Haematology Flashcards
How is the extrinsic pathway of the coagulation cascade started
External damage to endothelial tissue exposes tissue factor (3), activating it.
How is the intrinsic pathway of the coagulation cascade started
Collagen exposure activates 12 to 12a
Describe the extrinsic pathway of the coagulation cascade
3,7,10
endothelial damage = 3 (tissue factor) -> 3a.
3a = 7 -> 7a
7a + calcium -> activate 10 to 10a
Describe the intrinsic pathway of the coagulation cascade
12,11,9,8,10
Collagen exposure causes activation of 12 -> 12a
12a = 11 -> 11a
11a activates 8 and 9 to 8a and 9a.
8a and 9a activate 10 to 10a.
Describe the common pathway of the coagulation cascade
10a and 5a and calcium -> 2 to 2a (thrombin).
2a activates 1 (fibrinogen) to 1a (fibrin)
2a activates Stabilising factor (13) to 13a, which forms stable clot with 1a and calcium.
What is PT, and how is this used to calculate INR. Reasons INR may be raised
Prothrombin time - Coagulation speed through extrinsic pathway (3,7,10)
INR = (patient’s PT/reference PT)
Vit K deficiency, Anticoags, liver disease, disseminated intravascular coagulation
What is APTT and what conditions affect this BUT NOT PT
Activated Partial Thromboplastin Time
Coagulation speed through intrinsic pathway
Affected by:
haemophilia A, B and Von Willebrand Disease
Give MCV values in microcytic, normocytic and macrocytic anaemias
Avg RBC volume
Micro - MCV <80
Normo - MCV 80-95
Macro - MCV 95+
General anaemia signs
Pale skin
Conjunctival pallor
Bounding pulse/tachycardia
Dizziness
Fatigue
Postural hypotension
General anaemia symptoms
Tiredness, short of breath, headaches, palpitations, dizziness, syncope
Causes of microcytic anaemia
TAILS
T - Thalassaemia!
A - Anaemia of chronic disease
I - Iron deficiency anaemia!
L - Lead poisoning
S- Sideroblastic anaemia!
Causes of normocytic anaemia
Can be haemolytic or non haemolytic.
AAAH
A - Acute blood loss
A - Anaemia of chronic disease
A - Aplastic anaemia
H - Haemolytic anaemias (other card)
Normocytic haemolytic causes of anaemia (5)
Normocytic
Sickle cell
G6PD
AHA
Hereditary spheryocytosis
Malaria
Causes of macrocytic anaemia
Can be Megaloblastic (large RBC) or normoblastic.
Megaloblastic - Due vitamin deficiency leading to impaired DNA synthesis preventing cells from dividing normally.
- B12 deficiency
- Folate deficiency
Normoblastic -
- Alcohol
- Hypothyroidism
- Liver disease
- Drugs such as azathioprine
How is iron normally stored and made available?
- Iron exists bound to haem/myoglobin (Fe2+) or unbound (Fe3+)
- Fe2+ absorbed directly into duodenum so Fe3+ must first be turned into Fe2+ by ferri-reductase enzymes
- Fe2+ ions bind to ferritin in duodenal cells for storage
- When iron required, Fe2+ turned into Fe3+ by hephaestin
- Fe3+ binds to transferrin for transport where it is delivered to tissue
Define Iron Deficient Anaemia with MCV, and give risk factors
Anaemia caused by low blood iron (Most common anaemia). Microcytic anaemia
- Bowel Cancer
- Pregnancy
- Blood loss
- IBS/IDS
- Coeliac
- H Pylori infection (also proton pump inhibitor use)
Causes of iron deficiency anaemia
- Increased loss (e.g. chronic GI blood loss) (Most common)
> Colon cancer
> Gastric ulceration
> NSAID/Aspirin use - Malabsorption (Coeliac, helicobacter pylori, gastrectomy)
- Increased need (pregnancy, growing children)
- Dietary deficiency (rarer)
6 Signs and 5 symptoms of Iron Deficient Anaemia
- Pallor
- Conjunctival pallor
- Atrophic Glossitis (smooth tongue due to atrophy of papillae on surface of tongue)
- Koilonychia (spoon shaped nails)
- Angular cheilosis (mouth corner ulcers)
- Dry rough skin
Dyspnoea, fatigue, headache, restless leg syndrome
Investigations of iron deficient anaemia
1st - FBC -> low MCV, low Hb (MICROCYTIC)
Serum iron
Serum ferritin
Transferrin saturation (serum iron/total iron binding capacity) ALL LOW
TIBC will be high (negative correllation)
Signs specific to iron deficiency anaemia
Pica - Cravings for non food items as food
Hair loss
Restless leg syndrome
Why is acid required for iron absorption?
Stomach acids keep iron in soluble Fe2+ form. When acid drops it changes to Fe3+, which is insoluble
Management of iron deficient anaemia with side effects
Treat underlying cause
- Oral iron supplements: ferrous sulphate, ferrous fumarate
Side effects: constipation, diarrhoea, nausea, black stools
Pernicious anaemia definition with MCV and pathophysiology
B12 deficiency due to autoimmune destruction of intrinsic factor (megaloblastic)
Intrinsic factor is secreted by parietal cells and is essential for absorption of B12 in ileum. Antibodies form against intrinsic factor or parietal cells, causing atrophy of gastric mucosa, preventing absorption of vitamin B12.
Pernicious Anaemia Investigations
1st - FBC - macrocytic, megaloblastic anaemia (raised MCV)
Blood film - Hypersegmented neutrophils and oval macrocytes (both b12 and folate deficiency)
Serum cobalamin (B12) - decreased
Schilling test (B12 absorption test)
GOLD: Parietal cell and intrinsic factor antibodies
What does blood film show in B12 or Folate deficiency
Hypersegmented neutrophils and oval macrocytes
What is the Schilling test
test for pernicious anaemia; radiolabelled B12 given and absorption measured. Later repeated with IF administration to see if B12 absorption increases
Signs and symptoms of pernicious anaemia and folate deficiency
Main clinical features same in megaloblastic anaemia, except severe neuropathy only in B12
Pallor, dyspnoea, headache, tachycardia, tachypnoea, weakness, lethargy, glossitis (inflammation of tongue),
Peripheral neuropathy: Personality changes, incontinence, paraesthesia, ataxia (loss of control of body movements), optic neuropathy.
