Module 2 exam 1 lecture 3 Flashcards
What kind of protease is thrombin
Seriine protease
WHat are the two main proteins involved in clotting
Serine protease(thrombins)
Glycoproteins
name the serine pro-coagulant factors
XII, XI, X, IX, VII, II
protein C acts as an
anticoagulant
what factors does protein C cleave
cleaves factors Va, VIIIa and inactivates them
what are glycoproteins
Cofactors that localize factors to a particular region, they are procoagulatory
example of glycoproteins
factors VIII, v, III
Protein C and protein S complex
ANticoagulatory complex
what is the target for heparins
Anti-thrombin
is anti thrombin pro or anti coagulatory
anticoagulatory
how is antithrombin anticoagulatory
because It binds to a number of different factors and inactivate them and target them to be degraded
Calcium is sometimes referred to as
Factor IV
Why is calcium important in this context
It is an important co factor because it links different protease factors to phospholipid membrabne
What does transglutaminase do? Also called
Cross-links fibrin-fibers (factors XIII)
what is fibrinogen/fibrin
The substrate protein for factor IIa that polymerizes to form a clot
Where are CF (clotting factors ) produced?
CF (except for VWF) are made in liver
what is VWF
is a circulating factor that binds to collagen in damaged BV and recruits platelets
where is VWF made?
Endothelium (Factor VIII is also produced in endothelium)
Can liver disease affect coagulation?
yes, clotting factors are produced there.
What are the two different scenarios that lead to coagulation
Intrinsic and extrinsic pathway.
Explain the extrinsic pathway
Requires a protein or factor that is not present in bloodstream to come into contact with the blood. (important when vessel is damaged and blood leaks out)
Explain the intrinsic pathway
Triggered when collagen is exposed on the wall of the BV
What is the most important step in intrinsic pathway
activation of factor IX (9)
Extrinsic pathway MOA
Blood encounters tissue factor C (thromboplastin), which recognizes factor 7, leading to activation of factor 10
where do extrinsic and intrinsic pathways merge
activation of factor X
what does faxtor X do?
cleaves pro-thrombin to thrombin
how long does it take extrinsic pathway to start clot formation
15 seconds
where are factors VII and x found
in blood.
how is TF activated?
by binding to factor VII
what does factor VII do?
cleaves factor X and activates it to factor Xa
summarize actions of factor VII and x
factor x and factor VII are contents of the blood. IIf they are in BV, they will not encounter any TF. Once there is damage to the blood and it leaks, factor VII binds TF. Factor VII is actiavted and it can cleave factor x to factor Xa
how is factor X turned on in intrinsic pathway?
by factor ix (9)
the initiator of common pathway os factor
X
factor x does what?
cleaves prothrombin to thrombin
What happens once thrombin is activated
cleaves fibrinogen to fibrin, fibrin forms clot
thrombin also activates
factor 13 (transglutainase)
what does factor 13 (transglutaminase do?)
Crosslinks the fibrin strands and stabilizes the clot
examples of positive feedback activity in clotting
-thrombin has a positive feedback activity in the activation of coagulation
-platelet activation increases activation of factors VII and factor X
How does thrombin activation have a positive feedback
activates cofactors factor V and factor VIII, enhancing activity
feedback mechanisms that dcerease coagulation
Antithrombin
Protein C system
Factor Xa
use of calcium chelators in collecting blood smaple?
preserves platelet function in storage.
What are the 3 different lab tests for coagulation
Calcium only
Calcium and partial thromboplastins (just phospholipids and kaolin)
Calcium and thromboplastins
Give the time ranges for the different lab tests for coagulation
Calcium only -2-4 minutes
calcium and partial thromboplastins -26-33 seconds
calcium and thromboplastins- 12-14 seconds
What is INR? What is its use?
international normalized ratio. It is used to normalize the prothrombin time test from lab to lab to set standard.
What is normal INR
0.8-1.2
INR number that makes pt at risk for hemorrhage
> 3
why do we use anticoagulants
Preventing excessive clotting that can lead to stroke, MI, unstable angina, DVT, pulmonary embolism
Vitamin K is an antagonist for
Warfarin
MOA of coumadin (warfarin) inhibiting vit K
Coumadin inhibits vit-K epoxide reductase, blocking reduction of vitK epoxide to its active form.
Warfarin acts by inhibiting synthesis of
Factors VII, IX, X, II
How does warfarin inhibit factors VII, IX, X, II
dirsupts ability of calicum to bring these factors to phospholipid membrane
Why does warfarin have a delayed action of onset? how long does it take?
It has to deplete the circulatory pool of clotting factors before it has an effect. takes 3-5 days
Why is dosing warfarin so tricky
Warfarin is metabolized by CYP2C9, which is the most variable CYP in pt population.
what to do if bleeding on warfarin
DX warfarin, give vit K (in serious hemorrhage, plasma replaces CF faster than vit K)
Direct target of warfarin? which enantiomer is active?
vit K epoxide reductase (VKORCL)
S enantiomer
How does warfarin necrosis happen? What do we do to combat this?
Protein C becomes depleted 1st before other CFs. This leads to pro coag state. Heparin can be given along side warfarin to combat this
ADE of warfarin
Hemorrhage, drug-drug i/a
contraindications of warfarin
dementia, psychosis, alcohol/drug abuse
What are drugs that diminish warfarins anticoag effect?
VIT K, antibiotics that kill intestinal flora, SSRIs, anabolic steroids
for emergency situations like acute major bleeding, how do we reverse warfarins effects?
exogenous vit K with prothrombin complex via IV
Heparin ROA
IV or SQ
How do heparins work?
via activation of a protein called antithrombin-3
What does antithrombin 3 do?
it has the ability to bind to factors IIa (thrombin) and factor X (10a) and inactivate them, anti coag effect
heparin structure? synthetic version name
long chain polysaccharide with negatively charged sulfates that bind to antithrombin 3. Fondaparine is synthetic part
How does heparin change the interaction between thrombin and factor X?
