Antiplatelet, anticoagulant and thrombolytic drugs and the mechanism of clotting Flashcards
What is the starting process in almost all clot formations?
It begins with a local event that causes damage to the wall
What does the damage to the endothelial wall expose?
Tissue factor and collagen
What does the exposed collagen bind to?
vWF
What does collagen bound vWF act as ?
a cross bridge because it will also allow the platelets to bind to it through the glycoprotein Ib (GP Ib) receptor on the platelet surface.
What is the receptor on the platelet that binds to vWF – collagen complex?
Glycoprotein Ib
How is the binding of the platelet to the blood vessel further stabalised ?
Interactions are formed by Integrin A2 B1 and glycoprotein VI on the platelet binding to collagen
Which two things initiate platelet activation?
Glycoprotein VI anchoring and thrombin
What does the platelet do in response to activation?
a. 1.changes shape (extends pseudopodia) which then gives aggregated platelets
b. 2.The platelet also starts to synthesise thromboxane A2 (TA2,)
How is TA2 formed?
It is formed from arachidonic acid through the enzyme COX1
TA2 acts in both an —– and ____ manner.
TA2 acts in both an autocrine and paracrine manner.
what is the receptor called that TA2 binds to?
GPCRTXA2
what does the binding of TA2 to GPCR TXA2 do?
causes the release of
i) 5-hydroxytryptamine (aka seratonin) and ADP
ii) vWF and factor V
what do the dense granules release?
5- hydroxytryptamine (5-HT) (aka seratonin) and ADP
what do the alpha granules release?
vWF and factor V
why do the blood vessels vasoconstrict?
because TXA2 acts directly on smooth muscle and also 5-HT binds to receptors on the surface causing vasoconstriction
what does ADP bind to ?
platelet GPCR P2Y12 receptors
what does the binding of ADP do? 3 things
i) activation of further platelets
ii) Increases the expression of glycoprotein IIb and IIIa receptors
iii) causes exposure of acidic phospholipids on the platelet surface - this facilitates the formation of the clot
what do GP IIb and IIIa do?
they are binding points for fibrinogen on the platelet surface
what is the KEY event in the coagulation cascade?
the production of protease thrombin (factor IIa) that cleaves fibrinogen to fibrin to form a solid clot
what is coagulation?
the conversion of the soft plug to form a solid clot which assists in the healing process.
- what does the tissue injury expose ?
matrix tissue factor (thromboplastin)
2.which factor binds to TF?
VII - this complex TF:VIIa is now active
3.what does the TF:VIIa complex do?
activates factor X (x- Xa)
- what does the activates Xa bind to ?
Va
- what does the Complex VaXa do?
converts prothrombin to thrombin - this is the key player
- what is the first thing that thrombin does?
activates further platelets - in doing so it causes the release of factor V from alpha granules in the platelet cytoplasm - when these factors reach the surface they become active
- what does thrombin do to TF:VII (8) ?
It liberates factor VIII which then becomes active
8.what does thrombin do to XI?
converts it to XIa
9.how is IX activated?
by wither TF- VIIa or XIa
- what does IXa do?
binds with VIIIa to convert X to Xa
- what dies the Xa form a complex with in order to bind prothrombinase?
Va
12.what does the Xa and Va complex do?
convert II to IIa
13.what does thrombin do?
cleaves fibrinogen, forming fragments that spontaneously to form fibrin
- Which factor then cross links the polymer to form a fibrin fibre network and a solid clot ?
VIIIa
what are the main components of arterial thrombus?
white thrombus: mainly platelets in a fibrin mesh and relatively few RBCs
where do arterial thrombus normally do to cause problems ?
they embolise and if this happens in the carotid arteries , then can get a stroke
what are arterial thrombus normally treated using?
antiplatelets
what are the main components of venous thrombus?
white head, jelly like tail and fibrin rich red thrombus
what normally happens to venous thrombi?
if detaches forms an embolus that usually lodges in the lung (pulmonary embolism)
also can get DVT
what are venous thrombi treated with?
anticoagulants
which clotting factors require post-translational modification for subsequent function of the active factors?
