Haematology Flashcards
(180 cards)
1
Q
What is Antiphospholipid syndrome?
A
Characterized by the presence of antiphospholipid antibodies (APL) in the plasma, venous and arterial thromboses, recurrent foetal loss and thrombocytopenia
2
Q
What is the aetiology of Antiphospholipid syndrome?
A
APL are directed against plasma proteins bound to anionic phospholipids (e.g. b2 glycoprotein-I)
APL may develop in susceptible individuals (e.g. those with rheumatic diseases such as SLE) following exposure to infectious agents
Once APL are present, a ‘second-hit’ is needed for the development of the syndrome
Complement activation is critical for pregnancy complications
3
Q
What is the epidemiology of Antiphospholipid syndrome?
A
Can occur in patients without an underlying systemic autoimmune disease (primary APS) or with other autoimmune disease (also known as secondary APS), particularly systemic lupus erythematosus (SLE)
More common in young women
Accounts for 20% of strokes in <45-year- olds and 27% of women with >2 miscarriages
4
Q
What are the presenting symptoms of Antiphospholipid syndrome?
A
Recurrent miscarriages History of arterial thromboses (stroke), venous throm- boses (DVT, pulmonary embolism) Headaches (migraine) Chorea (involuntary movement) Epilepsy
5
Q
What are the signs of Antiphospholipid syndrome on physical examination?
A
Features of thrombocytopenia: petechial rash or symptoms of mucosal bleeding
Arthralgia/arthritis
Livedo reticularis: mottled purplish discoloration of the skin, which can be blanching or non-blanching on pressure
Signs of SLE (malar flush, discoid lesions, photosensitivity)
Valvular disease (cardiac murmur): UNCOMMON
6
Q
What are the appropriate investigations for Antiphospholipid syndrome?
A
Lupus anticoagulant assays: positive on 2 occasions, 12 weeks apart, clotting assays showing effects of APL on the phospholipid-dependent factors in the coagulation cascade
ELISA testing for Anticardiolipin antibody (of IgG or IgM) and anti-b2-GPI antibodies
ANA, ds DNA, extractable nuclear antigen antibodies: elevated in SLE
Bloods:
-FBC (low platelets), ESR (usually normal), U&Es (APL nephropathy), clotting screen (prolonged APTT)
7
Q
What is Aplastic anaemia?
A
Characterized by diminished haematopoietic precursors in the bone marrow and deficiency of all blood cell elements (pancytopaenia)- no abnormal cells
8
Q
What is the aetiology of Aplastic anaemia?
A
Most often Idiopathic (>40%):
-May be due to destruction or suppression of stem cells by autoimmune mechanisms
Acquired:
-Drugs (chloramphenicol, NSAIDs, gold, alkylating agents, antiepileptics, sulphonamides, methotrexate), chemicals (DDT, benzene), radiation, viral infection (B19 parvovirus, HIV, EBV), paroxysmal nocturnal haemoglobinuria
Inherited:
-Fanconi’s anaemia, dyskeratosis congenita (associated with reticulated hyperpigmented rash, nail dystrophy and mucosa leukoplakia)
9
Q
What is the epidemiology of Aplastic anaemia?
A
Annual incidence: 2–4 in per million
Can occur at any age
Slightly more common in males
10
Q
What are the presenting symptoms of Aplastic anaemia?
A
Slow (months) or rapid (days) onset Anaemia: -Tiredness -Lethargy -Dyspnoea Thrombocytopaenia: -Easy bruising -Bleeding gums -Epistaxis Leukopenia: Increased frequency and severity of infections
11
Q
What are the signs of Aplastic anaemia on physical examination?
A
Anaemia: Pale Thrombocytopaenia: Petechiae, bruises Leukopaenia: -Multiple bacterial or fungal infections No hepatomegaly, splenomegaly or lymphadenopathy
12
Q
What are the appropriate investigations for Aplastic anaemia?
A
1st line:
-FBC: 2 or more cytopenias among the following:
*Hb <100 g/L (<10 g/dL)
*Platelet <50 × 10⁹/L
*Absolute neutrophil count <1.5 × 10⁹/L
Reticulocyte count: low or absent reticulocytes
Bone marrow biopsy (and cytogenetic analyses):
-Hypocellular marrow with no abnormal cell population
-Marrow space is composed mostly of fat cells and marrow stroma
-Exclusion of other causes e.g. lymphoma, leukaemia, malignancies, myeloma
Others:
Blood film: To exclude leukaemia (absence of abnormal circulating white blood cells)
13
Q
What is the criteriea for severe aplastic anaemia?
A
Marrow showing <25 % of normal cellularity
OR
Marrow showing <50 % of normal cellularity, <30% of the cells are haematopoietic plus 2 of the following:
-neutrophils < 0.5x10⁹/L
-platelets < 20x10⁹/L
-reticulocytes < 40x10⁹/L
14
Q
What is Blood product transfusion?
A
A lifesaving procedure to treat hemorrhages and to improve oxygen delivery to tissues
15
Q
What are the indications for Blood product transfusion (red cell)?
A
Symptomatic anemia (causing shortness of breath, dizziness, congestive heart failure, and decreased exercise tolerance)
Acute sickle cell crisis
Acute blood loss of more than 30 percent of blood volume
16
Q
What are the indications for Blood product transfusion (fresh frozen plasma)?
A
Can be used for reversal of anticoagulant effects
17
Q
What are the indications for Blood product transfusion (Platelet transfusion)?
A
To prevent haemorrhage in patients with thrombocytopenia or platelet function defects
18
Q
What are the indications for Blood product transfusion (Cryoprecipitate)?
A
Used in cases of hypofibrinogenemia, which most often occurs in the setting of massive hemorrhage or consumptive coagulopathy
19
Q
What are the possible complications of Blood product transfusion?
A
Acute complications occur within minutes to 24 hours of the transfusion, whereas delayed complications may develop days, months, or even years later
*Infections are less common because of advances in the blood screening process
Non-infectious complications (acute): -Acute haemolytic reaction -Allergic/Anaphylactic reaction -Coagulation problems in massive transfusion -Metabolic derangements -Septic or bacterial contamination -Transfusion-associated circulatory overload Non-infectious complications (delayed): -Delayed haemolytic reaction -Iron overload -Post-transfusion purpura
Infectious complications:
- Hepatitis B virus
- Hepatitis C virus
- Human T-lymphotropic virus 1 or 2
- Human immunodeficiency virus
20
Q
What is Disseminated intravascular coagulation (DIC)?
A
An acquired syndrome characterised by activation of coagulation pathways, resulting in formation of intravascular thrombi and depletion of platelets and coagulation factors
Thrombi may lead to vascular obstruction/ischaemia and multi-organ failure
21
Q
What is the aetiology of Disseminated intravascular coagulation (DIC)?
A
Disease states that trigger systemic activation of coagulation may lead to DIC. Causes include:
- Sepsis/severe infection, major trauma or burns
- Some malignancies (acute myelocytic leukemia or metastatic mucin-secreting adenocarcinoma)
- Obstetric disorders (amniotic fluid embolism, eclampsia, abruptio placentae, retained dead fetus syndrome)
- Severe organ destruction or failure (severe pancreatitis, acute hepatic failure)
- Vascular disorders (Kasabach-Merritt syndrome or giant haemangiomas, large aortic aneurysms)
- Severe toxic or immunological reactions (blood transfusion reaction or haemolytic reactions, organ transplant rejection, snake bite)
22
Q
What is the epidemiology of Disseminated intravascular coagulation (DIC)?
A
Many conditions can cause DIC, therefore, the overall incidence is difficult to determine
Seen in any severely ill patient
23
Q
What are the presenting symptoms of Disseminated intravascular coagulation (DIC)?
A
The patient is severely unwell with symptoms of:
- The underlying disease
- Confusion
- Dyspnoea
- Evidence of bleeding
24
Q
What are the signs of Disseminated intravascular coagulation (DIC) on physical examination?