Associated symptoms/conditions of pernicious anaemia
Myxoedema
Thyroid disorders
Addisons
Stomach cancer
Vitiligo
Management of pernicious anaemia
Treatment of underlying cause
B12 supplementation - Oral cyanocobalamin or IM hydroxycobalamin
Folic acid (should never be given without B12, prevent degeneration of spinal cord)
What can occur if a folate deficiency is corrected before a B12 deficiency?
Subacute combined degeneration of the spinal cord
What causes macrocytosis without anaemia?
Alcohol
Pathophysiology of sickle cell anaemia
Autosomal recessive gene mutation on beta globin chain (where valine replaces glutamic acid on 6th amino acid) causes “HbS” variant. (HBB gene on chromosome 11)
Under stress (infection, hypoxia, dehydration, acidosis, cold temperature), RBCs sickle, and HbS polymerises, leading to haemolysis or capillary obstruction (sickle cell crises).
initially, they can return to normal shape but eventually lose membrane flexibility and remain sickled.
Sickle cell disease’s relation to malaria
Sickle cell is more common in Africa, India, Middle East. Sickle cell trait (one copy of the gene) reduces severity of malaria. Selective advantage to having sickle cell trait in areas with malaria.
What are classic signs of any haemolytic anaemia?
Jaundice, Scleral icterus (yellow pigment of eyes), gallstones
(caused by haemolysis releasing bilirubin into the blood)
How is sickle cell screening conducted?
Guthrie heel prick test on newborns at 5 days of age
What does SCT screening screen for?
Sickle cell
Thalassaemia
Haemoglobin disorders
What are the 4 sickle cell crises
- Sequestration Crisis. RBCs sickle in spleen. Abdominal pain secondary to splenomegaly. Autosplenectomy.
- Aplastic crisis. Infection with parovirus B19 causes bone marrow suppression. causing sudden onset pallor, fatigue, anaemia. Reduced reticulocyte count.
- Haemolytic crisis - jaundice
- Vaso-occlusive crisis - seperate card
(+Acute chest syndrome - acute cough, chest pain, dyspnoea)
Signs and symptoms of sickle cell anaemia and of its crises
Anaemia symptoms and jaundice (haemolytic!), worse after stressors
- Various crises, causing autosplenectomy/splenomegaly, bone and chest pain. (NB femoral head susceptible to avascular necrosis)
- Dactylitis
- Priapism
Signs of the vaso-occlusive crises in different areas in sickle cell anaemia.
Bone, ACS, Spleen, CNS, Genitalia
Bone - Dactylitis, Avascular necrosis, osteomyelitis
Lungs - Acute chest syndrome. Dyspnoea, chest pain, hypoxia. New chest infiltrates
Spleen - auto splenectomy, splenomegaly
CNS - Stroke
Genitalia - Priapism - prolonged, painful erection
Investigations for sickle cell anaemia
1st - Newborn screening - guthrie heel prick
- FBC - normocytic anaemia with reticulocytosis (young RBC)
- Blood film - Sickled RBCs, Howell-Jolly bodies
- GOLD: Hb Electrophoresis - HbS chains with absent HbA
- Sickle cell solubility test - HbS insoluble plasma goes cloudy
What investigations may be helpful in sickle cell crises
Sputum/ blood cultures
Arterial blood gas
FBC
Liver function test
Chest or bone X ray
Management of sickle cell crises
HYDRATION! (IV fluids to prevent sickling)
Analgesia
Oxygen
Antibiotics if infective crisis
Blood transfusion if severe anaemia
General management of sickle cell disease
- Hydroxycarbamide (stimulates HbF (foetal haemoglobin), which does not sickle)
- Prophylactic phenoxymethylpenicillin in children
- Pneumococcal vaccine
- Haematopoietic stem cell transplant Last resort
- Blood transfusions (risk of iron overload so iron chellation must be done too)
Define thalassaemia and give it’s epidemiology
Autosomal recessive haemoglobinopathy that causes a microcytic anaemia. Prevalent in areas of malaria (Mediterranean, south Asian, African) as thalassaemia protective against it. (selective advantage)
Pathophysiology and subtypes of alpha thalassaemia
Autosomal recessive, leads to deletions of up to 4 alpha genes on chromosome 16 (2 on each)
1 deletion - Silent carrier
2 deletions - Alpha thalassemia minor/trait. Mild symptoms.
3 deletions - Haemoglobin H (HbH) disease. HbH has 4 beta chains (inability to produce alpha chains). Moderate anaemia, HbH cause
4 deletions - Hb Bart’s Hydrops Fetalis syndrome (Alpha thalassaemia major). Hb has high affinity for O2 so tissues not oxygenated. Cardiac failure and massive hepatosplenomegaly causes oedema all over (Hydrops fetalis). Fetus usually dies before birth or in first year.
How does severe hypoxia lead to splenomegaly
Hypoxia causes bone marrow, liver and spleen to increase RBC production. Causes enlargement of liver, spleen and bone marrow.
Pathophysiology of beta thalassaemia
Autosomal recessive point mutations on 2 beta genes on chromosome 11, causing impaired or absent beta chain synthesis.
1 partially or completely defective gene (Bᵀ B) - Beta Thalassaemia Minor (trait). Asymptomatic or mild/absent anaemia.
2 partially defective genes or 1 and 1 completely defective(Bᵀ Bᴼ). - Beta Thalassaemia intermedia. Moderate anaemia, splenomegaly
2 completely defective genes (Bᴼ Bᴼ) - Beta Thalassaemia Major. Complete absence of beta globin, severe anaemia and lifelong transfusion is needed. Hepatosplenomegaly.
Free alpha chains accumulate in RBCs and damage membrane -> Haemolysis, causing jaundice and secondary haemochromatosis
Why does thalassaemia sometimes not present at birth?
HbF is still in the circulation at first.
Signs/symptoms of thalassaemia
- Chipmunk facies (more in beta) - enlarged forehead/cheeks due to extramedullary haematopoiesis
- Hair on end appearance on X ray
- Growth retardation
- Hepatosplenomegaly
- Jaundice
(OEDEMA IN Hb Barts (Hydrops fetalis))
Anaemia symptoms: Pallor, palpitations, fatigue, failure to thrive
Investigations in Thalassaemia
FBC - Microcytic, hypochromic (less Hb=less oxygen) anaemia. High iron/ferritin
Blood film: Microcytic, hypochromic RBC. Target cells
Hb electrophoresis (GOLD): HbH (beta tetramers) in alpha, HbA2 in beta thalassaemia (+ low HbA)
Skull X ray: Hair-On-End appearance.
