Lecture 16 - Anticoagulants Flashcards
Antithrombotics
drugs that interfere with the platelet function
Anticoagulants
drugs which interfere with the coagulate cascade
Thrombolytics
drugs which dissolve the clot
asprin
COX 1 and 2 inhibitor
clopidogrel
ADP receptor antagonist
abciximab
GP IIb/IIIa antagonist
heparin
antithrombin III activator
LMW heparin
antithrombin III activator
protamine sulfate
binds heparin and LMW heparin
warfarin
vitamin K antagonist
vitamin K
needed to activate coagulation factors
dabigatran
direct thrombin inhibitor
idarucizumab
binds direct thrombin inhibitors
rivaroxaban
direct factor Xa inhibitor
andexanet alfa
binds direct factor Xa inhibitors
tissue plasminogen activator
activates plasminogen
List some drugs which prevent the formation of a platelet plug (anti platelet drugs)
asprin
clopidogrel
abciximab
List some anticoagulants
heparin LMW heparin warfarin dabigatran rivaroxaban
List some antidotes
protamine (for heparin)
vitamin K (for warfarin)
idarucizumab (for dabigatran)
andexanet alfa (for rivaroxaban)
List a fibrinolytic agent
tissue plasminogen activator (t-PA)
Hemostasis
the process of arresting the loss of blood from injured vessels
Hemostatic plug
- first step after injury, makes platelets stick to each other
- formed by aggregated platelets and then stabilized by cross-linked fibrin fibers
Thrombosis
unwanted formation of a hemostatic plug or clot inside a blood vessel or heart chamber
Thrombus
- blood clot attached to a blood vessel
- may obstruct flow (harmful)
- pieces may break off which then “plug” capillaries
Emboli
- portion of thrombus that breaks away
- clot floating in the blood
- if “mobilized” will get stuck in capillaries
- damage depends on where it lodges (heart, brain, lung)
An _____ clot is platelet rich
arterial
A ____ clot is red blood cell rich
venous
Describe Atherosclerosis
- atherosclerosis (build up of cholesterol) may partially obstruct flow in artery
- eventually the plaque damages the endothelium - thrombus forms
- blood flow is blocked by the atherosclerosis and the thrombus
- if thrombus ruptures - emboli lodge in capillary and block flow
How do thrombotic disorders involve arteries?
- damaged endothelial layer stimulates thrombus formation
- atherosclerosis damages endothelial layer of arteries
- physical damage caused by: balloon angioplasty, stenting
- if artery perfuses the brain:
- emboli lodge in cerebral capillary
- acute ischemic stroke
- if artery perfuses the heart muscle:
- emboli lodge in coronary artery
- acute myocardial infarction
How do thrombotic disorders involve veins?
- involves red blood cells and less platelets
- so anti platelet drugs less effective in veins
- more related to “stagnant flow” in veins and/or atria
- problem post surgery, long term bed rest or just sitting (long plane rides)
- clots form and if dislodge (emboli) - flow to capillaries in the lungs - known as pulmonary embolism
- two major sites where venous clots form:
1) lower leg veins (DVT)
2) right atria (if atria not contracting properly)
Hemostasis involves 3 steps:
Describe them
1) Formation of a platelet plug
a) platelet adhesion
b) platelet activation
c) platelet aggregation
2) Coagulation - clot formation
- stabilizes clot (platelet plug)
- thrombin increases fibrin formation (re-enforces platelet plug)
3) Fibrinolysis - clot dissolving (as wound heals - removes clot)
Describe the drugs that affect hemostasis (they affect the 3 steps)
1) Platelet inhibitors:
a) COX inhibition - aspirin
b) ADP receptor block - clopidogrel
c) GP IIb/IIIa block - abciximab
2) Anticoagulants
a) thrombin inhibition - heparin
b) vitamin K antagonist - warfarin
c) thrombin antagonist - dabigatran
d) factor Xa inhibitor - rivaroxaban
3) Thrombolytic Agents
a) fibrin breakdown - tPA (tissue plasminogen activator)
Intact endothelium would normally release to ____ to stabilize the platelet - inhibit mediator release and prevent GPIIb/IIIa receptor activation on platelets
PGI2
Damage to the endothelium exposes ______. Platelets adhere to this collagen which results in a change in platelet shape and the release a number of mediators (ADP, TxA2, serotonin, etc). These mediators activate and attract other platelets and activate GPIIb/IIIa receptors.
