Final Year MB ChB Revision

Lecture

Haematology

Dr M Drummond
Cons Haem, GGH & BOC
 Topics

Anaemia (most clinically relevant types)

       Haemolytic disease
        Coagulation disorders
       Thrombocytopenia
       Leukaemia/Lymphomas/Myeloma

In no particular order……
Malignancy
 Haem Malignancy
• History is crucial:
– Wt loss (10% in 6 months)
– Night Sweats
– Fever

– Itch (after shower?)

– Fatigue / lethargy / (symptoms of anaemia)
– Bruising / bleeding
– Bone pain
 Examination
• To include:
– Mouth (?ulcers, haemorrhage, thrush, tonsillar
enlargement)
– Skin (purpura, rash, infiltration)
– Fundi (?haemorrhages, infection)
– LNs, liver & spleen
 Haem Malignancy:
• Don’t get too caught up in terminology!!
• 159 separate entities!
• Concentrate on broad categories & clinical features
– Lymphoma (lumpy: HL, NHL)
– Leukaemia (liquid:)
• Acute & chronic
• Myeloid & lymphoid
– Myeloma (marrow: bone disease, paraprotein)
– MPDs:
• PRV, ET, MF (CML). (marrow, blood, spleen)
Symptom
Distribution
in haem Sweats / Marrow Splenom Lymphad Bone
Wt loss Itch
malignancy
fever Failure egaly enopathy Disease

Lymphoma
++++ ++++ ++ ++ ++ ++++ +
/ LPDs

Acute
Leukaemia
+ + 0/+ ++++ + 0/+ 0

Myeloma

0/+ ++ 0 ++ 0 0 ++++

MPDs
(Myeloproli
ferative +++ +++ +++ + ++++ 0 0
disorders)
Lymph Node Groups
 Lymphadenopathy (1):
• Site
• Size
• Consistency (rubbery vs craggy)
• Tenderness
• Fixed
 Lymphadenopathy (2)
• Generalised:
– EBV, CMV, HIV
– Brucellosis, syphilis
– Toxoplasma
– Lymphoma or CLL
– (occasionally CT disease)
• Localised
– Acute or chronic infection
– Neoplasia (cancer, lymphoma)
 Splenomegaly (1)
• ULN: 13cm in long axis (USS or CT)
• May occasionally be ‘tippable’ in slim healthy individual
• Causes of splenomegaly in UK (exams)
– Myelofibrosis
– Lymphoma
– Gauchers disease
• Causes of massive splenomagaly in UK:
– Myelofibrosis
– CML (treatment so effective don’t see this in exams)
– (rarely) lymphoma
 Splenomagaly (2)
• features:

– Enlarges towards right IF

– Cant get above it
– Moves with respiration
– Notch

– Dull to percussion
Spleen Examination 2: line of resonance
 Lymphoma
• Cancer of lymphatic system

• 2 main sub types

– Hodgkin Lymphoma
– Non Hodgkin lymphoma

14
 Ann Arbor Staging System
• I = single LN region (I) or single extralymphatic
organ or site (IE)
• II = ≥ 2 LN areas, same side of diaphragm (II) or
with ltd localised EN extension (IIE)
• III = LN areas on both sides of diaphragm (if
includes spleen IIIS)
• IV = extensive disease of ≥1 extralymphatic organ
eg liver, bone marrow
• A/B
• Bulk

15
 HL - clinical features
• Asymptomatic LN enlargement (70%)
• Mass on CXR
• Sites
– Neck 60-80%
– Mediastinal ~60%
– Axillae 10-20%
– Inguinal 6-12%
– Infradiaphragmatic ~10%

16
 Hodgkin Lymphoma
• Bimodal age distribution
– Peak 20-30’s
– 2nd peak >50 yrs
• Usually arises in LN and spreads to
adjacent LN areas
• Later, haematogenous spread to liver,
lungs
 HL - clinical features
• B symptoms
– unexplained fever >38 degrees
– night sweats
– weight loss >10% body wt in 6 months
• generalised pruritis
• alcohol induced LN pain
– <10% but highly specific

18
Hodgkin
Lymphoma

CT Chest at
diagnosis
Mediastinal
mass

CT
post treatment
with chemotx.
And radiotherapy
Complete
remission
 Non Hodgkins Lymphoma

