Haematology Flashcards
What are the main constituents of coagulation?
- Vessel wall lined by endothelium
- Platelets - derived from megakaryocytes in marrow
- Coagulation factors in un-activated state
- Inhibitors of coagulation
- Fibrinolytic system and inhibitors
What do endothelial cells do?
- Line blood vessels and form a barrier
- Produce thrombomodulin and heparin sulphate to inhibit thrombin production
- Enzymes to degrade platelet granule-derived molecules
- Prostacyclin and nitric oxide (NO) to reduce platelet adhesion
What are some features of platelets?
- Fragments of megakaryocyte cytoplasm
- Budded off into lumen of marrow sinusoids
- Production stimulated by thrombopoetin (TPO) - liver derived
- Circulate for 5-10 days with ~30% stored in spleen
- Form a plug when attracted by lowered prostacyclin and by collagen exposure
- Thromboxane A2 and serotonin from platelets cause vasoconstriction
How do platelets adhere to vessel walls?
Via Von Willibrand’s factor and Glycoprotein Ib
How do platelets adhere to each other?
Via Glycoprotein IIb-IIIa and fibrinogen
What are the two pathways in the coagulation cascade?
Intrinsic and extrinsic
What are some inhibitors of the coagulation cascade?
- Protein C activated by thrombomodulin-thrombin complex and with co-factor -Factor S - Va and VIIIa are degraded
- Antithrombin (previously antithrombin III) inhibit Xa and IIa
- Heparin cofactor II inhibits IIa
- Heparin stimulates antithrombin and heparin cofactor II
How is coagulation measured?
- Full bloods count - includes platelet count/size/granules but is a poor assessment of platelet function - specialised tests of aggregation can be done
- Ref range 150-400 times 10 to the power of 9 /L
- Easy bruising and purpura when <30-50 (thrombocytopenia)
- Risk of major bleeding if <10
How does prothrombin time testing work?
- All coagulation tests are done on citrated plasma - removes Ca2+
- At 37 degrees thromboplastin (brain extract) and Ca2+ added
- Measure time till clot forms - extrinsic and common pathway
- Prolonged by low levels of II, X and VII
- Warfarin reduces active II, VII, IX and X so a useful measure of dose - expressed as international normalised index
Explain the activated partial thromboplastin test (APTT)
- Ca2+, kaolin and phospholipids added to citrated plasma
- Measure of intrinsic and common pathway
- Prolonged in haemophilia and by heparin
What is fibrinogen?
- Final substrate for making fibrin
- Can be measured by clot density or by thrombin time - thrombin and Ca2+ added to citrated plasma
What are some features of haemophilia A and B?
-X linked defect in VIII or IX gene
-Commonly a new mutation so no family history (1 in 3)
-Approx 1:5000 of males
Female heterozygotes (carriers) not affected
-Can be very mild - chance finding or issue for surgery
-Severe (<1% VIII level) - frequent bleeds into joints and soft tissues
How is haemophilia treated?
- Historically - no treatment - then fresh frozen plasma
- Porcine and then recombinant factor replacement
- Issues of hepatitis B or C and HIV
Describe Von Willebrand disease
- Usually autosomal dominant
- Defect in platelet adhesion and binding of VIII
- Up to 1% of population
- Mild disease - easy bruising, heavy periods
- Severe disease - similar to haemophilia
Describe Von Willebrand disease
- Usually autosomal dominant
- Defect in platelet adhesion and binding of VIII
- Up to 1% of population
- Mild disease - easy bruising, heavy periods
- Severe disease - similar to haemophilia
What is disseminated intra-vascular coagulation (DIC)?
- Activation of clotting cascade due to trauma, malignancy (eg prostate cancer), sepsis and amniotic fluid embolism
- Causes depletion of clotting factors and damage due to clot
What blood products are used to help blood clot/prevent bleeding?
- Platelets - derived from blood donation
- Fresh frozen plasma - 200ml plasma from blood donation - contains coag factors in normal proportions - dose 15ml/kg
- Cyroprecipitate - pools of 5 donations using precipitate at 4C - concentrated fribrinogen, von Willebrand factor and VIII
- Specific coag factors eg IX, VIII and fibrinogen
Describe tranexamic acid
- Anti-fibrinolytic drug
- Oral or IV
- Inhibits activation of plasminogen to plasmin
- Uses in trauma/GI bleeding/ post op or delivery
What does warfarin do?
Inhibits production of vitamin K in reduced form
What are some positive aspects of warfarin?
- Established for decades
- Cheap
- Easily measurable effect
- Can be reversed with vitamin K or factor concentrate
What are some negative aspects of warfarin?
