anticoags Flashcards
Explain thrombus formation
activated platelets adhere to vascular endothelium and express P-selectin
microparticles accumulate and bind to platelets and the p selectin
tissue factor leads to thrombin generation which leads to fibrin clot formation
What receptors are at the platelet membrane and what do they bind
GP Ia: binds collagen
GP Ib: binds vWF
GP IIb/IIIa: fibrinogen and other molecules
Explain the clotting mechanism at the site of vascular wall injury
Platelet membrane receptors bind clotting factors
Antiplatelet prostacyclin is released
Aggregating substances from degranulating platelet are released (ADP, thromboxane A2, and 5-HT)
What is hemostasis
maintains integrity of circulatory system after blood vessel injury
hemostatic clots stay localized to vessel wall and do not impair blood flow
pathologic clots causing VTE do result in impaired blood flow
-this is followed by fibrinolysis (clot degradation)
What are some clotting factors and what affects them
Prothrombin: heparin, dabigatran, warfarin
Proconvertin (factor VII): warfarin
PTC (factor IX): warfarin
Factor X: heparin, rivaroxiban, apixaban, edoxaban, warfarin
Protein C&S: warfarin
Plasminogen: thrombolytic enzymes, aminocaproic acid
What is the goal in treating with anticoags
prevent VTE in high risk by:
prevent thrombus extension and embolization
reduce recurrence risk
prevent long term complications (post thrombotic syndrome, chronic thromboembolic pulm HTN)
What are the different anticoag therapies available
Aspirin: anti-platelet
Warfarin: vitamin K antagonist
Heparin: antithrombin (inactivates factor Xa)
LMWH: indirect antithrombin w/ factor Xa inhibitor
Fondaparinux: indirect factor Xa inhibitor
DOAC: direct Xa inhibitors
Dabigatran: Direct thrombin inhibitor
What are Chest guidelines on patients with DVT of leg or PE and no cancer
for long term (first 3 months) anticoag therapy, Dabigatran, Rivaroxiban, apixaban, or edoxaban should be used over vitamin K antagonists
How do you incorporate initial parenteral anticoagulation
Give it before dabigatran and edoxaban
do NOT give it before rivaroxiban and apixaban
Overlap it with VKA therapy
How is heparin dosed
weight based! and admin as continuous IV infusion
How does heparin work
binds endothelial cells and macrophages, and plasma proteins
Neutralize platelet factor 4 released from active platelets
Reduce capacity of heparin-antithrombin comples to inhibit factor Xa bound to active platelets
What are the limitations of heparin
poor bioavailability at low dose
dose dependent clearance
variable anticoag response
reduced activity in vicinity of platelet rich thrombi
limited activity against factor Xa incorporated in the prothrombinase complex, and thrombin bound to fibrin
What are the ADE of heparin
MC: bleeding!
thrombocytopenia (PLT <100k or 50% decrease)
osteoporosis
elevated transaminases
How do you monitor heparin
activated PTT or anti-factor Xa level
How do you reverse heparin’s effect
IV protamine sulfate neutralized heparin
-mix of basic polypeptides isolated from salmon sperm that bind heparin with high affinity and result in protamine heparin complexes that are cleared
What are features of heparin induced thrombocytopenia
PLT levels fall 5-10 days after starting heparin
MC with unfractionated heparin, less common with LMWH
MC in surgical pts and those with cancer
VTE > ATE
How do you manage heparin induced thrombocytopenia
Stop heparin!!
Give a diff anticoag (lepirudin, argatroban, bivalirudin, fondaparinux, rivaroxiban)
Do not give PLT transfusions
Do not give warfarin until PLT count returns to baseline
Eval for thrombosis, esp. DVT
How does LMWH work
Same as heparin!
Binds AT-III which inactivates thrombin, factor IXa, Xa, and XIIa
What are LMWH agents
Enoxaparin (lovenox)
Dalteparin (fragmin): surgical prophylaxis, extended cancer VTE Tx
Fondaparinux (Arixta): AT-III mediated selective inhibition of factor Xa
What is the principle difference in the activity of UFH and LMWH
Relative inhibition of factor Xa and thrombin!
UFH: anti Xa:IIa ratio is 1:1
LMWH: anti Xa:IIa ratio is 4:1 - 2:1
What are advantages of LMWH
Predictable anticoag dose response= can be given subQ QD-BID as prophylaxis and Tx
Lower incidence of thrombocytipenia= safer for short or long term admin
Reduced need for routine monitoring: safer for extended admin
Initiating anticoag therapy with Lovenox is
Weight based!
but all basically 1mg/kg q12 hrs?