B cell T cell

Low grade High

High grade Low
grade grade
 Non Hodgkin Lymphoma
• Wide variation in presentation
• localized or generalised lymphadenopathy
• low grade or high grade
• in extranodal sites may mimic carcinoma
• variable prognosis
• accurate sub-classification is essential for
planning treatment
 Low grade NHL
• Tends to be widely disseminated at
presentation often involving bone marrow
• Indolent clinical course
• Incurable
 High grade NHL
• Tends to be more localised
• despite rapid growth, 50% are curable
 Aetiology of lymphoma
• EBV: Hodgkin Lymphoma,Post transplant
lymphomas, AIDs related Lymphomas, NK
lymphomas
• HTLV-1. Adult T cell leuk./lymphoma
• Helicobacter: Low grade gastric lymphomas
• Autoimmune disease: eg Sjogrens and low
grade B cell lymphomas of Sal. Gland
• Coeliac disease: T cell lymphoma of small bowel
 Multiple Myeloma
• Neoplastic proliferation of plasma cells
• Involves bone marrow
• presents with
– lytic lesions in bones
– immunosuppression
– anaemia
– monoclonal gammopathy
– renal failure
• ‘prodrome’: MGUS (3% of >70s)
X Ray in myeloma

Multiple
lytic
lesions in
skull and
humerus
 Leukaemia Classification

Myeloid

Acute

Leukaemia lymphoid

Chronic

Myeloid

Pre-leukaemic conditions eg myelodysplasia, myeloproliferative disorders

 Chronic Leukaemias
• Myeloid
– CML
– CMML, CEL, CNL
• Lymphoid
– CLL
– Hairy Cell Leukaemia
– Prolymphocytic
 CML
• Excess myeloid cells (neutrophils, eos &
basophils) & plts in blood
• WCC generally >100, plts often >1000
• Splenomegaly, night sweats
• Late middle age (60 yrs)

• Now very effectively managed with TKIs

 Chronic lymphocytic leukaemia (CLL)
Incidence of CLL

 Most common form of leukaemia in

the West, rare in Asian populations
(incidence 3 cases per 100,000)

Cases/100,000
 Majority of cases occur in later life.
 Treatable but in most cases not
curable.

 Increasing numbers of cases Age

detected at routine screening of

older population.
 New drugs are having a significant
impact.
 Lymphadenopathy,
hepatosplenomegaly, B symptoms,
marrow failure
 Acute Leukaemia
• Medical emergency
• High, Normal, or low WCC
• Marrow failure
• Blasts (immature cells) Marrow +/- blood
• Often vague prodrome

• Potentially curable
• ALL vs AML
Symptom
Distribution
in haem Sweats / Marrow Splenom Lymphad Bone
Wt loss Itch
malignancy
fever Failure egaly enopathy Disease

Lymphoma
++++ ++++ ++ ++ ++ ++++ +
/ LPDs

Acute
Leukaemia
+ + 0/+ ++++ + 0/+ 0

Myeloma

0/+ ++ 0 ++ 0 0 ++++

MPDs
(Myeloproli
ferative +++ +++ +++ + ++++ 0 0
disorders)
 Malignancy
• Neutropaenic Sepsis
– ? Likely – most chemotherapy regimens neutrophils
down by day 8-10
– Rapid assessment necessary
– Culture
– Don’t delay for CXR etc

– Prompt administration of IV antibiotics (Taz/Gent;

meropenem)
– Meticulous supportive care
Anaemia
 Normal Ranges

• Red Cells (MCV 80-100fl)

– Hb 12.0-16.0 g/dl females
Hb 13.0-18.0 g/dl males
• White Cells
– 4.0-11.0 x 109/l
• Platelets
– 150-400 x 109/l
 History & Exam
• Symptoms of anaemia
• Blood Loss
• FH
• PMH (eg gastrectomy)
• DHx (eg aspirin, NSAIDs)
• Diet

• Koilonychia, glossitis
• Jaundice
• Lymphadenopathy / hepatosplenomegaly
• PR & FOB testing
 Ferritin
• Serum ferritin correlates well with liver and
macrophage stores
• N range 15-300 ug/ml
• Mean adult male level: 100; mean adult
premenopausal female level 30.
• <15, specific for depletion of iron stores; normal
values do not exclude this!! Values >300 are not
usually indicative of iron overload (Acute Phase
Reactant)!!
• Use of BM for iron stores
• Ferritin <50 cw absent stores in RA, IBD
 Assessing iron status
• IDA: ferritin Lo (absent on BM); TIBC Hi, Serum
transferrin satn (STS) Lo (<15%);

• Haemochromatosis: ferritin hi; TIBC lo; STS Hi;

HFE gene mutation.
• Anaemia of chronic disorders: ferritin N or Hi;
TIBC lo; STS lo; STR N.

