Haem - Non-Malignant Flashcards
Anaemia - General
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
Microcytic Anaemia - Key Differentials and Ix
Key differentials (FAST): Fe deficiency anaemia Anaemia of Chronic disease Thalassaemia Sideroblastic anaemia
Key investigations:
Peripheral blood smear
Iron studies
Iron Deficiency Anaemia - Causes
Commonest cause is blood loss - bleeding until proven otherwise
Iron Deficiency Anaemia - Key Features
Key features
Peripheral blood smear – pencil cells. Also microcytic, hypochromic anisocytosis and poikilocytosis.
Iron studies – ↓iron, ↓ferritin, ↑transferrin, ↑TIBC
FBC – reactive thrombocytosis
Iron Deficiency Anaemia - Rx
Investigate underlying cause, iron supplementation
Thalassemia General
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
Sideroblastic Anaemia - Causes
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.
Sideroblastic Anaemia - Key Features
Iron studies – ↑iron, ↑ferritin, ↓transferrin, ↓TIBC
Peripheral blood smear – basophilic stippling
Bone marrow – ringed sideroblasts
Sideroblastic Anaemia - Rx
Treat underlying cause, regular transfusions. Pyridoxine (vit B6 promotes RBC production).
Macrocytic Anaemia - Key Differentials and Ix
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
Macrocytic Anaemia - Megaloblastic
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)
B12 Def - Causes
Dietary - often vegans (found in meat and dairy products)
Malabsorption
Stomach - pernicious anaemia
Terminal ileum - ileal resection, Crohn’s, bacterial overgrowth, tropical sprue, tapeworms
Folate Def - Causes
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
B12 Def - Rx
IM hydroxocobalamin
Folate def - Rx
Oral folate
Macrocytic Anaemia - Non-megaloblastic
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
Normocytic Anaemia - Key Differentials and Ix
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
Anaemia of Chronic Disease
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.
Haemolytic Anaemia - Causes
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
Hereditary Spherocytosis
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
Hereditary Elliptocytosis
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
G6PD
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
Pyruvate Kinase Deficiency
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)
Haemoglobinopathies - general
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
Sickle Cell Disease - Genetics
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
Sickle Cell Disease - Key Features & Diagnosis
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
Sickle Cell Disease - Rx
Management – vaccination, folate supplementation, hydroxyurea (increases % HbF), supportive for acute crisis
Chronic - all should be on penicillin V, pneumovax, HIB vaccine
Beta Thalassemia - Genetics
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)
Beta Thalassemia - Key Features
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
Beta Thalassemia - Rx
Regular blood transfusions, iron chelation (desferrioxamine), folate supplementation
Alpha Thalassemia
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
Autoimmune Haemolytic Anaemia
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
Paroxysmal Nocturnal Haemoglobinuria
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
Microangiopathic Haemolytic Anaemia
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
Haemolytic Uraemic Syndrome
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
Thrombotic Thrombocytopenic Purpura
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
Haemostasis and Thrombosis - Background
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
Which pathway is used to monitor heparin therapy?
Intrinsic - APTT
Which pathway is used to monitor warfarin therapy (INR)
Extrinsic - PT
Haemostasis
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
von Willebrand Disease Subtypes
Subtypes
Type I – autosomal dominant, quantitative defect
Type II – autosomal dominant, qualitative defect
Type III – autosomal recessive, quantitative and qualitative defects
von Willebrand Disease - Key Features
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)
von Willebrand Disease - Rx
Desmopressin, vWF and factor VIII concentrates
Acute Immune Thrombocytopenia
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.
Chronic Immune Thrombocytopenia
Commonly adults, M:F 1:3
No trigger
Long-term relapsing-remitting, treatment with steroids, IVIG or splenectomy
Haemophilia A
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
Haemophilia B
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
DIC
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.
Liver disease
Acquired coagulation disorder
↓ synthesis of II, V, VII, IX, X, XI and fibrinogen
↓ absorption of vitamin K
Abnormalities of platelet function
Vitamin K Deficiency
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
Virchow’s triad
VTE RFs
Vessel wall injury, blood hypercoagulability, blood stasis.
Factor V Leiden
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
Antithrombin deficiency
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
Protein C/S Deficiency
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
DVT Prophylaxis
Daily subcutaneous LMWH (prophylactic dose), TED stockings
DVT Management
LMWH (treatment dose) followed by Warfarin or Apixaban/Rivaroxaban/Edoxaban (DOACs)
Investigation based on Wells Score for VTE
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
Obstetric Haem - Background
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.
Haemolytic Disease of the Newborn
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
HELLP Syndrome
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
Acute Transfusion Reactions - Anaphylaxis
Symptoms occur within minutes
Risk increases in patients with IgA deficiency
Acute Transfusion Reactions - ABO incompatibility
Symptoms occur within minutes to hours
Intravascular haemolysis – IgM-mediated
Acute Transfusion Reactions - Bacterial Contamination
Symptoms occur within minutes to hours
More commonly occurs with platelet transfusion
Acute Transfusion Reactions - Febrile Non-Haemolytic Transfusion Reaction
Rise in temperature of ≤1ºC without circulatory collapse
Caused by release of cytokines by leukocytes and prevented by leukodepletion
Acute Transfusion Reactions - Transfusion Associated Circulatory Overload (TACO)
Symptoms of pulmonary oedema/fluid overload occur within hours
Look for signs of heart failure: ↑JVP, ↑PCWP (pulmonary capillary wedge pressure)
Acute Transfusion Reactions - Transfusion-Related Acute Lung Injury
Symptoms similar to TACO
Caused by interaction with anti-HLA antibodies in donor blood with recipient
Absence of heart failure
Delayed Transfusion Reactions - Delayed-haemolytic transfusion reaction
Occurs within 1 week
Extravascular haemolysis – IgG-mediated
Delayed Transfusion Reactions - Graft vs Host Disease
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
Warfarin Reversal
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)
Reversing Anticoagulants
Heparin/LMWH: Protamine
Rivaroxaban, apixaban: Prothrombin complex concentrate (PCC)
Dabigatran: Antibody (Idarucizumab - expensive) or PCC
Aspirin / clopidogrel: platelet transfusion