- Lots of drug interactions to enhance or inhibit effect
- Slow onset - several days
- Unpredictable dose need
- Needs regular blood testing
- Risk of bleeding
- Narrow therapeutic window
How can the effects of warfarin be increased?
- Amoxycillin - reduce gut vit K
- Erythromycin, statins, acute alcohol intake - enzyme inhibition
- Aspirin, clopidogrel, NSAIDS - increase bleeding risk - platelet function and GI mucosal damage
How can the effects of warfarin be decreased?
-Rifampicin, carbamazepine, phenytoin, chronic alcohol intake - enzyme induction
What are some indications for warfarin?
- Deep vein thrombosis (DVT) and pulmonary embolism (PE) - short or long term depending on whether recurrent and/or provoked
- Prosthetic heart valve replacement
- Atrial fibrillation to reduce stroke risk
What can be used to determine risk of a stroke?
CHA2DS2-VASc score
What are the two types of direct oral anticoagulants (DOACs) and give some examples
- Xa inhibitors e.g apixaban, rivaroxaban, edoxaban
- Direct thrombin inhibitors e.g dabigatran
What would favour warfarin over DOACs?
- Established drug
- Cheap - but needs monitoring
- Can be reversed
- Effect can be easily measured
- Can be used with poor renal function
What would favour DOACs over warfarin?
- Good trial evidence
- No monitoring needed
- Lower bleeding risk
- As effective for stroke prevention
- Reversal agents recently available (but expensive)
- Short half life
Describe heparin
- Naturally occurring anticoagulant
- Can be extracted from lung and liver
- Given as IV - unfractionated - half life <1 hour
- Binds to and activates anti-thrombin so reducing Xa and thrombin generation
What are some adverse effects of heparin?
- Pain at site of injection
- Increased bleeding risk
- Osteoporosis with prolonged use
- Heparin-induced thrombocytopenia - antibody mediated, 5-10 days into treatment
How can aspirin be used to modify platelet function?
- Low doses e.g 75-150mg/day cause irreversible inhibition of COX-1 so less thromboxane A2 production - less aggregation of platelets
- Typically used after transient ischaemic attack (TIA) or myocardial infarction
- Some effect in stroke prevention in AF but not as effective as warfarin/DOACs
- Increase in GI bleeding risk, dyspepsia
Describe clopidogrel
- Inhibit ADP induced platelet aggregation
- Used with aspirin to prevent recurrent myocardial infarction
- Used in ischaemic stroke and TIAs
- Increased risk of dyspepsia and GI bleeding
How long will aspirin and clopidogrel effects last and why?
No reversal agents for aspirin and clopidogrel so effect will last the duration of platelet lifespan - 5-10 days
How long will aspirin and clopidogrel effects last and why?
No reversal agents for aspirin and clopidogrel so effect will last the duration of platelet lifespan - 5-10 days
Describe thrombolytic drugs
- Drugs to increase activation of plasminogen to plasmin
- Tissue plasminogen activators (tPA) e.g streptokinase and alteplase - used for thrombolysis
- Cause breakdown of fibrin and fibrinogen
- Increased risk of bleeding in hours after dose
- Stenting and clot removal are alternative treatments
What are some symptoms of anaemia?
- Short of breath
- Muscle pain on exertion
- Dizzy
- Angina
What are some symptoms of anaemia?
- Short of breath
- Muscle pain on exertion
- Dizzy
- Angina
What are some clinical signs of anaemia?
- Pallor in skin and conjuctiva
- Tachycardia
- Rapid breathing
- Peripheral oedema if severe anaemia
- Signs relating to cause of anaemia
What are some clinical signs of anaemia?
- Pallor in skin and conjuctiva
- Tachycardia
- Rapid breathing
- Peripheral oedema if severe anaemia
- Signs relating to cause of anaemia
How does the body adapt to anaemia?
- Mild anaemia likely to cause no symptoms unless extreme exertion
- Cardiac output increases - rate and stroke volume
- Changes in distribution of blood flow
- Change in )2 dissociation curve
How is anaemia classified?
- Under production or increased loss of red blood cells
- Congenital or acquired
- Acute or chronic
- By mean cell volume - microcytic/normocytic/ macrocytic
What does MCV stand for?
Mean cell volume
What does MHC stand for?
Mean cell Hb
What does MCHC stand for?