Genetic testing also diagnostic
Management of thalassaemia
- Blood transfusions
- Iron chellation (oral deferiprone)
- Splenectomy may be needed
- Stem cell transplantation only curative option
Complications of thalassaemia
GASH
Gallstones
Aplastic crisis (parovirus B19)
Secondary haemochromatosis
Hypersplenism
Microcytic anaemias
Iron deficiency
Alpha/beta thalassaemia
Sideroblastic anaemia
Normocytic anaemias
Haemolytic
- Sickle cell
- Hereditary spherocytosis
- G6PD Deficiency
- Malaria
- Autoimmune haemolysis
Non haemolytic
- CKD
- Aplastic
Macrocytic anaemias
Megaloblastic
- B12 and folate deficiency
Non megaloblastic
- Hypothyroid, Alcohol excess, liver disease
Sideroblastic anaemia definition, inheritance pattern and blood film result
Defective Hb synthesis causes defective RBCs that cant carry oxygen as well (sideroblasts). X linked recessive, or acquired.
Functional Fe deficiency (serum high but not used in Hb synthesis)
Blood film: Microcytic w/ Ringed sideroblasts and basophilic stippling.
Define G6PD deficiency
X linked deficiency of Glucose-6-Phosphate Dehydrogenase enzyme, making RBC more susceptible to damage by oxidation
Role of G6PD normally
- Free radicals produced by body which can damage RBCs through DNA, protein and cell membrane damage.
- Glutathione acts as an antioxidant, donating an electron to free radicals, turning them into water and oxygen, but becoming oxidised itself.
- Glutathione reductase uses NADPH to donate an electron back to glutathione and NADP+ is formed.
- G6PD reduces NADP+ back to NADPH using a G6P (which is a metabolite of glucose, so we have lots of it).
Pathophysiology of G6PD
Defective G6PD enzymes produced with shorter half lives, leading to reduced NADPH and glutathione so RBCs are unprotected from free radical damage. Damaged Hb precipitate in cell to form Heinz Bodies and when spleen tries to remove this, it takes a bite out of the RBC, forming bite cells.
Bilirubin from haemolysis is converted to urobilin, giving urine a dark tea-like colour
Epidemiology of G6PD (2)
X linked so more common in men
Found in areas with malaria (Africa, Mediterranean, SE Asia)
Common triggers of G6PD
Fava beans
Soy products
Red wine
Metabolic acidosis
Infections (pneumonia, sepsis)
Malaria drugs (chloroquines)
Signs and symptoms of G6PD
Asymptomatic until exposed to oxidative trigger
- Jaundice
- Dark Tea-coloured urine (urobilin)
- Back pain (indicates kidney damage + urine)
- Splenomegaly
- Anaemia symptoms (Pallor, fatigue, tachycardia, dizziness, palpitation )
Investigations in G6PD
FBC: Low RBC, High reticulocyte
Blood film: Heinz bodies, bite and blister cells
Unconjugated bilirubin: high
GOLD: G6PD enzyme assay
Management of G6PD
Avoid triggers, transfusion if severe.
Epoetin alfa if kidneys damaged
Define hereditary spherocytosis
Autosomal dominant (can be recessive) haemolytic anaemia caused by a defect in spectrin and ankyrin (membrane proteins) causing RBCs to become spherical.
Key signs of hereditary spherocytosis
Neonatal jaundice
Splenomegaly
Anaemia symptoms
Investigations and diagnostic criteria in hereditary spherocytosis
FBC - Normocytic anaemia AND raised MCHC (mean corpuscular haemoglobin concentration)
Blood film - Spherocytes
High bilirubin and urobilinogen
Diagnostic criteria
- Family history
- Typical features
- Positive lab findings (Spherocytes, Raised MCHC)
Treatment of hereditary spherocytosis
Splenectomy
(Lifelong penicillin to prevent post-splenectomy sepsis)
Blood transfusion + Folic acid
Classifications (3 categories) of autoimmune haemolytic anaemia
Extrinsic - Immune system attacks RBCs
Intrinsic - RBCs have a defect
Extravascular - Destruction by spleen/liver (so normal haptoglobin)
Intravascular - RBC destruction within blood vessels
Warm - Haemolysis at 37C (IgG antibodies) (most common)
Cold - Haemolysis at 0-10C (IGM antibodies)
3 consequences of intravascular RBC destruction
1) Jaundice - Unconjugated bilirubin in blood
2) Tea-like urine - Unconjugated bilirubin in blood converted to urobilin by liver
3) Kidney disease - Hb broken down to Haemosiderin which is deposited in renal tubular cells
Signs and symptoms of AHA
Pallor
Jaundice
Fatigue
Shortness of breath
Hepatosplenomegaly (Extravascular)
Oliguria (Renal insufficiency - long term intravascular)
Investigation and treatment in AHA
Coombs test positive (agglutination test)
IgG and CD3 = Warm
CD3 alone = cold
Steroids/splenectomy
Patient presents with recent travel and fever what should you suspect?
Malaria
Define malaria
Notifiable protozoal parasitic infection of Plasmodium genus protozoa
5 protozoa species that cause malaria, and the one that causes complicated malaria
P. falciparum (most common and causes complicated)
P. ovale
P. vivax
P. malariae
P. knowlesi
Pathophysiology of malaria
Protozoal infection transmitted by female Anopheles mosquitos.
Sporozoite in mosquito’s salivary glands transmitted through bite into persons bloodstream, where they travel to the liver. They reproduce asexually here, killing hepatic cells and maturing into merozoites. They then enter the blood and invade RBCs, maturing into gametocytes, which reproduce sexually. Spleen detects most of these and destroys them, causing haemolytic anaemia.
P. falciparum generates a sticky protein that causes RBCs to clump together, occluding small vessels. This blocks blood flow, infected cells cannot reach spleen, and also causes organ failure.
Signs and symptoms of malaria
Signs:
- Anaemia
- Jaundice
- Hepatosplenomegaly
- Blackwater fever (malarial haemoglobinuria)
Symptoms:
- Fever
- Chills
- Headache
- Fatigue
- Diarrhoea
- Vomiting
Investigations in malaria
1st and GOLD: blood film
Thick - locates parasites (malaria?)
Thin - identifies Plasmodium species and identifies % of cells infected (species?)
