3.B-Venous Thromboelism Flashcards
What is primary hemostasis?
involves vasoconstriction and platelet adhesion/aggregation
What is secondary hemostasis?
process where fibrin is formed
classic clot production
What is fibrin?
small insoluble proteins that form tight complexes
What are the general causes of clot formation?
hypercoaguable state
venous stasis
vascular wall injury
What causes hypercoagulability?
coagulation exceeds natural mechanisms
genetic causes
malignancies
What causes venous stasis?
immobility (hospitalized patients, bedrest, minimal activity)
obstruction
impaired circulation
How does vascular wall injury promote clot formation?
exposure of blood to tissue factor, collagen, subendothelial tissue
-strong initiators of primary and secondary hemostasis
Describe the clotting process.
platelets adhere and aggregate on injured/exposed area
clotting cascade activated by platelets and injury
generate fibrin clot–>reinforce platelet plug
as time passes:
-damaged tissue covered
-triggering signals reduced dramatically
-anticoagulant and fibrinolytic pathways predominate
-clot disappears, tissue heals
Describe the intrinsic pathway.
XII–>XIIa (via intrinsic molecules)
XI–>XIa (via XIIa)
IX–>IXa (via XIa)
X–>Xa (via IXa)
promthrombin (II)–>thrombin (IIa)
What are some intrinsic molecules that can activate the instrinc pathway?
activated platelets
circulating molecules
foreign bodies
Describe the extrinsic pathway.
VII–>VIIa (via tissue factor)
X–>Xa (via VIIa)
prothrombin (II)–>thrombin (IIa)
What are the properties of thrombin?
activates fibrinogen to a fibrin clot
amplifies its own product (+ve feedback)
activates platelets
pro-inflammatory effects
activates endogenous anticoagulant system
True or false: thrombin can activate its own inhibition
true
What are the two classes of orally administered anticoagulants?
vitamin K antagonists
direct oral anticoagulants (DOACs)
What are examples of vitamin K antagonists?
warfarin
acenocoumarol
What do vitamin K antagonists do?
inhibit the production of vitamin-K dependent clotting factors
How are vitamin K clotting factors activated?
carboxylation reaction via reduced vitamin K
Where are vitamin K dependent factors synthesized?
liver
-not active until carboxylation
Which vitamin K factors are coagulation factors?
II
VII
IX
X
Which vitamin K factors are anti-coagulant factors?
proteins C and S
Which enzyme does warfarin target?
vitamin K reductase
-lowers the supply of reduced vit K available to active vit K
clotting factors
What is the difference between S-warfarin and R-warfarin?
S-warfarin: most of the anticoagulant action, metabolized by
CYP 2C9
R-warfarin: 5x less potent, metabolized by CYP 3A4 and 1A2
What is the mechanism of action for warfarin?
inhibits synthesis of vit K-dependent factors
True or false: warfarin has an effect on clotting factors already in circulation
false
the onset of anti-coagulation is therefore slow
Which clotting factor has a short half life? What is the implication of this?
VII (half life of 6 hours)
fools the INR
How long does it take for the full anticoagulation effect of warfarin? Which factor is mainly responsible for this?
6 days because there needs to be a reduction in all factors
IIa (half life of 72 hours)
Is there a set dose for warfarin?
no
dosing requirements are highly variable
individuals require close monitoring
Why is the dosing so variable for each person with warfarin?
polymorphisms in CYP2C9 and vitamin K reductase
Which pathway does warfarin impact more completely?
extrinsic pathway
-effects can be monitored using PT (prothrombin time)
What is the ratio used to monitor warfarin?
international normalized ratio (INR)
What does an INR of 1 mean? What if it was 2-3?
