Haem - Non-Malignant

Question 1

Anaemia - General

Answer 1

Hb <135 g/L in males and <115 g/L in females

Causes: decreased production, increased destruction, dilution

Classified based on MCV: microcytic (<80 fL), normocytic (80-100 fL), macrocytic (>100 fL)

Arise from disease processes affecting synthesis of haem, globin or porphyrin

Question 2

Microcytic Anaemia - Key Differentials and Ix

Answer 2

Key differentials (FAST):
Fe deficiency anaemia
Anaemia of Chronic disease 
Thalassaemia
Sideroblastic anaemia

Key investigations:
Peripheral blood smear
Iron studies

Question 3

Iron Deficiency Anaemia - Causes

Answer 3

Commonest cause is blood loss - bleeding until proven otherwise

Question 4

Iron Deficiency Anaemia - Key Features

Answer 4

Key features
Peripheral blood smear – pencil cells. Also microcytic, hypochromic anisocytosis and poikilocytosis.
Iron studies – ↓iron, ↓ferritin, ↑transferrin, ↑TIBC
FBC – reactive thrombocytosis

Question 5

Iron Deficiency Anaemia - Rx

Answer 5

Investigate underlying cause, iron supplementation

Question 6

Thalassemia General

Answer 6

α-thalassaemia, β-thalassaemia, thalassaemia trait

Key features
Peripheral blood smear – basophilic stippling, target cells
Iron studies – all normal

Management – iron supplementation, regular transfusions, iron chelation

Question 7

Sideroblastic Anaemia - Causes

Answer 7

Congenital or acquired (myelodysplastic disorders, post chemo, irradiation, ALCOHOL EXCESS, lead excess, anti-TB drugs, myeloproliferative disease)

Ineffective erythropoiesis –> iron loading in the bone marrow –> haemosiderosis.

Results in endo, liver and cardiac damage due to iron deposition.

Question 8

Sideroblastic Anaemia - Key Features

Answer 8

Iron studies – ↑iron, ↑ferritin, ↓transferrin, ↓TIBC
Peripheral blood smear – basophilic stippling
Bone marrow – ringed sideroblasts

Question 9

Sideroblastic Anaemia - Rx

Answer 9

Treat underlying cause, regular transfusions. Pyridoxine (vit B6 promotes RBC production).

Question 10

Macrocytic Anaemia - Key Differentials and Ix

Answer 10

FATRBC
Foetus (pregnancy)
Antifolates (e.g. phenytoin)
Thyroid (hypothyroidism)
Reticulocytosis (e.g. with haemolysis)
B12/Folate Deficiency
Cirrhosis (alcohol excess or liver disease)
Myelodysplastic syndromes 

Key differentials:
Megaloblastic anaemia - vitamin B12 deficiency, folate deficiency
Alcohol
Hypothyroidism

Key investigations:
Peripheral blood smear
LFTs
TFTs

Question 11

Macrocytic Anaemia - Megaloblastic

Answer 11

Vitamin B12 or folate deficiency

How to differentiate?
Duration – months for folate deficiency, years for vitamin B12 deficiency (we have stores for 6months for folate but 1-2 years for B12)

Clinical findings – vitamin B12 deficiency associated with neurological changes

Serum methylmalonic acid – elevated in vitamin B12 deficiency

Schilling test – positive in vitamin B12 deficiency 2º to pernicious anaemia

Drug history – phenytoin inhibits folate absorption

Management – vitamin supplementation (need to supplement B12 BEFORE folate otherwise may mask B12 deficiency –> neuro damage)

Question 12

B12 Def - Causes

Answer 12

Dietary - often vegans (found in meat and dairy products)

Malabsorption
Stomach - pernicious anaemia
Terminal ileum - ileal resection, Crohn’s, bacterial overgrowth, tropical sprue, tapeworms

Question 13

Folate Def - Causes

Answer 13

Poor diet
Increased demand: pregnancy, or increased cell turnover (haemolysis, malignancy, inflammatory disease, renal dialysis)
Malabsorption: coeliac, tropical sprue
Drugs: alcohol, anti-epileptics (phenytoin), methotrexate, trimethoprim

