Haematology Flashcards
Raised INR + warfarin
Any major bleeding:
- Stop warfarin
- IV vitamin K 5mg
- PTT
Minor bleeding:
- INR > 8.0
- Stop warfarin
- IV vitamin K 1-3mg
- INR 5.0-8.0
- Stop warfarin
- IV vitamin K 1-3mg
No bleeding:
- INR > 8.0
- Stop warfarin
- PO vitamin K 1-3mg
- INR 5.0-8.0
- Withhold 1-3 doses
Warfarin + heparin cover
Upon initiation of warfarin therapy, protein C production is reduced
This causes a temporary pro-coagulant state, requiring LMWH cover
Anticoagulant mechanisms
Streptokinase derivatives e.g. alteplase, duteplase
- Bind plasminogen activator to increase generation of plasmin and therefore fibrin degradation
A2PY antagonists e.g. clopidogrel
- Binds platelet A2PY ADP receptors and inhibits them
- Therefore inhibits platelet aggregation
Glycoprotein IIb/IIIa receptor antagonists e.g. tirofiban, eptifibatide
- Inhibits to prevent fibrinogen-to-platelet binding
Vitronectin receptor inhibition e.g. abciximab
- Binds the vitronectin receptor on platelets, smooth muscle, and endothelial cells
Antithrombin III activators e.g. heparin
- Activates ATIII to inactivate thrombin and other proteases
Vitamin K antagonists e.g. warfarin
- Competitive inhibition of vitamin K binding sites
- Inhibit synthesis of factors II, VII, IX, X and proteins C, S, Z
Factor Xa inhibitors e.g. rivaroxaban, apixaban, edoxaban
Direct thrombin inhibitors e.g. dabigatran
Hodgkin’s disease
Epidemiology:
- Bimodal - 20s, 60s
- Association with EBV
Classical (90%):
- Nodular sclerosing
- Most common
- Lymphocyte-rich
- Best prognosis
- Lymphocyte-deplete
- Mixed cellularity
Non-classical (10%):
- Nodular lymphocyte-predominant
Features:
- B symptoms
- Generalised lymphadenopathy
- Pain on drinking alcohol
Investigations:
- Bloods
- Imaging
- Lymph node biospy
- Classically see Reed-Sternberg cells (owl-eyes)
Complications
- Nephrotic syndrome
- minimal change disease
Haemophilia A
Factor VIII deficiency
- X-linked
- 1/5000 males
Features:
- Prolonged bleeding time
- Spontaneous deep bleeding - haemarthrosis, GI tract, cerebral
Classification:
- Mild (>5% activity)
- Moderate (1-5% activity)
- Severe (<1% activity)
- Present with spontaneous bleeding
Investigations:
- Prolonged APTT, normal PT
- Reduced factor VIII activity on assay, normal vWF
- Genetic testing
Management:
- Preventative
- Factor VIII injections (octocog alfa) ever 48h
- On-demand or pre-procedure
- Desmopressin
- Octocog alfa
Paroxysmal nocturnal haemoglobinuria (PNH)
Genetic condition leading to reduction in cell surface GPI on bone marrow-derived cells, impaired CD55 and CD59 presentation, and therefore inappropriate complement activation and lysis
- X-linked
- PIGA mutation
- Prevents anchoring of CD55/CD59
Features:
- Haemolytic anaemia
- Thrombocytopenia
- Intermittent haemoglobonuria
- Abdominal pain
- Renal dysfunction
- Silent thrombosis
Investigations:
- Bloods
- Haemolytic anaemia
- Thrombocytopenia
- Leucopenia
- Urine
- Haemoglobinuria
- Flow cytometry
- Poor CD55/CD59 expression
Management:
- Eculizumab
- C5 inhibitor
- Requires Abx prophylaxis
- Blood transfusion
- Stem cell transplant
Heparin-induced thrombocytopenia
Aetiology:
- Formation of anti-platelet factor 4 IgG
- A type II hypersensitivity response
- 5% of people exposed to heparin
- Most common with unfractionated heparin
Features:
- A 50% fall in platelet count beginning 5-14 days after initial exposure, or 2-3 days if has had previous exposure
- Thrombotic phenomena
- Haemorrhage (less common)
Management:
- Discontinuation of heparin
- Supplementary anticoagulation e.g. direct antithrombin inhibitors (argatroban)
Myelofibrosis
A chronic myeloproliferative disorder characterised by medullary fibrosis, extramedullary haematopoiesis, anaemia
- Associated with JAK2 mutation
- Presents in 60s
- Insidious onset
Features:
- Splenomegaly secondary to extramedullary haematopoiesis
- Fatigue
- Abdominal fullness
- Hepatomegaly
Investigations:
- Bloods
- Anaemia +/- thrombocytopenia
- Normal WCC
- Blood film
- Leukoerythroblastosis
