Anticoagulants Flashcards
The three basic mechanisms of hemostasis are
Vasoconstriction, platelets, and clotting factors
Basic steps in hemostasis
1) Vasoconstriction
2) Formation of platelet plug
3) Activation of clotting cascade
4) Formation of fibrin blood clot
5) Clot retraction and dissolution
Primary hemostasis
Occurs immediately
Results in platelet plug
Exposed subendothelial collagen attracts platelets which start to adhere to each other
Factors involved in primary hemostais (also causes local vasoconstriction)
vWF
CF VIII
ADP
Adhered platelets release ________ and use _____ and _____ as a connecting agent
TXA2
Fibrinogen and vWF
Platelet degranulation agents
5-HT, Histamine- vasoconstrictors
Thromboxane- vasoconstriction/degranulation
ADP- promotes adherence and degranulation
CF Va, VIIIa, IXa
Platelet factor 4 (heparin neutralizing factor)
Secondary hemostasis takes place over what kind of time frame?
Minutes to hours
What is the end product of the coag cascade in secondary hemostasis?
FIBRIN
This forms the meshwork of protein that helps to stabilize the platelet plug and trap other cells
Basic intrinsic pathway (PTT)
Factor XIIa–> Xa–>Prothrombin–> Thrombin
Fibrinogen–> Fibrin
Basic extrinsic pathway (PT)
Tissue factor and Factor VIIa–> Xa–>
Prothrombin–> Thrombin
Fibrinogen–> Fibrin
Natural anticoagulants
PCI2 Antithrombin III Heparin Protein C Protein S
After a clot forms and stabilizes, it then
Retracts
How does clot retraction work?
Platelets trapped in the fibrin mess contain actinomyosin-like contractile proteins, which squeeze out protein-free serum. This mostly takes place within the first hour.
Describe the fibrinolytic system
Mediated by plasmin,which becomes activated by coagulation and inflammation substances
Plasmin splits fibrin and fibrinogen into fibrin degradation products
Antiplatelet aggregation agents
5 oral
3 IV
Oral agents- aspirin, ticlopidine, clopidogrel, prasugrel, ticagrelor
IV- abciximab, eptifibatide, tirofiban
What does aspirin inhibit? What type of inhibition is it?
COX inhibitor
Irreversible! Remember platelets are around for about 10 days.
Aspirin is indicated for
Prevention of recurrent ischemic events, such as stroke, MI, and symptomatic PVD
ASA dose
81-325mg qday
ASA precautions
Children (Reye’s syndrome)
Pregnancy
CV- blocks ACE, BB, and diuretic effects d/t prostaglandin inhibition
Asthmatics- results in increased leukotriene production
Increased bleeding with other anticoags
Treatment for over anti-coagulation with ASA?
Platelet transfusion, otherwise you gotta wait a long time
How does ticlopidine (ticlid) work?
Blocks APD receptor on platelets and inhibits fibrinogen binding
When is ticlopidine used?
Same indications as ASA, usually used for ASA intolerance
Ticlopidine is bad news bears because…
It causes extreme neutropenia, thrombotic thrombocytopenic purpura, GI upset (really..?), and its also teratogenic
Clopidogrel (Plavix) works by
Irreversibly blocking ADP receptor on platelet and inhibits fibrinogen binding
Used for same stuff as ASA, usually as dual therapy with ASA (more effective, also more bleeding)
Clopidogrel dosing
Loading dose of 300mg or 600mg
Daily dose of 75mg
Clopidogrel precautions
Metabolized by CYP2C19, may need increased dosing due to genetic variation
Inhibits CYP450
Severe renal/hepatic disease, reduce dose
For alllllll of these drugs using more than one will…
Increase your risk of bleeding
Clopidogrel pts most at risk of bleeding?
Elderly, underweight, previous TIA/stroke
Bleeding treatment on clopidogrel
Stop drug
GIve platelets
Prasugrel (Effient) what is it? When might a pt be on it?
New thienopyridine, better risk reduction than clopidogrel, but also causes more fatal bleeding events
Often used in clopidogrel non-responders
Prasugrel dosing and precautions
10mg qday
Active bleeding
Previous stroke/tia, underweight, >75- consider 5mg qday
Risk of bleeding during CV surg is 4x greater than clopidogrel. Don’t use pre-cath.
Ticagrelor (Brilinta) works by ______? How does it compare to clopidogrel?
Blocks ADP receptors by allosteric antagonism
Better than clopidogrel for mortality reduction post MI/stroke, but also more bleeding and much higher rate of fatal ICH
Ticagrelor uses and dosing
Prevention of recurrent ischemic events after stroke, ACS, and post PCI
180mg once, 90mg bid thereafter
Always as dual therapy with ASA unless contraindicated
Ticagrelor precautions
ASA more than 100mg aday
Hepatic dysfunction
Hold for >5 days pre-surg
BID dosing
Contraindications- active bleeding, ICH history
How do GPIIb/IIIa inhibitors work? Uses? 3 drugs-
Block GPIIb/IIIa receptor, which prevents fibrinogen binding
Used for ACS and PCI
Abciximab (ReoPro), Eptifibatide (Integrilin), Tirofiban (Agrastat)
Abciximab (ReoPro) is used for _______? When used with heparin what’s the aPTT goal? Downsides?