Mean cell Hb concentration
Describe microcytic
- MCV = 60-80fl
- Iron deficient
- Thalassaemia
Describe normocytic
- MCV = 80-100fl
- Blood loss
- Anaemia of chronic disease
- Renal impairment
Describe macrocytic
- MCV = 100-120fl
- Megaloblastic anaemia
- B12/folate deficiency
- Myelodysplasia
Describe iron deficiency anaemia
- Commonest cause of anaemia worldwide
- Typically reduction in MCV (microcytic) to 65-80, then in Hb, low ferritin, low transferrin saturation with iron
- Rest of blood count normal - Raised platelets if bleeding
Describe iron deficiency anaemia
- Commonest cause of anaemia worldwide
- Typically reduction in MCV (microcytic) to 65-80, then in Hb, low ferritin, low transferrin saturation with iron
- Rest of blood count normal - Raised platelets if bleeding
What are some causes of Iron deficiency anaemia?
- Poor intake
- Blood loss e.g menstrual
- GI tract - haematemesis or melaena e.g peptic ulcer/cancer/angiodysplasia/hookworm
- Malabsorption - coeliac disease
- Increased need e.g growth spurt/pregnancy
What are some clinical features of iron deficiency?
- Pale
- Tachycardia
- Koilonychia
- Hair loss
- Pica
- Glossitis/angular stomatitis
- Features relating to the cause e.g weight loss/abdominal pain/ bowel change/ heavy periods
How can one investigate for iron deficiency?
- Be guided by history - recent and past clinical findings
- Confirm iron def by lo ferritin and typical FBC
- Screen for coeliac disease
- Upper and lower endoscopy for all except pre-menopausal women
- Consider other imaging/capsule endoscopy
How do we orally treat people with iron deficiency?
- Oral-replacement with sufficient iron for long enough period e.g ferrous sulphate 200mg, 2 or 3 per day, 65mg elemental iron per dose
- Side effects: nausea/abdominal pain/constipation - dose related - may improve if changed to ferrous gluconate or fumarate
- Typically patients need 3 months of iron after correction of anaemia to build up iron stores
- Treat underlying cause
- Rise in Hb generally 10g/l per week if not bleeding
What parenteral treatments are used for people with iron deficiency?
- Intramuscular - not used now - painful, multiple doses, stains skin
- Intravenous - ferric carboxymaltose (ferinject) - over 15-30mins, often need 2 doses - iron dextran (cosmofer) - over 4-6 hours after a test dose
- All IV iron preparation can cause flu like symptoms and a small risk of hypersensitivity reaction or anaphylaxis
Describe B12 deficiency
- Typically a macrocytic anaemia - MCV 100-120 and later a pancytopenia, often bilirubin and LDH raised
- Can also cause peripheral neuropathy - demyelination and posterior column damage
- B12 result can be falsely low in pregnancy/oral contraceptive/ on metformin
- Pernicious anaemia - gastric atrophy and auto antibodies to parietal cells and intrinsic factor preventing absorption
- Strict vegan or terminal ileal disease also possible
How is B12 deficiency treated?
- Hydroxocobalamin 1 mg IM alternate days for 5 doses then 3 monthly if confirmed ongoing need e.g pernicious anaemia
- Cyanocobalamin available orally but not available on prescription
How is B12 deficiency treated?
- Hydroxocobalamin 1 mg IM alternate days for 5 doses then 3 monthly if confirmed ongoing need e.g pernicious anaemia
- Cyanocobalamin available orally but not available on prescription
Describe folate deficiency
- Blood count and film appearance same as B12 deficiency
- Limited stores of folate so deficiency can develop in weeks
- Causes - poor intake, increased use e.g pregnancy/haemolysis, malabsorption, drugs e.g anti-epileptics or trimethoprim
- Replacement with oral folic acid 5mg per day
- Pre-conception folic acid reduces neural tube defects
Describe anaemia due to blood loss
- Hb immediately after blood loss will be normal
- Drop after fluid replacement
- Each 500ml loss gives approximate drop of Hb by 10-15 g/l
- Reticulocyte response within hours/days
- May need blood transfusion to replace loss e.g trauma/GI bleed/ around delivery
Describe anaemia of chronic disease
-Typically a normocytic anaemia associated with chronic inflammatory disease
-Plentiful iron stores but poor transfer to RBC due to hepcidin and cytokines
-History of chronic disease, inflammatory marker increased e.g CRP/ESR/plasma viscosity
Will respond to treatment of underlying disease
Describe anaemia of chronic disease
-Typically a normocytic anaemia associated with chronic inflammatory disease
-Plentiful iron stores but poor transfer to RBC due to hepcidin and cytokines
-History of chronic disease, inflammatory marker increased e.g CRP/ESR/plasma viscosity
