o Anaemia (pallor, cardiac flow murmur)
o Neutropaenia (infections)
o Thrombocytopaenia (purpura or ecchymoses)
o Gum hypertrophy
o Lymphadenopathy
o Spleen NOT enlarged (except in CMML)
```
109
Identify appropriate investigations for myelodysplasia
```
• Bloods
o FBC - pancytopaenia
• Blood Film
o Normocytic or macrocytic red cells
o Variable microcytic red cells in RARS
o Low granulocytes
o Granulocytes are not granulated
o High monocytes in CMML
• Bone marrow aspire or biopsy
o Hypercellularity
o Ringed sideroblasts (haemosiderin deposits in the mitochondria of erythroid precursors forming an apparent ring around the nucleus)
```
o Abnormal granulocyte precursors
o 10% show marrow fibrosis
110
Define myelofibrosis
• Disorder of haematopoietic stem cells characterised by progressive bone marrow fibrosis in associated with extramedullary haematopoiesis and splenomegaly
• Pathogenesis:
o Abnormal megakaryocytes release cytokines that stimulate fibroblast proliferation and collagen deposition in bone marrow
o This results in extramedullary haematopoiesis in the spleen and liver
111
Explain the aetiology/risk factors of myelofibrosis
* Primary stem cell defect is UNKNOWN
* It results in increased numbers of abnormal megakaryocytes with stromal proliferation secondary to growth factors released by megakaryocytes
* 30% of patients have a previous history of polycythaemia rubra vera or essential thrombocythaemia (overproduction of platelets by the bone marrow)
112
Summarise the epidemiology of myelofibrosis
* RARE
| * Peak onset: 50-70 yrs
113
Recognise the presenting symptoms of myelofibrosis
```
• ASYMPTOMATIC - diagnosed after routine blood count
• Systemic Symptoms
o COMMON:
• Weight loss
• Anorexia
• Fever
• Night sweats
• Pruritis
o UNCOMMON:
• LUQ pain
• Indigestion (due to massive splenomegaly)
• Bleeding
• Bone pain
• Gout
```
114
Recognise the signs of myelofibrosis on physical examination
* SPLENOMEGALY
| * Hepatomegaly (present in 50-60%)
115
Identify appropriate investigations for myelofibrosis
• Bloods
o FBC
• Initially variable Hb, WCC and platelets
• Later stages --> anaemia, leukopaenia, thrombocytopaenia
o LFTs - abnormal
• Blood Film
o Leucoerythroblastic changes (red and white cell precursors in the peripheral blood)
o 'Tear drop' poikilocyte red cells
• Bone Marrow Aspirate or Biopsy
o Aspiration usually unsuccessful - 'dry tap' (due to fibrosis)
o Trephine biopsy shows fibrotic hypercellular marrow, with dense reticulin fibres on silver staining
116
Define normocytic anaemia
• Anaemia with a normal MCV (80-100).
117
Explain the aetiology/risk factors of normocytic anaemia
• Causes:
o Decreased production of normal-sized blood cells (e.g. anaemic of chronic disease, aplastic anaemia)
o Increased production of HbS (sickle cell disease)
o Increased destruction of red blood cells (e.g. haemolysis, post-haemorrhagic anaemia)
o Uncompensated increase in plasma volume (e.g. pregnancy, fluid overload)
o Vitamin B2 deficiency
o Vitamin B6 deficiency
118
Summarise the epidemiology of normocytic anaemia
• COMMON
119
Recognise the presenting symptoms and signs of normocytic anaemia
• Typical symptoms and signs of anaemia (depends on severity)
o E.g. breathlessness, fatigue, conjunctival pallor
120
Identify appropriate investigations for normocytic anaemia
* FBC - check Hb and MCV
| * Check history for haemorrhage
121
Define polycythaemia
```
• An increase in haemoglobin concentration above the upper limit of normal for a person's age and sex. Classified into:
o Relative Polycythaemia = normal red cell mass but low plasma volume
o Absolute (True) Polycythaemia = increased red cell mass
```
122
Explain the aetiology/risk factors of polycythaemia
• Polycythaemia Rubra Vera
o Characterised by clonal proliferation of myeloid cells
o They have varied morphologic maturity and haematopoietic efficiency
o Mutations in JAK2 tyrosine kinase are involved
• Secondary Polycythaemia
o Appropriate increase in erythropoietin
• Due to chronic hypoxia (e.g. chronic lung disease, living at high altitude)
• This leads to upregulation of erythropoiesis
o Inappropriate increase in erythropoietin
• Renal (carcinoma, cysts, hydronephrosis)
• Hepatocellular carcinoma
• Fibroids
• Cerebellar haemangioblastoma
• Secondary polycythaemia may be due to erythropoietin abuse by athletes
• Relative Polycythaemia
o Dehydration (e.g. diuretics, burns, enteropathy)
o Gaisbock's syndrome