Initiating anticoag therapy with Fondaparinux is
weight based! <50 kg= 5mg qd. 50-100kg= 7.5mg qd
Start warfarin on 2nd day of Tx, but continue Fonda until INR >2 (at least 24 hours)
What meds are affected by pork allergy
Heparin
LMWH (EXCEPT fondaparinux!!)
What should Enoxaparin NOT be used in
patients with cancer
-it can be used as prophylaxis in hip/knee replacement, abd surgery, acute med illness, and DVT Tx
What should Dalteparin NOT be used in
DVT/PE treatment
Knee replacement surgery
-can be used in hip replacement, abd surgery, acute med illness, and VTE cancer prophylaxis
What are properties of heparins
Large acidic polysaccharide polymers Parenteral admin site of action: blood Onset: rapid, minutes MOA: binds AT-III and inactivates factor IXa, Xa, XII Monitoring: aPTT for UFH Antidote: protamine IV for UFH Use: acute, over days Use in pregnancy: yes!
What are properties of warfarin
Small lipid soluble molecule PO site: Liver Onset: slow (days); limited by halflives of normal factors MOA: interferes w/ synthesis of vitamin K dependent clotting factors (II, VII, IX, X) Monitor: PT/INR Antidote: vitamin K if Sx. plasma Use: chronic, wk-mo Pregnancy: No! it is teratogenic*
What is warfarin also known as
rat poison!
What is the MOA of warfarin
Inhibits VK poxide reductase= interferes with synthesis of functional VK= No VK dependent clotting factors
-Used in VTE, PE, preventing clots in AFIB or cardiac valve replacement
PO has delayed onset and offset activity
What are ADE of Warfarin
Bleeding! can use VK to reverse effects
thrombosis early in therapy is 2/2 protein C deficiency
*Monitor PT/INR
What drugs does warfarin interact with
CYP450 inducers: decreases effect
CYP450 inhibitors: increases effect
What clotting protein does vitamin K block first
Factor VII!!! (4-6 hour half life)
Then protein C (9 hour half life)
Lastly Protein S (60 hr half life)
What are some contraindications to warfarin
Hypersensitivity Hemorrhagic tendencies recent eye surgery or CNS lumbar block anesthesia or traumatic surgery malignant HTN Adherence concerns (need to monitor)
What are the DOACs
Apixaban (eliquis)
Betrixiban
Edoxaban
Rivaroxaban (xarelto)- most bioavailable (80%)
Dabigatran: prodrug! converted in liver to active form. most renally excreted drug (80%)
How do DOACs work
Bind active site of Factor Xa and inhibit enzyme action
-Used for VTE, PE, preventing stroke in AFib pts
Fixed PO dose
ADE of DOACs are
bleeding! no specific reversal agent
Do not need to monitor these patients or dose adjust, but can check factor Xa test
What DOACs should NOT be used in VTE prophylaxis after orthopedic surgery
Dabigatran (pradaxa)
Edoxaban (also do NOT use this in extended VTE Tx; >6 months)
What is important to note about administering Rivroxiban
When using for extended VTE Tx (>6 months), give the dose WITH food!
The only time you have the option, w/ or w/o food, is short term VTE prophylaxis after ortho surgery
What DOAC is good to use in ESRD
Apixaban!