A
Signs of the underlying aetiology, fever, evidence of shock (hypotension, tachycardia, oliguria)
Acute DIC:
-Petechiae
-Purpura
-Ecchymoses
-Epistaxis
-Mucosal bleeding
-Overt haemorrhage
-Signs of end organ damage (e.g. local infarction or gangrene), respiratory distress, oliguria caused by renal failure
Chronic DIC:
-Signs of deep venous or arterial thrombosis or embolism
-Superficial venous thrombosis, especially without varicose veins
25
What are the appropriate investigations for Disseminated intravascular coagulation (DIC)?
Blood:
FBC:
-Decreased platelets (due to excessive consumption)
-Decreased fibrinogen (due to excessive consumption)
-Prolonged prothrombin time
-Elevated D dimer
-Raised fibrin degradation products
Peripheral blood film:
-Red blood cell fragments (schistocytes)
Other investigations according to aetiology
26
What is Haemolytic anaemia?
Premature erythrocyte breakdown causing shortened erythrocyte life span (<120 days) and anaemia
27
What is the aetiology of Haemolytic anaemia?
Hereditary causes:
-Membrane defects e.g. Hereditary spherocytosis
-Metabolic defects e.g. G6PD deficiency
-Haemoglobinopathies e.g. Sickle cell disease, Thalassaemia
Acquired causes:
-Autoimmune: Warm and cold antibodies attach to erythrocytes causing intravascular and extravasular haemolysis
-Isoimmune: Transfusion reaction, haemolytic disease of the newborn
-Drugs: Penicillin, quinine
-Trauma: Microangiopathic haemolytic anaemia caused by red cell fragmentation in abnormal microcirculation (e.g. haemolytic uraemic syndrome, DIC, malignant hypertension, pre-eclampsia), artificial heart valves
-Infection: Malaria, sepsis
-Paroxysmal nocturnal haemoglobinuria: rare disorder resulting in an acquired RBC membrane defect and subsequent haemolysis
28
What is the epidemiology of Haemolytic anaemia?
Common
Genetic causes are prevalent in African, Mediterranean, Middle Eastern populations
Glucose-6-phosphate dehydrogenase deficiency, is the most common deficiency of erythrocyte enzymes that results in a shortening of the erythrocyte lifespan
-Hereditary spherocytosis is the most common inherited haemolytic anaemia in northern Europe
Warm antibody haemolytic anaemia is the most common form of autoimmune haemolytic anaemia, and affects more women than men
29
What are the presenting symptoms of Haemolytic anaemia?
Jaundice
Haematuria
Anaemia: fatigue, dyspnoea
Possible symptoms of systemic illness
30
What are the signs of Haemolytic anaemia on physical examination?
Pallor (anaemia)
Jaundice
Hepatosplenomegaly
31
What are the appropriate investigations for Haemolytic anaemia?
Bloods:
-FBC*: first test: (low Hb, increased reticulocytes (>1.5%), raised MCV, also elevated unconjugated bilirubin, low haptoglobin, increased mean corpuscular haemoglobin concentration-MCHC)
-Haptoglobin binds free Hb, with low plasma values suggestive of increased free Hb
-Increased LDH
Blood film:
-Leucoerythroblastic picture
-Macrocytosis
-Nucleated erythrocytes or reticulocytes
-Polychromasia
-Identifies specific abnormal cells, such as spherocytes, elliptocytes, sickle cells, fragmented erythrocytes, malarial parasites, erythrocyte Heinz bodies (denatured Hb, stained with methyl violet seen in G6PD deficiency)
Others:
-Urinalysis: Haemoglobinuria is present in intravascular haemolysis (dipstick positive for blood, no RBCs)
-LFTs: elevated in liver disease, alcoholic cirrhosis in particular
-Creatine and Urea: May also be elevated due to direct toxic effects of drugs or infection (haemolytic uraemic syndrome)
32
What is Haemolytic uraemic syndrome?
Characterised by microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury
There are two forms:
1. D + (diarrhoea-associated form)
2. D - (no prodromal illness identified)
33
What is the aetiology of Haemolytic uraemic syndrome?
An aetiological factor causing endothelial injury (glomerular capillary bed) resulting in platelet aggregation, release of unusually large vWF multimers and activation of platelets and the clotting cascade:
- FH
- Shiga toxin-producing strains of Escherichia coli,
- Infectious HUS (non-Shiga toxin-related) is caused by non-E coli organisms, including streptococcal species
- Secondary HUS: exposure to drugs (e.g., ciclosporin, some chemotherapy agents, targeted cancer agents), bone marrow transplant, and pregnancy
34
What is the epidemiology of Haemolytic uraemic syndrome?
Shiga toxin-producing Escherichia coli (STEC) HUS is most common in young children (<5 years), but it can be seen at any age with decreasing frequency in older children and adults
Occurs more often in summer in epidemics and is the most common cause of acute renal failure in children
35
What are the presenting symptoms of Haemolytic uraemic syndrome?
GI: Severe abdominal colic, watery diarrhoea that becomes bloodstained**(most common symptom)
General: Malaise, fatigue, nausea, fever <38oC
Renal: Oliguria or anuria, haematuria
36
What are the signs of Haemolytic uraemic syndrome on physical examination?
```
Pallor (from anaemia)
Slight jaundice (from haemolysis)
Possible abdominal tenderness
```
37
What are the appropriate investigations for Haemolytic uraemic syndrome?
FBC: anaemia, thrombocytopenia, increased LDH, low haptoglobin
Prolonged prothrombin time
Serum electrolytes: abnormalities may include hyperkalaemia, hyponatraemia, hypernatraemia, acidosis (due to bicarbonate loss), hyperphosphataemia- due to diarrhoea and acute kidney injury
Clotting: Normal Plt, APTT and fibrinogen levels, abnormality may indicate DIC
Blood smear/film: presence of schistocytes (fragmented RBCs)
Renal function/creatinine: creatinine increased
Stool culture
Blood culture, PCR
38
What is Haemophilia?
Are bleeding disorders from an inherited (X-linked recessive inheritance pattern) deficiency of a coagulation factor
39
What are the different subtypes of Haemophilia?
1. Haemophilia A: (most common). Caused by a deficiency in factor VIII (8)
2. Haemophilia B: Caused by a deficiency in factor IX (Christmas disease) (9)
3. Haemophilia C: (rare), caused by a deficiency in factor XI (11)
40
What is the aetiology of Haemophilia?
Congenital haemophilia has an X-linked recessive pattern of inheritance and so boys/men are exclusively affected, although many female carriers experience bleeding symptoms requiring appropriate management
A variety of genetic mutations in the factor VIII and XI genes have been described- 30 % of cases are new mutations
Factor VIII is a vital co-factor in the intrinsic pathway of the coagulation cascade
Activated factor IX activates factor X
(converts factor X->Xa)
41
What is the epidemiology of Haemophilia?
Incidence of haemophilia A is 1 in 5,000 males and for haemophilia B is 1 in 30,000 males
Affects all ethnic groups and has a worldwide distribution
42
What are the presenting symptoms of Haemophilia?
Symptoms usually begin from 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 usually asymptomatic, but may have low-enough levels to cause excess bleeding after trauma, or menorrhagia and bleeding following surgery or childbirth
43
What are the signs of Haemophilia on physical examination?
Multiple bruises.
Muscle haematomas
Haemarthroses
Joint deformity
Nerve palsies (nerve compression by haematoma)
Signs of iron-deficiency anaemia- pallor, Koilonychia (spoon nails)
44
What are the appropriate investigations for Haemophilia?
Activated partial thromboplastin time: usually prolonged; may not be prolonged in mild cases (factor levels >30%)- reflects the activity of the intrinsic and the common pathway
*Coagulation factor assays:
-Factor VIII and/or factor IX assay: decreased or absent factor VIII or IX levels; severity is based on level of factor present
-A one-stage method is more commonly used as it is simple and readily automated
Others:
-FBC: usually normal, performed to rule out thrombocytopenia as a cause of bleeding- anaemia may be present
-Prothrombin time: evaluate the extrinsic and common pathways of coagulation- normal
-Plain x-rays: used to describe the clinical progression of arthropathy, acute joint bleeding (haemarthrosis), or bone changes more consistent with chronic arthropathy
-MRI and ultrasound: may detect soft-tissue bleeding and its consequences at an early stage
45
What is Immune thrombocytopenic purpura (ITP)?