• Occurs in young male smokers with hypertension, which results in a decrease in plasma volume and an apparent increase in red cell count
123
Summarise the epidemiology of polycythaemia
* Annual UK incidence: 1.5/100,000
| * Peak age: 45-60 yrs
124
Recognise the presenting symptoms of polycythaemia
* Headaches
* Dyspnoea
* Tinnitus
* Blurred vision
* Pruritis after hot bath
* Night sweats
* Thrombosis (DVT, stroke)
* Pain from peptic ulcer disease
* Angina
* Gout
* Choreiform movements
125
Recognise the signs of polycythaemia on physical examination
• Plethoric complexion (red, ruddy)
* Scratch marks from itching
* Conjunctival suffusion (redness of the conjunctiva)
* Retinal venous engorgement
* Hypertension
* Splenomegaly (in 75% of cases)
* Signs of underlying aetiology in secondary polycythaemia
126
Identify appropriate investigations for polycythaemia
```
• Required for Diagnosis
o FBC
• High Hb
• High haematocrit
• Low MCV
• Isotope Dilution Techniques
o Allows confirmation of plasma volume and red cell mass
o Distinguishes between relative and absolute polycythaemia
• Polycythaemia Rubra Vera
o High WCC
o High platelets
o Low serum EPO
o JAK2 mutation
o Bone marrow trephine and biopsy shows erythroid hyperplasia and raised megakaryocytes
• Secondary Polycythaemia
o High serum EPO
o Exclude chronic lung disease/hypoxia
o Check for EPO-secreting tumours
```
127
Define sickle cell disease
• A chronic condition with sickling of red blood cells caused by inheritance of haemoglobin S (HbS)
o Sickle Cell Anaemia = Homozygous HbS
o Sickle Cell Trait = Carrier of one copy of HbS
o Sickle Cell Disease = includes compound heterozygosity for HbS and:
• HbC (abnormal haemoglobin in which glutamic acid is replaced by lysine at the 6th position in the beta-globin chain)
• Beta-thalassemia
128
Explain the aetiology/risk factors of sickle cell disease
• Autosomal recessive
• Caused by a point mutation in the beta-globin gene resulting in the substitution of glutamic acid in position 6 by valine
• This results in the formation of abnormal haemoglobin S
• Deoxygenation of HbS alters the conformation resulting in sickling of red cells
• Sickling makes the red cells more fragile and inflexible
• These sickled red cells are prone to:
o Sequestration and destruction (reduced red cell survival ~ 20 days)
o Occlusion of small blood vessels causing hypoxia, which leads to further sickling and occlusion
• Factors that precipitate sickling:
o Infection
o Dehydration
o Hypoxia
o Acidosis
129
Summarise the epidemiology of sickle cell disease
* Rarely presents before 4-6 months (because HbF can compensate for the defect in adult haemoglobin)
* Common in Africa, Caribbean, Middle-East and other areas with a high prevalence of malaria
130
Recognise the presenting symptoms of sickle cell disease
• Symptoms secondary to VASO-OCCLUSION or INFARCTION:
o Autosplenectomy (splenic atrophy or infarction)
• Leads to increased risk of infections with encapsulated organisms (e.g. pneumococcus, meningococcus)
o Abdominal Pain
o Bones
• Painful crises affect small bones of the hands and feet causing dactylitis in CHILDREN
```
• Painful crises mainly affect the ribs, spine, pelvis and long bones in ADULTS
o Myalgia and Arthralgia
o CNS
• Fits and strokes
o Retina
• Visual loss (proliferative retinopathy)
• Symptoms of SEQUESTRATION CRISIS
o NOTE: sequestration crises occur due to pooling of red cells in various organs (mainly the spleen)
o Liver --> exacerbation of anaemia
o Lungs --> acute chest syndrome
• Breathlessness
• Cough
• Pain
• Fever
o Corpora cavernosa
• Persistent painful erection (priapism)
• Impotence
```
131
Recognise the signs of sickle cell disease on physical examination
• Signs secondary to VASO-OCCLUSION, ISCHAEMIA or INFARCTION
o Bone - joint or muscle tenderness or swelling (due to avascular necrosis)
o Short digits - due to infarction in small bones of the hands
• Retina - cotton wool spots due to retinal ischaemia
• Signs secondary to SEQUESTRATION CRISES
o Organomegaly
• The spleen is ENLARGED in early disease
• Later on, the spleen will reduce in size due to splenic atrophy
o Priapism
• Signs of anaemia
132
Identify appropriate investigations for sickle cell disease
```
• Bloods
o FBC
• Low Hb
• Reticulocytes:
HIGH - in haemolytic crises
LOW - in aplastic crises
o U&Es
• Blood Film
o Sickle cells
```
o Anisocytosis (variation in size of red cells)
o Features of Hyposplenism:
• Target cells
• Howell-Jolly bodies
• Sickle Solubility Test
o Dithionate is added to the blood