• NB Haemosiderin. Soluble iron storage protein,

predominantly in macrophages. Found in urine in
chronic intravascular haemolysis.
 Case 1 Female 18yrs

Hb: 8
MCV: 65

WBC: 5
Plts: 150
ESR: 5
Case 1 Female 18yrs
 Case 1 Female 18yrs

 Serum ferritin 3 NR 15-300

 Menorrhagia
 Iron replacement
 No further investigation
 Case 2
• 27 yr old female
– Hb 4.5, MCV 122
– WCC 4.0, Plts 145

Film: oval
macrocytes,
hypersegmented
neutrophils
Diagnosis: severe megaloblastic anaemia

“Delayed nuclear maturation in the bone

marrow due to defective synthesis of DNA”

In clinical practice almost always caused by

B12 or folate deficiency

May see some megaloblastic change in the context of certain drugs (eg
methotrexate, azathioprine) or alcohol.
 Clinical Features
• Common: Pancytopaenia
Glossitis
Diarrhoea
PV discomfort

• B12 Deficient SACD

DO NOT GIVE FOLATE IN ISOLATION UNLESS

SIGNIFICANT B12 DEFICIENCY HAS BEEN
EXCLUDED!
 Vitamin B12 Deficiency

Reduced Intrinsic Factor Pernicious Anaemia

Gastrectomy

Intestinal Malabsorption Crohn’s Disease

Ileal Resection
Stagnant Loop Syndrome
Fish Tapeworm

Dietary Deficiency Vegans

 Folate Deficiency

Dietary Deficiency Alcoholics

Malabsorption Coeliac Disease

Tropical Sprue
Small Bowel Disease / Resection

Increased Requirements Pregnancy

Haemolysis
Malignancy
 Learning Points
• B12 and Folate deficiency commonest cause of
megaloblastic anaemia
• Chronic. Transfusion rarely required and may be
dangerous!
• Take haematinic assays before transfusion!
• Majority of diagnoses can be made without
invasive / extensive investigation
 Anaemia 1
Pattern

• Isolated; IDA, haemolysis, bleeding

• Part of pancytopaenia B12/folate deficiency,
marrow failure (eg aplastic anaemia) or hypersplenism
 Anaemia 2
• Describe as
• Size (80-100fl)
• Haemoglobinisation of cells (MCH,
MCHC)
• ie: hypochromic microcytic (IDA,
thalassaemia, ACD)
• Normochromic normocytic (acute blood loss,
2o anaemia or ACD)
• Macrocytic (B12/folate, liver dis, alcohol,
hypothyroid, reticulocytosis)
 Reticulocyte count

• Normal range, <2%

• Anaemia plus reticulocytosis
• Haemolysis
• Blood loss
• Anaemia, no reticulocytosis
• 2o anaemia
• CRF
• B12/folate
• SAA

Ask for and use the reticulocyte count!!

 Anaemia 3
• Defective production of RBCs
– IDA, B12 & folate deficiency
– 20 anaemias
– BM failure (eg SAA, leukaemia, MDS etc)
– Renal Failure
– Thalassaemias
– Pure red cell aplasia
– Congenital dyserythropoiesis

Usually low retic count!!

 Anaemia 4
• Reduced red cell survival
– Haemolysis (intrinsic vs extrinsic)
– Blood loss (acute vs chronic)
– Enzyme deficiency
• Pooling of normal rbcs in large
spleen
• Sequestration of abnormal rbcs in
spleen
Usually High retic count!!
 Anaemia 5
Defining the cause
• Clinical background
• 16 yr old female vs. 45 yr old male; drugs; diet;
previous surgery; splenomegaly; jaundice
• Automated analyser
• Size, hb, WCC and plt count
• Blood film
• Shape of red cells: tear drop cells, nucleated red
cells, polychromasia, fragments, target cells,
spherocytes
• Abnormal population eg blast cells
• Leucorythroblastic (‘stressed’ BM, infiltration,
severe B12/folate)
 Case: Male 28yrs

Hb: 7.6
MCV: 128

WBC: 14
Plts: 326
ESR: 5
Case: Male 28yrs
 Case Male 28yrs

Reticulocytes 350 (NR 50-100)

Bilirubin 112
LDH 2500 NR <220
Direct Coombs test: positive
Auto immune haemolytic anaemia
Case Male 28yrs
 Haemolytic anaemia: Inherited

• Red Cell Membrane disorders

» HS, HE

• Red Cell enzyme disorders

» G6PD & PK deficiency
 Haemolytic anaemia: Acquired
• Immune (DAT+ve):
» Autoimmune (warm vs cold)
» Alloimmune (transfusion reactions, HDN)

• Non-immune
» Infection (malaria, clos, perfringens, septicaemia etc)
» Chemical / physical agents (burns, lead poisoning etc)
» Mechanical injury (heart valves, MAHA etc)
» Acquired membrane disorders (eg liver disease, PNH)
 Haemolytic Anaemia
• Laboratory features
• Anaemia: polychromasia; spherocytes (HS,
AIHA); fragments (MAHA)
• Reticulocytosis
• Raised bilirubin (generally 30-50)
• Raised LDH
• Absent haptoglobins
• Folic Acid Deficiency (chronic HA, acute
aggravation)
• Iron Deficiency (Chronic IV haemolysis;
increased urinary haemosiderin but not in EV
haemolysis)
 Clotting

