Drugs affecting coagulation Flashcards
1
Q
Thrombus forms
A
in vivo
2
Q
Clot forms
A
in vitro (operating table, test tube)
3
Q
Coagulation is
A
formation of a fibrin thrombus/clot in blood vessel
4
Q
Thrombosis
A
formation of a haemostatic plug in a blood vessel in the absence of blood loss
5
Q
arterial thrombus
A
- white
- platelets + white blood cells in a fibrin mesh
- usually associated with atherosclerosis
- can embolize, leading to vessel obstruction and infarction
6
Q
venous thrombus
A
- red
- fibrin, platelets, red blood cells
- usually associated with blood stasis (DVT)
- can embolize leading to pulmonary or cerebral emboli
7
Q
What does blood vessel damage trigger?
A
- vasoconstriction
- platelet adhesion and activation (primary) + fibrin formation (secondary)
- leads to development of a thrombus
8
Q
What is the mechanism of vasoconstriction in haemostasis?
A
- collagen from damaged vessel is exposed to tissue factor
- leads to adhesion of platelets, causing them to activate
- ADP and 5-hypoxytryptomine (serotonin) are released from platelets
- serotonin is a powerful vasoconstrictor
9
Q
What is the mechanism of platelet activation and adhesion in haemostasis?
A
*activation is target of number of drugs*
- activated platelets release ADP
- induces other platelets to activate and change shape
- granules secreted (ADP, 5-HT)
- activates other platelets
- synthesize mediators (thromboxane)
- platelets aggregate
- adhere by fibrinogen bridging between glycoprotein GPIIb/IIIa receptors
- = formation of soft plug
10
Q
How does platelet activation trigger thromboxane production?
A
- activation of platelets results in activation of phospholipase A2
- PLA2 liberates arachidonic acid from the membrane
- COX –> thromboxane
- thromboxane then stimulates further platelet activation
11
Q
What are some stimuli for platelet activation?
A
- collagen
- thrombin
- thromboxane
- ADP
12
Q
What is the mechanism of fibrin deposition in haemostasis?
A
- fibrinogen (soluble) –> fibrin (insoluble) by thrombin (protease)
- thrombin produced by activation of prothrombin, it is not present in plasma like fibrinogen
13
Q
How is prothrombin activated?
A
- via the coagulation cascade (secondary haemostasis)
14
Q
What is the intrinsic pathway of the coagulation cascade?
A
- occurs in vitro (test tube)
- intrinsic to the blood
- exposed collagen or other material, negative charges (e.g. glass) induce clotting
15
Q
What is the extrinsic pathway of the coagulation cascade?
A
- extrinsic - in vivo
- extrinsic to the blood, involving the vessel rather than the blood itself
- exposed collagen activates tissue factor (thromboplastin)
- fewer steps (therefore faster) than intrinsic pathway
16
Q
What is the common pathway of the coagulation cascade?
A
- extrinsic and intrinsic pathways lead to the formation of Xa from X
- this activates prothrombin to thrombin
- thrombin cleaves fibrinogen to fibrin to form the stable clot
17
Q
How is blood coagulation controlled?
A
- inhibition of thrombin and factor Xa by antithrmobin
- fibrinolysis by plasmin
- formed from activation of plasminogen through inactivation of its imhibitor activated protein C
18
Q
What are the 3 factors that contribute to haemostasis and thrombosis?
A
- hypercoaguability
- blood stasis
- vessel damage
19
Q
What are examples of blood stasis promoting thrombosis?
A
- atrial fibrillation
- cerebral or renal embolism
- DVT
- pulmonary embolism
20
Q
What are the anticoagulation drug targets?
A
- coagulation (fibrin formation)
- platelet adhesion and activation
- fibrinolysis
21
Q
Vitamin K
A
- procoagulant
- essential for formation of clotting factors:
- II, VII, IX, X (2, 7, 9, and 10 - Melbourne TV stations)
- all require glutamate carboxylation after syntehsis
- reduced Vit K is a cofactor
- inhibited by coumarin derivatives (warfarin) that inhibit vitamin K reduction
22
Q
Heparin
A
- injectible anticoagulant
- acute, short-term use
- targets fibrin formation by enhancing activity of antithrombin III
- large, negatively charged
23
Q
Warfarin
A
- oral anticoagulant
- prolonged therapy
- targets fibrin formation
- coumarin derivative
- inhibits reduction of vitamin K
- tf inhibits carboxylation of glutamate and production of 2, 7, 9, and 10
- only active in vivo
- delated onset of action bc factor half-lives are long
- overdoes tx with Vit K
24
Q
Low molecular weight heparins
A
- e.g. Clexane
- same effect on Xa, lesser effect on thrombin
- similar anticoagulant effects
- longer half life
- can be used daily, at home
- can be teratogenic in combination with warfarin
25
Q
Clexane
A
LMW Heparin (injection)
26
Q
How is heparin anticoagulation monitored?