Syndrome characterized by immune destruction of platelets resulting in bruising or a bleeding tendency
46
What is the aetiology of Immune thrombocytopenic purpura (ITP)?
Often idiopathic
Acute ITP is usually seen after a viral infection in children, while the chronic form is more common in adults
Associated with:
-Infections (malaria, EBV, HIV)
-Autoimmune diseases (e.g. SLE, thyroid disease)
-Malignancies
-Drugs (e.g. quinine)
Autoantibodies that bind to platelet membrane proteins (glycoprotein IIb/IIIa and Ib/ IX) which results in thrombocytopaenia (low numbers of platelets)
47
What is the epidemiology of Immune thrombocytopenic purpura (ITP)?
Acute ITP presents in children between 2-7 years Chronic ITP is seen in adults
Four times more common in women
48
What are the presenting symptoms of Immune thrombocytopenic purpura (ITP)?
Easy bruising
Mucosal bleeding
Menorrhagia
Epistaxis
49
What are the signs of Immune thrombocytopenic purpura (ITP)?
Visible petechiae
Bruises (purpura or ecchymoses)
Typically, signs of other illness (e.g. infections, wasting, splenomegaly) would suggest other causes
50
What are the appropriate investigations for Immune thrombocytopenic purpura (ITP)?
*FBC and peripheral blood smear: platelet count <100 × 10⁹/L (<100 × 10³/microlitre), helps distinguish between rue thrombocytopenia and pseudothrombocytopenia
-Clotting screen (normal PT, APTT, fibrinogen), autoantibodies (antiplatelet antibody may be present but not used routinely for diagnosis, anticardiolipin
antibody, antinuclear antibody)
Bone marrow: To exclude other pathology. Normal or elevated megakaryocytes
Diagnosis of exclusion: Exclude myelodysplasia, acute leukaemia, marrow infiltration
51
What is Leukaemia, acute myeloblastic (AML)?
Malignancy of primitive myeloid lineage WBCs (myeloblasts) with proliferation in the bone marrow and blood
52
What is the aetiology of Leukaemia, acute myeloblastic (AML)?
1. Myeloblasts, arrest at an early stage of development, with varying cyto-genetic abnormalities (e.g. gene mutations and chromosome translocations)
2. Myeloblasts then undergo malignant transformation and proliferation, with subsequent replacement of normal marrow elements
3. Resulting in bone marrow failure
53
What is the epidemiology of Leukaemia, acute myeloblastic (AML)?
*Most common acute leukaemia in adults
| Incidence increases with age.
54
What are the presenting symptoms of Leukaemia, acute myeloblastic (AML)?
Symptoms of bone marrow failure:
-Anaemia (lethargy, dyspnoea)
-Bleeding (thrombocytopaenia) or DIC(Disseminated intravascular coagulation-blood clots form throughout the body)
-Opportunistic or recurrent infections
Symptoms of tissue infiltration:
-Gum swelling or bleeding
-CNS involvement (headaches, nausea, diplopia-double vision): especially with particular variants
55
What are the signs of Leukaemia, acute myeloblastic (AML) on physical examination?
Signs of bone marrow failure:
-Pallor
-Cardiac flow murmur
-Ecchymoses (discolouration of skin from bleeding underneath)
-Bleeding
-Opportunistic or recurrent infections (e.g. fever, mouth ulcers, skin infections, Pneumocytis Pneumonia- PCP)
Signs of tissue infiltration:
-Skin rashes
-Gum hypertrophy
-Deposits of leukaemic blasts may rarely be seen in the eye (chloroma), tongue and bone – in the latter may cause fractures
56
What are the appropriate investigations for Leukaemia, acute myeloblastic (AML)?
Bloods:
-FBC (reduced Hb, reduced platelets, variable WCC)
-Raised Uric acid
-Raised LDH
-Others: clotting studies, fibrinogen and D-dimers (when DIC is suspected)
*Blood film: AML blasts may show cytoplasmic granules or Auer rods
*Bone marrow aspirate or biopsy:
-Hypercellular with >30 % blasts (immature cells)
Immunophenotyping: Antibodies against surface antigens to classify lineage of abnormal clones
Immunocytochemistry: Myeloblasts granules are positive
[Cytogenetics: For diagnostic and prognostic information]
57
What is Leukaemia, acute lymphoblastic (ALL)?
Malignancy of the bone marrow and blood characterized by the proliferation of lymphoblasts (primitive lymphoid cells)
58
What is the aetiology of Leukaemia, acute lymphoblastic (ALL)?
1. Lymphoblasts, arrest at an early stage of development, with varying cytogenetic abnormalities (e.g. gene mutations and chromosome translocations)
2. Lymphoblasts then undergo malignant transformation and proliferation, with subsequent replacement of normal marrow elements
3. Resulting in bone marrow failure and infiltration into other tissues
59
What is the epidemiology of Leukaemia, acute lymphoblastic (ALL)?
Most common malignancy of childhood.
The peak incidence occurs between 2 and 5 years of age
Second peak in the elderly
60
What are the risk factors/associations of Leukaemia, acute lymphoblastic (ALL)?
Environmental: radiation, viruses
Genetic: e.g. Down’s syndrome, neurofibromatosis type 1, increased risk in siblings
61
What are the presenting symptoms of Leukaemia, acute lymphoblastic (ALL)?
Symptoms of bone marrow failure:
-Anaemia (fatigue, dyspnoea)
-Bleeding (spontaneous bruising, bleeding gums, menorrhagia)
-Opportunistic infections (bacterial, viral, fungal, protozoal)
Symptoms of organ infiltration:
-Tender bones
-Enlarged lymph nodes
-Mediastinal compression (in T-cell ALL)
-Meningeal involvement (headache, visual disturbances, nausea)
62
What are the signs of Leukaemia, acute lymphoblastic (ALL) on physical examination?
```
Signs of bone marrow failure:
Pallor
-Bruising
-Bleeding
-Infection (e.g. fever, GI, skin, respiratory systems)
Signs of organ infiltration:
-Lymphadenopathy
-Hepatosplenomegaly
-Cranial nerve palsies
-Retinal haemorrhage or papilloedema on fundoscopy
-Leukaemic infiltration of the anterior chamber of the eye (mimics hypopyon)
-Testicular swelling
```
63
What are the appropriate investigations for Leukaemia, acute lymphoblastic (ALL)?
Bloods:
-FBC (normochromic normocytic anaemia, reduced platelets, variable WCC)
-Raised uric acid, raised LDH, clotting screen
Blood film: Lymphoblasts evident
Bone marrow aspirate or trephine biopsy:
-Hypercellular with >30 % lymphoblasts
-Immunophenotyping: Using antibodies for cell surface antigens e.g. CD20
Lumbar puncture (and CSF analysis): For CNS involvement.
CXR: May show mediastinal lymphadenopathy, thymic enlargement, lytic bone lesions
Bone radiographs: Mottled appearance with ‘punched-out’ lesions (e.g. skull caused by leukaemic infiltration)
64
What are the classifications for Leukaemia, acute lymphoblastic (ALL)?
Morphologic classification(French–American–British classification):
L1: Small lymphoblasts, scanty cytoplasm.
L2: Larger, heterogenous lymphoblasts.
L3: Large lymphoblasts with blue or vacuolated cytoplasm.
65
What is Leukaemia, chronic myeloid (CML)?
A malignant clonal disease characterized by proliferation of granulocyte precursors in the bone marrow and blood
*distinguished from AML by its SLOWER progression
66
What is the aetiology of Leukaemia, chronic myeloid (CML)?
Malignant proliferation of stem cells. Three stages:
1. Relatively stable chronic phase of variable duration (average of 4–6 years)
2. Accelerated phase (3–9 months)
3. Acute leukaemia phase (blast transformation)
67
What is the epidemiology of Leukaemia, chronic myeloid (CML)?
Incidence increases with age, mean 40–60 years
| 4 times more common in males
68
What are the presenting symptoms of Leukaemia, chronic myeloid (CML)?