Question 14

B12 Def - Rx

Answer 14

IM hydroxocobalamin

Question 15

Folate def - Rx

Answer 15

Oral folate

Question 16

Macrocytic Anaemia - Non-megaloblastic

Answer 16

Alcohol, hypothyroidism, pregnancy

How to differentiate?
History – features of hypothyroidism
Clinical findings – hepatomegaly, gynaecomastia, abdominal veins, ascites, jaundice
LFTs – ↑AST, ↑ALT, ↑GGT, AST:ALT >2:1
TFTs – ↑TSH, ↓T3/T4, anti-thyroid peroxidase antibodies

Management – treat underlying cause

Question 17

Normocytic Anaemia - Key Differentials and Ix

Answer 17

Acute blood loss
Anaemia of chronic disease
Bone marrow failure
Renal failure
Hypothyroidism
Haemolysis
Pregnancy 

Key differentials
Haemolytic: inherited or acquired (immune-mediated, non-immune-mediated)
Non-haemolytic: anaemia of chronic disease, failure of erythropoiesis

Key investigations
Peripheral blood smear
DAT
CRP, ESR

Question 18

Anaemia of Chronic Disease

Answer 18

Infection, inflammation, malignancy

Key features
Inflammatory markers – raised CRP, ESR
Iron studies – ↑iron, ↑ferritin, ↓transferrin, ↓TIBC

Management – treat underlying cause

Ferritin high as Fe sequestered in macrophages to deprive invading macrophages of Fe.

Question 19

Haemolytic Anaemia - Causes

Answer 19

INHERITED
Membrane defect: hereditary spherocytosis, hereditary elliptopcytosis

Enzyme defect: G6PD deficiency, pyruvate kinase deficiency

Haemoglobinopathies: sickle cell, thalassemias

ACQUIRED
Immune:
Auto-immune - warm or cold
Allo-immune - haemolytic transfusion reactions

Non-Immune:
Microangiopathic - paroxysmal nocturnal haemoglobinuria, MAHA
Macroangiopathic - mechanical e.g. metal valves, trauma
Infections i.e. malaria/Drugs

Question 20

Hereditary Spherocytosis

Answer 20

AD inheritance
Defect in the vertical interaction of the red cell membrane
Spectrin/ankyrin deficiency

Key features
Peripheral blood smear: spherocytes, polychromasia
Positive osmotic fragility test
Positive eosin-5-maleimide (most sensitive test)
(will have -ve DAT test as not autoimmune mediated)

Management – folate supplementation, splenectomy

Question 21

Hereditary Elliptocytosis

Answer 21

AD inheritance
Spectrin mutations
Defect in the horizontal interaction of the red cell membrane

Severity ranges from hydro foetalis to symptomatic

Erythrocytes are elliptical in shape on blood film

Question 22

G6PD

Answer 22

X-linked recessive

G6PD generates NADPH via pentose phosphate pathway

Key features
Episodes of acute haemolysis (anaemia and jaundice) following exposure to oxidative stress (e.g. fava beans, mothballs, drugs- sulfonamides, aspirin etc)
Peripheral blood smear: Heinz bodies, bite cells
Intravascular haemolysis: ↑unconjugated bilirubin, ↓haptoglobin, haemoglobinuria

Management – avoidance of triggers, supportive care, transfuse if severe

Diagnosis - enzyme assay 2-3 months after attack

Question 23

Pyruvate Kinase Deficiency

Answer 23

Autosomal recessive
Clinical features: may present with severe neonatal jaundice, splenomegaly, haemolytic anaemia

Rx- most don’t require treatment (but can include blood transfusion/splenectomy)

Question 24

Haemoglobinopathies - general

Answer 24

Genetic disorders of globin chain synthesis

Haemoglobin
HbA (α2β2) – late foetus, infant, child and adult
HbA2 (α2δ2) – infant, child and adult
HbF (α2ɣ2) – foetus, infant