collagen
_____ crosslinks platelets and holds them together
fibrin
List the 3 steps of a clot
1) formation of platelet plug
2) formation of clot
3) breakdown of clot (if no longer needed)
Describe step 1 (formation of platelet plug)
- damaged endothelium: collagen exposed
- platelets stick to exposed collagen
- platelets activated: release mediators (TxA2, ADP, serotonin) to excite other platelets
- released mediators activate resting platelets and recruit to the platelet plug
- activation of GPIIb/IIIa receptors binds fibrin linking platelets
- avalanche of platelet aggregation
How do you prevent plug formation?
1) selective change in prostaglandin levels (possible?)
- increase/maintain endothelial prostacyclin
- decrease thromboxane A2 levels in platelets
ex. COX inhibitor (aspirin)
2) block effects of released mediators
- block ADP receptor
ex. clopidogrel
3) prevent GPIIb/IIIa receptor coupling
- block GPIIb/IIIa receptor
ex. abciximab
NSAIDs are _____ ______
platelet inhibitors (prevent formation of platelet plugs)
Where do NSAIDs act?
inhibit COX enzymes
MOA of asprin
- aspirin blocks COX irreversibly (it never lets go)
* once blocked, a cell would need to produce new COX to be able to synthesize prostaglandins
What do COX enzymes do?
- COX is the enzyme necessary for the formation of PGs
- PGs are ubiquitous and do many things
- in platelets, COX produces TxA2 which promotes aggregation
- in vascular endothelium, COX produces PGI2 which acts on platelets to increase stability (less likely to aggregate)
- a balance between TxA2 and PGI2 determines how “sticky” the platelets will be
Platelets lack a _____ and cannot generate new COX.
- life span of a platelet is 7-10 days
- so for the life of the platelet (up to 10 days) - no COX, no TxA2
nucleus
____ endothelial cells do have a nucleus - produce more COX and therefore PGI2. This shifts the balance to PGI2 thus impeding aggregation
vascular
Aspirin can be used as a ______ Tx
prophylactic
- baby aspirin 81 mg daily
- following MI - start w higher dose
- used to prevent cerebral schema and MI (both caused by emboli lodging in these capillary beds)
Aspirin may produce problems associated with increased _______
bleeding
- hemorrhagic stroke (stroke due to bleeding into brain)
- GI bleeding
- easy bruising
Clopidogrel MOA
- prevents ADP from binding to platelets
- this prevents activation of the GP IIb/IIIa receptor on platelets
- fibrinogen is now unable to link platelets
- aggregation is significantly decreased
What is clopidogrel used for?
- effective in preventing ischemic stroke and MI
- given routinely during stent insertion during a MI
- bleeding may be prolonged and hard to stop
- easy bruising (bleeding)
Clopidogrel is a _______
pro-drug
hepatic conversion to active form
Clopidogrel:
genetic variation of CYP2C19 causes a ______ effect
decreased
Clopidogrel:
_______ ADP receptor antagonist
irreversible
Clopidogrel:
prolongs bleeding for ____ days
7-10
Clopidogrel:
AE?
- neutropenia
- thrombotic thrombocytopenia purport (TTP)
- hemorrhage (increased by the co-administraton of ASA)
- GI hemorrhage (2% per year)
- Cerebral hemorrhage (0.1-0.4 per year)
- Co-use of NSAIDs discouraged
Clopidogrel:
Minor adverse effects?