Features of complicated malaria
- Cerebral (vascular occlusion, coma etc)
- Acute respiratory distress syndrome
- Renal failure (proteinuria, haematuria)
- Bleeding
- Shock
What protozoa most likely to cause relapse in malaria and why?
P ovale and vivax
can form hypnozoites in liver, which emerge later
Preventative measures in malaria
Full body clothing
Insecticide treated bed nets
Prophylaxis (chloroquine) before travel to endemic areas
Indoor insecticide sprays
Empty stagnant collections of water
Treatment of malaria
Complicated: IV artesunate (quinine+doxycycline)
Uncomplicated: Fluids
- Chloroquine - treat acute infection
- Primiquine - kill hypnozoites
Define aplastic anaemia
Pancytopenia (deficiency of all 3 blood components, RBC, WBC, platelets) where bone marrow fails and hemopoietic stem cell production halts.
Leads to anaemia, leukopenia, thrombocytopenia
Give causes of aplastic anaemia
Idiopathic
Radiation
Infection (EBV, parovirus B19)
investigations in aplastic anaemia
FBC - anaemia, thrombocytopenia, leukopenia
BM biopsy - low haematopoietic stem cells
Erythropoietin - raised
Signs of aplastic anaemia
Anaemia symptoms +
Increased bleeding
Chest pain/SOB
Reccurent infections
How does CKD cause anaemia
Reduced Erythropoietin production by kidneys
Risk factors for folate deficiency
- Elderly
- Poverty
- Alcohol
- Pregnancy
- Crohns or coealiac
- Malnutrition
Define folate deficiency
Deficiency in folate (vitamin B9) causing a macrocytic megaloblastic anaemia
Pathophysiology of folate deficiency
Folate is a cofactor in amino acid metabolism and DNA/RNA synthesis
DNA impairment affects bone marrow a lot (as it divides most) leading to pancytopenia.
Folate also essential for foetal development, can lead to neural tube defects (Spina bifida)
Signs/symptoms of folate deficiency
Pallor
Fatigue
Dyspnoea
Headache
Pancytopenia features
NO NEUROPATHY (There is in B12 deficiency)
Differentials to rule out in folate deficiency
B12 deficiency
Aplastic anaemia
Treatment of folate deficiency
Folic acid tablets
- Always give with B12 unless confirmed B12 normal. Correcting folate with low B12 can cause neurological disease
Causes of folate deficiency
Poor intake (poor, alcoholic, elderly)
Increased demand (pregnancy, haemolysis)
Malabsorption disease (Crohns, coeliac)
Antifolate drugs (methotrexate, trimethoprim)
Non megaloblastic, macrocytic causes of anaemia
- Hypothyroidism
- Alcohol excess (toxic to RBC, depletes folate)
- Liver disease
What is leukaemia
The uncontrolled proliferation of non functional blood blast cells. Leukaemia cells divide rapidly and take up space in the bone marrow, less energy and space available for normal cells. The lack of functioning blood cells leads to leukaemia symptoms, and increased infection and bleeding risk
General leukaemia symptoms
Bone pain, bleeding, bruising, infections, anaemia
- Lymphadenopathy and lymph node pain
- Petechiae (red dots under skin) or petechial rash
- Hepatosplenomegaly
- Easy bruising
- Fatigue
- Weight loss
- Fever
mnemonic to help remember ages of leukaemia onset
ALL CeLLmates have CoMmon AMbitions
ALL - under 5 and over 45
CLL - Over 55
CML - Over 65
AML - Over 75
Define acute lymphoblastic leukaemia with epidemiology
Proliferation of lymphoblasts (mostly B cell). Associated with Down syndrome, radiation and t(12;21). Bimodal age distribution, first peak (75% of cases) at 5 years old, second at 50. In T cell ALL, thymus enlargement may be seen
Investigations in ALL
FBC - anaemia, thromocytopenia, leukocytosis (High WBC, low everything else)
Blood film - Lymphoblasts
Nuclear TdT staining - positive
Bone marrow aspiration GOLD - At least 20% bone marrow infiltration
Treatment of ALL
1 - Supportive with blood and platelet transfusions. IV fluids and a hickman line.
2 - Chemotherapy + Allopurinol (prevent tumour lysis syndrome)
First with prednisolone (4-8 weeks then high dose chemo)
Complications and poor prognostic factors of ALL
Myelosuppression
Neutropenia/Neutropenic sepsis
Age <1 year or >10 years
t(9;22)
Hypodiploidy
Adult relapse
Complications of chemotherapy
Stunted growth in children
Tumour lysis syndrome
Infertility
Neurotoxicity
Infections/immunodeficiency
Neutropenia
Chronic lymphocytic leukaemia definition and epidemiology
- Neoplastic proliferation of partially/ fully mature B lymphocytes.
- Most common adult leukaemia
- Can present asymptomatically due to gradual onset, noticed during FBC
- Causes general leukaemia symptoms + non tender lymphadenopathy and splenomegaly
Investigations in CLL
- FBC - anaemia, thrombocytopenia, lymphocytosis
- Blood film - Smudge cells (aged or fragile WBCs rupture to leave smudge) + spherocytes if active haemolysis
- Flow cytometry - Positive markers for CLL e.g. CD5, CD19, CD20, CD23
- Immunoglobulins - Low (B cells dont fully differentiate into plasma cells)
Treatment of CLL
Early stage - Monitoring using FBC every 3-12 months
Late stage - Chemotherapy + allopurinol.
Radiotherapy may help lymphadenopathy
Stem cell transplant and Ig transplant
Blood transfusion
Complications of CLL
Richter transformation - Transformation into a high grade non-Hodgkin lymphoma. (Rapid progressing lymphadenopathy, fever night sweat weight loss (B), raised LDH
Autoimmune haemolytic anaemia
Small lymphocytic lymphoma (Cells move to lymphatic system and settle at nodes)
Hypogammaglobulinaemia
Signs and symptoms of leukaemia
Bone pain, bleeding, bruising, infections, anaemia
- Lymphadenopathy and lymph node pain
- Petechiae (red dots under skin) or petechial rash
- Hepatosplenomegaly
- Easy bruising
- Fatigue
- Weight loss
- Fever
Acute myeloid leukaemia definition, subtypes and epidemiology
- Neoplastic proliferation of myeloblasts, with important subtypes;
- APML - t(15;17) promyelocyte accumulation with Auer rods. Can cause DIC.
