ANTICOAGULANTS and ANTIPLATELET AGENTS
1. Review the coagulation cascade, platelet aggregation and clot formation
Platelet GPIb-IX-V receptor complex binds to Von Willebrand Factor on exposed collagen (tethering)
 This adhesion is inhibited by nitric oxide and prostaglandins on intact endothelial surfaces
 his binding, as well as release of thrombin from tissue factor, activates the platelets
Activated platelets:
 Signal the activation of integrins that bind strongly to collagen and other collagen ligands (vWf & fibronectin)
 Integrins signal the release of agonists ADP, ATP, platelet activating factor, platelet factor 4, serotonin, vWf, and thromboxane A2 from
platelet granules, which amplifies integrin signaling and thrombus growth/platelet aggregation
Aggregation
 the released agonists and collagen bind to receptors on activated platelets to increase intracytoplasmic calcium
 platelets change from smooth to a spiny sphere
 plasma membrane arachidonic acid released and converted to prostaglandin H 2 by COX1 & thromboxane synthase (potent platelet
activator)
 GPIIb/IIIa, resting platelet membrane integrin, undergoes an inside out signaling that initiates an affinity for fibrinogen
 Platelet aggregation occurs as GPIIb/IIIa bridge between fibrinogen molecules as well as vWf
o Fibrinogen is synthesized by the liver and binds to sites on activated platelets
o vWf is secreted from platelet granules and endothelial cells
Coagulation system involves the sequential activation of inactive clotting factors/proteins circulating in the blood
 Intrinsic pathway = triggered by damage to endothelium  contact between Factor XII (Hageman Factor) and negatively charged
substances like collagen, phospholipids, and platelet plug that are located beneath and exposed by injured endothelial tissue. This leads
to Factor XIIa which converts FXI to Factor XIa. Factor XIa catalyzes reaction of factor IX to Factor IXa. Factor IXa along w/ cofactor VIIIa form tenase complex, which activates Factor X to Factor Xa.
 Extrinsic pathway = triggered only if cells surrounding blood vessel are damaged, leading to the leakage of TF. The exposure of factor
VII to tissue factor (factor III or thromboplastin) forms an activated TF-FVIIa complex that catalyzes activation of factor IXa & Xa
 Common pathway: meet at factor Xa ….
o Fibrin clot is produced during the final common coagulation pathway during which the tenase complex/plasminogen activator
initiates the conversion of prothrombin to thrombin and finally fibrinogen to fibrin
 Important to know the pathway because important for lab monitoring
o PTT (Intrinsic pathway): Heparin, Angiomax (bivalirudin), Argatroban (measure PTT)
o Xa (Common pathway): LMWH, fondaparinux (measure anti-Xa)
o PT/INR (Extrinsic pathway): Coumadin (warfarin) (measure INR)
 INR is correction factor for variation between labs
2. Describe medications which affect hemostasis including mechanism of action and adverse effects (♦ = safe in pregnant pts)
ANTI-PLATELET MEDICATIONS
Aspirin
 Mechanism of Action: irreversibly inhibits COX  inhibits prostaglandin synthesis, including thromboxane A2, which is one agent
responsible for irreversible plt activation & aggregation
o Hold aspirin 2-3 days before surgery (although some effects of aspirin likely to persist 1-2 weeks)
 AEs: dyspepsia, bleeding, asthma exacerbation, rare rash, hepatotoxicity, thrombocytopenia
 Monitor: CBC, platelets, serum Cr
 Avoid in children < 16 yo with recent/current viral illness or recent live vaccine d/t risk of Reye’s syndrome
o Classic features of Reye’s = rash, vomiting, liver damage (fatty liver, hepatomegaly), & life-threatening encephalopathy
Drug (Brand)
Aspirin
Dose
81 – 325 mg QD
Comments
- recommended in pts w/o contras with unprovoked proximal DVT or PE who are stopping anticoagulation
- AHA/ASA: recommend aspirin 81 mg QD ir 100 mg Q48 hrs for pts at high risk for stroke, including in CKD
* aspirin should NOT be used to prevent stroke among pts whose sole risk factor is DM or asymptomatic PAD *
- ADA: consider aspirin for women ≥ 50 w/at least one additional major risk factor (family hx of premature ASCVD, HTN, smoking, HLD, or
albuminemia) & not at increased bleed risk
Platelet P2Y12 Inhibitors
 Mechanism of Action: inhibits ADP-induced platelet aggregation thru interaction w/ P2Y12 receptor
 AEs: bleeding, dyspepsia, rare rash, headache
 Monitor: CBC, platelets
 All are irreversible, except ticagrelor
 ALL REQUIRE A LOADING DOSE & lots of drug interactions!