- Teardrop poikilocytes
- BMAT
- Initially hypercellular, then fibrotic
Management:
- Symptomatic support
e.g. blood transfusion, hydroxyurea
Complications:
- Severe anaemia
- Splenic infarction
- Thrombocytopenia
- Severe bony pain
- Hyperuricaemia
Myelofibrosis - prognostic risk factors
DIPSS criteria
- Age > 65
- Hb < 10 g/dL
- Leucocyte count > 25 x 109 L
- Circulating blasts ≥1%
- Constitutional symptoms
- Requirement for RBC transfusion
- Platelets < 100 x 109 L
- Unfavourable karyotype
Chronic myeloid leukaemia
Malignancy resulting from BCR-ABL fusion oncogene (t 9;22)
3 phases
- chronic (asymptomatic)
- 3-10 years
- accelerated (progression)
- Gradual transformation into acute leukaemia
- 2-15 months
- blast crisis (acute progression)
- 3-6 months, inevitably fatal
- May not go through accelerated phase
Features:
- B symptoms
- Splenomegaly + LUQ discomfort
- Epistaxis
- Arthralgia
Investigations:
- Bloods
- High WCC, low RBCs, high or low PLT
- Elevated LDH, K+, uric acid
- Blood film
- High numbers of mature myeloid cells,
granulocyte left shift
- t(9;22) on cytogenetic analysis/FISH
- BMAT
- Granulocytic hyperplasia
Management:
- Tyrosine kinase inhibitors e.g. imatinib
- Allogenic stem cell therapy
Progression - 5-10% risk in first 2 years, then 10% risk for the following years
Chronic myeloid leukaemia - phase definitions
Chronic phase
- Minimal symptoms
- < 10% circulating blasts
Accelerated phase
- 10-19% circulating blasts
- 20% peripheral basophils
- Persistent thrombocytopenia/cytosis resistant to therapy
- Increasing splenomegaly and WCC resistant to therapy
- Cytogenetic evidence of clonal evolution
Blast crisis
- Blasts 20% of circulating WCC or nucleated bone marrow cells
- Extramedullary blast proliferation
- Large foci of blasts on bone marrow biopsy
Chronic lymphocytic leukaemia
Epidemiology:
- The most common leukaemia in the West
- Predominantly older adults (70+)
Pathophysiology:
- Monoclonal expansion of CD5+CD19+CD23+ B lymphocytes
- Poor prognosis associated with TP53, NOTCH1, ATM, BIRC3, SF3B1 mutations
Features:
- Often asymptomatic and diagnosed on routine blood tests
- B symptoms
- SOB, fatigue, pallor
- Splenomegaly
- Recurrent infections
- Autoimmune pathology e.g. AIHA, ITP
Investigations:
- Bloods
- Raised WCC with lymphocytosis > 5 x 109/L
- Anaemia and thrombocytopenia
- Blood film
- Smear cells
- Flow cytometry
- CD5+, CD19+, CD20+, CD23+
Management:
- Observation if early/asymptomatic
- Chemotherapy
- Fludarabine + cyclophosphamide + rituximab
- Allogenic stem cell transplant
- Esp. if have TP53 mutations
Complications:
- Hypogammaglobulinaemia
- Autoimmune haemolytic anaemia
- Immune thrombocytopenic purpura
- Richter transformation
Multiple myeloma
Malignancy of plasma cells, thought to evolve from MGUS
- MGUS - < 30g/L paraprotein, no organ
damage
- Myeloma - >30g/L paraprotein, >10% clonal
plasma cells in bone marrow, +/- symptoms
Features:
- Back pain - pathological fractures
- Hypercalcaemia - thirst, constipation, confusion
- Renal impairment - oligouria
- Normocytic anaemia - fatigue, pallor
- Weight loss
- Recurrent infections (functionally immunosuppressed)
- Hyperviscosity (esp. IgA disease)
Investigations:
- Bloods incl. FBC, U&Es, electrophoresis, serum free light chains, beta-2-microglobulin
- Imaging - XR for fractures, whole-body MRI
- Bone marrow biopsy
Management:
- Treatment only indicated where symptomatic with aim to slow disease and complications
- Autologous transplantation if tolerated
- Dexamethasone +/- bortezomib or
thalidomide or VAD
- Bone support via bisphosphonates
Alpha-thalassaemia
Reduced or absent production of alpha-globin chains
- Mutations in HBA1 or HBA2
Subtypes:
- 1 mutation - silent
- 2 mutations - alpha-thalassaemia minor
- 3 mutations - HbH disease
- 4 mutations - Hb Barts/hydrops fetalis (fatal)
Features:
- Minor:
- Asymptomatic or mild symptoms
- HbH:
- Anaemia - periodic haemolysis
- Jaundice
- Splenomegaly
- Growth restriction
Beta-thalassaemia
Reduced or absent production of beta-globin chains.
