Background

• The primary risks of not using anticoagulants are DVT (deep vein thrombosis) and PE (pulmonary embolism). 
• DVT: Blood clots in veins, can be anywhere in the body, most commonly in deep veins of the legs, thighs, and pelvis.
• PE: The clot can break off, travel back to heart, and be pumped into the lungs, causing pulmonary embolism.
• Clots formation: damaged blood vessel walls are covered by platelets, fibrin which form a clot to prevent further bleeding. The coagulation cascade begins as soon as the injury occurs to a blood vessel. The cascade has 2 pathways: intrinsic (contact activation pathway, minor pathway), and extrinsic (tissue factor pathway, activated by trauma or tissue damage)
• Anticoagulants prevent clots from forming and expanding but do not break existing clots (only by tissue plasminogen activator, t-PA)
• Anticoagulation also prevents stroke, and treat ACS- acute coronary syndrome.
• DOAC – direct oral anticoagulants (direct thrombin inhibitors & factor Xa inhibitors) have been in the spotlight in preventing and managing thromboembolic events. They target thrombin and factor Xa directly. Thrombin is the final enzyme in the clotting cascade that produces fibrin, formed by proteolytic cleavage of prothrombin by factor Xa. 
• DOACs have various advantages compared with VKA: 1. predictable profiles without routine coagulation monitoring. 2. Little food and drug interactions (minimal CYP metabolism). 3. Rapid onset and offset of action, short half-life (10+ hrs Vs. days).

 

Treatment

• AFib can cause clots in heart, when eject to the brain can cause stroke (cardioembolic stroke) and TIA (transient ischemic attack).
• Patients with mechanical heart valves have the highest risk of clotting, and are treated with warfarin only.
• Majority of AFib patients do not have valve problems and are called nonvalvular AFib.

 

CHADS2- VASc scoring system

• Stands for congestive heart failure, hypertension, age ≥75 (x2), diabetes, stroke (x2), vascular disease, age 65 to 74 and sex category (female). 2 points for stroke, priorTIA or thromboembolism and > 75 yo.
• Count the number of risk factors and select appropriate anticoag treatment.

 

 Anticoagulants, antiplatelets, Vs. fibrinolytics?

Injectable anticoagulants are for ACS and VTE (prevention and treatment); oral anticoagulants are mainly for VTE (prevention and treatment) and stroke prevention (with AFib).AFib

• Oral anticoagulants are mainly for Afib (stroke prevention), and DVT/PE (treatment and prevention), they are not indicated for ACS (platelet aggregation is the main target)..
• Antiplatelets (ASA, clopidogrel) are mainly for ACS and prevention of stroke/TIA. Dual antiplatelets therapy (DAPT) are for patients who have had an ACS. (Antiplatelets are not enough to treat VTE).
• Fibrinolytics are used for STEMI and acute ischemic stroke, they break down existing clots, and are associated with very high risk of bleeding.

 

 

Heparin

• MOA: Binds antithrombin (AT, causing a conformational change which increase AT activity 1000X), which then inactivates thrombin factor IIa and Xa. 
• HIT (heparin induced thrombocytopenia): a drop in PLT count > 50%, less common from LMWH.

UFH

• VTE prevention: 5000 U SQ Q8-12 hr; treatment: 80 U/kg bolus, 18u/kg/hr infusion.
• ACS/STEMI: 60 U/kg bolus, 12u/kg/hr infusion. (Heparin has a short half-life, therefore common in acute conditions ACS and VTE). 
• SE: heparin-induced thrombocytopenia (HIT),bleeding (ecchymosis, epistaxis, gingival, GI), thrombocytopenia (TCP), hyper-K (K is a major intracellular electrolyte), osteoporosis (long-term).
• CI: active bleeding, TCP, HIT, hemophilia.
• Do not give IM due to hematoma risk.
• Monitor: activated partial thromboplastin time (aPTT, 6-hrs post-dose, and Q6H until therapeutic range, then daily); platelet, Hgb/Hct.
• Antidote: protamine -1mg reverse 100 u heparin, max dose: 50mg.
• Heparin flush (HepFlush): used to keep IV line open, fatal error in neonates (10 vs 100 u/ml) 

