Anticoagulants Flashcards
Extracted from porcine (PIG) intestine (the majority) or bovine (COW) lungs where heparin is stored in
mast cells
**Anticoagulant effects are produced by binding to
anti-thrombin (AT)
[previously known as anti-thrombin III].
AT is a circulating
serine protease
**Heparin binds to AT enhancing the rate of thrombin-AT complex formation by
1,000 to 10,000 times
**Factors that are inhibited by AT:
Xa, IX, XI, XII
anticoagulation depends on the presence of adequate amounts of circulating
AT
Heparin potency is based on in vitro comparison with a
known standard
a unit of heparin is defined as the vol of heparin-containing solution that will prevent 1ml of….
- 1ml of citrated sheeps blood
- from clotting for 1 hour
- after the addition of 0.2ml of 1:100 calcium chloride
Heaprin 1ml with 0.2ml caCl (1:100) will not clot in citrated sheep blood for:
1 hour
In the US, heparin must contain at least 120 (USP) units per milliliter. this equates to
120units/mL
**Precise pathway of heparin elimination is
uncertain
the influence of renal and hepatic dx on heparin is
less than other anticoagulants
Heparin is used for multiple purposes:
- Prevention and tx of venous thrombosis
- Prevention and tx of pulmonary embolism
- Acute coronary syndromes
- Perioperative anticoagulation for extracorporeal circulation and hemodialysis (bypass)
Onset of action for heparin is
immediate
Labs used to monitor heparin.
NORMAL ranges:
Established Therapeutic Levels:
WNL: aPTT: 30-35 seconds
Therapeutic: 45 - 87.5 seconds
aPTT is used to monitor heparin and maintain a ration of
1.5 to 2.5 times normal values for aPTT
Prolonged aPTT > 120 secs can be shortend by
omitting a dose.
-this is b/c heparin has a brief elim. half time
Generally low dose heparin may not require monitoring. This is because the doses and schedule are
well known
Some hospitals will monitor low dose heparin using an anti-Xa assay in place of aPTT because of the
potential variability of low dose and high dose regimens of heparin
ACT - Activated clotting time is used for higher heparin concentrations such as those used in
CABG
ACT is performed by mixing whole blood with an activating substance w/LARGE SURFACE such as (2)
“Activators”
- Celite
- Kaolin
activators
ACT acts on which pathway?
What Factor initiates activation of the clotting cascade?
activation through the classic INTRINSIC Pathway
Factor XII initiates activation of the clotting cascade
Activator (celite and kaolin) speeds up teh clotting time to normal values of aprox.
100-150 secs (1.5-2.5 mins)
depending on device used
*to measure the ACT and are based on detecting the onset of clot formation
ACT results between devices may be interchangeable? True/False
FALSE
results b/w devices may not be interchangeable
ACT is reliable for
high heparin concentrations >1.0 unit/ml
ACT May be influenced by: (4)
- Hypothermia
- Thrombocytopenia (low platelets increase clotting time)
- Presence of contact activation inhibitors (aprotinin)
- Preexisting coagulation deficiencies (fibrinogen, factor XII, factor VII)
In Aprotinin Therapy: it is recommended to use which activator-ACT? why?
kAolin-ACT rather than celite-ACT
as kaolin binds to aprotinin to minimize its effect.
• For cardiac surgery, a baseline ACT is determined:
Before IV administration of heparin
3- minutes after administration
At 30 minutes intervals thereafter
**Target ACT in CABG surgeries is controversial but ranges between
350 – 400 seconds
ACT values may be misleading during CABG d/t heparin induced anticoagulation b/c of the effects of what two elements on the measurement system?
Hypothermia
Hemodilution
Allergic reaction to heparin are rare. If an IMMEDIATE reaction is noted….
HIT should be suspected
Reversal for HIT:
Protamine
Protamine is found in
salmon sperm
- strong alkaline
- polycationic (positive)
- low molecular weight protein
- found in salmon sperm
These are true of what medication:
Protamine
Protamine is positively charged alkaline that combines with the negatively charged acidic heparin to form a stable complex that is .
devoid of anticoagulant activity
*This complex is removed by the reticuloendothelial system within 20 minutes.
