Pharmacology of Haemostatis and Thrombosis Flashcards
Platelet Activation and Adhesion
- endothelial injury exposes sub-endothelial
collagen - Von Willebrand factor binds to the exposed
collagen - other side of Von Willebrand Factor has
binding sites for platelets via GP IB-IX-V
complex (glycoprotein) - tethers platelets to Von Willebrand factor
which is tethered to exposed sub-
endothelial collagen - platelets stick to other platelets and big
platelet plug is formed - platelets become activated upon binding to
Von Willebrand’s Factor - activated platelets can now bind to
fibrinogen - via specific binding glycoproteins: GPIIbIIIa
(GP2b3a) - facilitates further platelet aggregation
(clustering) - Tx receptor on platelet membrane binds
thromboxin - P2Y12 receptor on platelet membrane
binds ADP - GPIIbIIIa crosslinks with fibrinogen to
crosslink with further platelets (fibrinogen
between two platelets) - activated platelets generate thromboxane
A2 from arachidonic acid using enzyme
cyclooxygenase (platelet agonists) - binds to Tx receptor on other platelets
promoting more aggregation, adhesion
and activation - thrombin and ADP are also platelet
agonists - cyclooxygenase results in the release of
prostacyclin from the endothelium, which
inhibits platelet aggregation (acts as a
negative feedback loop) and causes
vasodilation
Bernard souilier disease
- deficiency of GP Ib-IX-V complex
- hard to form platelet plug
platelets not tethered to Von Willebrand’s
Factor - platelet disorder leads to increased bleeding
Glanzmann’s thrombasthenia
- bleeding disorder
- deficiency of GPIIbIIIa
- can’t recruit and aggregate platelets
Core Drug: Aspirin:
- chemical name
- common uses (2)
- acetylsalicylic acid
- has anti-inflammatory effects so often
used for fever/pain - disrupts platelet function
Core Drug: Aspirin: side effects:
- peptic ulceration
- rash
- hearing loss/tinnitus (high doses)
- Reye’s Syndrome:
- brain and liver damage in children
given aspirin for viral illnesses - *** DO NOT GIVE CHILDREN
Core drug: Aspirin: Mechanism of Action:
- blocks production of prostaglandins and
thromboxanes - aspirin is an IRREVERSIBLE inhibitor of
cyclooxygenase 1 (COX 1 ) - cyclooxygenase 1 converts arachidonic acid
into thromboxane A2 into useable form - hence no further aggregation, adhesion
and activation of platelets as without
thromboxane less cross-linking between
platelets - WILL ALSO INHIBIT RELEASE OF
PROSTACYCLIN AT HIGH DOSES (COUNTER-
INTUITIVE) 5grams a day is high - Gastric lining resistance to acid is
prostaglandin dependent and hence side
effects of gastric and peptic ulceration
Cyclooxygenase 1 causes release of —– from injured endothelium resulting in —————- and ———-
- prostacyclin
- inhibits platelet aggregation
- causes vasodilation
Thromboxane A2 vs Prostacyclin
At low doses of aspirin,
- selectively inhibits platelets
- platelets can not synthesise new COX
- endothelial can synthesise new COX
- hence thromboxane A2 not released so
less platelet aggregation and
vasoconstriction - but prostacyclin released so inhibition of
platelet aggregation and vasodilation
Aspirin low doses
Core Drug: Aspirin: Clinical Use: Arterial Disease:
- in all patients with established vascular
disease:
- IHD (MI, angina)
- Cerebrovascular Disease
- Peripheral Vascular Disease
Advantages of core drug aspirin use for arterial disease:
- improves prognosis, less mortality, less
adverse events (MI, stroke) - mainstay drug - cheap ++++
Low dose of aspirin is
75-325 mg/day
300mg during MI
daily normal dose is 75mg
Core Drug: Clopidogrel: Mechanism of action:
- binds to P2Y12 receptor on platelet
- inhibitor of P2Y12 receptor
- combats acute coronary stent thrombosis
Clopidogrel vs aspirin
- more effective than aspirin
- similar safety profile
Clopidogrel vs aspirin
- more effective than aspirin
- similar safety profile
Core Drug: Clopidogrel: Clinical Use:
- part of “dual anti-platelet therapy” DAPT
- post MI and elective coronary stenting
- recurrent stroke despite aspirin
- first line for peripheral arterial disease
Core Drug: Clopidogrel: side effects:
- bleeding; affects timing of major surgery
(have to stop few days before) - rash
- increased bleeding DAPT because two anti-
platelets
Core Drug: Clopidogrel: Resistance:
- 30% do not get full effect
Tirofiban: mechanism of action, side effects:
- potent inhibitor of GPIIbIIIa, which
crosslinks platelets via fibrinogen - “final common pathway” of platelet
aggregation - very powerful anti-thrombotic drug
- carries very high bleeding risk
- only given during high risk coronary stent
procedures: Primary PCI for STEMI, high
risk coronary anatomy