- Acute monocytic leukaemia - Monoblast accumulation without Auer rods. Gums infiltrated.
- Affects older people, most common over 75s.
- Associated with Pataus (trisomy 13), Downs (trisomy 21) syndrome, benzene + radiation exposure
Symptoms specific to AML
Mouth ulcers
DIC (APML)
Gum infiltration/ hypertrophy
Investigations in AML
FBC - Low RBC, platelets. High WBC
Blood film - Blasts and Auer Rods
Bone marrow aspiration - >20% infiltration into bone marrow
Immunophenotyping - checks cell lineage, confirms AML
Management in AML
- IV Fluid via hickman line
- Chemotherapy + Allopurinol (prevent tumour lysis syndrome)
- All-trans retinoic acid in APML, allows blasts to mature into neutrophils
- BM transplant
Define APML with pathophysiology
Acute ProMyelocytic Leukaemia (t15;17)
Disrupts retinoic acid receptor, promyelocytes can’t differentiate
What are Auer rods
Aggregates of myeloperoxidase found in AML that increase risk of clotting (DIC)
Patient with AML suddenly has lots of blood clots, what complication has occured
Disseminated Intravascular Clotting
CML definition and pathophysiology
Uncontrolled proliferation of myeloid cells - usually granulocytes. Associated with t(9;22) - PHILADELPHIA CHROMOSOME.
- BCR-ABL genes fused, permanently activating Tyrosine Kinases, causing proliferation of myeloid cells. Rapid proliferation can lead to Acute Leukaemia (or Blast Crisis)
Phases of CML
Chronic (asymptomatic) <10% blast cells
Accelerated (Further progression) 10-19% blast cells >20% basophils
Blast crisis (terminal phase, mimicks acute leukaemias) >20% blast cells, pancytopenia
Signs of CML
Severe hepatosplenomegaly
Abdominal tenderness/fullness due to hepatosplenomegaly
May show features of gout due to purine breakdown
Investigations in CML
FBC - Very high WCC across spectrum of myeloid cells, low Hb, high Urate
Blood film - Granulocytes
Cytogenetics - Philadelphia chromosome t(9;22)
LDH raised in leukaemia but unspecific
Management of CML
Chemotherapy +- Allopurinol
Tyrosine kinase inhibitor (Imatinib)
Stem cell transplant if severe or if goes to blast phase
Define myelodysplasia/ myelodysplastic syndrome
Dysplasia of myeloblasts in bone marrow but less than 20% infiltration. Causes cytopenia meaning death usually due to infection/bleeding. Increase in blast % causes progression to acute leukaemia
Define lymphoma and give the two types with their differences
Neoplastic proliferation of lymphoid cells (B cells).
- Hodgkins (has Reed-Sternberg cells, spread is contiguous (one node to next) and effects rarely extra nodal)
- Non-Hodgkins (No RS cells, non contiguous spread and goes extra nodal (GI, skin, brain etc)
Risk factors and epidemiology for Hodgkins lymphoma
- EBV infection history
- Family history of lymphoma
- Post transplant
- HIV
- Bimodal (15-35 and >60)
Subtypes of Hodgkins lymphoma
- Nodular sclerosing: most common
- Nodular lymphocyte predominant (popcorn cells - RS variant)
- Lymphocyte rich
- Lymphocyte depleted (worst prognosis)
- Mixed cellularity
Risk factors and epidemiology for Hodgkin’s lymphoma
- EBV infection history
- Family history of lymphoma
- Post transplant
- HIV
- Bimodal (15-35 and >60)
Signs/ symptoms of Hodgkin’s lymphoma
Lymphadenopathy (usually cervical, axillary, inguinal)
- Fixed, hard, rubbery, painless(!). Spread is contiguous
Splenomegaly
Alcohol induces lymph node pain
B symptoms
- Fever, night sweats, weight loss
Pruritus (itching)
Staging/classification used for lymphoma
Ann-Arbor (1,2,3,4/A,B)
1 - 1 region of lymph nodes affected
2 - 2 or more, same side of diaphragm
3 - Involvement on both sides of diaphragm
4 - Widespread involvement including organs
A - No B symptoms
B - B symptoms
Pathology associated with Classical and nodular sclerosing Hodgkin’s lymphoma
Classical - usually painless cervical lymphadenopathy
NS - Mediastinal lymphadenopathy, which may cause cough, chest pain and may compress superior vena cava, dilating neck veins and increaing JVP
Investigations in Hodgkin’s lymphoma
FBC - Low Hb/platelets
CXR - Mediastinal lymphadenopathy and widened mediastinum can be used for Ann Arbor.
PET-CT Scan of thorax/abdomen/pelvis - Staging
Lymph node biopsy GOLD - Reed sternberg cells
Differentials for lymphoma
Hodgkin’s/non hodgkin’s
Lymphadenopathy from other malignancies
Infectious Mononucleosis (glandular fever) - enlarged, tender lymph nodes, sore throat. Usually due to EBV
Management of Hodgkin’s lymphoma
1A-2A - ABVD chemotherapy
- Adriamycin
- Bleomycin
- Vinblastine
- Dacarbazine
2A-4B - Longer courses of chemotherapy and radiotherapy
Complications of radiotherapy and chemotherapy treatment
Radio - Hypothyroid, lung fibrosis, secondary malignancy
Chemo - Myelosuppression, Nausea, Alopecia, Infertility
Define Non Hodgkin’s lymphoma
All lymphomas without Reed-Sternberg cells. Can spread extra nodally (skin, stomach, GI tract, bone marrow, spinal cord). Usually due to a genetic mutation in lymphocyte.