A
- APTT test (activated partial thromboplastin time)
- time to clot formation in citrated plasma after addition of Ca, contcat activator, and phoshoplid
- measure of intrinsic pathway
27
Q
What are the adverse effects of heparin?
A
- haemorrhage (increased risk of bleeding and CVAs)
- thrombocytopaenia (platelet deficiency)
- osteoporosis
28
Q
What are the adverse effects of warfarin?
A
- haemorrhage
- titrate dose, determine dose w/INR
- can be reversed w/Vit K, fresh frozen plasma
29
Q
Why is warfarin considered a ‘moody drug’?
A
- orally active and rapidly absorbed
- but strongly bound to plasma protein (99%)
- unbound form is active
- changes with changes in blood plasma levels
- tf levels and anticoagulant effects are very labile
- diet high in Vit K will outcompete warfarin
30
Q
What causes increased warfarin activity?
A
- vitamin K deficiency
- hepatic disease (impaired synthesis of clotting factors and plasma proteins)
- hypermetabolic states (increased metabolsim of clotting factors)
- drug interactions:
- impaired platelet aggregation (aspirin)
- competition for plasma protein binding (NSAIDs)
- competition for Cyt-p450 pathway reduces clearance (cimetidine - H2 blocker for gastric ulcers, alcohol)
31
Q
What causes decreased warfarin activity?
A
- pregnancy
- drug interactions
- induction of liver enzymes (barbituates, alcoholism increases clearance)
- vit K supplements
32
Q
How is warfarin activity monitored?
A
- prothrombin time (PT)
- time to clot formation of plasma after addition of Ca2+ and tissue factor/thromboplastin
- measures extrinsic pathway
- INR
- ratio of patient PT to normal PT
- varies with disease (++synthetic valves, +DVT)
33
Q
Clopidogrel
A
- ADP receptor antagonist
- oral administation, as a prodrug
- prevents binding of ADP to its receptor on platelets
- prevents activation of glycoprotein IIb/IIIa complex
- this inhibits platelet aggregation
- more routinely used as an antiplatelet drug than abciximab which is more expensive and has to be given IV
34
Q
platelet activation and adhesion
Aspirin
A
- inhibits COX, thereby inhibiting thromboxane synthesis
- this inhibits platelet aggregation
35
Q
What are the drugs used to affect platelet activation and adhesion?
A
- ADP receptor antagonists (clopidogrel)
- thromboxane synthesis inhibitors (COX inhibitors e.g. aspirin)
- glycoprotein IIa/IIIb receptor antagonists (tirofiban, abciximab)
36
Q
Tirofiban
A
- glycoprotein IIb/IIIa receptor antagonist
- stop platelet aggregation by blocking binding of fibrinogen to the receptor
37
Q
Abciximab
A
- glycoprotein IIb/IIIa receptor antagonist
- stop platelet aggregation by blocking binding of fibrinogen to the receptor
- IV use (large molecular weight) in high risk acute coronary syndromes (v. expensive)
38
Q
What are the guidelines for use of drugs affecting platelet activation and adhesion?
A
- indicated in less severe anticoagulative states than warfarin e.g. arterial stent or increased risk of DVT
- adjunctive therapy with aspirin
- in patients intolerant to aspirin
- post iscahemic heart disease
- atrial fibrillation (stroke prevention)
39
Q
What is the mechanism of low-dose aspirin therapy?
A
- low dose because 90% eliminated first pass (liver) tf readily absorbed
- binds to platelets at portal vein before entering liver for metabolism
- reduces thromboxane syntehsis from platelets in portal vein by inhibition of COX-1
- decreases platelet aggregation and decreases vasoconstriction
- retained PGI2 (prostacyclin) from endothelium (COX production not affected)
- inhibits platelet aggregation and promotes vasodilation
40
Q
What are the fibrinolytic drugs?
A
- streptokinase
- alteplase
41
Q
What is the general mechanism of fibrinolytic drugs?
A
- plasminogen is activated in the presence of activated protein C
- yields plasmin, a protease that destroys the clot (fibrinolysis)
- tf streptokinase and alteplase activate plasmin to promote fibrinolysis
42
Q
Streptokinase
A
- activates plasminogen –> plasmin
- IV administration (large molecular weight)
- derived from streptomyces (streptococcus) bacterium
- tf it is antigenic and stimulates the immune system to produce Abs
- tf it can only be used once though it is cheap and effective
43
Q
Alteplase
A
- human recombinant tissue plasminogen activators (hrtPA)
- not antigenic tf given to pt who have had streptokinase
- IV administration (short half-life)
- active on fibrin-bound plasminogen
- it is tf considered ‘clot selective’
- very expensive, ~$1000/vial, need ~2 for a 70kg pt