- rash
- respiratory (upper respiratory infections, rhinitis, shortness of breath, cough)
Abciximab:
MOA
- the activated GP IIb/IIIa receptor is important to “aggregate” platelets
- abciximab is a monoclonal antibody against this receptor
- this prevents fibrinogen from binding and joining platelets
- aggregation of platelets can not occur, prevents forming a plug
- Potential problems for bleeding/bruising
- Given IV
What is coagulation?
stabilizing the clot (platelet/fibrin plug)
What are coagulation/clotting factors?
proteins in the blood
Describe the coagulation process
- part of complex cascade to ultimately form fibrin strands
- fibrin strands strengthen/stabilize the platelet plug
There are two pathways involved in the coagulation process: Describe them
Two pathways result in thrombin and ultimately fibrin formation:
1) Intrinsic pathway - factors released from site of damage
2) Extrinsic pathway - tissue factors released from elsewhere
What is the purpose of the pathways?
Both pathways are complicated and involve a number of coagulation factors.
Purpose of pathways: conversion of prothrombin to thrombin
What does thrombin do?
converts fibrinogen to fibrin (the threads to hold and strengthen the clot)
Without fibrin, the platelet plug _____
dissolves
Thrombin generation is essential for the conversion of ???
fibrinogen to fibrin (stabilizes clot)
What does vitamin K do?
Vit K is an important cofactor in the synthesis of many of the coagulation factors (Factors 2, 7, 9, 10).
Low vitamin K is associated with ??
bleeding disorders
__________ naturally inactivates thrombin and factor Xa (decreasing fibrin formation)
Antithrombin 3
see diagram on slide 27
extrinsic & intrinsic pathway
okay
Describe the interactions between platelet activation and coagulation cascade (4)
1) Platelet-derived polyphosphates activate intrinsic pathway
2) Activated platelets present a pro-coagulant surface (phophatidylserine rich) for Factors X and II activation
3) Thrombin (Factor IIa) is a platelet agonist
4) Thrombin converts fibrinogen to fibrin which binds to platelet and stabilizes the clot
Where does heparin work?
Heparin works to prevent coagulation (stabilization of the clot)
Where is heparin normally found?
in mast cells
What forms is heparin given as?
unfractionated heparin and low molecular weight heparin (LMWH)
What does heparin lead to?
- heparin (via antithrombin) leads to thrombin inactivation
- heparin increases the inactivation of coagulation factors (thrombin)
- heparin binds to antithrombin and increases its activity, thereby increasing thrombin inactivation
What does antithrombin III do?
antithrombin III naturally degrades thrombin and a number of other coagulation factors (it slowly inactivates these clotting factors)
_____ increases the rate at which antithrombin inactivates these factors
heparin
*as a result, thrombin is degraded faster.
With less _____, there is less conversion of fibrinogen to fibrin, less fibrin is formed, this prevents the expansion of the thrombi
thrombin
*see diagram on slide 30
Heparin:
Prevents the expansion of the thrombi by blocking ____ formation
fibrin
Heparin:
What is used for?
used in prevention of arterial and venous thrombosis
Heparin and LMWH are anticoagulant of choice for use in ______
pregnancy
Heparin does not cross the ______
placenta (safe for the fetus)
What is the antidote for excessive bleeding caused by heparin?
protamine sulfate (given IV)
What is the main difference between heparin and LMWH?
heparin is has a variable anticoagulant response
LMWH has a predictable anticoagulant response
*read chart on slide 32
What does warfarin do?
- It is a coumarin
- Prevents coagulation
- Vitamin K antagonist
What does vitamin K do?
is a cofactor for activation of many coagulation factors
What is a downside of using warfarin?
- Requires constant monitoring (INT measured)
- Anticoagulation effects take 8-12 hours to be effective (slow to act)
- *if immediate effect needed - have to start with heparin and then switch to warfarin
What is the antidote for excessive bleeding caused by warfarin?
vitamin K
What is Enoxaparin?
a form of LMWH
What does Enoxaparin do?
accelerates (1000x) effects of anti-thrombin III
*higher specificity for factor X over factor II
Enoxaparin is not _____ active
orally
Uses of Enoxaparin?