1: no anticoagulant effect
2-3: intensity of anti-coagulation is increased
What are the drug interactions to be aware of with warfarin?
metabolism: 2C9, 3A4/1A2
bleeding: antiplatelets, other anticoagulants, herbals
vitamin K
displacement: sulfonamides, ASA
absorption: iron, magnesium, zinc (reduce warf absorption)
Which compounds can accelerate clotting?
substances intrinsic to the plasma
-reduce clotting time to 26-33s
-activated partial thromboplastin time (aPTT)
substances extrinsic to the plasma
-reduce clotting time to 12-14s
-prothrombin time (PT)
What are the common blood tests to assess clotting ability based on blood samples?
PT
aPTT
What are some differences between DOACs and warfarin?
DOACs more predictable (INR monitoring not required)
DOACs have faster onset (hours vs days)
DOACs have lower risk of bleeding
DOACs are more expensive
What are some DOACs?
dabigatran etexilate (Pradaxa)
rivaroxaban (Xarelto)
apixaban (Eliquis)
Edoxaban (Lixiana)
What do all DOACs end in?
-aban
Which factor does each DOAC target?
dabigatran: thrombin (IIa)
rivaroxaban: Xa
apixaban: Xa
edoxaban: Xa
Which DOAC is a prodrug?
dabigatran
What are the two main advantages of DOACs over warfarin?
single dose-no need for monitoring
fast onset
True or false: DOACs work on existing clotting factors
true
What will be secreted by an intact endothelium adjacent to damaged tissue?
antithrombotic substances
prevents extension of clot to healthy cells
What are the endogenous anti-thrombotic substances?
thrombomodulin
herparan sulfate
fibrinolytic factors
What does thrombomodulin do?
converts Protein C to its active form aPC
-aPC degrades vit K dependent clotting factors
-uses protein S as a cofactor
What does heparan sulfate do?
binds to antithrombin
antithrombin inhibits IIa, Xa, and other activated clotting factors in the intrinsic pathway
What do plasminogen activators do?
converts plasminogen to plasmin
classified as a fibrinolytic
What does plasmin do?
degrades fibrin into soluble products
What are the two types of plasminogen activators?
tissue type plasminogen activators (t-PA)
-predominant type secreted by endothelial cells
-promotes intravascular fibrinolysis
U-PA or urokinase
-secreted in response to inflammatory stimuli
-promotes extravascular fibrinolysis
What are common parenteral anticoagulants?
heparin
low molecular weight heparin
fondaparinux
What are some characteristics of unfractionated heparin?
obtained from gut mucosa of animals
mixture of proteins
short half life (<60min)
IV or SQ
What is the mechanism of action of UFH?
binds to antithrombin
heparin-AT complex: inactivates IIa and Xa
inactivates several factors in intrinsic pw
What are LMWH and Fondaparinux derivatives of?
UFH
Does LMWH have the same inhibitory effect on Xa and IIa?
no
3:1 inhibitory effect on Xa:IIa
True or false: Fondaparinux has Xa and IIa activity
false
only Xa activity
What are some characteristics of LMWH?
smaller fragments
lower binding affinity for plasma proteins/cells
cleared by kidney (UFH unaffected by renal dysfunction)
better bioavailability
longer half life
no monitoring of bleeding time needed
Which people do you have to be careful about use of LMWH and Fondaparinux?
kidney disease
What are some characteristics of Fondaparinux?
smaller pentasaccharide sequence
anti-Xa only
renal clearance
predictable dose response
SQ administration
no monitoring of bleeding time
What are the direct thrombin inhibitors?
lepirudin
desirudin
bivalirudin
argatroban
What is the mechanism of action of direct thrombin inhibitors?
inhibit IIa
True or false: all direct thrombin inhibitors are parenteral formulations
true
What is venous thrombosis?
pathologic clots in veins without obvious damage
often occurs in areas of disturbed flow
Which areas of the body are common for venous thrombosis?
calf
thigh
What does venous thrombosis result in?
poor tissue drainage–>edema and inflammation–>pulmonary embolism
What is venous thrombosis mainly composed of?
fibrin and RBCs
How is venous thrombosis managed/prevented?
anticoagulants
How can we monitor the effect of UFH?
aPTT
True or false: PT may be used for dabigatran
false
aPTT may be used for dabigatran