 Effects seen in 3-7 days
Drug (Brand)
Clopidogrel
(Plavix)
Prasugrel
(Effient)
Ticagrelor
(Bilinta)
Dose
75 mg Q24hr ± 300600mg loading dose
60mg loading dose
then 10 mg Q24hr
180 mg loading dose,
then 90 mg Q12hr
PK
- requires activation by liver
- irreversible
- requires activation by liver
- irreversible
- does NOT require liver activation
- reversible
Cagrelor
(Kangreal)
30 mcg/kg bolus, then
4 mcg/kg/min infusion
- requires activation by liver
- irreversible
Comments
2C19 & 3A4 substrate
Hold for 5 days before surgery
3A4 substrate
Prasugrel = CONTRA after TIA or Stroke
AE of dyspnea
3A4 substrate & 2C9 inhibitor
Ticagrelor = USE IN CIRRHOSIS PTS!
PAR-1 Antagonist
 Mechanism of Action: reversible antagonist of protease-activated receptor-1 (PAR-1) expressed on platelets, inhibits thrombin-induced
and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation
o Note: due to it’s very long half-life, vorapaxar is effectively irreversible
 AEs: bleeding, anemia, rash, depression
 Monitor: CBC
 AVOID in patients w/hx of stroke, TIA, intracranial hemorrhage or severe hepatic impairment
 Vorapaxar = for pts w/ prior MI or PAD
Drug (Brand)
Vorapaxar (Zontivity)
Dose
2.08 mg QD in combo w/aspirin or clopidogrel
Comments
- Vorapaxar = for pts w/ prior MI or PAD
Dipyridamole
 Mechanism of Action: vasodilator that inhibits plt aggregation by inhibiting adenosine uptake & cGMP activity
 AEs: bleeding, HA, abdominal pain, diarrhea, nausea, dyspepsia
 Monitor: CBC, platelets
 Dipyridamole = for stroke prevention after TIA
Drug
Aggrenox (dipyridamole ER 200 mg / aspirin 25 mg)
Dose
1 capsule PO Q12 hr ~ generally taper, often
starting w/Qhs dosing for 1st week to prevent HA
Comments
- Dipyridamole = for stroke prevention after TIA
FIBRINOLYSIS IMPACTING MEDICATIONS
(fibrinolysis = endothelial cells secrete tissue plasminogen activator or t-PA at sites of injury which binds to fibrin and converts plasminogen to
plasmin, which digests fibrin; PAI-1 & PAI-2 inactive t-PA, while α2-antiplasmin inactivates plasmin)
Fibrinolytics
 Mechanism of Action: convert plasminogen to plasmin, which in turn breaks down fibrinogen, destabilizing the clot
 AEs: bleeding, rare angioedema
 Alteplase (t-PA, Activase, Cathflo) = most commonly used
o dose depends on indication, but NEVER EXCEED 100 mg for any indication
 Alteplase (t-PA, Activase, Cathflo) = for (1) acute ischemic stroke, (2) severe, total occlusion PE, (3) acute MI (at centeres where
PCI is not readily available), (4) catheter clearance, & more
Fibrinolysis Inhibitors
 Mechanism of Action: aminocaproic acid inhibits the activation of plasminogen to plasmin (useful in some bleeding disorders)
 AEs: thrombosis, myopathy, hypotension, abdominal discomfort, diarrhea, blood dyscrasias
 Monitor: CBC, fibrinogen, BUN, Cr
 Aminocaproic acid & tranexamic acid = used to block fibrinolysis in pts w/severe bleeding disorders or in surgery w/severe
bleeding
HEPARINS (safe in pregos/lactation b/c large molecules unlikely to cross)
Unfractionated Heparin (UFH) ♦
 Mechanism of Action: directly activates anticlotting factor antithrombin III (ATIII), allowing ATIII to more quickly inactivate
factors 9, 10, & 2 (thrombin)
 AEs: bleeding, rare thrombocytopenia, alopecia, hepatotoxicity, hypersensitivity reactions