Diagnosis made with Hb electrophoresis

Disorders – thalassaemia, sickle cell disease

Question 25

Sickle Cell Disease - Genetics

Answer 25

``` Autosomal recessive (chromosome 7) Glu --> Val mutation at codon 6 on the β globin chain --> HbS ``` HbSS (full sickle cell), HbAS (trait), HbSC (one sickle gene, one defective B), HbSβ (sickle from one parent, beta thal trait from other) SS manifests at 3-6 months --> coincides with decreasing HbF

Question 26

Sickle Cell Disease - Key Features & Diagnosis

Answer 26

Key features Haemolytic crisis, sequestration crisis, aplastic crisis, infection (Streptococcus pneumoniae – sepsis, Salmonella – osteomyelitis) Peripheral blood smear: sickle cells, target cells Sickle solubility test positive in HbSS and HbAS Hb electrophoresis Guthrie test at birth

Question 27

Sickle Cell Disease - Rx

Answer 27

Management – vaccination, folate supplementation, hydroxyurea (increases % HbF), supportive for acute crisis Chronic - all should be on penicillin V, pneumovax, HIB vaccine

Question 28

Beta Thalassemia - Genetics

Answer 28

Reduced synthesis of β globin chain (Chromosome 11) Major (homozygous), intermedia and minor (heterozygous) Β0 – no expression of the gene Β+– some expression of the gene Β – normal gene β- thalassaemia minor (e.g. or β+/ β or β0/ β ) β- thalassaemia intermedia (e.g. β+/ β+ or β0/ β+) β- thalassaemia major (β0/ β0)

Question 29

Beta Thalassemia - Key Features

Answer 29

Major – severe anaemia requiring regular blood transfusions Intermedia – genetically complex, moderate reduction in β globin chain production Minor – benign but important genetically Clinical presentation: Skull bossing, maxillary hypertrophy, hairs on end skull x-ray. Hepatosplenomegaly. Diagnosis - Hb electrophoresis

Question 30

Beta Thalassemia - Rx

Answer 30

Regular blood transfusions, iron chelation (desferrioxamine), folate supplementation

Question 31

Alpha Thalassemia

Answer 31

Reduced synthesis of α globin chain (Chromosome 16) (excess B chains) Hb Barts (x4), HbH (x3), trait (x2), silent (x1) Key features Hb Barts – fatal in utero, hydrops foetalis HbH – severe anaemia in childhood, hepatosplenomegaly Trait – mild anaemia Silent – asymptomatic Management – regular blood transfusions, iron chelation (desferrioxamine), folate supplementation

Question 32

Autoimmune Haemolytic Anaemia

Answer 32

Immune-mediated destruction of red blood cells, DAT positive Warm Mediated by IgG Associated with CLL, SLE, methyldopa Extravascular haemolysis Cold Mediated by IgM Associated with Mycoplasma, EBV, hepatitis C Intravascular haemolysis Management – treat underlying cause, steroids, rituximab

Question 33

Paroxysmal Nocturnal Haemoglobinuria

Answer 33

Acquired loss of protective surface GPI markers on RBCs (platelets + neutrophils) → complement-mediated lysis → chronic intravascular haemolysis especially at night. Morning haemoglobinuria, thrombosis (+Budd- Chiari syndrome – hepatic v thromb). Diagnosis: immunophenotype shows altered GPI or Ham's test (in vitro acid-induced lysis). Treatment: iron/folate supplements, prophylactic vaccines/antibiotics. Expensive monoclonal antibodies (eculizumab) that prevents complement from binding RBCs

Question 34

Microangiopathic Haemolytic Anaemia

Answer 34

Non-immune-mediated, small vessel disease Damage to endothelial cells within the vasculature --> fibrin deposition and platelet aggregation --> fragmentation of red blood cells Key features Peripheral blood smear: schistocytes, thrombocytopenia Disorders – HUS, TTP, DIC Distinguish from DIC with normal APTT, PT, fibrinogen (DIC would make you consume all of your clotting factors. DIC can cause MAHA but they are separate entities. DIC causing MAHA is consumptive but MAHA itself is not consumptive_ Management – treat underlying cause, supportive

Question 35

Haemolytic Uraemic Syndrome

Answer 35

Commonly caused by Escherichia coli O157:H7 – Shiga-like toxin More frequent but less severe in children Key features Symptoms occur after a diarrhoeal illness – do not give antibiotics to treat Triad of MAHA, thrombocytopenia, acute renal failure (self-limiting in children) Features of MAHA on peripheral blood smear Management – supportive care

Question 36

Thrombotic Thrombocytopenic Purpura

Answer 36