o In sickle cell disease you get increased turbidity
• Haemoglobin Electrophoresis
o Shows HbS
o Absence of HbA (if homozygous HbS)
o High HbF
• Hip X-Ray
o Femoral head is a common site of avascular necrosis
• MRI or CT Head
o If there are neurological complications
133
Generate a management plan for sickle cell disease
```
• ACUTE (PAINFUL CRISES)
o Oxygen
o IV Fluids
o Strong analgesia (IV opiates)
o Antibiotics
• Infection Prophylaxis
o Penicillin V
o Regular vaccinations (particularly against capsulated bacteria e.g. pneumococcus)
• Folic Acid
o If severe haemolysis or in pregnancy
• Hydroxyurea/Hydroxycarbamide
o Increases HbF levels
o Reduces the frequency and duration of sickle cell crisis
• Red Cell Transfusion
o For SEVERE anaemia
o Repeated transfusions (with iron chelators) may be required in patients suffering from repeated crises
• Advice
o Avoid precipitating factors, good hygiene and nutrition, genetic counselling, prenatal screening
• Surgical
o Bone marrow transplantation
o Joint replacement in cases with avascular necrosis
```
134
Identify the possible complications of sickle cell disease
```
• Aplastic crises
o Infection with Parvovirus B19 can lead to a temporary cessation of erythropoiesis (which can cause red cell count to plummet in sickle cell patients because their red cells have a shortened life span and can't tolerate a cessation of erythropoiesis)
• Haemolytic crises
• Pigment gallstones
• Cholecystitis
• Renal papillary necrosis
• Leg ulcers
• Cardiomyopathy
```
135
Summarise the prognosis for patients with sickle cell disease
• Most patients with sickle cell disease who manage their disease well will survive until around the age of 50 yrs
• Mortality is usually the result of:
o Pulmonary or neurological complications in ADULTS
o Infection in CHILDREN
136
Define thalassemia
• A group of genetic disorders characterised by reduced globin chain synthesis
137
Explain the aetiology/risk factors of thalassemia
• Autosomal recessive
• Result in an imbalance of globin chain production and deposition in erythroblasts and erythrocytes
• This leads to:
o Ineffective erythropoiesis
o Haemolysis
o Anaemia
o Extramedullary haematopoiesis
• TYPES:
o ALPHA THALASSEMIA - reduction in alpha-globin chain synthesis. There are FOUR alpha-globin genes on the chromosome.
• 4 gene deletion = Haemoglobin Barts Hydrops Fetalis (intrauterine death)
• 3 gene deletion = Haemoglobin H --> microcytic hypochromic anaemia and splenomegaly
• 2 gene deletion = Alpha 0 thalassemia --> microcytic hypochromic red cells, NO ANAEMIA
• 1 gene deletion = Alpha+ thalassemia --> microcytic hypochromic red cells, NO ANAEMIA
o BETA THALASSEMIA
• Beta Thalassemia Major (homozygous beta thalassemia) --> little or no beta-chain synthesis
• Beta Thalassemia Intermedia - mild defect in beta-chain synthesis leads to:
Microcytic anaemia
Reduced alpha-chain synthesis
Increased gamma-chain synthesis
• Beta Thalassemia Trait (heterozygous carrier state)
ASYMPTOMATIC
Mild microcytic anaemia
Increased red cell count
138
Summarise the epidemiology of thalassemia
* WORLDWIDE
| * Most common in the MEDITERRANEAN and areas of the Middle-East
139
Recognise the presenting symptoms of thalassemia
```
• Beta Thalassemia Major
o Anaemia
o Presenting at 3-6 months
• This is when the change from HbF to HbA takes place
• Failure to thrive
• Prone to infection
• Alpha or Beta Thalassemia Trait
o May be ASYMPTOMATIC
o Detected during routine blood tests or due to family history
```
140
Recognise the signs of thalassemia on physical examination
```
• Beta Thalassemia Major
o Pallor
o Malaise
o Dyspnoea
o Mild jaundice
o Frontal bossing
o Thalassaemia facies (facial features caused by marrow hyperplasia)
```
```
o Hepatosplenomegaly (due to erythrocyte pooling and extramedullary haematopoiesis)
o Patients with beta-thalassemia intermedia may also have these signs
```
141
Identify appropriate investigations for thalasemia
```
• Bloods
o FBC
• Low Hb
• Low MCV (microcytic anaemia)
• Low MCH
• Blood Film
o Hypochromic microcytic anaemia
o Target cells
o Nucleated red cells
o High reticulocyte count
• Hb Electrophoresis
o Absent or reduced HbA
o High HbF
• Bone Marrow
o Hypercellular
o Erythroid hyperplasia
• Genetic Testing (rarely used)
• Skull X-Ray
o 'Hair on end' appearance in beta thalassemia major
• This is caused by expansion of marrow into the cortex
```
142
Define vitamin B12 deficiency
• Having insufficient vitamin B12 to meet demands.