- Mutations in HBB
- Leads to accumulation and precipitation of
alpha-globin chains, damaging RBCs
Subtypes:
- 1 mutation - minor/trait
- 2 mutations - intermedia or major
Features:
- Trait:
- Microcytic anaemia
- Major:
- Anaemia - haemolysis and reduced production
- Jaundice
- Splenomegaly
- Growth restriction
Management:
- Major - RBC transfusion + iron chelation
- Intermedia - occasional transfusions e.g. during stress, pregnancy
Complications:
- Iron overload
IgA deficiency
Features:
- 90% asymptomatic
- Recurrent GI, respiratory, and sinus infections
- Increased frequency allergies and autoimmune disease
IgA deficiency
Features:
- 90% asymptomatic
- Recurrent sinus, respiratory, and GI infections
- Increased incidence of allergies and autoimmune disease
IgG2 deficiency
Features:
- Increased susceptibility to polysaccharide-coated bacteria e.g. Haemophilus
- Recurrent otitis media, respiratory tract
infections
- Absent response to pneumococcal vaccine
IgG3 deficiency
Features:
- Increased susceptibility to Moraxella catarrhalis
- Recurrent sinusitis
Waldenstrom’s macroglobulinaemia
A form of low-grade NHL characterised by B cell malignancy and IgM paraprotein
- Typically 60-70yr, M > F
Features:
- Anaemia
- Generalised muscle weakness
- Serum hyperviscosity - mucosal and retinal bleeding
- Purpura
- Hepatosplenomegaly
- Lymphadenopathy
- Peripheral neuropathy
- Headaches
Investigations:
- Normocytic anaemia
- Rouleaux formation
- Electrophoresis - IgM paraprotein band
- Bone marrow - hypercellularity, plasmacytosis
Management:
- Bendamustine-rituximab therapy +/- plasmapheresis
Complications:
- Cryoglobulinaemia
- Renal failure
- Pancytopenia
Amyloidosis
A group of diseases in which abnormal proteins (amyloid fibrils) build up in tissue and cause organ damage
Aetiology:
- AL
- light chains
- idiopathic or associated with myeloma etc.
- AA
- inflammation
- e.g. RA, IBD etc.
- Aβ2M
- dialysis-related
- Hereditary/old age
Features:
- Kidney deposition -> failure
- 20% AL, 50% AA develop ESRF
- Heart deposition
- cardiomyopathy, heart blocks, heart failure
- Gastrointestinal
- diarrhoea, malabsorption, jaundice, bleeding
- Other:
- Hypothyroidism
- Arthralgia
- Purpura
Management:
- Supportive
- Treat underlying cause
e.g. stem cell transplant for AL amyloidosis
Heyde syndrome
Triad of aortic stenosis, GI bleeding, and acquired von Willebrand syndrome
Pathophysiology:
- Shear stresses + increased velocity across stenotic aortic valve cause unfolding and activation of vWF
- Uses up vWF and so less is available for normal clot formation, in particular predisposing to GI bleeding
Management:
- Aortic valve replacement
Iron-deficiency anaemia
Screening:
- FBC - Hb low, microcytic
- Film - anisocytosis, poikilocytosis, hypochromia,
pencil cells
- Iron studies - low iron, low ferritin, high TIBC
and transferrin, low transferrin saturations
Diagnosis:
- FIT test +/- endoscopy
- Urine dip for haematuria
- Screen for nosebleeds, heavy periods, long-term NSAID/PPI use
Management:
- Oral iron
- Usually OD, sulphate or fumarate
- Aiming for Hb increase of 10 g/dL over 14
days
- IV iron
- If oral iron ineffective or not tolerated
Sideroblastic anaemia
Anaemia with presence of sideroblasts
- perinuclear halo of iron deposition due to
impaired incorporation into Hb
Aetiology:
- Congenital
- Usually X-linked deficiency in heme synthesis
- Acquired
- Myelodysplastic syndromes
- Copper or B12 deficiency
- Lead or Zinc overdose
- Alcohol
Megaloblastic anaemia
Anaemia with presence of megaloblasts
- Enlarged RBCs + hypersegmented neutrophils
Aetiology:
- B12 deficiency
- Intake - vegans, malnutrition
- Absorption - pernicious anaemia, gastritis,
Crohn’s, SIBO
- Folate deficiency
- Intake
- Absorption - Coeliac, ETOH, liver disease
- Utilisation - anticonvulstants, malignancy
Presentation:
- Anaemia
- Mild jaundice - due to ineffective erythropoiesis
- Glossitis
- Angular stomatitis