Asymptomatic in up to 40–50 % and is diagnosed on routine blood count
Hypermetabolic symptoms:
Weight loss, malaise, sweating
Bone marrow failure symptoms: Lethargy, dyspnoea, easy bruising, epistaxis (infection is rare)
Others:
-Abdominal discomfort and early satiety
-Occasionally presents with gout or hyperviscosity symptoms (visual disturbance, headaches)
-May present during blast crisis with symptoms of AML or ALL
69
What are the signs of Leukaemia, chronic myeloid (CML) on physical examination?
Splenomegaly: Most common physical finding (90%)
Signs of bone marrow failure:
-Pallor
-Cardiac flow murmur
-Bleeding
-Ecchymoses (discolouration of skin from bleeding underneath)
70
What are the appropriate investigations for Leukaemia, chronic myeloid (CML)?
Bloods:
-FBC: grossly raised WCC, low Hb, raised basophils /eosinophils/ neutrophils, variable platelets
-Raised uric acid, low neutrophil alkaline phosphatase, high vitamin B12 and B12-binding protein
Blood film: Shows immature granulocytes in peripheral blood
Bone marrow aspirate or biopsy:
Hypercellular with raised myeloid–erythroid ratio
71
What is Leukaemia, chronic lymphocytic (CLL)?
Characterized by progressive accumulation of functionally incompetent lymphocytes, which are monoclonal in origin
*There is an overlap between CLL and non- Hodgkin’s lymphomas
72
What is the aetiology of Leukaemia, chronic lymphocytic (CLL)?
Malignant cells may accumulate as a result of their inability to undergo apoptosis (partly due to overexpression of BCL2 and Fas-inhibitory molecules)
73
What is the epidemiology of Leukaemia, chronic lymphocytic (CLL)?
90% are >50 years
Men more than Women
Rare in Asians
74
What are the presenting symptoms of Leukaemia, chronic lymphocytic (CLL)?
Asymptomatic: Up to 40–50 % diagnosed on routine blood count
Systemic symptoms:
-Lethargy, malaise, night sweats
Symptoms of bone marrow failure:
Recurrent infections (bacterial, viral, fungal), herpes
zoster, easy bruising or bleeding (e.g. epistaxis)
75
What are the signs of Leukaemia, chronic lymphocytic (CLL) on physical examination?
Non-tender lymphadenopathy (often symmetrical)
Hepatomegaly
Splenomegaly
Later stages: signs of bone marrow failure:
-Pallor
-Cardiac flow murmur
-Purpura/ ecchymoses (discolouration of skin from bleeding underneath)
76
What are the appropriate investigations for Leukaemia, chronic lymphocytic (CLL)?
CLL may be associated with autoimmune phenomena: -Haemolytic anaemia (10 %)
-Thrombocytopaenia or a combination of both (Evan’s syndrome)
Bloods:
-FBC: gross lymphocytosis, 5–300x109/L, anaemia, low platelets)
-Anaemia may be due to bone marrow infiltration, hypersplenism or autoimmune haemolysis
-Reduced serum immunoglobulins
Blood film:
-Small lymphocytes with thin rims of cytoplasm and smudge/smear cells
Bone marrow aspirate or biopsy:
-Lymphocytic replacement (25–95 %) of normal marrow
elements
Immunophenotyping shows the malignant cell to be a relatively mature B cell with weak surface expression of monoclonal IgM or IgD
*CT (chest, abdomen, and pelvis): On the basis of the patient’s symptoms
77
What are Lymphomas?
Neoplasms of lymphoid cells, originating in lymph nodes or other lymphoid tissues
78
What is the aetiology of Hodgkin’s Lymphoma?
Unknown- likely to be a result of an environmental trigger in a genetically susceptible individual
*The presentation of HL (fevers, night sweats, lymphadenopathy) suggests an infectious aetiology- the EBV genome has been detected in 50% of Hodgkin’s lymphomas
79
What is the epidemiology of Hodgkin’s Lymphoma?
Bimodal age distribution, with peaks 20–30 years and >50 years
More common in males
Annual European incidence is 2–5 in 100,000
80
What are the presenting symptoms of Hodgkin’s Lymphoma?
```
Painless enlarging mass (most often in neck, occasionally in axilla or groin)- may become painful after alcohol ingestion
‘B’ symptoms:
-Fevers >38C
Night sweats
Weight loss >10% body weight in last 6 months
Other:
-Pruritus
-Cough
-Dyspnoea
-Chest pain/discomfort
*with intrathoracic disease
```
81
What are the signs of Hodgkin’s Lymphoma on physical examination?
Non-tender firm rubbery lymphadenopathy:
-Cervical, axillary or inguinal
Splenomegaly, occasionally hepatomegaly
Skin excoriations (scratch marks)
Signs of intrathoracic disease (e.g. pleural effusion, superior vena cava obstruction)
82
What are the appropriate investigations for Hodgkin’s Lymphoma?
Bloods:
-FBC: Anaemia of chronic disease, leucocytosis, raised neutrophils, raised eosinophils. Lymphopaenia (abnormal reduction) with advanced disease
-Raised ESR and CRP
-LFTs (raised LDH, raised transaminases if liver involved)
*Lymph node biopsy: Hodgkin's cell can be a characteristic Reed-Sternberg cell
Bone marrow aspirate and trephine biopsy: Involvement seen only in very advanced disease
Imaging:
-CXR: mediastinal mass, large mediastinal adenopathy
-CT of thorax, abdomen and pelvis: may show enlarged lymph nodes and other sites of disease
-Gallium scan, PET scans: involved sites appear bright
83
What is Non-Hodgkin’s Lymphoma (NHL)?
A diverse group consisting of 85% B cell, 15% T cell and NK cell forms, ranging from indolent (little/no pain) to aggressive disease and referred to as low, intermediate and high grades
84
What is the aetiology of Non-Hodgkin’s Lymphoma (NHL)?
Complex process involving the accumulation of multiple genetic lesions (activation of oncogenes by chromosomal translocations and inactivation of tumour suppressor genes by chromosomal deletions or mutations)
The genome in certain lymphoma subtypes has been altered by the introduction of foreign genes via a number of oncogenic viruses: EBV has been detected in cases of Burkitt’s lymphoma and of AIDS- associated lymphomas
85
What are some of the factors associated with the development of Non-Hodgkin’s Lymphoma (NHL)?
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Radiotherapy
Immunosuppressive agents
Chemotherapy
HIV, Hep B V, Hep C V
Connective tissue diseases e.g. SLE
Inherited and acquired immunodeficiency syndromes
```
86
What is the epidemiology of Non-Hodgkin’s Lymphoma (NHL)?
Incidence increase with age
More common in males
More common in the West
87
What are the presenting symptoms of Non-Hodgkin’s Lymphoma (NHL)?
```
Painless enlarging mass: Often in neck, axilla or groin
Systemic symptoms (*less frequent than in Hodgkin’s):
-Fever
-Night sweats
-Weight loss > 10 % body weight
-Symptoms of hypercalcaemia.
Symptoms related to organ involvement (*extranodal disease is more common in NHL than in Hodgkin’s lymphoma):
-Skin rashes
-Headache
-Sore throat
-Abdominal discomfort
-Testicular swelling
```
88
What are the signs of Non-Hodgkin’s Lymphoma (NHL) on physical examination?
```
Painless firm rubbery lymphadenopathy:
Cervical, axillary or inguinal
Oropharyngeal (Waldeyer’s ring of lymph nodes) involvement
Skin rashes:
-Mycosis fungoides (well-defined indurated scaly plaque-like lesions with raised ulcerated nodules caused by cutaneous T-cell lymphoma) and Sezary’s syndrome
Abdominal mass
Hepatosplenomegaly
Signs of bone marrow involvement:
-Anaemia, infections or purpura
```
89
What are the appropriate investigations for Non-Hodgkin’s Lymphoma (NHL) on physical examination?
Bloods:
FBC (anaemia, neutropaenia and thrombocytopaenia if bone marrow involved)
-U&Es, uric acid
-Raised ESR and CRP, raised LDH, LFTs (elevated transaminases with liver involvement), Ca2+ (may be raised)
-HIV, HBV and HCV serology (in select patients)
Blood film: Lymphoma cells may be visible in some patients, nucleated red blood cells
Lymph node biopsy: histopathologic evaluation
Bone marrow aspiration and biopsy: important for staging
Skin biopsy: useful for infiltration diagnosis
Imaging:
-PET scanning: increased uptake at involved sites
-CT plus PET scanning is of particular value for evaluation of extranodal involvement (staging)
90
What is Macrocytic anaemia?