Deficiency of ADAMTS13 (ABs against it) --> decreased break down of multimers of vWF (stay in vessels like cheese wire and chop up RBCs) Can be inherited or acquired Key features Pentad of MAHA, thrombocytopenia, acute renal failure, neurological symptoms, fever High mortality rate Management – supportive care, plasma exchange

Question 37

Haemostasis and Thrombosis - Background

Answer 37

Disorders of primary or secondary haemostasis Primary – platelet adhesion and aggregation (quantitative and qualitative defects) Secondary – coagulation cascade (inherited and acquired) Disorders of thrombosis occur as a result of Virchow’s triad Inherited – factor V Leiden, anti-thrombin deficiency, protein C/S deficiency Acquired – HIT, malignancy, immobilisation

Question 38

Which pathway is used to monitor heparin therapy?

Answer 38

Intrinsic - APTT

Question 39

Which pathway is used to monitor warfarin therapy (INR)

Answer 39

Extrinsic - PT

Question 40

Haemostasis

Answer 40

Dysfunction in primary haemostasis --> bleeding disorders (superficial bleeding) Qualitative defect in platelets – von Willebrand disease Quantitative defect in platelets – ITP, HIT Dysfunction in secondary haemostasis --> coagulation disorders (deep bleeding) Inherited disorders – haemophilia A, haemophilia B Acquired disorders – liver disease, vitamin K deficiency

Question 41

von Willebrand Disease Subtypes

Answer 41

Subtypes Type I – autosomal dominant, quantitative defect Type II – autosomal dominant, qualitative defect Type III – autosomal recessive, quantitative and qualitative defects

Question 42

von Willebrand Disease - Key Features

Answer 42

Mucocutaneous bleeding ↓platelet adhesion, ↓factor VIII, abnormal ristocetin ↓platelet count, ↑bleeding time, ↑APTT, normal PT Differentials include Bernard-Soulier disease (large platelets) and Glanzmann’s thrombasthaenia (normal ristocetin)

Question 43

von Willebrand Disease - Rx

Answer 43

Desmopressin, vWF and factor VIII concentrates

Question 44

Acute Immune Thrombocytopenia

Answer 44

Predominantly children, M:F 1:1 Preceding infection Self-limiting, treatment with steroids and IVIG if platelet count ↓↓↓, major bleeding Sudden onset generalised petechiae and purpura. Bleeding from the gums/mucous membranes.

Question 45

Chronic Immune Thrombocytopenia

Answer 45

Commonly adults, M:F 1:3 No trigger Long-term relapsing-remitting, treatment with steroids, IVIG or splenectomy

Question 46

Haemophilia A

Answer 46

X-linked recessive Factor VIII deficiency Key features Spontaneous, deep bleeding, haemarthrosis Normal platelet count, normal bleeding time, ↑APTT, normal PT More common than Haemophilia B Management – factor VIII concentrate

Question 47

Haemophilia B

Answer 47

X-linked recessive Factor IX deficiency Key features Spontaneous, deep bleeding, haemarthrosis Normal platelet count, normal bleeding time, ↑APTT, normal PT Management – factor IX concentrate

Question 48

DIC

Answer 48

Acquired coagulation disorder Widespread activation of coagulation. Clotting factors and platelets are consumed → ↑ risk of bleeding Causes: Malignancy, sepsis, trauma, obstetric complications, toxins. Low plts, low fibrinogen, high FDP/D-Dimer, long PT/INR. Rx- Treat the cause and give transfusions, FFP, platelets, cryo etc.

Question 49

Liver disease

Answer 49

Acquired coagulation disorder ↓ synthesis of II, V, VII, IX, X, XI and fibrinogen ↓ absorption of vitamin K Abnormalities of platelet function

Question 50

Vitamin K Deficiency

Answer 50

Vitamin K necessary for synthesis of factors II, VII, IX and X, protein C/S Secondary to malabsorption, warfarin, antibiotic therapy Key features Factor VII first factor to be depleted Normal platelet count, normal bleeding time, ↑APTT, ↑PT Differentials include liver disease (↓platelet count), scurvy (corkscrew hair) Management – vitamin K replacement, prothrombin complex concentrate (PCC), FFP

Question 51

Virchow's triad

Answer 51

VTE RFs | Vessel wall injury, blood hypercoagulability, blood stasis.

Question 52

Factor V Leiden

Answer 52

Autosomal dominant – most common inherited prothrombotic disorder Present in 5% of caucasian population Key features Resistance to protein C --> failure to degrade factor V --> hypercoagulable state Predisposition to venous thromboembolism (arterial thromboembolism rare) Management – long-term anti-coagulation

Question 53

Antithrombin deficiency

Answer 53