- Peripheral neuropathy
Investigations:
- Low B12/folate
- Megaloblasts and hypersegmented neutrophils on film
- High LDH + bilirubin
Pernicious anaemia
A cause of B12 deficiency and therefore megaloblastic anaemia
Features:
- Anaemia
- Mild jaundice
- aka lemon coloured
- due to ineffective erythropoiesis
- Glossitis
- Angular stomatitis
- Peripheral neuropathy
Investigations:
- 1st line - intrinsic factor antibody
- 2nd line - gastric parietal cell antibody
Management:
- IM B12 initially MWF for 2 weeks then maintenance every 3 months
Iron biochemistry
Key proteins:
- Ferritin
- Binds intracellular iron for storage
- Part of the acute phase response
- Transferrin
- Binds iron to transfer in the blood
- Suppressed in the acute phase response
- Hepcidin
- Suppresses iron absorption in the gut and
inhibits release from intracellular storage
- An acute phase reactant
Iron test interpretation:
- Ferritin
- Low = low iron stores
- High = acute phase state, liver damage
(leakage), iron accumulation, metabolic
syndrome
- TIBC
- Low = chronic disease/acute phase state
- High = iron deficiency
- Transferrin saturation
- Low = iron deficiency, chronic disease
- High = iron overload or supplementation
Intra- and extra-vascular haemolysis
Aetiology:
- Intravascular
- DIC
- TTP
- HUS
- HELLP
- PNH
- Transfusion reaction
- Prosthetic valves
- Extravascular
- Autoimmune - warm (CLL, HL, SLE) or cold
(mycoplasma)
- Intrinsic RBC defects
- Hypersplenism (e.g. malaria, portal HTN)
- Lead poisoning
Investigations:
- Decreased haptoglobin
- Increased LDH and unconjugated bilirubin
- Typically no Hb leak in extravascular and will have less deranged LDH and haptoglobin
Autoimmune haemolytic anaemia - types
Warm
- IgG-mediated
- Causes:
- Spherocytosis
- Autoimmune e.g. SLE, RA
- Malignancy e.g. CLL, lymphoma
- Drugs e.g. penicillins, levodopa
- Management:
- Steroids or steroid-sparing drugs
- If chronic, consider splenectomy
Cold
- IgM-mediated, milder
- Causes:
- Infection e.g. mycoplasma, EBV
- Rarely, autoimmune
- Management
- Avoid the cold
- Immunosuppression
- Warm transfusions
- No benefit from splenectomy
Sickle cell anaemia
Pathophysiology:
- Glu -> Val in the haemoglobin beta-chain
- Causes chain to become insoluble and crystallise whilst in the deoxy state
- Haemolysis
- Cell deposition/entrapment in small blood
vessels
Features:
- Chronic haemolytic anaemia
- Hyposplenism
- Increased infection risk
Management:
- Avoid any triggers for crises
- Vaccination + prophylactic antibiotics if hyposplenic
- Hydroxycarbamide
- Stimulates production of HbF which does not
sickle
- Exchange transfusion
- Bone marrow transplant
Complications:
- Stroke
- Avascular necrosis of the large joints (e.g. hip)
- Pulmonary HTN
- Priapism
- CKD secondary to papillary necrosis
- Retinopathy
- Acute chest crisis
- Acute pain crisis
- Osteomyelitis of the long bones
Sickle cell crises
Vaso-occlusive crisis:
- Small blood vessels blocked by sickled RBCs causing distal ischaemia
- Risk factors
- Dehydration
- Raised haematocrit
- Features:
- Extreme pain
- Fever
- Management:
- High-flow oxygen
- Analgesia
- Hydration
Splenic sequestration crisis:
- Massive RBC sequestration in the spleen, mainly affecting young children
- Features:
- Acute drop in Hb
- Splenomegaly
- Abdominal pain and distension
- Shock
- Management:
- Blood transfusion +/- IV fluids
- Prophylactic splenectomy
Aplastic crisis:
- Usually triggered by infection with parvovirus B19
- Features:
- Pallor + fatigue
- Drop in Hb with low reticulocytes
- Management
- Supportive blood transfusions
Acute chest crisis:
- Can be infective (e.g. pneumonia) or non-infective (e.g. PE, pulmonary vaso-occlusion)
- Features:
- Fever or respiratory sympotms
- New infiltrates on CXR
- Management:
- Treat underlying cause
- Supportive oxygenation/ventilation
Transfusion reactions
Acute haemolytic reaction
- Due to ABO incompatibility
- Features:
- Urticaria
- Fever
- Hypotension