Anaemia associated with a high MCV of erythrocytes (>100 fl in adults)
91
What is the aetiology of Macrocytic anaemia?
Megaloblastic anaemia:
*-Vitamin B12 deficiency (e.g. reduced absorption)
*-Folate deficiency (reduced intake e.g. alcoholics, elderly, anorexia)
-Drugs: methotrexate, hydroxyurea, azathioprine
Non-megaloblastic:
*-Alcohol excess
*-Liver disease
-Myelodysplasia
-Multiple myeloma
-Hypothyroidism
-Haemolysis
-Drugs: tyrosine kinase inhibitors: imatinib, sunitinib
92
What is the epidemiology of Macrocytic anaemia?
More common in the elderly and females
Annual worldwide incidence of pernicious anaemia in those >40 years old is 25 in 100,000 (most common cause of vitamin B12 deficiency in the West)
93
What are the presenting symptoms of Macrocytic anaemia?
```
Non-specific signs of anaemia:
-Tiredness
-Lethargy
-Dyspnoea
FH of autoimmune disease
PMH of gastrointestinal surgery
Symptoms of the cause, e.g. weight loss, diarrhoea, steatorrhoea in coeliac disease
```
94
What are the presenting symptoms of Macrocytic anaemia?
```
Non-specific signs of anaemia:
-Tiredness
-Lethargy
-Dyspnoea
FH of autoimmune disease
PMH of gastrointestinal surgery
Symptoms of the cause, e.g. weight loss, diarrhoea, steatorrhoea in coeliac disease
```
95
What are the signs of Macrocytic anaemia on physical examination?
```
Sign of anaemia:
-Pallor
-Tachycardia
There may be signs of the cause, e.g. malnutrition, jaundice, hypothyroid appearance
Signs of pernicious anaemia:
-Lemon-tinted skin (mild jaundice)
-Glossitis (red sore tongue)
-Angular stomatitis (cheilitis)
-Weight loss
Signs of vitamin B12 deficiency:
-*Peripheral neuropathy
-Ataxia
-Subacute combined degeneration of the spinal cord, optic atrophy, dementia
```
96
What are the appropriate investigations for Macrocytic anaemia?
Bloods:
-FBC: low Hb, raised MCV, pancytopenia in megaloblastic anaemia
-LFTs: raised bilirubin as a result of ineffective erythropoiesis or haemolysis
-ESR, TFT, serum vitamin B12, red cell folate,
-Antibodies against parietal cells or intrinsic factor (IF)
-Serum protein electrophoresis (exclude myeloma)
Blood film:
-Large erythrocytes (macrocytes)
In megaloblastic anaemia:
-Macroovalocytes, hypersegmented neutrophil nuclei (>5 lobes)
$chilling’s test: (test for pernicious anaemia)
-Part I: radiolabelled vitamin B12 is given orally and IM non-radioactive B12 is given to saturate vitamin B12-binding proteins
-Reduced radiolabelled vitamin B12 in a 24-h urine collection indicates reduced absorption
-Part II: Part I repeated with oral IF
-If radiolabelled vitamin B12 is now detected in urine, the cause is likely to be IF deficiency from pernicious anaemia or gastrectomy
Bone marrow biopsy (rarely necessary): Megaloblasts (nucleated red cells) or myelodysplastic changes
97
What is the management of Macrocytic anaemia?
Pernicious anaemia:
-IM hydroxycobalamin (thrice weekly for 2 weeks, then every 3 months for life)
Folate deficiency:
-Oral folic acid: 5 mg/day for 1–4 months, or until complete haematologic recovery occurs
-*Vitamin B12 deficiency must be treated first if present (folic acid may worsen neurologic complications of untreated vitamin B12 deficiency)
98
What are the complications of Macrocytic anaemia?
In pernicious anaemia there is an increased risk of gastric cancer
*In pregnancy, folate deficiency predisposes to spinal cord anomalies
99
What is the prognosis of Macrocytic anaemia?
Majority are treatable if there are no complications
100
What is Microcytic anaemia?
Anaemia associated with low MCV (<80 fl)
101
What is the aetiology of Microcytic anaemia?
*Iron-deficiency (commonest cause):
-Blood loss e.g. gastrointestinal tract, urogenital tract, hookworm infection
-Reduced absorption: Small bowel disease, Post-gastrectomy
-Increased demands: Growth, Pregnancy
-Reduced Intake: Vegetarians
Others:
-Anaemia of chronic disease: often normocytic but may be microcytic
-Thalassaemia
-Sideroblastic anaemia: Abnormality of haem synthesis, can be inherited (X-linked), or secondary to alcohol, drug
102
What is the epidemiology of Microcytic anaemia?
Iron-deficiency anaemia is the commonest form of anaemia worldwide
103
What are the presenting symptoms of Microcytic anaemia?
```
Non-specific symptoms:
-Tiredness
-Lethargy
-Malaise
-Dyspnoea
-Pallor
Exacerbation of pre-existing angina or intermittent claudication
Family history of any causative diseases
*Lead poisoning: Anorexia, nausea, vomiting, abdominal pain, constipation, peripheral nerve lesions
```
104
What are the signs of Microcytic anaemia on physical examination?
Signs of anaemia, e.g. pallor of skin and mucous membranes, brittle nails and hair
If long-standing and severe, spoon-shaped nails (koilonychia)
Signs of cause:
-Glossitis: Atrophy of tongue papillae
-Cheilitis: Angular stomatitis, erythema and maceration of the skin adjacent to the angle of the mouth
-Thalassaemias
Lead poisoning: Blue gumline, peripheral nerve lesions (wrist or foot drop), encephalopathy, convulsions, reduced consciousness
105
What are the appropriate investigations for Microcytic anaemia?
Bloods:
-FBC: low Hb, low MCV, reticulocytes)
-Serum iron (low in iron deficiency)
-Iron-binding capacity (high in iron deficiency)
-Serum ferritin (low in iron deficiency)
-Serum lead (if poisoning suspected)
Blood film:
-Iron-deficiency anaemia: Microcytic (small), hypochromic (central pallor >one-third cell size), anisocytosis (variable cell size), poikilocytosis (variable cell shapes)
If iron-deficiency anaemia in >40 years and post-menopausal women:
-Upper GI endoscopy, colonoscopy and investigations for haematuria should be considered if no obvious cause of blood loss
Sideroblastic anaemia:
-Dimorphic blood film with a population of hypochromic microcytic cells
Lead poisoning:
-Basophilic stippling (coarse dots represent condensed RNA in the cytoplasm)
Hb electrophoresis: For haemoglobin variants or thalassaemias
106
What is the management of Microcytic anaemia?
Iron deficiency:
- Oral iron supplements (e.g. 200 mg ferrous sulphate tablets containing 65 mg of elemental iron, twice or thrice daily taken with food)
- If oral iron intolerance or malabsorption, consider parenteral iron supplements (beware risk of anaphylaxis)
- Monitor Hb and MCV, aiming for Hb rise of 1 g/dL/week
Sideroblastic anaemia: Treat the cause (e.g. stop causative drugs). Pyridoxine can be used in inherited forms. If no response, consider blood transfusion and iron chelation
Lead poisoning: Remove the source, dimercaprol, D-penicillamine
107
What are the complications of Microcytic anaemia?
High-output cardiac failure, complications of the cause
108
What is the prognosis of Microcytic anaemia?
Depends on the underlying cause
| Iron deficiency anaemia is good once treated with supplements
109
What is multiple myeloma?
Haematological malignancy characterized by proliferation of plasma cells in the bone marrow resulting in bone lesions and production of a monoclonal immunoglobulin in the serum and/or urine
110
What is the aetiology of multiple myeloma?
Unknown
Genetic inheritance may play a role and/or a viral trigger
Chromosomal aberrations are frequent, certain cytokines (e.g. IL-6) act as potent growth factors for plasma cell proliferation
Multiple myeloma is associated with ionizing radiation, agricultural work or occupational chemical exposures (benzene)
111
What is the epidemiology of multiple myeloma?