Give 3 types of B cell origin Non Hodgkin’s lymphoma
- Diffuse Large B cell Lymphoma (DLBCL) ⇒ Most common & High Grade (aggressive)
- Follicular Lymphoma ⇒ Low grade (slow)
- Burkitt Lymphoma ⇒ HIGHLY aggressive with starry sky appearance on microscope (usually associated with EBV in Africa, with extra nodal involvement including jaw. Outside of Africa, abdomen more common)
Signs/symptoms of Non-Hodgkin’s lymphoma
- Fixed, hard, rubbery, painless lymphadenopathy. Spread is non-contiguous
- May have extra nodal manifestations
- Hepatosplenomegaly (more common in NHL)
B symptoms
Fever, night sweats, weight loss
Extra nodal manifestations in NHL
Skin - lesions and itching
GI tract - Bowel obstruction
Spinal cord - Compression, loss of sensation
BM - Pancytopenia
Investigations in NHL
FBC - pancytopenia if BM affected
LDH - Increases as prognosis worsens (increased cell turnover/proliferation)
Lymph node biopsy GOLD - No reed-sternberg/popcorn cells
CXR, PET of chest, abdomen, pelvis - for staging
Lumbar puncture to check for CNS involvement
Treatment of Non-Hodgkin’s lymphoma
Rituximab + Chemotherapy (R-CHVP)
Rituximab (mAB - targets CD20 on B cells)
C - cyclophosphamide
H - hydroxydaunorubicin
V - Vincristine
P - Prednisolone
Intrathecal Methotrexate for prophylaxis
Low grade may not need treatment
Treatment of Non-Hodgkin’s lymphoma
Rituximab + Chemotherapy (R-CHVP)
Rituximab (mAB - targets CD20 on B cells)
C - cyclophosphamide
H - hydroxydaunorubicin
V - Vincristine
P - Prednisolone
Intrathecal Methotrexate for prophylaxis in CNS involvement
Low grade may not need treatment
Define Multiple Myeloma with epidemiology
Cancer of differentiated B lymphocytes (plasma cells)
70+ years, Afro-Caribbeans
Pathophysiology of Multiple Myeloma
Neoplastic plasma cells release abnormal antibodies consisting only of paraprotein light chains. Light chains can form amyloid proteins, causing amyloidosis. CRAB symptoms
C - Calcium - Hypercalcaemia caused by neoplastic cells releasing cytokines, activating osteoclasts via RANK receptor. Causes bone resorption.
R - Renal insufficiency - nephrocalcinosis and deposition of free light chains (Bence Jones proteins) in kidney tubules disrupt renal function. Results in Bence Jones proteins in urine.
A - Anaemia. Bone marrow infiltration causes reduced haematopoiesis. Pancytopenia
B - Bone pain. Bone lesions, fractures and pain caused by Osteoclast activation, inhibits osteoclast inhibition and suppresses osteoblasts. Common in skull, spine, long bones, ribs.
Signs/symptoms of Multiple myeloma
OLD Crab
70 +
- hyperCalcaemia symptoms: Bones, stones, abdominal moans, psychiatric groans
- Renal insufficiency: Urinary frequency + Bence Jones in urine
- Anaemia - Fatigue, SOB, tachycardia
- B - Bone pain (especially back)
Investigations in Multiple Myeloma
- FBC normocytic, normochromic
- Blood film - Rouleaux formation
Urine:
- Urine dipstick - Bence Jones protein
- Urine electrophoresis - Paraprotein band or “M” spike (IgG/IgA)
- Bone Marrow Aspiration GOLD - >10% monoclonal plasma cells in BM
Imaging:
- Full body MRI to determine BM infiltration and find lesions
- Imaging using CXR - Skull/spine etc. Raindrop skull, Osteolytic lesions
Diagnostic criteria in multiple myeloma
One or more biomarkers
- BM plasma cells >10%
- >1 focal lesion on MRI
- involved : uninvolved free light chain ratio >100
or
CRAB end organ damage
Treatment of Multiple Myeloma
Supportive then. Chemotherapy +- stem cell transplant
- No NSAID (renal impairment)
- Bisphosphonate (suppress osteoclast activity, reduce fracture)
- Anaemia correction
- DVT prophylaxis - LMWH or aspirin
Chemotherapy:
<70 - bortezomib, thalidomide and dexamethasone
>70 - bortezomib, prednisolone and melphalan
Complications of Multiple Myeloma
- Fractures
- Chronic pain
- Hyper viscosity
- Renal failure
- Pancytopenia
- Recurrent infections
Risk factors for HIV
- Regular unprotected sex
- IV drug use/needle sharing
- Blood transfusion
- Parent with HIV (vertical transmission)
Define HIV with types/epidemiology
HIV is a retrovirus (RNA virus) that infects cells of immune system (CD4+ cells; T helper cells, macrophages, dendritic cells). This causes immunodeficiency leading to AIDS (Acquired ImmunoDeficiency Syndrome)
Two main strains
HIV-1: Most common/virulent
HIV-2: West Africa, better outcomes
What 3 ways is HIV transmitted?
- Sexual (Male on male particular risk)
- Parenteral (needlestick/ needle sharing)
- Vertical (breastfeeding/vaginal delivery)
Pathophysiology of HIV
HIV use gp120 to bind to CD4 on immune cells. It uses this and a coreceptor (e.g. CXCR4 on T cells or CCR5 on macrophages) to allow it to inject it’s single RNA strand into the cell.
The virion’s RNA is transcribed to dsDNA using reverse transcriptase which is integrated into the host DNA. As a result, the immune cell transcribes and translates new HIV viruses.
HIV replication is flawed, and makes many variants (e.g. R5 strain which binds to CCR5 on macrophages)
Phases of HIV infection
Acute infection (12 weeks): rapid viral reproduction causing flu like symptoms. Viral load is high and antibodies are produced, causing viral load to drop and symptoms to subside.
Chronic (latent) phase (2-10 years): Virus increases slowly whilst T cells slowly decrease. Opportunistic infections can develop but CD4 count stays over 500 cells/mm³ so can be fought off. As this drops, more AIDS-like symptoms develop.
Late stage HIV/AIDS: CD4 count drops <200mm³, with dramatic increase in viral load and development of AIDS-defining illness.
Symptoms of HIV/AIDS
Acute (CD4>500/mm³)
- Flu like (malaise, fever, sore throat, diarrhoea, maculopapular rash)
Chronic/latent (CD4 500-200 mm³)
- Fever
- Persistent lymphadenopathy
- Opportunistic infections such as EBV (causing hairy leukoplakia) or oral candidiasis (NON DEFINING)
- TB can reactivate
AIDS defining
- persistent fever, fatigue, weight loss, diarrhoea, visual loss
- Presence of AIDS defining conditions
AIDS defining conditions
Infections body can normally fight off
- Recurrent bacterial pneumonia
- Pneumocystis pneumonia
- Fungal infection (candidiasis)
- Cytomegalovirus
- TB
Tumours
- Kaposi sarcoma (skin lesions!)