- Haemoglobinuria
- Investigations:
- Low Hb and haptoglobin
- Raised LDH and bilirubin
- Positive DAT
- Management:
- Stop any blood products
- Inform lab
- Supportive care
Febrile non-haemolytic reaction
- Thought to be due to cytokine release from donor WBCs
- Management:
- Pause or slow blood transfusion
- Paracetamol + antihistamine
Transfusion-associated circulatory overload
- Pulmonary oedema and overload
- Risk is increased in patients with cardiac failure, renal impairment, severe anaemia, and rapid transfusion
- Management:
- Supportive care + diuresis
Transfusion-associated lung injury
- A form of ARDS, thought to be triggered by massive neutrophil activation
- Features
- Dyspnea and tachypnea
- Fever
- Hypotension
- Investigations
- CXR
- Management
- Supportive care
Other consequences:
- Hyperkalaemia
- Due to haemolysis of transfused blood
- Hypocalcaemia
- Citrate used to prevent transfused blood
from clotting can chelate Ca2+
- Consider IV calcium
- Clotting abnormalities
- Dilution of host clotting factors
- Consider FFP + platelets following every 4
units RBCs
- Transmission of infections
- Iron overload
Blood product irradiation
Similar to leucodepeleted transfusions, the aim is to prevent transfusion-associated GvHD
Indications:
- Hodgkins lymphoma
- Previous bone marrow/HSC transplant
- Treatment with certain chemotherapies
- Congenital immunodeficiency
- CAR-T therapy
- Alemtuzumab
- Aplastic anaemia receiving anti-thymocyte globulin (ATG) treatment
Products affected:
- RBCs
- Platelets
- Granulocytes
Polycythaemia vera
Pathophysiology
- Pathological increase in erythropoiesis in the absence of raised EPO
- Usually due to an activating mutation in JAK2
- Can also have increased platelets and granulocytes
Presentation
- Ruddy complexion
- Conjunctival suffusion
- Hyperviscosity
- VTE
- Stroke
- Headaches
- Blurred vision
- Basophilia and increased histamine
- Pruritus
- Gastric ulcers
- Splenomegaly
Investigations
- FBC + Blood film
- Bone marrow biopsy
Management
- Supportive
e.g. antihistamine for itch, aspirin for VTE, PPIs
for ulcers
- Frequent venesection
- Hydroxycarbamide or interferon
Myeloproliferative disorders
Disorders due to proliferation of a single type of stem cell
- Polycythaemia vera (erythroid)
- Essential thrombocythaemia
(megakaryocytes)
- Primary myelofibrosis (HSCs)
All have the potential to transform into AML, often seen clinically as the development of B symptoms
- 1-2% risk per year
- 12% risk overall
Investigations:
- BMAT - myelofibrosis
- Blood film - poikilocytes and blasts
Myelodysplastic disorders
Clonal disorders of myeloid stem cells leading to pancytopenia
Often remains asymptomatic until symptoms of cytopenias develop
Often idiopathic in the elderly
Secondary causes include chemicals (benzenes, chemotherapy, other bone marrow failure disorders)
Prolonged disease can progress to AML (when blasts > 20%)
ALL
Features:
- Associated with Down’s syndrome
- Can be associated with the philadelphia chromosome
- Most common in children < 5 yr
Presents with pancytopenia, hepatosplenomegaly, and B symptoms
CLL
Features:
- Commonly B lymphocytes
- Slowly progressive B symptoms and pancytopenia
- Warm haemolytic anaemia
- May rarely undergo Richter transformation into DLCBL
Blood film
- Smear/smudge cells
AML
Features:
- Can be the consequence of a chronic haematological disorder (MDS, MPS)
- Circulating blasts > 20%
- Pancytopenia + B symptoms
- AMPL can lead to DIC
Blood film:
- High levels of circulating blasts
- Presence of Auer rods
CML
Classically associated with the Philadelphia chromosome and so susceptibility to RTK inhibitors
Occurs in three phases:
- Chronic
- Asymptomatic leucocytosis
- Accelerated
- 10-20% circulating blasts
- Begin to develop symptomatic cytopenias
- Blast
- >20% circulating blasts
- Severe pancytopenia
- Main cause of death in CML
Features:
- B symptoms
- Pruritus
- Splenomegaly
- Hyperviscosity