Usually, this interaction is very slow. Heparin increases the speed by 100x.
Where are heparins usually found? LMWH action?
Heparins are usually found on mast cells.
LMWH are too small to bind antithrombin and thrombin. They will have a greater specificity for inhibition of factor Xa
Heparins act by accelerating
antithrombin rxns to inactivate thrombin and factor Xa
do heparins bind directly to Xa or thrombin?
No, they bind to antithrombin and accelerate the interaction of antithrombin with either thrombin or factor Xa, causing them to be inactive and cleared.
Clinical use of heparin? t1/2? onset?
Anticoagulant effective immediately for 30 min-180 mins. anticoag effect when therapy is dx
adverse effects of heparin?
Type 1 HIT- type 1, mild, decrease in platelets by 25%
Type 2 HIT- severe, develops 7-12 days after starting therapy
osteoporosis
How to reverse effects of heparin during life threatening bleeding? MOA?
Use protamine sulfate because it has positive charges that will bind tightly to heparin.
It can NOT reverse fondaparinux
How does type 2 heparin induced thrombocytopenia occur?
develops 7-12 days after starting heparin. Occurs as a result of interaction of heparin and a protein called PF-4
MOA of thrombocytopenia
PF4 on surface of platelet binds heparin. Heparin removes the pF4 from the platelet and form a complex that can be recognized by antibodies. In type 1 platelets are removed. in type 2 it causes thrombosis
rank HIT risk in LMWH, Fondaparinux, and heparin
Heparin>LMH>fondaparinux
name the two LMWH. How is LMWH obtained?
dalteparin, enoxaparinFrom the depolymerization of unfractured heparin.
COmpare LMH and heparin in terms of bioavailability, efficacy, dosing and monitoring, side effects?
Equal efficacy
less frequent dosing than heparin (longer half life)
no monitoring needed
increased bioavailability
lower incidence of side effects
MOA of fondaparinx
indirectly inhibits factor Xa by selectively binding antithrombin
ROA and use of fondaparinux
Given SQ and used for venous thromboembolism and prophylaxis in patinets undergoing surgery
ROA of warfarin? onset? Reversal time?
Oral, longtime to onset, long time to reverse
Heparin moa? onset?
works fast, binds antithrombin and accelerates its ability to inactivate thrombin
Name DOAC/NOAC drugs
Direct factor Xa inhibitors
Rivaroxaban
apixaban
edoxaban
betrixaban
Direct thrombin inhibitors
Dabigatran
RivaroXAban and apiXAban MOA? t1/2? indication?
Both small molecules that bind the active site of factor Xa serine protease. (its in the name)
rivaroxaban- 5-9hrs
apixanab- 12 hrs
Both indicated for the tx/prevention of VT and PE
Rivaroxaban and apixaban excreted by?
When to not use them
renally, dose reduction in renally impaired patient needed. Risk of hematoma/paralysis in spine puncture/epidural
Edoxaban MOA? Indication? ROA?
Xa inhibitor, indicated for tx/prophylaxis of VT and PE, orally available
Edoxaban excreted by?
Renally, NOT IN USE in patients with CRCL>95
side effects of edoxaban?
Risk of hematomal paralysis in pts undergoing soinal puncture or epidural.
For every drug with Xa in it (direct Xa inhibitors)
indication
MOA
Moa- Xa inhibitor
indication- VT and PE
risk of ischemic event upon premature dx
paralysis in patients undergoing epidural and spinal puncture
fixed dosing
monitoring not required
betrixaban excreted
renally and hepatially. Dose reduction in impairments in both
antidote for reversal for apixaban and rivaroxaban
Andexanet
How does andexanet work? ROA? blackbox warning?
mimics factor Xa and binds drug, but lacks enzymatic activity. Given IV. blackbox for increase risk for thromboembolic event
when is andexanet given?
unconrolled bleeding after administration of apixaban or rivaroxaban
besides factor X, the ultimate serine protease involved in cleaving fibrinogen to fibrin is
thrombin
factor X cleaves
prothrombin to thrombin
Name DTI drugs
Lepirudin
Bivalirudin
Argatroban
Dabigatran
How do DTIs work? What do they do?
They bind to active site of thrombin, to the xosite or both. Inhibit platelet aggregation (anticoag)
Difference between DTI and heparin
DTI can inhibit fibrin bound to thrombin, Heparin can not inhibit thrombin once bound to fibrin;
Lepirudin MOA, ROA, indication, reversible or irreversible? Bivalent or no?
ROA- IV
MOA- bivalent (binds active and exosite)
used to treat heparin induced thrombocytopenia (HIT)
irreversible
Bivalirudin ROA, MOA, indication, bivalent or no? irreversible or no? half life?
Bivalent short peptide
cleared in 25 minutes
given IV
reversible with rapid onset and short duration
bivalirudin and argatroban bind in the
arg-pro motif. It is a recognition site for thrombin
Argatroban indication? bivalent? reversible or irreversible? ROA?
DTI approved for HIT or coronary artery thrombosis
IV
Reversible
Not bivalent, binds active site
Only DTI orally available
Dabigatran
Dapigatran dosing and indication
Dosed BID
Prevents stroke
It is a prodrug
Drug used to reverse effects of dabigatran
Idarucizumab (does not work for other DTIs)
DOAC drugs and indication
rivaroxaban, apixaban, edoxaban, dabigatran
non-vascular A-fib, DVT, PE (tx or prevention)