It has the lowest renal excretion, at only 25%
What do current guidelines say about long term DVT and PE prevention
Full dose anticoag therapy is recommended for min. 3 months after DVT or PE
Patients at high risk may benefit from extended Tx
Low dose DOAC is safer than full dose traditional anticoag for extended Tx
*Consider low dose DOAC for patients requiring long term VTE prevention after 3-6 months of acute Tx
What are reversal agents for DOACs
Dabigatran: Praxbind
Rivaroxiban, Apixaban, LMWH: Andexanet (FDA approved)
Ciraparantag: UFH, LMWH, Rivaroxaban, Apixaban, Edoxaban, Dabigatran
What is the VTE treatment PO only strategy
Day 0-7: Apixaban high dose Wk 2-6 mo: Apixaban med dose >6 months: Apixiban low dose OR Day 0-21: Rivaroxaban 15mg Day 22->6 mo: Rivaroxaban 20mg
What is the VTE Tx Switch strategy
Day 0-5: UFH, LMWH, or Fondaparinux
Day 5- >6mo: Dabigatran or Edoxaban
What is the VTE Tx overlap strategy
Day 0-6: UFH, LMWH, or Fondaparinux
Day 0- >6mo: Warfarin PO daily
What is appropriate duration of VTE Tx
Initial duration to effectively treat acute 1st episode of VTE: 3 months
This reduced recurrent VTE risk
What is INR goal range for warfarin therapy
2-3
Except if with a mechanical valve: 2.5-3.5 (lifelong therapy)
What is the way to remember the color of warfarin tabs
Please Let Granny Brown Bring Peaches To Your Wedding Pink -1 Lavender -2 Green -2.5 Brown -3 Blue -4 Peach -5 Teal -6 Yellow -7.5 White -10
How do you start warfarin therapy
Day 1: 5mg
2-3 days later: if INR <1.5, continue at 5. >3, hold and recheck next day
5-7 days later: if INR <1.5, increase to 7.5-10. If >3, reduce to 0-.25mg
How frequently do you check INR when initiating warfarin therapy
Every 2-3 days until INR in therapeutic range on 2 consecutive checks
Every week until 2+ checks in therapeutic range
Every 2 weeks until 2+ checks in therapeutic range
Every 4 weeks when dose is stable
What is a basic way you can adjust warfarin dose based on INR (if goal is 2-3)
<1.5: increase 10-20% TWD
1.5-1.9: increase 5-10% total weekly
2-3: no change
3-1.4: decrease 5-10% total weekly
4.1-5: hold 1-2 doses and decrease 10% total weekly
-If goal is 2.5-3.5, hold 1-2 doses and decrease 10% if INR is 4.6-5
How frequently do you check warfarin when maintaining warfarin therapy
After 1 week if starting or stopping interacting med, changing diet or activity level
Every 1-2 wks if 5-10% dose adjustment needed
Every 4 wks if maintained on same stable dose <3 mo.
Every 6-8 weeks if pt on same stable dose 3+ mo
Every 12 weeks if pt on same stable dose for 6+ mo
What factors indicate warfarin sensitivity
Increased INR response Baseline INR >1.5 65+ y/o ABW <45kg (actual < ideal) Malnourished/NPO >3 days Hypoalbuminemia Chronic diarrhea Significant dug interactions Decompensated HF Increased bleeding risk Thrombocytopenia Cirrhosis/total bili >2.4 Hx alcohol abuse ESRD GI bleed in past 30 days Surgery in the past 2 weeks IC bleed in past 30 days
What are key concepts in managing warfarin
dose adjustments should be made on current total weekly dose
consider trends in INR when making management decisions
consider pt ht, wt, age with dose requirements
Consider repeating INR in same day if value is very diff. than expected
Consider no dose adjustments for INR on low end or high end, retest in 1-2 weeks
Consider no dose adjustments for INR above or below therapeutic range by 0.5 or less. retest in 1-2 wks
Monitor more frequently in first month of initiation
Consider extending monitoring more frequently in first 3 mo. of in-range INR
CoaguCheck XS machine is only accurate for INR 0.8-8
If pt INR is 5-10 (supratherapeutic), how do you proceed
Recommend against use of VK
Hold 1-2 doses, check INR in 24 hrs
Resume lower dose when INR in range
If pt INR is >10 (supratherapeutic), how do you proceed
Give VK 2.5-5mg
Hold 2 doses, check INR in 24 hrs
Repeat VK prn
Resume lower dose of warfarin when INR is in range
Pearl on holding warfarin
Holding warfarin 1 dose drops INR by appx. 1
How do you transition from LMWH to warfarin
Need min. 5 days of warfarin therapy and pt INR in goal range for min 24 hours before you can d/c Lovenox
day 1: initiate lovenox and warfairn
day 4: check INR. cont or adjust dose if needed
day 6: check INR. cont or adjust dose if needed
day 7: check INR. dc lovenox if INR in goal range for 24 hrs, or continue lovenox until it occurs