Used in ACS with planned PCI
aPPT goal of 60-85 sec
Most expensive in its class and most prolonged effects
Eptifibatide uses and dosing considerations
Used for ACS and PCI
Dosing based on serum creatinine
<2.0 mg/dl- 2.0 mcg/kg/min for up to 72 hours
2.0-4.0 mg/dl- 1.0mcg/kg/min for up to 72 hours
GPIIb/IIIa inhibitors- How do you treat bleeding?
Abciximab (ReoPro)- reverse with platelets
Eptifibatide (Integrilin) and Tirofiban- turn it off and wait
Temporary interruption of anti-platelet therapy should take place _______ prior to surgery
7-10 days
Anti-platelet therapy should resume ________ post-op as long as hemostasis is achieved
within 24 hours or next AM
For pts at high risk of CV events, when should ASA/Clopidogrel be stopped?
ASA should NOT be discontinued
Clopidogrel should be stopped at least 5 days prior to surg
How does heparin work and what is it used for?
Activates antithrombin III–> increases inhibition of thrombin IIa and Factor Xa 1000 fold
Used for DVT prophylaxis/treatment, PE treatment, ACS, when warfarin is started or contraindicated
Heparin dosing for DVT prophylaxis
5000 units SubQ q8hrs (q12hr dosing sometimes…for NeuroSurg, ESRD)
IV infusion heparin dosing
Weight-based bolus
Weight-based infusion
Protocol adjusted by aPTT or anti-Xa values (q6hrs until stable, then qday)
Drawbacks of heparin
Variable effect, frequent titration
DOES NOT inhibit clot-bound thrombin
Heparin reversal agent
Protamin 1mg/100u of heparin
Incidence of HIT
1% @ 7 days
3% @ 14 days
HIT type I
Non-immune mediated, BENIGN
Mild drop in platelets, <4 days, not progressive nor associated with thrombosis
HIT type II
Immune mediated, more typical onset and MORE BAD
Always follows heparin exposure (check history)
Reduction in platelets to <150,000 OR 50% reduction from PRE-HEPARIN exposure
Typically 7-14 after initial exposure, but may be much shorter if pt was exposed in the past
Thrombocytopenia occurs what percent of the time with heparin therapy? More common in UF or LMWH?
about 2-5
More common in UF heparin
Typical pt/platelet count/onset time for thrombocytopenia
Surg>med>OB
38,000-60,000
Typical onset (66%)- exposure of 5-14 days
Delayed (3-5%)- exposure of 2-6 weeks
Rapid (25-30%) hours-days (usually has history of heparin exposure and circulating antibodies from previous 100 days)
HITT (HIT with thromboembolism)
% of cases
Venous vs Arterial
Mortality rate and amputation rate
10-25% of cases
Venous (4x more common)- DVT, PE, venous limb gangrene, dural sinus thrombosis
Arterial- CVA, limb ischemia, skin necrosis, MI, gut ischemia, adrenal/renal/spinal artery infarcts
25-30% mortality, 25% amputation rate
HIT lab tests
ELISA
- measures titer of IgG to heparin-PF4 complex
- simple and readily available
- 90% sensitive, 80% specific
SRA
- detects platelet activation
- labor intensive, usually a send-out lab
Management of HIT
Stop all pro-thrombocytopenic drugs
STOP heparin (FOREVER) and START non-heparin anti-coag (usually Argatroban)
Check history for heparin exposure
Remove all sources of heparin (flushes, coated devices, sq DVT prophylaxis)
LMWH (Enoxaparin) MOA and uses
~5,000 daltons in size
Binds antithrombin III and inhibits factor Xa
Used for DVT prophylaxis, ACS, and VTE treatment
How can the effects of LMWH be checked?
Anti-Xa levels, but this is not routinely done
In what pt population on LMWH therapy would you want to monitor anti-Xa levels
Pregnant women
Precautions with LMWH
Use weight based dosing for obese pts
Not recommended in severe renal insufficiency, decrease dose by 50% if no alternative
Contraindicated in spine surg and patients with epidural catheters
Can protamine reverse LMWH?
Yes, but only ~60% reversal
How does Fondaparinux (Arixtra) work? What is it used for?
It is a synthetic factor Xa inhibitor. Binds with anti-thrombin III to potentiate Xa inhibition (300x). No effect on IIa (thrombin).