- Non Hodgkins lymphoma
Investigations in HIV
Investigations must be confirmed
1st
- HIV antibody test (false negative for 3 months after initial exposure)
- p24 antigen test
Any negative testing requires repeat after 3 months
Confirmatory
- Repeat p24 or antibody test or use Western blot (detects p24, gp120, gp41)
How is HIV screened for
Antibody tests in those who present with infectious disease
How is HIV monitored
- CD4 count (1200-500 normal, 500-200 latent, <200 AIDS). Lower = greater risk of opportunistic infection
- Viral load (HIV RNA per ml of blood) Undetectable <50 copies per ml. Left untreated this number can reach 100,000s
Treatment of HIV with additional prophylaxis
Antiretroviral - aim to increase CD4 count
- 2 Nucleoside reverse-transcriptase inhibitors (NTRI) + protease inhibitor or non nucleoside reverse-transcriptase inhibitor
Additional prophylaxis:
- Co-trimoxazole prophylaxis against pneumocystis jirovecii pneumonia
- Vaccinations
- Condom usage
- C section and breastfeeding cessation in pregnancy
Define polycythaemia
Erythrocytosis - A high concentration of Red Blood Cells in blood, causing an increase in PCV (Packed cell volume - proportion of cells in blood volume)
Give secondary causes of polycythaemia
- Obstructive sleep apnoea
- COPD
- Alcohol
- Dehydration
- Hypoxia
- Increased Erythropoietin
Define polycythaemia vera
JAK2 mutation causing increased numbers of RBCs in blood. PCV and haematocrit increase.
PCV - Packed cell volume: proportion of cells in blood volume
Haematocrit - Proportion of RBCs in haematocrit
Pathophysiology of polycythaemia vera
Normally, kidneys release erythropoietin which binds to haematopoietic stem cells and activates the JAK2 (Janus Kinase 2) gene, causing division into RBC
In mutation, JAK2 always active, and division occurs even without erythropoietin. This causes increased RBCs most of all, but also increased neutrophils and platelets, causing hyper viscosity.
What can polycythaemia develop into, and how does it do this?
Myelofibrosis
- In time, these haematopoietic cells start to die out and scar tissue forms, causing bone marrow failure. This causes pancytopenia (anaemia+ thrombocytopenia+ leukopenia)
- Extramedullary haematopoiesis (production of blood outside of BM) occurs and splenomegaly or hepatomegaly can occur.
signs/symptoms of polycythaemia
Signs
- Excessive itching, especially after a bath (due to increased basophils and mast cells releasing histamine)
- Erythromelalgia: Pain redness swelling in hands and feet
- Plethoric appearance
- Conjunctival plethora
- Splenomegaly
Symptoms
- Blurred vision
- headache
- Dizziness
- Increased sweating
Investigations in polycythaemia vera
FBC - High Hb, RBC, WBC, platelet, haematocrit, PCV
Erythropoietin - Low/normal in primary, possible high in secondary
Bone marrow biopsy - look for fibrosis
Abdominal USS - Check for splenomegaly
GOLD: Cytogenetics: JAK2 gene mutation
Management of polycythaemia vera
1 - Venesection (regular removal of blood, aim to bring haematocrit to normal)
Aspirin to prevent blood clots
Hydroxycarbamide can be given to reduce RBC
Ruxolitinib JAK2 inhibitor
Complications of Polycythaemia
- Gout and kidney stones -Increased cell turnover causes buildup of uric acid
- Splenomegaly
- Myelofibrosis!!
- Leukaemia
Clotting related:
- Stroke
- MI
- DVT
- Budd-Chiari syndrome (liver veins are blocked by blood clot)
(also paradoxically has a bleeding risk)
Define thrombocytopenia, and the 2 conditions that cause it
- Low platelet count
- Immune Thrombocytopenic purpura (ITP)
- Thrombotic thrombocytopenic purpura (TTP)
Define ITP with epidemiology
Immune thrombocytopenic purpura
Antibodies created against platelets, which bind to them causing them to be destroyed in the spleen. Can be primary or secondary
More prevalent in children and elderly. Women>men
Signs/symptoms of ITP
Mostly asymptomatic, but in severe cases causes:
- Purpura/purpuric rash (red/purple spots beneath skin caused by bleeding under skin)
- Petechiae
- Easy and long bleeding
- Menorrhagia/nose bleeds
Investigations in ITP
FBC - isolated thrombocytopenia (Leukocyte/haematocrit normal)
Blood film - Megakaryocytes and large platelets (if concurrent AHA, spherocytes present)
Abdominal ultrasound check for splenomegaly
Treatment of ITP
Prednisolone and IV IgG
Splenectomy if severe
Define TTP
Thrombotic thrombocytopenic purpura.
Tiny blood clots develop throughout small vessels using up platelets and causing thrombocytopenia, bleeding under the skin and systemic issues.
Pathophysiology of TTP
Problem with ADAMTS13 protein (deficiency or autoimmunity against) means it cannot inactivate von Willebrand factor, which enables platelet adhesion. These clot in small vessels and said clots break up RBCs, causing haemolytic anaemia.
As it affects small vessels, it is known as a microangiopathy
Signs/symptoms of TTP
5 classical symptoms
- Thrombocytopenia
- Microangiopathic haemolytic anaemia
- Fever
- Renal insufficiency causing haematuria and reduced output.
- Neurological symptoms (headache, confusion, seizures, focal abnormalities, coma)
also
Purpuric rash, bleeding.
TTP vs ITP symptoms and how you get it
ITP usually well systematically, rashes and bleeding main symptoms. Acquired
TTP has systematic effects. Inherited
Investigations in TTP
ADAMTS13 decreased
FBC - Thrombocytopenia and normocytic, normochromic microangiopathic anaemia
Blood film - Schistocytes (fragmented blood cells)
Unconjugated bilirubin and LDH raised
PTT/APTT normal
Management of TTP
Plasmapharesis/plasma exchange
Prednisolone + Rituximab (monoclonal antibody against B cells)
Side effect of heparin treatment that causes thrombocytopenia
Heparin induced thrombocytopenia
Antibodies against heparin form, targeting platelet factor 4 protein on platelets.
Define glandular fever with its cause and its other name
Infectious mononucleosis
Caused by EBV and associated with Hodgkin’s, Burkitt’s and nasopharyngeal carcinoma
Presentation of glandular fever
Classic triad
Fever, pharyngitis, lymphadenopathy
Usually presents in adults and young children
Shows atypical lymphocytes on blood film
How does glandular fever spread and what are its complications
Spread through saliva (kissing, sexual activity)
Lifelong latent infection, can cause chronic fatigue
Define haemophilia and give its 2 subtypes
Inherited severe bleeding disorders, both affect intrinsic pathway (increase APTT), causing decrease in function or quantity of clotting factors.