LMWH

• Drugs: Enoxaprin (lovenox), Dalteparin (Fragmin), Tinzaparin (Innohep)
• MOA: works similar to heparin except inhibition is much greater for Factor Xa (than Factor IIa). 
• BBW: recent epidural/spinal anesthesia are at risk of hematoma & paralysis
• CI: history of HIT, active bleed, hypersensitivity to pork, sulfite allergy(tinzaparin)
• SE: bleeding/anemia, increase LFTs, thrombocytopenia, hyperkalemia, injection site reactions (bruising), pregnancy (B).
• No real antidote, but protamine can be used. Do not expel air bubble.
• Monitor: platelet, Hgb/Hct, SCr, anti-Xa level only in pregnancy (peak level 4-hr post-dose), , more predictable response than heparin.
• Do not expel air bubbles from syringe (can cause loss of drug).
• Enoxaprin dosing:
• VTE prophylaxis: 30mg SC Q12 or 40mg QD (30mg QD in CrCl<30) 
• VTE treatment: 1mg/kg SC Q12 or 1.5mg/kg QD (1mg/kg QD in CrCl < 30)
• STEMI treatment: 30mg bolus + 1mg/kg SC (lower dose in >75 yo or CrCl < 30)

 

Direct thrombin inhibitor (DTI)

• Drugs: lepirudin (Refludan), argatroban (Novastan), bivalirudin (Angiomax), dabigatran (Pradaxa, the only oral antithrombin).
• MOA: bind directly to thrombin, instead of enhancing antithrombin activities; Prevent thrombin from cleaving fibrinogen to form fibrin.
• Do not cross-react with HIT antibodies. Drug of choice in HIT. Prevents more stroke than warfarin and favored in CHEST guidelines.
• SE: bleeding (as with all anticoagulants, and more GI bleeding), dyspepsia, gastritis-like symptoms, do not use in pregnancy.
• CI: major active bleeding, patients with mechanical heart valves. 
• Pradaxa should not be stored in pill boxes, and must be stored in the original container due to the potential breakdown from moisture result in loss of potency. Once opened, use within 4 months. Missed dose: take dose if >6 hours from next dose
• Treatment (VTE & Non-valvular AF): 150mg BID if CrCl > 30 ml/min (80% elimination through urine).
• FYI: Antidote idarucizumab (Praxbind) inj. was approved in 2015 by FDA. It is a monoclonal antibody fragment, and is administered to patients of significant dabigatran level. It should not be given to patients of normal thrombin time.
• bivalirudin (Angiomax)
• Used in cardiac cath lab, reduce dose when CrCl <30 ml/min.

 

Vitamin K antagonist: Warfarin 

• MOA: Vitamin K increases the coagulant activity of K dependent clotting factors II, VII, IX, and X (produced by liver).
• SE: bleeding (Monitor INR), skin necrosis, purple toe syndrome.
• CI: pregnancy (category X), malignant hypertension, bacteria endocarditis, alcoholism, history of fall.
• Despite the popularity of NOAC, warfarin is still widely prescribed for patients at risk for venous or arterial thromboembolism. 
• When warfarin is started, the vitamin K dependent clotting factors must be depleted before the full efficacy of warfarin is seen, and this depletion takes several days, for patients needing immediate anticoagulation, overlapping with a fast acting anticoagulation is needed (e.g: heparin).
• Narrow therapeutic range and many variables affect a patient’s response to warfarin (genetics, dietary vitamin K, disease states, albumin level, drug interactions etc.), closely monitor INR (international normalized ratio).
• Prothrombin time (PT) is the measure of how fast the blood clots, measured in seconds, when PT is converted to the standard units, it is INR. Normal INR range 2-3 (2.5-3.5 in mechanical heart valve).
• Patients on warfarin should maintain a consistent dietary V-K intake (highest content from green leafy veggies), the key is consistency. In fact, patients on warfarin consume the highest amount of dietary V-K have more stable INR that those consume less.
• Reduce dose (Warfarin is highly protein bound) in: elderly, debilitated, malnourished, amiodarone, liver disease, recent surgery, CHF. 
• Antidote: Phytonadione [Mephyton] oral or V-K IV infusion (SC/IM should not be used due to unpredictable response/hematoma) given in INR > 10 unless active bleeding. Phenindione is another V-K antagonist rarely used due to agranulocytosis and hepatitis.
• lots of drug interactions due to CYP (2C9 substrate, avoid use with tamoxifen)
• Inducers (e.g: phenobarbital/phenytoin, rifampin, primidone, SJW) ↓ INR 
• Inhibitors (e.g: amiodarone, Bactrim, azole, macrolide, metronidazole) ↑INR.
• ↑ bleeding, but not INR: NSAIDS, ASA, ibuprofen (but not celecoxib), Plavix, ticlopidine, prasugrel, ginkgo.