Used in ACS, PE/DVT prophylaxis, DVT treatment
Fondaparinux dosing, contraindications, reversal
7.5mg subq qday for prophylaxis, 10mg for VTE or wt >100kg
Contraindicated for CrCl< 30 ml/min, spinal puncture/anesthesia
No known reversal, FFP ineffective. Discontinue drug and provide supportive care.
Direct thrombin (IIa) inhibitors
Hirudin, lepirudin, desirudin, hirulog, argatroban (reversible), bivalirudin
Used in HIT (argatroban, lepirudin)
PCI (Bivalirudin)
Toxicities, interactions, and bleeding treatment for direct thrombin inhibitors
Bleeding
Lepirudin and Desirudin can only be used once on a patient d/t anaphylaxis risk
Increased bleeding with other anti-coagulants
Stop infusion, may respond to factor VII, FFP, and cryoprecipitate
What does warfarin interfere with?
Production of vitamin K dependent clotting factors (II, VII, IX, X) and carboxylation of natural anticoagulants protein C and protein S
What is warfarin used for?
DVT, a-fib, mechanical heart valve thrombosis prevention
Long-term VTE treatment
The INR goal for most warfarin indications is
- 0-3.0
2. 5-3.0 in high risk pts
For uncomplicated DVT/PE what is the normal duration of warfarin therapy?
3 months
When transitioning to warfarin, how long should heparin or LMWH overlap for?
1-2 days
What genetic variants can require changes in warfarin dosing?
Variations in CYP2C9 can decrease warfarin metabolism
Variations in vitamin k expoxide reductase can require dose reductions
Warfarin toxicities
Bleeding, birth defects, cutaneous necrosis
Warfarin interactions
Increased effect- Amiodarone CImetidine Acetaminophen Phenylbutazone
Decreased effect- Sucralfate Cholestyramine Spironolactone Barbiturates Vitamin k containing foods
Warfarin reversal
Vitamin K, IV or PO
FFP
In terms of surgery, when should warfarin be stopped and restarted?
5 days prior to OR
Restarted 12-24 hours post-op if normal hemostasis has been achieved
High risk patients can be bridged with heparin up to 4-6hrs pre-op
What does dabigatran (pradaxa) inhibit? What is it used for?
It is a direct thrombin inhibitor (IIa)
Stroke prevention in non-valvular a-fib and VTE prophylaxis after total knee/hip replacement
110mg bid for high bleeding risk or renal impairment , otherwise 150mg bid
How does dabigatran to warfarin?
150mg dose is superior for reduction of stroke and systemic embolism with no difference in bleeding.
110mg dose in noninferior for prevention and has a 20% reduction in bleeding risk
All of the new oral anticoagulants (dabigatran, rivaroxaban, and apixaban) have what disadvantages?
High cost (bid dosing for apixaban), no antidote, no assay for monitoring, and no long term data.
Rivaroxaban (Xarelto) MOA, uses, and dosing
Direct factor Xa inhibitor
Used for stroke and systemic embolism prevention in a-fib
20mg qday
How does rivaroxaban compare to warfarin?
noninferior, similar bleeding risk, but decreased risk of ICH and fatal bleeding
Advantages of dabigatran
No routine monitoring needed
Less influenced by diet and other drugs
Rapid time to peak action (1 hr)
Short half like (12-14 hrs) in pts with normal renal function
Apixaban (Eliquis) MOA, uses, dosing
Direct Xa inhibitor
Used for stroke and systemic embolism prevention in a-fib
5mg bid
How does apixaban compare to other anti-coags
Clear benefit over ASA for patients unable to take warfarin
Superior to warfarin for prevention and reduced risk of bleeding, in particular lower rates of ICH and mortality
Fibrinolytic drugs and how they work
Streptokinase, Urokinase, t-PA, Tenecteplace (TNK-ase)
Plasminogen activators convert plasminogen to plasmin–> plasmin causes fibrinolysis
Uses for fibrinolytics
Acute ST-elevation MI
Acute ischemic stroke (within 6 hours of symptom onset) t-PA only
Urokinase only for PE or central line de-clotting
tPA dosing vs TNKase dosing
tPA 10 units over 2 min, repeat in 30 minutes
TNKase 30-50mg given as a one time bolus over 5 seconds
Absolute contraindications for fibrinolytics
Previous hemorrhagic stroke
Ischemic stroke in last 3 months or acute within last 3 hours
Known intracranial neoplasm
Active internal bleeding, excluding menses
Suspected aortic dissection
SIgnificant closed head or facial trauma within 3 months
Relative contraindications for fibrinolytics
BP > 180/110, treating it is ok in terms of removing this contraindication
Severe chronic HTN
INR>2.5, use of other anticoagulants
Known bleeding disorder
Non-compressible vascular puncture
Recent trauma within 2-4 weeks (traumatic CPR)
Major surg <3 weeks
Recent internal bleeding or PUD (2-4 weeks)
Pregnancy
For streptokinase allergy or prior exposure (5 days to 2 years)