**Protamine Dose:
1mg for every 100 units of circulating heparin
*Example: 1000units of heparin given 1 hour ago. Currently 500 units circulating. Protamine dose (1mg x 5) = 5mg
Half life of Heparin
approx. 1 hour
* this is considered for protamine dosing
Two commonly administered LMWH
- enoxaparin
2. dalteparin
- Heparin has an anti-Xa to an anti-IIa activity of 1:1
- Enoxaparin has a corresponding ration varying between 4:1 and 2:1
-Pharmacokinetics of enoxaparin and dalteparin between patients are more consistent than heparin because they
bind less to proteins than does heparin.
VTE is thought to be better treated with LMWH than heparin in these patients:
-high risk medical and surgical patients
LMWH is greatly prolonged in
renal failure
with kidney failure, what should be used as an antigoagulant?
UFH
In pts with normal renal function, surgery should be delayed how long after the last dose of LMWH?
With renal dysfunction?
12 hours
renal = > 12 hours
Protamine neutralizes LMWH.
True or false?
False
Protamine does NOT neutralize LMWH
Fondaparinux is also known as:
Arixtra
Fondaparinux is a synthetic anticoagulant LMWH used for:
DVT
PE
Alt tx. for HIT (d/t long duration or use for concerns of sensitization)
Unique feature of use for Fondaparinux :
Once a day administration
-15 hour half time
Can Fondaparinux be used in pts with renal dysfunction?
it should not be
*renal elimination
Danapariod (Orgaran) LMWH compound that attenuates ______ formation principally by _______.
- Fibrin Formation
- by binding to AT (antithrombin)
Danapariod (orgaran) is primarily eliminated by
the kidneys
Surgery is associated with a 20-fold increase in
R/O VTE
risk of VTE with surgery is associated with a
20-fold increase
in general surgery patients, DVT incidence is
10-40%
DVT is higher still (than general surgery) in what populations:
- High Risk Surgery patients:
- Orthopedic
- Thoracic
- Cardiac
- Vascular
Heparin and warfarin are the only drugs minimally affected in patients with
renal failure or dysfunction
Risk of DVT is more protracted after hip surgery than after
general
-when it develops during the first few post op days
due to the risk of VTE/DVT correlated to surgery, what is an intervention done on all patients while in the OR to prevent?
compression stockings/ SCDs
• Surgical technique for hip surgery, which kinks the femoral vein, seems to stimulate proximal DVT in operated leg.
Therefore, what is most likely to develop?
Calf vein thrombosis is more likely to develop in either leg
what is common and life threatening in major trauma
VTE
with major trauma, a PE occurs in what % of pts
2-22%
The 3rd most common cause of death in pts who survive the first 24hrs after a trauma is:
Fatal PE
Bivalidrudin is a heparin replacement for what type of patients?
HIT+ patients
-for cardiac surgery on or off pump
When do you stop Bivalirudin before surgery?
4-6hours before
What patients need a dose adjustment for the use of Bivalirudin?
Renal impairment
-20% elminated by renal
Argatroban is a synthetic direct thrombin inhibitor indicated for the use of
prophylaxis and tx of thrombosis
*In patients with or at risk of HIT undergoing PCI
Does argatroban need to be adjusted in renal patients?
NO
-Hepatic elimination
What DT inhibitors where first isolated from leeches?
- Lepirudin
- Desirudin
“L for L” Leeches and Lepirudin/Desirudin
(“leechy”) Lepirudin was initially used in cardiac pts. Bleeding was a major problem due to its ability to
IRREVERSIBLY inhibit Thrombin
Desirudin was first derived from?
leeches
Desirudin is used to prevent
DVT after total hip or knee replacement
Oral anticoagulants are derivatives of
4-hyroxycoumarin (coumarin)
Most frequently used anticoagulant d/t predictable onset and duration is:
Warfarin
Warfarin dose starts at:
5-10mg
Average maintenance dose of Warfarin is:
5mg
MOA for Warfarin
-Inhibits vitamin K epoxide reductase
that converts Vit K dependent coag proteins into active forms.
Vitamin K dependent factors
“1972”
Factors II, VII, IX, and X
anticoagulation effects of PO or IV Warfarin are
delayed 8-12 hours
When should warfarin be stopped before surgery?