 Monitor: PTT or anti-Xa levels, CBC, platelets, K+
 Antidote = protamine 1 mg per 100 units of heparin, max 50 mg
Drug
UFH ♦
Dose
- prophylaxis: 5000 units Q12h or Q8h
- treatment: 10-20 units/kg/r on avg,
titrated to PTT or anti-Xa
Antidote
- protamine sulfate 1 mg per 100 units of
heparin, max 50 mg
Comments
- mixture of molecules of diff wt & activity
Low Molecular Weight Heparin (LMWH) ♦
 Mechanism of Action: primarily binds antithrombin to Xa, inactivating it to prevent clotting
 More predictable PK, less inter-pt variability than UFH
 Dosed based on weight ± renal function
 No routine monitoring required
 AEs: bleeding, rare thrombocytopenia, skin necrosis, skin hypersensitivity reactions
 Monitor: K+, CBC, platelets, serum Cr, anti-Xa levels for select pts
 BLACK BOX WARNING: spinal or epidural hematomas, including subsequent paralysis, may occur w/recent or anticipated
epidural or spinal anesthesia or LP in patients coagulated w/LMWH or heparinoide
o Hold LMWH before & after spinal procedure
o Observe pts closely for s/s of neural impairment
Drug
Enoxaparin
(Lovenox) ♦
Dalteparin
(Fragmin) ♦
Prophylaxis
40 mg Q24h or 30
mg Q12h
5000 units Q24h
Treatment
1.5 mg/kg Q24h or 1 mg/kg
Q12h
- 200 units/kg Q24 VTE
- 120 units/kg Q12 ACS
Antidote
- protamine sulfate 1 mg per 1
mg enoxaparin
Comments
- reduce dose in renal impairment
- may be better to do BID option in obese & old
- increase dose for overweight pts
Heparin-Induced Thrombocytopenia (HIT)
 Heparin & LMWH can bind to platelet factor 4 and cause immune-mediated HIT (risk lower w/LMWH)
 1-4% of all pts exposed to heparin for a week or more
 Rapid decline in platelets
 Thrombosis occurs in up to 50% of pts
 HIT Score:
o High (6-8): HIT is likely
o Intermediate (4-5): HIT is possible
o Low (0-3): HIT is unlikely
 Management of HIT:
o Send HIT antibody, serotonin release assay performed as confirmatory test if antibody is positive
o d/c all heparin products
o initiate tx w/ direct thrombin inhibitor (argatroban, bivalirudin) at therapeutic dose
 fondaparinux (Arixtra) can be used in select cases
o Once platelet count has recovered, initiate low-dose warfarin
o DOCUMENT HEPARIN ALLERGY
WARFARIN
Warfarin (Coumadin)
 Mechanism of Action: inhibits the synthesis of Vit K-dependent clotting factors (7, 9, 10, and 2)
 Warfarin does NOT inhibit activity of existing clotting factors so have to wait for depletion of factors to see effects of warfarin
o NOT therapeutic until at least 3-4 days and a couple days of therapeutic INR – should overlap warfarin w/heparin for the first two
“therapeutic INRs” b/c can be falsely therapeutic, reflecting depletion of factor 7 rather than body’s ability to halt clot expansion or
form new thromboses
 AEs: bleeding, TERATOGENIC, rare hypersensitivity reaction
 Monitor: INR (goal 2-3), CBC
 LOTS of DRUG INTERACTIONS (2C19, 1A2, 2C9, 3A4 substrate) & food interactions (vit K)
o High: kale, spinach, turnip greens, collar greens, swiss chard, parsley, mustard greens
o Moderate: Brussel sprouts, green leaf lettuce, broccoli, endive lettuce, romaine lettuce
 Guidelines against vit K for INR < 10 without bleeding (just hold dose with OUT giving vit K if not bleeding & INR < 10)
 BRIDGE THERAPY:
o MUST overlap w/warfarin therapy until INR is within therapeutic range for two consecutive days
o Minimum 5 days overlap
Drug
Usual Initial Dose
5 mg PO daily, titrate
w/caution, effect seen
in ~72 h, may take 5
days for full anticoag
effects
Other Doses
- Old, small, poor nutrition, hepatic impairment, CHF,
coadministration w/drugs that decrease warfarin
clearance = initial dose of 2.5
- young, fat, coadministration w/drugs that increase
warfarin clearance = initial dose of 7.5
Antidote
- vit K (phytonadione) 110 mg PO or IV; large
doses can result in
warfarin-resistance for up
to a week
Comments
Adjust dose by 10-15%
based on weekly total
warfarin dose
DIRECT ORAL ANTICOAGULANTS
-
No need for routine lab monitoring
Less drug interactions that warfarin
Onset w/in hours (no need for IV anticoagulant bridge at initiation)
Xa inhibitors & DTIs are recommended over warfarin in patients withOUT cancer who have a lower extremity DVT or PE
Compared to warfarin, they reduce risk of stroke and systemic embolism, reduce mortality, reduce risk of hemorrhagic stroke, but increase
rate of GI bleeding
- Expensive
- MOST should be AVOIDED in RENAL impairment
- Antidote only available for dabigatran
- Offset within hours:
o Rapid loss of efficacy w/missed doses, use caution in non-adherent pts
o Consider anticoagulant bridge if temporarily held for any reason other than signif bleeding
Xa Inhibitors
 Mechanism of Action: inhibit factor Xa
 3A4 & p-glycoprotein substrate
 AEs: bleeding
 No need for routine lab monitoring!!! YAY, but may monitor CBC
 CONTRA: pregos & lactating
Drug (Brand)
Rivaroxaban
(Xarelto)
Prophylaxis
10mg q24h
Treatment
- AF: 20mg q24h
- VTE: 15mg q12hr x 2 d then 20mg q24h
Comments
- reduce dose/avoid in renal or hepatic impairment
- 3A4 & P-gp substrate
Apixaban
(Eliquis)
2.5mg q12h
Edoxaban
(Savaysa)
N/A
Fondaparinux
(Arixtra)
2.5mg SQ q24h
5 mg q12h
- ONLY ONE W/DATA in RENAL IMPAIRMENT  REDUCE DOSE of
APIXABAN & USE IN RENAL IMPAIRMENT BC BEST ONE!!!!
- 3A4 & P-gp substrate
- 60 mg daily
- 30 mg daily if CrCl 15-30, wt ≤ 69kg or
on certain P-gp inhibitors
5-10 mg q24h depending on weight
- avoid in CrCl > 95 or < 15
- P-gp substrate
- reduce dose/avoid in renal impairment & weight < 50 kg
- only available as injection
Direct Thrombin Inhibitors (DTIs)
 Mechanism of Action: inhibit thrombin which prevents thrombin-induced conversion of fibrinogen to fibrin
 AEs: bleeding, hypotension, gastritis-like sx (dabigatran)
 Monitor: PTT, INR (Argatroban), CBC
 CONTRA: pregos & lactating
 Dabigatran (Pradaxa) preferred over coumadin for Afib, including paroxysmal Afib (but NOT valvular Afib)
Drug (Brand)
Dabigatran
(Pradaxa)
Dose
150mg q12h
Antidote
- Idarucizumab
(Praxbind) for
dabigatran
Comments
- Dabigatran = for non-valvular Afib
- BB Warning: against use w/mechanical valve
- reduce dose/avoid in renal impairment
- co-formulated w/acid to enhance absorption  dyspepsia
- do not crush/open capsule!
Bivalirudin
(Angiomax)
0.15 to 1.75 mg/kg/h
- Angiomax = for procedural anticoagulation OR anticoagulation in setting of HIT
- reduce dose in renal impairment
Argatroban
2-10 mcg/kg/min, titrate
to PTT
- Argatroban = for procedural anticoagulation OR anticoagulation in setting of HIT
- avoid in hepatic insufficiency