Pattern of Clotting Abnormalities

Over anticoagulation
APTT
Clotting Cascade PT

Intrinsic system Extrinsic system

Contact activation Tissue factor
XII VII

XI
IX
Final Common Pathway
VIII
X
PS/aPC V
II (prothrombin)
I (fibrinogen)
Clot (fibrin)
 Clotting Disorders

Inherited Acquired

Factor VIII & IX DIC Vit K

deficiency; Liver disease deficiency or
vWD antagonists
 Patterns of results in clotting
disorders
PT APTT TCT BT plts Fib

Haem A
N N N N N

Haem B
N N N N N

vWD
N /N N /N N N

DIC

warfarin N/ N N N N
 Clinical Bleeding
• Platelet disorders (eg aspirin, thrombocytopaenia
– Mucocutaneous

• Clotting disorders (eg haemophilia)

– Musculoskeletal
 Warfarin
Guidelines on Oral Anticoagulation: Brit J Haem 1998, 101, 374-387

• Commencing warfarin:
– Proteins C & S (natural anticoagulants) are Vit K
dependent
– Initial fall can promote thrombosis
– Therefore cover with heparin (at least 4 days and
for 2 days with therapeutic INR)
– Particular caution with protein C deficiency:
cautious introduction with heparin & no loading
dose
 Over Warfarinisation
Warfarin Guidelines: Brit J Haem, 1998, 101 374-387

• INR>8.0, no bleeding or minor bleeding

– If no other risk factors for haemorrhage (age>70,
previous bleeding) stop warfarin until <5
– if risk factors / minor bleeding: Vit K (1mg oral)

• INR>8.0, major bleeding

– IV Vit K (5-10mg)
– IV PCC (Octaplex) –sliding scale – (based on INR &
weight)
‘Haematological’ Rashes
Describe?
Classify?
This is palpable. ? Further investigations
 Purpura classification

palpable vasculitis

purpura Petaechiae (<3mm)

Non-palpable thrombocytopaenia
CT disorders

Ecchymotic (>3mm)
Clotting disorder
11 year old boy. ? Other symptoms / signs ?
 Purpura in BM failure
• Sites:
– local trauma, lower limbs, under dressings,
clothes (eg bra straps), mouth, but most
important: fundi
• Wet vs Dry purpura
– Avoid aspirin / NSAIDS
– Prophylactic platelet transfusion (threshold 10
– 20)
Thrombocytopaenia
 Thrombocytopaenia
• Plt count <150
• Few problems >50
• Most problems <20

• History: drugs, viral illness, malignancy

• Exam: spleen, liver, LNs, mouth & skin
 Case

• 6 year old. Flu like illness 3 weeks ago.

Spontaneous bruising and rash.

• Hb11.7, WCC 9.5, Platelets 5.

• What is it likely to be?

• What should you do as 1st basic Ix(s)?
 Causes of low plts
• Decreased Production
» Marrow Failure / infiltration
» Marrow Suppression (eg chemo /
radiotherapy/drugs/alcohol)
» Viral
» B12/Folate deficiency

• Increased Destruction
– Immune:
» ITP, drugs, infection
– Non-Immune:
» DIC, TTP, Cardiac Bypass.
Hyposplenism
 Guidelines for the prevention and treatment of
infection in patients with an absent or dysfunctional
spleen
BMJ 1996; 312; 430 -
434http://www.bcshguidelines.com/pdf/SPLEEN96.pdf

•Post Splenectomy / partial splenectomy patients

•Functional Hyposplenism
•Sickle cell anaemia / thalassaemia
•Lymphoproliferative disorders (eg NHL, HL CLL)
•Coeliac disease, IBD, dermatitis herpetiformis
Howell Jolly Bodies
 Infecting micro organisms
NB effect of age: children <5 have infection risk of 10%, adults <1%

• Encapsulated bacteria:
– Pneumococcus (mortality up to 60% in some cases)
– Haemophilus influenzae type B
– Meningococcus
• Others
– Malaria, E Coli, capnocytophaga canimorsus

Duration of risk: most occur within 2 years, up to a third at least 5 years later, and
some reports of 20 years later!
The risk of dying of serious infection is clinically significant and almost certainly
lifelong!!
 Antibiotic Prophylaxis
• Lifelong
– Phenoxymethylpenicillin (plus supply of amoxycillin
to hand)
– Erythromycin in allergic
• Antimalarial prophylaxis
• Prompt treatment (IV penicillin /
cephalosporin)
– Infective symptoms
– Animal bites!! (5 days of augmentin)
• Medic alert bracelets
 The End!!

Good Luck!!