II,VII,IX,X
VIIa, IXa, Xa that act as ____- proteases
VIIa, IXa, Xa that act as serine proteases
what is the specific reaction happening in post-translaitonal modification?
carboxylation of glutamate residues
factor II goes from being _______ to ______ with vitamin K modification. It is still inactive though
factor II goes from being descarboxythrombin to prothrombin with vitamin K modification. It is still inactive though
The carboxylase enzyme that mediates ______ ________ requires vitamin __ in its _____ form as an essential _____
The carboxylase enzyme that mediates gamma carboxylation requires vitamin K in its reduced form as an essential cofactor
what is the oxidised form of vitamin K called?
epoxide
what is the reduced form of vitamin K called?
hydroquinone
what is the enzyme that converts vitamin K from oxidised to reduced?
vitamin K reductase
what is the role of warfarin?
blocks vitamin K reductase so get get a reduced Gamma carboxylation of 2,7,9,10 and this interrupts the coagulation cascade
what are anticoagulants used for ? 4 things?
- deep vein thrombosis (DVT)
- prevention of post-operative thrombosis
- patients with artificial heart valves
- atrial fibrillation
what risks do anticoagulants carry?
haemorrhage
warfarin Blocks coagulation in ____, not in ___
Blocks coagulation in vivo, not in vitro
what is the downside of warfarin?
it has a low therapeutic ratio
what has to be checked regularly with warfarin?
INR
name 3 ways to potentiate warfarin action?
- liver disease – decreased clotting factors
- high metabolic rate – increased clearance of clotting factors
- drug interactions
name 3 ways to lessen warfarin action?
Physiological state – pregnancy (increased clotting factor synthesis) – hypothyroidism - reduce metabolism (decreased degradation of clotting factors)
- Vitamin K consumption
- drug interactions
how is warfarin overdose treated?
vitamin K administration or concentrate of plasma clotting factors
name the important inhibitor of coagulation in the body
antithrombin III
what is the action of AT III
it neutralises all serine protease factors by binding to their active sites in a 1 to 1 ratio
what is the action of heparin?
it binds to ATIII increasing its affinity for serine protease clotting factors to greatly increase their rat of inactivation
what clotting factors is heparin particularly aimed at?
Xa and IIa (thrombin)
what must heparin bind to to inhibit IIa?
both IIa and AT III
what must heparin bind to to inhibit Xa?
only AT III
give 2 examples of LMWH?
enoxaparin and dalteparin
when is heparin preferred to LMWH?
in renal failure because heparin is eliminated by routes other than the kidneys
which factor do LMWH and fondaparinux inhibit?
Xa
give 4 side effects of heparin and LMWH
- haemorrhage
- osteoporosis
- hypoaldosteronism
- hypersensitivity reactions
what substance inactivates heparin and is used in haemorrage?
protamine sulfate
name a new orally active agent that is a direct inhibitor of thrombin
dabigatran etexilate
name a new orally active agent that is a direct inhibitor of Xa
rivaroxiban
what are the advantages of the new orally active anticoagulant agents? 2
convenience of administration
predictable degree of anticoagulation, but no specific agent available to reduce haemorrhage in overdose
what are dabigatran etexilate and rivaroxiban used in?
to prevent venous thrombosis in patients undergoing hip and knee replacements
how does aspirin work on platelets?
it irreversibly blocks COX in platelets preventing TXA2 synthesis
how does aspirin work on endothelial cells
blocks COX inhibiting the production of antithrombotic prostaglandin I2
what is aspirin mainly used for?
thromboprophylaxis in pateints at high cardiovascular risk
what are the main side effects of aspirin?
gastrointestinal bleeding and ulceration
how does clopidogrel work?
links to the P2Y12 receptor by a disuphide bond producing irreverible inhibition
when is it used?
in patients intolerant to aspirin and alongside aspirin
how does tirofiban work?
blocks GPIIb IIIa receptor - preventing fibrin linking
what does plasmin do?
breaks fibrin into fibrin fragments to get clot lysis
what is the plasmin precursor?
plasminogen
what is the enzyme required to form plasmin
endogenous tissue plasminogen activator (tPA)
name three drugs that activate plasminogen
streptokinase, alteplase and duteplase
what is the role of fibrinolytics?
they are usedto reopen occluded arteries in acute MI or stroke
what is a side effect of streptokinase?
allergic reactions - should not be given to patients with recent streptococcal infections
alteplase and duteplase and more effective on ___ bound plasminogen than____ plasminogen
alteplase and duteplase and more effective on fibrin bound plasminogen than plasma plasminogen
what is used if there is a haemorrhage with fibrinolytics?
tranexamic acid which inhibits plasminogen activation