5 days
peak concentration of warfarin occurs in
1 hour
**warfarin % protein bound
what does this mean?
97%
-Long elimination half time of 24-36h
this medication crosses the placenta and results in exaggerated effects on the fetus
warfarin
can warfarin cross the placenta?
yes
exaggerated effects on fetus as well
warfarin is metabolized into inactive metabolites that are gonjugated with glucronic acid and ultimately excreted in
bile and urine
pts on VKA, perop check of what labs?
INR
pts on oral anticoagulants can have minor surgery with them? true or false
true
Minor surgeries can be performed on pts taking oral anticoagulants
**Major surgeries you want to stop oral agents how many days preop?
why?
1-3 days pre-op
to give PT time to return to w/in 20% of normal range
when do you want to restart oral anticoagulants post op?
1-7 days
• Newer oral anticoagulants have a rapid onset with therapeutic anticoagulation within hours of administration and do not
need routine monitoring
Xarelto (Rivaroxaban)
Eliquis (Apixaban)
these are both what type of agent
Direct Factor Xa Inhibitor
Xa=Xa
Xa=Xarelto (rivaroXaban), apiXaban (eliquis)
direct factor Xa inhibitors do not require
AT as a cofactor
Direct factor Xa inhibitors have _______ greater selectivity for factor Xa than other serine proteases
> 10,000 fold
**Epidural catheters should not be removed any earlier than hour many hours after the last dose of Xarelto?
18hrs
example was : 12p pt given xarelto, what’s the earliest catheter can be removed? A= 0600.
after having an epidural catheter removed, when can the pt have their next dose of xarelto?
no earlier than 6 hours after removal of catheter
**6-8hrs
Eliquis (apixaban) dosing and indications of use :
- BID
- Reduction of stroke and systemic embolism in a. fib.
- DVT prophylaxis following hip/knee surgery
- TX and reduction of DVT/PE
Direct Thrombin inhibitors are:
Pradaxa / Dabigatran Etexilate
*ximelagatran (off market now but drug that provided proof of principle that oral agents that act via direct inhibition of thrombin were an effective mode of action)
Pradaxa is approved for reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation,
treatment of DVT and PE in pts who have been tx with a parenteral anticoagulant for 5-10 day and to reduce the risk of
recurrence of DVT and PE in pts who have been previously treated.
Preferred measurement of effectiveness for pradaxa?
TT (or aPTT)
after a catheter is removed, when can the next dose of pradaxa be given?
2 hours after removal
ASA is considered an antiplatelet agent and is a mainstay tx for pts with:
- Atherosclerotic vascular disearse
- CAD
-therapy consistent w/the role of PLTs in atherosclerosis
ASA prevents formation of thromboxane A2 by:
IRREVERSIBLY acetylates cyclooxygenase
• Despite rapid clearance from body, effects of ASA on platelets are
irreversible and last for the life of the platelet (7-10 days)
- Stop 7-10 days prior to surgery
- Resume ASA ~ 24 hours post op after hemostasis
What are two platelet inhibitors that are PRODRUGS?
Clopidogrel (Plavix)
Prasugrel (Effient)
Both are Thienopyridines
plavix and effient irreversibly bind to P2Y12 receptors thereby blocking ADP binding.
when should these drugs be stopped prior to surgery?
regional?
• Stop 7 days before elective surgery and avoid regional until effects dissipated.
appear more effective than Plavix in preventing thrombosis, although they increase the incidence of major bleeding, a problem with efficacy of all anticoagulants.
Prasugrel (Effient)
Ticagrelor (Brilinta)
Platelet Glycoprotein IIB/IIIa Antagonists include:
Aggrastat (Tirofiban)
Integrelin (Eptifibatide)
ReoPro (abciximab)
the antidote for GP IIb/IIIa antagonists drugs is:
dialysis
**Especially ReoPro - stop 72 hrs pre-op; 12-24hr 1/2 life
the more potent produg is
Prasugrel (Effient)
The prodrug with resistance occurring in 20-30% of patients is
Clopidogrel (Plavix)
*most widely used agent
flood pg. 657
Protamine adverse reactions include:
- anaphylaxis
- acute pulmonary vasoconstriction
- RV Failure
- Hypotension
