Lecture 14 Haemostasis and Thrombosis Flashcards
What is the difference between haemostasis and thrombosis?
haemostasis is appropriate coagulation
thrombosis is inappropriate coagulation
haemostasis - name the factors involved in primary/secondary haemostais and the treatments
primary factors - platelets and VWF
primary treatment - platelet transfusion, desmopressin, VWF concentrate
secondary factors - clotting factors
secondary treatment - specific clotting factors
thrombosis - name the factors involved in arterial/venous thrombosis and the treatments
arterial factors - high pressure platelets
arterial treatment - antiplatelet drugs
venous factors - clotting factors
venous treatment - anticoagulants
What benefits are there from fresh whole blood?
platelets
red blood cells
plasma - multiple factors
What factors are found in fresh frozen plasma?
I, VII, VIII, VWF, IX, X, XI, XIII
What are the two mechanism of repair when a vessel is injured?
local vasoconstriction - platelet adhesion - platelet aggregation - haemostatic plug - fibrinolytic activity - repair of the vessel damage
local vasoconstriction - activation of coagulation cascade - fibrin formation - haemostatic plug - fibrinolytic activity - repair of the vessel damage
In primary haemostasis what three proteins/factors interact?
platelet
VWF
collagen
What causes platelet bleeding disorders?
inherited or acquired
thrombocytopenia - reduced platelet number
abnormal/reduced function of platelets
How are platelet bleeding disorders treated?
platelet transfusion
Give an example of a platelet bleeding disorder
Von Willebrand Disease
Give the pathophysiology, epidemiology and treatment of Von Willebrand Disease
most common inherited bleeding disorder ~1% population
autosomal dominant inheritance
milder than haemophilia
sites of bleeding - bruising, cuts, gyms, epistaxis, menorrhagia, post-operative, post-trauma
treatment - desmopressin and intermediate purity (from plasma) FVIII (IV)
Give examples of coagulation factor disorders
What are they deficient in?
haemophilia A (X-linked) - FVIII deficiency haemophilia B (X-linked) - FIX deficiency
Give the pathophysiology of haemophilia
autosomal recessive inherited condition - sex-linked
deficiency of fibrinogen - FII, FV, FVII, FX, FXI, FXIII
severity <1% severe/1-4% moderate/>5% mild
risks - haemarthorosis, haematoma
What is clotting factor I?
fibrinogen
What is clotting factor II?
prothrombin
What is the only non-plasma derived clotting factor?
clotting factor V
What are the three recombinant clotting factors?
clotting factors VII, VIII and X
What are the two types of thrombosis?
arterial - arterial circulation which is high-pressure system and platelet-rich
venous - venous circulation which is low-pressure and fibrin-rich
What are clinically linked to arterial thrombosis?
myocardial infarction
thrombotic stroke
What are clinically linked to venous thrombosis?
deep vein thrombosis (leg)
pulmonary embolism
Give examples of antiplatelet drugs
aspirin clopidogrel prasugrel ticagrelor cangrelor abcisimab eptifibatide tirofiban
Give examples of anticoagulant drugs
intravenous - unfractionated heparin
subcutaneous - low MW heaparin
oral - warfarin, dabigatran, rivaroxaban, apixaban, edoxaban
What is the most commonly prescribed vitamin K antagonist?
warfarin
What factors does unfractionated heparin and low molecular weight heparin act on?
clotting factors IXa, Xa and IIa
What is the pharmacokinetics of heparin?
glycosaminoglycan - binds to antithrombin to increase its activity
indirect thrombin inhibitor
monitor with APTT test
given by continuous infusion
What is the pharmacokinetics of low MW heparin?
smaller molecular made from heparin less variation in dose given subcutaneously renally excreted give once/day weight adjusting dosing treatment thrombosis and prophylaxis (preventative)
What is the pharmacokinetics of warfarin?
oral drug - completely and rapidly absorbed
99% plasma protein bound
inhibit production of factors II, VII, IX and X
peak effect 3-4 days after start of treatment
effect still present after 4-5 of stopping treatment
side effects - bleeding and embryopathy
Why is it important to personalise the dosage of warfarin in patients?
genotype CYP2C9 and VKORC1 mutations
CYP2C9 *1, 2, 3 mutation increases sensitivity
VKORC1 G-to-A mutation increases sensitivity
increased sensitivity required more monitoring and lower dosage
What other factors are important to take into account with dosing warfarin?
age sex ethnicity weight height smoking liver/kidney disease INR (international normalised ratio) multidrug interactions - amiodarone and statins
What are the pharmacokinetics for Dabigatran?
anticoagulant - IIa inhibitor
renal excretion 80%
half life 13-18 hours
protein binding 35%
What are the pharmacokinetics for Rivaroxaban?
anticoagulant - Xa inhibitor
renal excretion 67%
half life 5-9 hours healthy / 11-13 hours elderly
protein binding 95%
What are the pharmacokinetics for Apixaban?
anticoagulant - Xa inhibitor
renal excretion 25%
half life 8-13 hours
protein binding 87%
What are the pharmacokinetics for Edoxaban?
anticoagulant - Xa inhibitor
renal excrtion 35%
half life 9-11 hours
protein binding 50%
Give a specific example of direct oral anticoagulant reversal agents
dabigatran - idarucizumab - humanised monoclonal antibody fragment
rivaroxaban/apixaban/edoxaban - andexanet - recombinant modified inactive factor Xa molecule (not licensed yet)
What are the advantages of direct oral anticoagulants compared to warfarin?
rapid onset of action
fixed oral dosing - predictable anticoagulant effect
low potential for food/alcohol intolerance
low potential for drug interactions
no need for blood monitoring
What are the disadvantages of direct oral anticoagulants compared to warfarin?
renal elimination
no specific antidotes for Xa inhibitors
licensed only specific individuals