Annual incidence is 4 in 100,000, peak incidence in 70-year-olds
Afro- Caribbeans > white people > Asians
112
What are the presenting symptoms of multiple myeloma?
```
*May be diagnosed incidentally on routine blood tests
Bone pain:
-Often in back, ribs
-Sudden and severe if caused by pathological fracture or
vertebral collapse.
Infections: Often recurrent
General:
-Tiredness
-Thirst
-Polyuria
-Nausea
-Constipation
-Mental change (resulting from hypercalcaemia)
Hyperviscocity:
-Bleeding
-Headaches
-Visual disturbance
```
113
What are the signs of multiple myeloma on physical examination?
```
Pallor- anaemia
Tachycardia
Flow murmur
Signs of heart failure
Dehydration
Purpura
Hepatosplenomegaly
Macroglossia
Carpal tunnel syndrome
Peripheral neuropathies
```
114
What does CRAB stand for in multiple myeloma?
C: hyperCalcaemia
R: renal failure
A: anaemia
B: bone lesions
115
What are the appropriate investigations for multiple myeloma?
*Diagnostic test: serum/urine electrophoresis: Serum paraprotein (two-thirds IgG, one-third IgA)
Bloods:
-FBC (low Hb, normochromic normocytic)
-Elevated ESR and CRP (CRP may be normal with elevated ESR)-extent of advanced disease
-U&E (high creatinine, high Ca2+ in 45%), typically normal AlkPhos [renal impairment]
Blood film: Rouleaux formation (stacks or aggregations of RBC) with bluish background (high protein)
Skeletal survey- chest, pelvic or vertebral X-ray: Osteolytic lesions without surrounding sclerosis, osteopenia
*Bone marrow aspirate an biopsy: monoclonal plasma cell infiltration
116
What is Myelodysplasia?
Also known as myelodysplastic syndrome (MDS)
MDS is a type of blood cancer that affects the bone marrow and causes low levels of one or more types of blood cells in the blood
117
What is the aetiology of Myelodysplasia?
In most cases, the cause of MDS is unknown (primary MDS)
A small number of people develop MDS after treatment with chemotherapy or radiotherapy. This is called secondary or treatment-related MDS (t-MDS)
There are different types of MDS. These are based on:
-which blood cells (red cells, white cells or platelets) have become abnormal (single lineage/multi-lineage)
-how many immature blood cells (blasts) you have (excess blasts)
-if there is a chromosome change called del 5q in the blood cells
118
What is the epidemiology of Myelodysplasia?
MDS is more common in people aged over 70, but it can happen at any age
A genetic link is unlikely
119
What are the presenting symptoms/ signs of Myelodysplasia on physical examination?
May be asymptomatic and finding incidental
Signs of anaemia:
-Fatigue
-Dyspnoea
-Pallor
Recurrent infections (low numbers of WBC)
-Bruising or bleeding because of a low number of platelets
120
What are the appropriate investigations for Myelodysplasia?
FBC- Hb, WCC, MCV, platelets (depends on the type of cell affected)
Bone marrow biopsy
Cytogenetic tests: for chromosome change called isolated del (5q)
121
What is Myelofibrosis?
A reactive and reversible process common to many malignant and benign bone marrow disorders
122
What is the aetiology of Myelofibrosis?
The aetiology of primary myelofibrosis (PMF) is unknown
Chromosomal abnormalities are found in 40% of patients and around 30% of patients have previous history of polycythaemia rubra vera or essential thrombocythaemia
There are increased numbers of abnormal megakaryocytes (platelet precursor cells) with stromal proliferation as a secondary reactive phenomenon to growth factors from the megakaryocyte
123
What is the epidemiology of Myelofibrosis?
Rare- annual incidence 0.4 in 100,000
Peak onset 50–70 years
Seems to be more common in white people, and there is a male preponderance among adults but in younger children, girls are affected twice as frequently as boys
124
What are the presenting symptoms for Myelofibrosis?
```
Asymptomatic: Diagnosed after abnormal blood count
Systemic symptoms:
Common:
-Weight loss
-Anorexia
-Fever and night sweats
-Pruritus
Uncommon:
-Left upper quadrant abdominal pain
-Indigestion (caused by massive splenomegaly)
-Bleeding, bone pain and gout
```
125
What are the signs of Myelofibrosis on physical examination?
Splenomegaly (massive in 10%) is the main physical finding, hepatomegaly present in 50–60% of patients
126
What are the appropriate investigations for Myelofibrosis?
Bloods:
*-FBC: (usually the first test to order) anaemia; normal or abnormal cell counts, later leukopaenia and thrombocytopaenia)
-LFTs (abnormal)
*Blood film:
-teardrop-shaped RBCs*
-Presence of metamyelocytes, myelocytes, promyelocytes, myeloblasts, and nucleated RBCs in the circulation
*Bone marrow aspiration/biopsy: Aspiration usually unsuccessful (‘dry tap’)- marrow fibrosis
Bone marrow biopsy: marrow fibrosis (fibrotic hypercellular marrow with increased reticulin deposition)
127
What is Normocytic anaemia?
Anaemia associated with normal MCV (80-100 fl)
128
What is the aetiology of Normocytic anaemia?
```
Anaemia of chronic disease:
-Inflammation
-Neoplasia
Renal failure
Endocrine failure:
-Hypothyroidism
-Hypopuitarism
Marrow failure:
-Pure red-cell aplasia
-Aplastic anaemia
-Infiltration
Acute blood loss
Polymyalgia rheumatica
```
129
What is the epidemiology of Normocytic anaemia?
Anaemia of chronic disease is the commonest anaemia in hospital patients and the second most common anaemia after iron deficiency anaemia
130
What are the presenting symptoms/signs of Normocytic anaemia on physical examination?
Dyspnoea
| Fatigue
131
What are the appropriate investigations for Normocytic anaemia?
FBC: Low Hb, MCV (80-100g/L), ferritin normal or raised
Blood film/ bone marrow biopsy: bone marrow appearance is unremarkable
Other tests:
-B12, folate, TSH
-Haemolysis
132
What is the management of Normocytic anaemia?
Treat the underlying disease
Erythropoietin (hormone that stimulates RBC production) is effective in raising the Hb level and improving the quality of life (in those with malignant disease especially)
Iron given parenterally can safely overcome the functional iron deficiency
Inhibitors of inflammatory modulators are also effective
133
What is Polycythaemia?
An increase in haemoglobin (Hb) concentration above the upper limit of normal for a person’s age and sex
Classified into:
-Relative polycythaemia (normal red cell mass but low plasma volume)
-Absolute (true) polycythaemia ( high red cell mass)
134
What is the aetiology of Polycythaemia rubra vera?
Characterized by clonal proliferation of myeloid cells with variable morphologic maturity and haematopoietic efficiency (myeloproliferative neoplasm characterised clinically by:
-Erythrocytosis and often thrombocytosis, leukocytosis, and splenomegaly
Mutations in JAK2 tyrosine kinase participates in the pathogenesis
135
What is the aetiology of Polycythaemia?
Polycythaemia Rubra Vera
Secondary polycythaemia:
=Appropriate increase in erythropoietin:
-Caused by chronic hypoxia (e.g. chronic lung disease) leading to upregulation of erythrogenesis
=Inappropriate increase in erythropoietin:
-Renal (carcinoma, cysts, hydronephrosis)
-Hepatocellular carcinoma
-Fibroids
-Cerebellar haemangioblastoma
Secondary polycythaemia may be a feature of erythropoietin abuse amongst athletes
Relative polycythaemia:
- Dehydration (e.g. diuretics, burns, enteropathy)
- Gaisbock’s syndrome (seen in young male smokers with increased vasomotor tone and hypertension)
136
What is the epidemiology of Polycythaemia?
Annual UK incidence of polycythaemia rubra vera is 1.5 in 100,000
Peak age is 45–60 years (middle-older age)
137
What are the presenting symptoms of Polycythaemia?