 

Factor Xa inhibitors

• Drugs: rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Lixiana), and betrixaban (Bevyxxa), fondaparinux (Arixtra).
• MOA:These agents bind directly (“-Xa ban”) or indirectly (fondaparinux, through antithrombin) to Xa.   Factor Xa links intrinsic and extrinsic pathways to the final common blood coagulation pathway. Factor Xa converts prothrombin (PT) to its active form – thrombin. These agents bind directly to Xa, prevent Xa from cleaving PT to form thrombin. 
• SE: lower rates of serious and fatal bleeding events than warfarin, possible higher rates of GI bleeding. Caution: hepatic impairment.
• DI: most are CYP 3A4 or P-gp substrates, avoid use with 3A4 and P-gp inhibitors (azoles etc.)
• Antidote for direct Xa inhibitors: andexanet alfa (Andexxa).
• There are no parental direct factor Xa inhibitors, only oral drugs, however, the mechanism is similar to LMWH in a way that they also target factor Xa. 
• Once daily dosing (such as: Xarelto, Savaysa) is appealing, but if you miss just a few doses could raise thrombosis risk.
• Xarelto: VTE: 15 mg BID with food x 21 days, followed by 20 mg QD; AF: 20 mg QD with evening meal. (Or 15 mg QD for CrCl < 50 ml/min).
• Eliquis has least dependence on renal clearance; 2.5 – 10 mg BID; betrixaban (Bevyxxa): Long-acting inhibitor with a half-life of 19 – 27 hrs; Doses a

 

 Fondaparinux (Arixtra)

• MOA: Synthetic pentasaccharide, selectively inhibits Xa via AT binding, making it an indirect inhibitor of factor Xa.
• CI: weight < 50kg for prophylaxis, bacteria endocarditis, poor renal function (CrCl < 30)
• Prophylaxis 2.5mg SC QD; Treatment: 5mg QD (< 50mg), 7.5mg (50 - 100kg), 10mg (> 100kg)

Monitor anti-Xa levels, No antidote.

 

Quiz

1. Which of the following oral antithrombotic agents are approved for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE)? (Select ALL that apply.)
   1. ASA
   2. Apixaban
   3. Dabigatran
   4. Rivaroxaban
   5. Ticagrelor
2. Which of the following medications, if added to a regimen containing rivaroxaban, may cause a reduction in the efficacy of rivaroxaban? (Select ALL that apply.)
   1. Phenytoin
   2. Divalproex
   3. Carbamazepine
   4. Levetiracetam
3. Which of the following genes has genetic variations that can alter dosing requirements for warfarin? (Select ALL that apply.)
   1. CYP2D6
   2. VKORC1
   3. HLA
   4. CYP2C19
   5. CYP2C9

4. What does an INR measure?
   1. Prothrombin level
   2. Vitamin K level
   3. Clotting time
   4. Warfarin level
5. How does vitamin K reverse the action of warfarin and reduce clotting time?
   1. Binds to warfarin and inactivates it
   2. Inhibit metabolism of warfarin
   3. Increase excretion of warfarin
   4. Regenerate vitamin k dependent clotting factors

 

6. Which of the following is an indication of IV vitamin K in a patient taking warfarin?
   1. INR = 10
   2. Active severe bleeding
   3. Initiation of Macrobid
   4. INR = 5 and mild bleeding
7. How does warfarin work to decrease the risk of thrombosis?
   1. Blocks vitamin K receptors
   2. Inhibits the production of clotting factors
   3. Directly inhibits the conversion of fibrinogen to fibrin
   4. Causes lysis of the clot
8. Which of the following food have the highest amount of vitamin K content?
   1. Bananas
   2. Iceberg lettuce
   3. Tomatoes
   4. Cooked spinach

 

 

Answers (click to expand)

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