Will respond to treatment of underlying disease
Describe anaemia of renal failure
- Drop in Hb once creatinine clearance drops below 20-30 ml/min chronically
- Mainly due to lack of erythropoietin
- Contribution from blood loss at dialysis, inflammatory disease
- Responds well to erythropoietin e.g weekly or alternate weeks
Describe haemolysis related anaemia
- Increased RBC destruction, marrow can increase production 5-10 fold
- Can be acute or chronic, congenital or acquired
- Issues to do with RBC membranes, RBC enzymes and globin chains in Hb
Describe anaemia due to abnormal haemoglobin
- Haemoglobinopathy e.g sickle cell disease - single cell mutation causing Hb polymerisation in hypoxic cells in homozygotes
- Shortened RBC survival, reduced production
- Chronic anaemia and bone/liver/lung/ brain crisis ie acute infarction
- Treated by supportive care, hydroxycarbamide to increase HbF production
Describe thalassaemia
- Inbalance of globin chain production
- Beta thalassaemia - as Hb F (2 alpha 2 gamma chains) declines after birth - progressive anaemia
- Supportive care, transfusion, stem cell transplant
- Progressive iron overload
- Antenatal screen for Hb-opathy and thalassaemia
Describe thalassaemia
- Inbalance of globin chain production
- Beta thalassaemia - as Hb F (2 alpha 2 gamma chains) declines after birth - progressive anaemia
- Supportive care, transfusion, stem cell transplant
- Progressive iron overload
- Antenatal screen for Hb-opathy and thalassaemia
Describe anaemia due to myeloma
- B cell malignancy of mature plasma cells - produce monoclonal immunoglobin or light chains
- Presents as chance finding, anaemia, renal failure, hypercalcaemia, bone pain or fracture
- Treatment - supportive care, chemotherapy, radiotherapy
Describe anaemia due to marrow failure
- Myelodysplastic disorders - progressive decline in Hb, neutrophils, platelets, macrocytosis. Tendency to progress to acute leukaemia. Treated by supportive care, chemotherapy or stem cell transplant
- Aplastic anaemia - pancytopenia. Expected result post chemotherapy but can be drug induced e.g NSAIDs, chloramphenicol or idiopathic. Treated by supportive care, anti-thymocyte globulin, stem cell transplant
Describe anaemia due to marrow failure
- Myelodysplastic disorders - progressive decline in Hb, neutrophils, platelets, macrocytosis. Tendency to progress to acute leukaemia. Treated by supportive care, chemotherapy or stem cell transplant
- Aplastic anaemia - pancytopenia. Expected result post chemotherapy but can be drug induced e.g NSAIDs, chloramphenicol or idiopathic. Treated by supportive care, anti-thymocyte globulin, stem cell transplant
Where are red cell antigens found?
Red cell antigens are present on the surface of red blood cells
What naturally occurring antibodies to people with type O antigens have?
Anti-A and Anti-B
What naturally occurring antibodies to people with type A antigens have?
Anti-B
What naturally occurring antibodies do people with type B antigens have?
Anti-A
What naturally occurring antibodies do people with type AB antigens have?
None
What is the frequency of each type of antigen group in the UK?
- O = 46%
- A = 42%
- B = 9%
- AB = 3%
Describe rhesus system
- Antigens: c, C, D, e, E
- Coded for on chromosome 1 and inherited as a triplet
- Rhesus negative implies D negative
- No naturally occurring antibodies but can develop in response to pregnancy or transfusion
How can haemolytic disease develop in a newborn?
- Foetal red cells carrying antigens from the father transfer to maternal circulation
- Mother produces IgG antibodies
- Antibodies cross the placenta causing anaemia, jaundice, brain damage or foetal death
How can haemolytic disease develop in a newborn?
- Foetal red cells carrying antigens from the father transfer to maternal circulation
- Mother produces IgG antibodies
- Antibodies cross the placenta causing anaemia, jaundice, brain damage or foetal death
Describe the process of cross-matching blood
- Donor blood is checked for ABO, rhesus D and often other antigens and the bag is labelled. Also microbiology screening - HIV, hepatitis etc
- Recipient’s blood is checked for ABO and rhesus D group and the plasma screened for antibodies against a panel of red cell antigens
- Recipient’s plasma is mixed with donor red cells to check for agglutination
What are some transfusion reactions?
- Acute haemolytic reaction usually due to miss-matched blood, ABO most serious
- Delayed haemolytic reactions (new antibodies formed during transfusion)
- Urticaria or anaphylaxis
- Febrile reactions