What procedures are high risk for bleed
heart valve replacement CABG neuro, urologic, head/neck, abd, or breast cancer laminectomy kidney biopsy transurethral prostate resection polypectomy, variceal Tx, biliary sphincterotomy, pneumatic dilation PEG placement EGD guided FNA multiple tooth extractions vascular and general surgery Any major op lasting >45 min
How do you bridge therapy for high-mod risk of thromboembolism
4 days before surgery: dc warfarin
3 days before surgery: initiate LMWH
2 days before surgery: check INR
1 day before surgery: dc LMWH
1 day after surgery: resume warfarin
2 days after surgery: resume LMWH for low bleed risk procedure
3 days after surgery: resume LMWH for high bleed risk procedure
How do you switch from warfarin to LMWH
dc warfarin and start Dabigatran or Eliquis when INR <2
dc warfarin and start Rivaroxaban when INR <3
How do you switch rom LMWH to warfarin
Rivaroxaban: no data available
Dabigatran:
CrCl >50, start warfarin 3 days before dc dabigatran
CrCl 30-50, start warfarin 2 days before dc
CrCl 15-30, start warfarin 1 day before dc
When should you assess patients on anticoags
Extended therapy: at periodic intervals (ex. yearly)
w/ leg DVT or PE on warfarin: maintain INR 2-3
w/ leg DVT or PE, no cancer, no DOAC: warfarin preferred
Recommendations for pts with DVT
If home circumstance is adequate, initial Tx at home is better
Early ambulation is suggested over bed rest
Anticoag Tx alone is better than cath thrombolysis if DVT is acute and proximal LE
If acut and Sx leg DVT, do not use compression stockings
What are the thrombolytics
Alteplase, Reteplase
Tenecteplase
Streptokinase
Urokinase
How do thrombolytics work
convert plasminogen to plasmin which causes breakdown of clots
-Good for MI, DVT, PE, and ischemic stroke (t-PA)
Alteplase, Reteplase convert fibrin bound plasminogen targeting clots
Indications for the use of fibrinolytics
Ischemic chest discomfort lasting 20+ min, onset <12 hours
ST elevation in 2 contiguous leads (2+mm in men, 1.5+mm in women in V2-3 -OR- 1+mm in all other leads)
New LBBB
Absolute contraindications to fibrinolytics are
active internal bleeding (not menses) previous IC hemorrhage Ischemic stroke w/in 3 mo known IC neoplasm known structural cerebral vascular lesion (AVM) suspected aortic dissection significant closed head/facial trauma w/in 3 mo IC or intraspinal surgery w/in 2 mo severe uncontrolled HTN Use of streptokinase w/in 6 mo
What should STEMI/NSTEMI management include
*Aspirin! class 1 recc. for both Clopidogrel in addition to ASA is class 1 recc for both PCI in both is also a class 1 Prasugrel added to ASA is a class I for both Can also add Ticagrelor, or Cangrelor to ASA therapy
Warfarin and LMWH therapy recommendations in STEMI/NSTEMI include
UFH is a class I in both Enoxaparin is a class I in both Bivalirudin is a class I for both Fondaparinux is a class I for both
What are fibrinolytic recommendations in STEMI/NSTEMI
Fibrinolytic Tx: STEMI w/in 12 hrs, class I. NSTEMI, class III GPI inhibitors: NSTEMI class I (for abciximab). STEMI class IIa (for abciximab) Nitroglycerin: class I for both
Other pharm therapy for STEMI/NSTEMI
BB: class I for both (PO). class III for IV CCB: NSTEMI class I. Diltiazem for NATEMI/AMI class III ACE-I: class I for both ARB: class I for both Aldosterone antag: class I for both Morphine: class IIb for both if CP persists after drug Tx Statins: class I for both
Where do antiplatelet drugs work
ASA: inhibits thromboxane A2 synthesis by irreversibly inhibiting COX-1
Clopidogrel, prasugrel: irreversibly block P2Y12 (ADP receptor on PLT surface)
Cangrelor, ticagrelor: reversibly ind P2Y12 receptor
Abciximab, Eptifibatide, tirofiban: block fibrinogen and vWF binding to GP IIb/IIIa= inhibit final common pathway of platelet aggregation
Vorapaxar: targets PAR-1 (major thrombin receptor) and inhibits thrombin mediated platelet activation
What are the direct thrombin inhibitors and how do they work
Bivalirudin, Desirudin, Argatroban
Bind thrombin’s active site and inhibit it’s enzymatic action
Used as anticoag in patients w/ heparin induced thrombocytopenia
ADE of direct thrombin inhibitors
Bleeding!
monitor aPTT
What is the best direct thrombin inhibitor
Bivalrudin! No renal or liver clearance, and shorter half life so easier to control
-Desirudin is renally cleared, Argatroban has hepatic metabolism