143
Explain the aetiology/risk factors of vitamin B12 deficiency
* B12 is found in meat and animal protein foods
* Absorption occurs in the terminal ileum and requires intrinsic factor (produced by gastric parietal cells)
* Pernicious anaemia is an autoimmune condition involving gastritis, atrophy of all layers of the body and fundus of the stomach and loss of normal gastric glands, parietal and chief cells
• Pernicious anaemia leads to a lack of intrinsic factor
• Pernicious anaemia accounts for 80% of megaloblastic anaemia due to impaired vitamin B12 absorption
• Other causes of B12 deficiency:
o Gastric - gastrectomy, atrophic gastritis
o Inadequate intake (e.g. vegan)
o Intestinal - malabsorption, ileal resection, Crohn's affecting the terminal ileum, tropical sprue
o Drugs - colchicine, metformin
144
Summarise the epidemiology of vitamin B12 deficiency
* Peak age = 60 yrs
| * Vegans have a higher risk of dietary vitamin B12 deficiency
145
Recognise the presenting symptoms of vitamin B12 deficiency
```
• Typical anaemia symptoms
• Fatigue
• Lethargy
• Dyspnoea
• Faintness
• Palpitations
• Headache
• Neurological Symptoms
o Paraesthesia
o Numbness
o Cognitive changes
o Visual disturbances
```
146
Recognise the signs of vitamin B12 deficiency on physical examination
• Pallor
• Heart failure (can occur with severe anaemia)
• Glossitis
• Angular stomatitis
• Neuropsychiatric: irritability, dementia, depression
• Neurological
o Subacute combined degeneration of the spinal cord
o Peripheral neuropathy
147
Identify appropriate investigations for vitamin B12 deficiency
• There is NO gold standard for diagnosing vitamin B12 deficiency
• Measurement of serum B12 is not very accurate or reliable
• Other new tests: plasma total homocysteine, plasma methylmalonic acid, holotranscobalamin
• FBC and blood film
o Hypersegmented neutrophils
o Oval macrocytes
o Circulating megaloblasts
• Pernicious Anaemia Tests
o Anti-intrinsic factor antibodies
o Anti-parietal cell antibodies
o Schilling test
148
Define von Willebrand disease
• Bleeding disorder which may present with mucocutaneous bleeding (mouth, epistaxis, menorrhagia), increased bleeding after trauma and easy bruising
• There are THREE types of von Willebrand disease:
o Type 1 - the von Willebrand factor works well but there isn't enough of it
o Type 2 - there are normal levels of von Willebrand factor but it is abnormal and doesn't function correctly
o Type 3 - there is NO von Willebrand factor
149
Explain the aetiology/risk factors of von Willebrand disease
* Caused by abnormality in the expression/function of vWF
* Usually autosomal dominant
* vWF is an adhesive bridge between platelets and the damaged subendothelial collagen
* vWF also binds to factor VIII and prevents its degradation
150
Recognise the signs and presenting symptoms of von Willbrand disease
* Easy bruising
* Epistaxis - hard to stop
* Prolonged bleeding from gums after dental procedures
* Heavy or prolonged menstrual bleeding
* Blood in stools
* Blood in urine
* Heavy bleeding from a cut or other accident
151
Identify appropriate investigations for von Willebrand disease
* Bleeding time - HIGH
* APTT - HIGH
* Factor VIII - LOW
* vWF - LOW
* Ristocetin cofactor - reduced platelet aggregation by vWF in the presence of ristocetin