```
Headaches
Dyspnoea
Tinnitus
Blurred vision as a result of hyperviscosity
*Pruritus after hot bath
Night sweats
Thrombosis (DVT, stroke)
Pain resulting from peptic ulcer disease
Angina
Gout
Choreiform movements
```
138
What are the physical signs of Polycythaemia on physical examination?
Plethoric complexion (red-faced)
Scratch marks as a result of itching
Conjunctival suffusion (redness) and retinal venous engorgement
Hypertension
Splenomegaly (present in 75% of polycythaemia rubra vera)
Signs of underlying aetiology in secondary causes
139
What are the appropriate investigations for Polycythaemia?
Required for diagnosis:
-FBC: raised Hb (>16.5 g/dL in F, >18.5 g/dL in M), raised " haematocrit (>48-52%), low MCV
Distinguish between relative (normal red cell mass but low plasma volume) and absolute polycythaemia (high red cell mass):
- (Isotope dilution techniques) infusion of radiolabelled albumin and RBCs allow confirmation of plasma volume and red cell mass
Polycythaemia rubra vera: raised WCC and platelets, low serum erythropoietin. *JAK2 mutation. Bone marrow: erythroid hyperplasia and elevated megakaryoctyes
Others:
-Oxygen saturation
-Serum ferritin (normal unless coexistent with iron deficiency)
-Abdominal ultrasound: splenomegaly
-Vascular imaging: may demonstrate thrombosis
140
What is Sickle Cell Disease?
A chronic condition with sickling of red blood cells caused by inheritance of haemoglobin S (Hb S)
141
What are the different types of Sickle Cell Disease?
Sickle cell anaemia: Homozygosity for Hb S
Sickle cell trait: Carries one copy of Hb S
Sickle cell disease: Includes compound heterozygosity for Hb S and C and for Hb S and b-thalassaemia
142
What is the aetiology of Sickle Cell Disease?
Sickling occurs when red blood cells containing sickle haemoglobin become rigid and distorted into a crescent shape
In sickle cell anaemia, valine replaces glutamic acid at the sixth amino acid of the beta-globin chain, as a result of a recessive single gene mutation
This produces the abnormal protein, Hb S which is hydrophobic and insoluble resulting in sickling of red cells (formation of crescent shape cells) with increased fragility and inflexibility. They are prone to:
1. Sequestration and destruction, leading to reduced RBC survival (20 days)- rather than 120
2. Occlusion small blood vessels causing hypoxia which, in turn, causes further sickling and occlusion
143
What is the epidemiology of Sickle Cell Disease?
In England, sickle cell disease affects more than 1 in 2000 live births
Rarely presents before 4–6 months (because of continuous production of foetal haemoglobin)
Common in Africa, Caribbean, Middle East and areas with high prevalence of malaria (positive selection for the gene mutation)
144
What are the factors that precipitate sickling?
Infection
Dehydration
Hypoxia
Acidosis
145
What are the presenting symptoms for Sickle Cell Disease?
Symptoms secondary to vaso-occlusion or infarction:
- Autosplenectomy (splenic atrophy or infarction): Leading to increased risk of infections with encapsulated organisms (e.g. pneumococcus, Haemophilus influenzae, meningococcus, Salmonella)
- Abdominal pain.
- Bones: Painful crises affecting small bones of hands or feet (dactylitis) in children, and ribs, spine, pelvis and long bones in adults. Chronic hip or shoulder pain (avascular necrosis)
- Myalgia and arthralgia
- CNS: Can cause fits or strokes (e.g. hemiplegia)
- Retina: Visual loss (proliferative retinopathy)
Symptoms of sequestration crises (red cell pooling in various organs):
- Such as spleen, liver (hepatosplenomegaly)
- Exacerbation of anaemia
- Lungs: ‘Acute chest syndrome’: breathlessness, cough, pain, fever
- Corpora cavernosa: Persistent erection (pripiasm) and impotence
146
What are the signs of Sickle Cell Disease on physical examination?
Signs secondary to vaso-occlusion, ischaemia or infarction:
-Bone: joint or muscle tenderness or swelling (caused by avascular necrosis). Short digits (caused by infarction in small bones)
-Retina: Cotton wool spots from areas of ischaemic retina.
Signs secondary to sequestration crises:
-Organomegaly: Spleen is enlarged in early disease but later reduces in size because of splenic atrophy
Priapism: Persistent erection
Signs of anaemia: pallor
147
What are the appropriate investigations for Sickle Cell Disease?
1st line:
-DNA based assays: expensive
-Haemoglobin isoelectric fusing: IEF is the most commonly used test to determine the presence of the sickle cell gene, in older infants the amount of HbS will increase as HbF decreases; by 2 years of age the amount of HbS and HbF stabilises; patients with sickle cell anaemia will have no HbA
-Haemoglobin electrophoresis: Shows Hb S, absence of Hb A (in Hb SS) and high levels of Hb F
-Blood film: presence of nucleated red blood cells, sickle-shaped cells, and features of hyposplenism (target cells, Howell–Jolly bodies)
-FBC: anaemia (reticulocytes are high in haemolytic crises and low in aplastic crises)
-Iron studies: distinguish haemolytic anaemia from iron-deficiency anaemia
Others:
-Plain x-rays: confirm the presence of bone infarction, irregular margins or moth-eaten destruction with overlying periosteal new bone formation
-CXR: acute chest syndrome
148
What is the management of Sickle Cell Disease?
Acute (painful crises): Oxygen, IV fluids, strong analgesia (IV opiates), antibiotics
Infection prophylaxis(reduce threat of infections): Penicillin V. Regular vaccinations (e.g. against pneumococcus)
Folic acid: In severe haemolysis or in pregnancy
Hydroxycarbamide/hydroxyurea: Increases Hb F levels and reduces frequency and duration of sickle cell crisis
Red cell transfusion: For severe anaemia. Repeated transfusions with iron chelators may be necessary for those with frequent crises or after CNS crisis, maintain HbS below 30%
Exchange transfusion: In severe crises, before surgery, pregnancy
Advice: Avoid precipitating factors, good hygiene and nutrition, genetic counselling, prenatal screening
Surgical: Bone marrow transplantation in selected patients, joint replacement for avascular necrosis
149
What are the complications of Sickle Cell Disease?
```
Anaemia
Iron overload: Chronic exposure to blood transfusions can lead to end-organ damage in people with sickle cell disease
Aplastic crises (infection with B19 parvovirus, temporary cessation of erythropoiesis)
Haemolytic crises
Pigment gallstones
Cholecystitis
Renal abnormalities
Leg ulcers (local ischaemia)
Cardiomyopathy
```
150
What is the prognosis for Sickle Cell Disease?
Most of those with sickle cell disease, with good care, survive to 50 years
Major mortality is usually a result of pulmonary or neurological complications (adults) or infection (children)
151
What is Thalassaemia?
Group of genetic disorders characterized by reduced globin chain synthesis
152
What is the aetiology of Thalassaemia?
The autosomal recessive genetic defects result in an imbalance of globin chain production and deposition in erythroblasts and erythrocytes
This causes ineffective erythropoiesis (making of RBC), haemolysis, anaemia and extramedullary haemopoiesis (production of blood cells)
153
What are the different classifications of Thalassaemia?
a-Thalassaemia:
-Reduced a-Globin chain synthesis- Chromosome has 4 a-globin genes
-4 gene deletion: Hb Barts (c4) and intrauterine death
-3 gene deletion: Microcytic hypochromic anaemia, splenomegaly
-1-2 gene deletion: Microcytic hypochromic red cells; no anaemia
b-Thalassaemia major (homozygous b -thalassaemia):
-b-Globin gene mutations on chromosome 11 causes no or minimal b-chain synthesis
b-Thalassaemia intermedia:
-Mild defect in b-chain synthesis causing microcytic anaemia
-decreased a-chain synthesis or increased gamma-chains
b-Thalassaemia trait (heterozygous carrier):
-Asymptomatic
-Mild microcytic anaemia
-High red cell count
154
What is the epidemiology of Thalassaemia?