A - Deficiency in factor 8
B (Christmas disease) - Deficiency in factor 9
Prolongs clotting time, causing bleeding to be more severe.
What are the causes of haemophilia
Inherited
- X linked recessive (A- F8 gene, B- F9 gene) ∴ mostly affects males!
Acquired
- Liver failure (liver responsible for many clotting factors)
- Vit K deficiency
- Autoimmunity against a clotting factor
- DIC
Signs and symptoms of haemophilia
- Spontaneous, excessive, inappropriate bleeding
- Nose, gum, GI, urinary, intracranial bleeding for example
- Easy bruising
- Haemarthrosis (bleeding into joints)
Investigations of haemophilia
PT - normal
APTT - Prolonged (these conditions only affect intrinsic pathway!)
F8/F9 assay to show deficiency
Treatment of haemophilia
A: IV factor 8 + desmopressin (releases F8 stored in vessel walls)
B: IV factor 9
von Willebrand disease definition
Autosomal dominant mutation of vWF gene on chromosome 12 causing deficiency, absence or abnormal functioning of von Willebrand Factor. This causes excessive bleeding
vWF normal function
- Basis of platelet plug, attaches to collagen fibres and enables platelet adhesion
- Needed as a carrier for Factor 8, protecting it from degradation
von Willebrand disease types
1 reduced/defective vWF
2 Quantity fine but quality affected
2A - unable to bind platelets
2B - binds to platelets in blood, causing thrombocytopenia
2N - Cant bind to factor 8
3 No production
Investigations in vW disease
PT normal
APTT high
Normal F8/F9 (rule out haemophilia)
vWF low
Platelets normal except 2B
Management of vW disease
- Desmopressin stimulates release of vWF from Weibelpalade bodies
- vWF and factor 8 infusion
Define Disseminated Intravascular Clotting with pathophysiology
Haemostasis is process of balancing fibrin breakdown and deposition. In severe disease (Sepsis, malignancy, trauma, haemolysis) procoagulants released which tip in favour of clotting, leading to increased clotting around the body, causing organ ischaemia.
The depletion of platelets in this way means less available for actual bleeds so small damage leads to severe bleeding.
Leads to a patient with too much and also too little clotting
Investigations in DIC
PT - prolonged
APTT - prolonged
Platelets - low
Fibrinogen - low
D-Dimer - increased (fibrin degradation product when fibrin clots broken down)
Symptoms of DIC
Widespread ecchymoses
Bleeding from mouth and nose
Confusion
Bruising
Acutely ill and shocked patient
Treatment of DIC
Treat underlying cause
Fresh frozen plasma transfusion
Blood transfusion
Platelet transfusion
Define tumour lysis syndrome
Complication of chemotherapy that entails the release of intracellular components of tumour cells into the blood stream
What does Tumour Lysis syndrome cause to build up in blood
- Hyperkalaemia
- Hyperphosphataemia (which causes hypocalcaemia)
- Also DNA components such as purines and pyrimidines. Purine converted into hypoxanthine, xanthine then uric acid, which builds up in blood and can cause kidney injury (Hyperuricaemia)
Overall,
- Hyperkalaemia
- Hyperphosphataemia
- Hypocalcaemia
- Hyperuricaemia (causing kidney injury and gout)
Complications and treatment of Tumour Lysis Syndrome
- AKI (uric acid causes crystal deposition)
- Hypocalcaemia and hyperkalaemia can cause neurological dysfunction (Tetany seizures, numbness, tingling, spasms)
- Arrhythmias
- Heart failure
Treated with Allopurinol
Give all the causes of possible bleeding dysfunctions
Inherited (Haemophilia A,B, VW Disease)
Acquired (DIC)
Over anticoagulation
- Heparin (binds to antithrombin 3 and inactivates factor 10)
- Aspirin (COX inhibitor)
- Clopidogrel (P2Y12 inhibtor)
- Thrombolytic (alteplase)
What clotting factors rely on vitamin K
10, 9, 7, 2
(1972)
Warfarin MoA
Vitamin K antagonist (affecting factors 10, 9, 7 and 2)
How does myelofibrosis normally present? What does it show on blood film?
Pancytopenia and massive splenomegaly in a patient with Polycythaemia vera history
Teardrop poikilocytes
What are the 4 steps of platelet plug formation?
endothelial injury, platelet
adhesion, platelet aggregation
- Damage to a blood vessel causes exposure of collagen. Von Willebrand Factor (vWF) binds to collagen which acts as a molecular anchor for platelets to join.
- Platelets adhere to the damaged endothelium via vWF. When platelets adhere, they activate and degranulate– their shape changes and they release chemicals that keep the vessel constricted and draw more platelets to the damaged area. This positive feedback loop continues.
- The aggregation of platelets results in the formation of a plug that temporarily seals the break in the vessel wall.
- Following formation of the platelet plug, coagulation is activated to form a fibrin mesh which stabilises the platelet plug.
What are the healthy INR ranges in a normal person and a person on anticoagulants?
Normal - 0.8-1.2
Anticoagulant - 2.0-3.0
(increased value = increased bleeding risk, decreased value = thrombosis risk)
What 2 treatments are usually used to raise/lower INR?
Raise - Warfarin
Lower - Vitamin K
How should INR be lowered in patient on anticoagulants?
INR > 5
- Withhold 1-2 doses of anticoagulant
INR > 8
- Stop anticoagulant
- Administer IV or oral vitamin K
- Repeat INR after 24 hours
How should INR be lowered in patient on anticoagulants and bleeding?
Minor bleed
- Stop anticoagulants
- Administer IV vitamin K
- Repeat INR after 24 hours
Major bleed
- Stop anticoagulants
- Administer IV vitamin K
- Fresh frozen plasma or prothrombin complex
How should low INR be managed, for patient on warfarin?
Increase warfarin and give LMWH
(LMWH is faster acting - remove when INR normal)
How should patient on warfarin be managed pre surgery?
Stop warfarin 5 days before
- Bridging with LMWH if VTE in past 3 months, atrial fibrillation, stroke or TIA, which is stopped 24 hrs before surgery. (unless major bleed risk, then 48)
- Vitamin K day before surgery