- prevents post-op DVT/pulmonary embolism
- maintains extracorporeal circulation (surgery/dialysis)
- unstable angina
- ischaemic stroke
______:
- prevents the reactivation of vitamin K
- prevents activation of many coagulation factors
Warfarin
Warfarin:
Adverse effects?
- effects variable - too little or too much, must monitor constantly
- dietary vitamin K may alter bleeding/effects of warfarin
- bleeding disorders - major problem, have to monitor closely
- many drug interactions - increase or decrease metabolism
- dietary interactions - vitamin K
- avoid during pregnancy - teratogenic and may cause abortion
Is warfarin safe in pregnancy?
No - it is a teratogenic and may cause abortion !!!
Heparin is safe during pregnancy
What is INR?
International normalized ratio:
-In general this is a ratio of the patient’s (with warfarin) pro-thrombin time to that of a control subject (with no warfarin)
What is pro-thrombin time?
is a measurement (in seconds) of the extrinsic pathway
Target INR = ?
2.0 - 3.0
INR < 2 = ?
may lead to thrombotic complications
INR > 3 = ?
may lead to bleeding
Dabigatran is a ?
direct thrombin inhibitor
Rivaroxaban is a ?
direct factor Xa inhibitor
Compare Dabigatran and Rivaroxaban to Warfarin
D & R: orally active and more predictable than with warfarin - increasing in popularity
Heparin and warfarin have _____ therapeutic windows
narrow
Is there an antidote for Dabigatran and Rivaroxaban?
yes
Dabigatran:
direct orally active, irreversible, _____ inhibitor
thrombin
Dabigatran:
Does it require INR measurements?
No
Dabigatran:
Primary adverse effect?
bleeding, particularly if co-administered with an NSAID
Dabigatran: What drugs (other than NSAIDs) enhance bleeding?
SSRI/SNRI anti-depressants
Dabigatran:
Antidote for excessive bleeding?
idarucizumab
What is Idarucizumab?
- monoclonal antibody fragment that binds dabigatran
- binding affinity 350 times greater than seen with thrombin
Rivaroxaban:
Orally active, irreversible, direct ______ inhibitor
factor Xa
Rivaroxaban:
MOA?
- factor Xa inhibitor, prevents prothrombin conversion to thrombin, which prevents fibrinogen to fibrin
- prevents clot stabilization
- allows clot to be dissolved naturally
Rivaroxaban:
Does it require INR measurements?
No
Rivaroxaban:
Major adverse effect ?
enhanced bleeding with NSAIDs
Rivaroxaban:
Antidote for excessive bleeding?
andexanet alfa
- a modified factor Xa molecule that binds direct factor Xa inhibitors
- only molecule thus far to reverse direct factor Xa inhibitors
Fibrinolytic drugs are ??
clot busters
Describe the role of plasminogen
Plasminogen is converted to plasmin which breaks down fibrin, which breaks down the clot (busts the clot LOL)
What does increased plasmin mean?
increased fibrin breakdown and clot dissolution
Give an example of a thrombolytic drug (clot buster)
tissue plasminogen activator (tPA)
tPA:
MOA
activates plasminogen which gets converted to plasmin and then breaks down fibrin which breaks down the clot
tPA:
_____ the treatment the better
earlier
*at greater than 4.5 hour after symptom onset - benefit is uncertain
tPA:
Adverse effect ?
- these drugs do not distinguish between fibrin of a beneficial hemostatic plug and unwanted thrombi
- will decrease thrombi, but may cause bleeding in an unknown lesion (ex. peptic ulcer)
List 2 fibrinolytic inhibitors
Tranexamic acid
Aminocaproic acid
Describe the 2 fibrinolytic inhibitors:
Tranexamic acid
Aminocaproic acid
- lysine analogues
- bind to and inhibit plasmin and plasminogen
- stabilize clots
- used to reduce peri and post operative bleeding especially in patients with bleeding disorders
- used mouthwash, cream
go over review slide - slide 49
okay