Worldwide, but more common in the Mediterranean and areas of the Middle East
155
What are the presenting symptoms of Thalassaemia?
b-Thalassaemia major:
-Anaemia presenting at 3–6 months (when gamma-chain synthesis switches to b-chain synthesis)
-Failure to thrive, prone to infections
a- or b-Thalassaemia trait:
-May be asymptomatic
-Detected on routine blood tests or from a family history
156
What are the signs of Thalassaemia on physical examination?
b-Thalassaemia major:
-Pallor
-Malaise
-Dyspnoea
-Mild jaundice
-Frontal bossing and thalassaemic facies (marrow hyperplasia)
Hepatosplenomegaly (erythrocyte pooling, extramedullary haemopoiesis)
Patients with b-thalassaemia intermedia may also have these signs
157
What are the appropriate investigations for Thalassaemia?
1st line:
-FBC: (low Hb, low MCV, low MCH)
-Blood film: ypochromic, microcytic anaemia, target cells, nucleated red cells and elevated reticulocyte count
-Haemoglobin analysis:
beta-thalassaemia major: minimal to no Hb A, elevated Hb F and HbA2
beta-thalassaemia intermedia: decreased Hb A, elevated Hb F and HbA2
beta-thalassaemia trait: mostly Hb A, elevated Hb F and HbA2
-LFTs: may be mild to moderate hyperbilirubinaemia, most of it unconjugated
-Plain x-rays of skull: widening of the diploeic space, facial deformity, ‘Hair-on-end’ appearance (caused by expansion of marrow into cortex) in
b-thalassaemia major
-Abdominal ultrasound: liver and spleen enlargement
158
What is Thrombotic thrombocytopenic purpura (TTP)?
```
Triad of:
1. microangiopathic haemolytic anaemia
2. acute renal failure
3. thrombocytopaenia
Other features include: fever and fluctuating CNS signs
```
*Overlaps with haemolytic uraemic syndrome
159
What is the aetiology of Thrombotic thrombocytopenic purpura (TTP)?
The underlying cause might involve the production of unusually large von Willebrand factor (vWF) multimers- Von Willebrand factor (vWF) has a twofold role in haemostasis:
- It acts as a carrier protein for factor VIII, thereby protecting factor VIII from rapid degradation
- It acts as a bridge connecting platelets to damaged endothelium.
160
What is the epidemiology of Thrombotic thrombocytopenic purpura (TTP)?
TTP is a rare disorder which mainly affects adult females
161
What are the presenting symptoms and signs of Thrombotic thrombocytopenic purpura (TTP)?
```
Non-specific prodrome: Median time of symptom onset to diagnosis is 1 week
Severe neurological symptoms:
-Coma
-Focal abnormalities
-Seizures
-May also be mild: headaches, confusion
Fever
Abdominal pain
Nausea and vomiting
Diarrhoea
```
162
What are the appropriate investigations for Thrombotic thrombocytopenic purpura (TTP)?
Bloods:
-Platelet count: significantly low
-Haemoglobin: normocytic anaemia
-Haptoglobin: significantly decreased during haemolysis
Blood film: microangiopathic, fragmented red blood cells, raised reticulocytes, spherocytes
Urinalysis: renal abnormalities: proteinuria
U&Es: raised urea and creatinine
163
What is Vitamin B12 deficiency?
A common condition that can manifest with neurological, psychiatric, and haematological disorders
164
What is the aetiology of Vitamin B12 deficiency?
Vitamin B12 is an essential vitamin obtained only from diet or by supplementation
Dietary sources include animal and dairy products such as meat, poultry, milk, and eggs
Stores of vitamin B12 in the liver remain in the body for years, so vitamin B12 deficiency depends on chronic, long-term deficiency
Anything that decreases the intake or the absorption of vitamin B12 places people at risk of vitamin B12 deficiency. In general:
-Decreased dietary intake
-Diminished gastric breakdown of vitamin B12 from food
-Malabsorption from the gastrointestinal tract
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What is the epidemiology of Vitamin B12 deficiency?
Prevalence increases with advancing age
| May be more prevalent in vegans and strict vegetarians who don't get enough dietary supplementation
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What are the presenting symptoms of Vitamin B12 deficiency?
Symptoms of anaemia: dyspnoea, fatigue
*Paraesthesias: tingling, early and subtle symptom of neurological damage
Ataxia- uncommon
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What are the signs of Vitamin B12 deficiency on physical examination?
Decreased vibration sense
| Neurological findings
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What are the appropriate investigations for Vitamin B12 deficiency?
Bloods:
-Serum Vitamin B12: <148 picomols/L (<200 picograms/mL) indicates probable vitamin B12 deficiency
-FBC: elevated MCV, low haematocrit, low Hb
-Reticulocyte count: Low reticulocyte index indicates decreased production, unlike in haemolytic anaemia, in which reticulocyte index would be increased
Blood film: megalocytes, hypersegmented polymorphonucleated cells- causing megaloblastic anaemia
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What is Folate deficiency?
Classically presents as megaloblastic anaemia, with absence of neurological signs
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What is the aetiology of Folate deficiency?
Folate is present in dietary sources such as green leafy vegetables, legumes, and fruits. In addition, it is present in synthetic form, as folic acid, in fortified cereal-grain products
Can be due to decreased intake or intestinal malabsorption of folate (such as coeliac disease)
Increased demand in pregnancy, lactation, and prematurity can lead to folate deficiency
Increased loss of folate occurs in patients undergoing chronic dialysis, and decreased folate is seen in disorders of increased cell turnover, such as chronic haemolytic disease
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What is the epidemiology of Folate deficiency?
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The primary age groups affected:
-Pre-school children
-Pregnant women
-Older people
Thought to be a low prevalence in high income countries and high in low income countries
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What are the presenting symptoms of Folate deficiency?
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Symptoms of anaemia: dyspnoea, fatigue
Prolonged diarrhoea
Headache
Loss of appetite
Weight loss
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What are the signs of Folate deficiency on physical examination?
Pallor
| Other signs of anaemia
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What are the appropriate investigations for Folate deficiency?
Bloods:
-FBC: low Hb, elevated MCV and MCH
-Reticulocytes: low corrected reticulocyte count (decreased production)
-Serum folate: low
-Red blood cell folate: Low-better indicator of tissue folate status than serum folate
-Serum Vitamin B12: IMPORTANT TO EXCLUDE (can co-exist)
Blood film: Macrocytic anaemia, macrocytosis, anisocytosis, poikilocytosis, hypersegmented neutrophils
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What is Von Willebrand's disease?
The most common inherited bleeding disorder, due to either a quantitative or qualitative abnormality of von Willebrand factor (VWF)
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What is Von Willebrand factor (VWF)?
A plasma glycoprotein involved in blood clotting
- It acts as a carrier protein for factor VIII, thereby protecting factor VIII from rapid degradation
- It acts as a bridge connecting platelets to damaged endothelium
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What is the aetiology of Von Willebrand factor (VWF)?
VWD is usually due to a mutation in the von Willebrand factor (VWF) gene, usually autosomal dominant and occasionally recessive
There are also acquired forms, genetic and environmental factors that can affect VWF levels are:
age, blood type, thyroid status, inflammation, stress, and hormone levels
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What is the epidemiology of Von Willebrand factor (VWF)?
VWD is the most common inherited bleeding disorder
Males and females are affected equally, but because of the prominent symptom of menorrhagia, adolescent and adult women are more often diagnosed
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What are the presenting symptoms of Von Willebrand factor (VWF)?
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Bleeding from minor wounds
FH of bleeding
Menorrhagia: menses associated with soaking pads within 1 hour, anaemia, decreased ferritin, and pictorial blood assessment
Easy and excessive bruising
GI bleeding
Epistaxis
Uncommon: haematuria, haemarthrosis
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What are the appropriate investigations for Von Willebrand factor (VWF)?
Prothrombin time: (measure of the extrinsic pathway of coagulation), normally within reference range (12-15 seconds)
Activated partial thromboplastin time (APTT): prolonged
FBC: usually normal, may be low platelets
*von Willebrand factor antigen: diagnostic for VWD if <0.30 international units (IU)/mL
*von Willebrand factor assay: reduced platelet aggregation by vWF in the presence of ristocetin
Factor VIII activity: distinguish between types
Others:
TFTs, serum protein electrophoresis