Autosomal dominant Key features Carries highest risk of thrombosis Develop thromboembolism in unusual locations (e.g. splenic or mesenteric veins) Anti-thrombin assay used to make diagnosis Key differentials include protein C/S deficiency Management – long-term anti-coagulation with warfarin and argatroban

Question 54

Protein C/S Deficiency

Answer 54

Autosomal dominant Key features Predisposition to venous thromboembolism (arterial thromboembolism rare) Associated with warfarin-induced skin necrosis – initial pro-coagulant state --> ischaemia of skin vessels Protein C/S assay Management – long-term anti-coagulation with argatroban

Question 55

DVT Prophylaxis

Answer 55

Daily subcutaneous LMWH (prophylactic dose), TED stockings

Question 56

DVT Management

Answer 56

LMWH (treatment dose) followed by Warfarin or Apixaban/Rivaroxaban/Edoxaban (DOACs)

Question 57

Investigation based on Wells Score for VTE

Answer 57

High Wells score – Ultrasound affected limb for DVT / CTPA for PE Intermediate Wells score – D-DIMER: if high, ultrasound/CTPA; if low, rule out Low Wells score – consider other diagnosis

Question 58

Obstetric Haem - Background

Answer 58

Volume expansion --> ↑cardiac output, dilutional anaemia Thrombocytopenia – returns to normal post-partum Hypercoagulable and hypofibrinolytic state --> ↑risk of venous thromboembolism. Highest risk of VTE is postpartum.

Question 59

Haemolytic Disease of the Newborn

Answer 59

Prior sensitisation of Rh-negative women from previous pregnancy (make anti-D ABs to D antigen on foetal RBCs) Key features IgG-mediated Foetal anaemia, hydrops foetalis, neonatal jaundice, kernicterus Monitor foetus for anaemia with MCA doppler ultrasound Management – prevent sensitisation with anti-D Ig routinely at 28 weeks and within 72 hours of sensitising event, intra-uterine transfusion Always transfuses Rh-ve blood to Rh-ve women of childbearing age

Question 60

HELLP Syndrome

Answer 60

Haemolysis, elevated liver enzymes, low platelets Life-threatening complication associated with pregnancy (only happens in PET) Key features MAHA, ↑↑AST, ↑↑ALT, ↓platelets, normal APTT, PT Differentials include DIC (↑APTT, ↑PT, ↓fibrinogen), AFLP (marked transaminitis) Management – supportive, delivery of foetus

Question 61

Acute Transfusion Reactions - Anaphylaxis

Answer 61

Symptoms occur within minutes | Risk increases in patients with IgA deficiency

Question 62

Acute Transfusion Reactions - ABO incompatibility

Answer 62

Symptoms occur within minutes to hours | Intravascular haemolysis – IgM-mediated

Question 63

Acute Transfusion Reactions - Bacterial Contamination

Answer 63

Symptoms occur within minutes to hours | More commonly occurs with platelet transfusion

Question 64

Acute Transfusion Reactions - Febrile Non-Haemolytic Transfusion Reaction

Answer 64

Rise in temperature of ≤1ºC without circulatory collapse | Caused by release of cytokines by leukocytes and prevented by leukodepletion

Question 65

Acute Transfusion Reactions - Transfusion Associated Circulatory Overload (TACO)

Answer 65

Symptoms of pulmonary oedema/fluid overload occur within hours Look for signs of heart failure: ↑JVP, ↑PCWP (pulmonary capillary wedge pressure)

Question 66

Acute Transfusion Reactions - Transfusion-Related Acute Lung Injury

Answer 66

Symptoms similar to TACO Caused by interaction with anti-HLA antibodies in donor blood with recipient Absence of heart failure

Question 67

Delayed Transfusion Reactions - Delayed-haemolytic transfusion reaction

Answer 67

Occurs within 1 week | Extravascular haemolysis – IgG-mediated

Question 68

Delayed Transfusion Reactions - Graft vs Host Disease

Answer 68

Symptoms include diarrhoea, liver failure, skin desquamation and bone marrow failure Donor lymphocytes recognise recipient’s HLA as foreign and attack gut, liver, skin and bone marrow Prevent by irradiating blood components for immunosuppressed recipients

Question 69

Warfarin Reversal

Answer 69

INR ≤5 – lower or omit next dose INR 5-9 – either omit next dose or oral vitamin K INR >9 – omit next dose + oral vitamin K Any bleeding – omit next dose + IV vitamin K + PCC or FFP (the higher the INR, the more likely the pt is to bleed)

Question 70

Reversing Anticoagulants

Answer 70

Heparin/LMWH: Protamine Rivaroxaban, apixaban: Prothrombin complex concentrate (PCC) Dabigatran: Antibody (Idarucizumab - expensive) or PCC Aspirin / clopidogrel: platelet transfusion