Summary of anti-platelet drugs:
Core Drug: Warfarin: Mechanism of action and class:
- Anti-coagulant
- Vitamin K antagonist
- inhibits gamma carboxylation of
the vitamin K dependent coag
factors 2,7,9,10 and production of
proteins C and S - 2 = prothrombin (common)
- 7 = extrinsic
- 9 = intrinsic
- 10 = common
1972 was the diSCo era
Core Drug: Warfarin: Pharmacokinetics:
- 3-4 day lag of effect
- narrow therapeutic window:
- monitor INR
- aim for INR 2-3
Core Drug: Warfarin: interactions:
- alcohol
- green veg
- many drugs
- metabolised by liver P450 enzyme
group
Core Drug: Warfarin: Clinical Uses:
First line:
- mechanical heart valves
- mitral stenosis with atrial fib
BEing superseded by DOACs:
- stroke prophylaxis in AF
- DVT
- PE
Warfarin: Side Effects:
- bleeding: slow reversal with vitamin K, rapid reversal with blood factors
- birth defects (teratogenic) = crosses
placenta - Warfarin-induced skin necrosis:
- protein C, S
- transient hypercoagulable state
on warfarin induction
- so overlap with heparin
Core Drug: Heparin: molecular mechanism and class:
- anti-coagulant
- unfractionated heparin
- binds to and activates anti-
thrombin - antithrombin inhibits coagulation l
factors: - 2 = thrombin = common
- 7 = extrinsic
- 9 = intrinsic
- 10 = intrinsic
- 11 = intrinsic
- 12 = intrinsic
- 2+7= 9….10,11,12
- mainly inhibits intrinsic pathway
hence can measure using APTT
Core Drug: Tinzaparin: Molecular mechanism and class:
- anti-coagulant
- low molecular weight heparin
- binds to and activates anti-
thrombin - antithrombin inhibits coagulation
factors: - 2 = thrombin = common
- 7 = extrinsic
- 9 = intrinsic
- 10 = intrinsic
- 11 = intrinsic
- 12 = intrinsic
- 2+7= 9….10,11,12
- mainly inhibits intrinsic pathway
hence can measure using APTT
Core Drug: Enoxaparin: molecular mechanism and class:
- anti-coagulant
- low molecular weight heparin
- binds to and activates anti-
thrombin - antithrombin inhibits coagulation
factors: - 2 = thrombin = common
- 7 = extrinsic
- 9 = intrinsic
- 10 = intrinsic
- 11 = intrinsic
- 12 = intrinsic
- 2+7= 9….10,11,12
- mainly inhibits intrinsic pathway
hence can measure using APTT
A patient with a metallic valve is anticoagulated, would you give:
A = heparin
B = warfarin with INR target 2 to 3
C = DOAC
D = warfarin with INR target for 3 to 4
b = warfarin
Core Drug: Heparin: Pharmacology:
- how quickly effects seen
- route of administration
- measurement
- efficacy
- rapid onset of action
- IV or IS
- units
- Variable efficacy: monitor effect,
APTT, aim for 1.5-2.5 x control
Core Drug: Heparin: Side Effects:
- bleeding
- antidote: protamine-potent
vasodilator - HIT
Core Drug: Tinzaparin: Side Effects:
- bleeding
- antidote: protamine-potent
vasodilator - HIT
Core Drug: Enoxaparin: Side Effects:
- bleeding
- antidote: protamine-potent
vasodilator - HIT
Core Drug: When is unfractionated heparin used? Why?
- chronic kidney disease
- dialysis, bypass machines etc
- VERY LARGE PULMONARY EMBOLI
bit safer
Core Drug: Enoxaparin/Tinzaparin: Pharmacology:
- route of administration
- efficacy
- clearance?
- subcutaneously
- very reliable absorption, no
monitoring required - RENAL CLEARANCE
Core Drug: Enoxaparin/ Tinzaparin: Clinical Uses:
Acute:
- MI
- AF
- PE, iliofemoral DVT
- VTE prophylaxis
Side effect of any heparin is HIT. What is HIT?
- heparin induced thrombocytopenia
- very dangerous
- caused by antibodies
- bind to complexes of heparin and
platelet factor 4:
- activates platelets causing
prothrombotic effect
- falling platelet count
- extension of a previously
diagnosed blood clot, or a new
blood clot elsewhere (skin
necrosis)
What does DOAC stand for?
Direct Oral AntiCoagulants
Core Drug: Dabigatran: Molecular mechanism and class:
- anticoagulant
- DOAC
- direct inhibitor of thrombin
(coagulation factor 2) - affects the conversion of fibrinogen
into fibrin monomer and ultimately
into fibrin clots
Core Drug: Rivaroxaban: Molecular Mechanism and Class:
- anticoagulant
- DOAC
- directly inhibitcoagulation factor Xa
(10) - less thrombin generated from
prothrombin
Core Drug: Dabigatran: Clinical Uses:
- DVT
- pulmonary embolism
- atrial fibrillation
- post hip/knee prophylaxis
Core drug: Rivaroxaban: Clinical Uses:
- DVT
- pulmonary embolism
- atrial fibrillation
- post hip/knee prophylaxis
Benefits of DOACs than Warfarin
- more reliable action:
- higher dose = more effective,
same bleeding
- lower doses = as effective, less
bleeding
- no monitoring of effect - fewer interactions than warfarin
Core Drug: Dabigatran: Are effects reversible?
Antidote: Idarucizumab
Core Drug: Rivaroxaban: Are effects reversible?
Antidote: Andexanet
