Anticoagulants Quiz (Overview)

Direct-acting oral anticoagulants (DOACs)

Warfarin

Low molecular weight heparins (LMWHs)

Warfarin

Factor Xa inhibition

Unfractionated heparin (UFH)

Direct thrombin inhibitors (DTIs)

Dabigatran (Pradaxa)

Acute coronary syndromes (ACS)

Antiplatelet drugs

To prevent blood clots from forming

Bleeding

Acute coronary syndromes

Embolus

Liver

Intrinsic pathway and extrinsic pathway

To inhibit fibrin formation

Blood stasis

Anticoagulation

Prevent clot formation

False

True

True

True

True

True

False

The American College of Chest Physicians (CHEST)

Warfarin is a vitamin K antagonist that inhibits the carboxylation (activation) of clotting factors 11, VII, IX, and X by blocking the action of vitamin K.

LMWHs inhibit factor Xa more specifically than unfractionated heparin.

Direct thrombin inhibitors are used when there is heparin-induced thrombocytopenia (HIT) or when HIT develops in the hospital setting.

The primary function of anticoagulants in the coagulation process is to inhibit the clotting cascade and prevent or reduce clot formation.

The two pathways that lead to fibrin formation in the coagulation cascade are the contact activation pathway (intrinsic pathway) and the tissue factor pathway (extrinsic pathway).

Anticoagulants are commonly used for acute coronary syndromes (ACS), prevention of cardioembolic stroke, and prevention/treatment of venous thromboembolism (VTE), which refers to deep vein thrombosis (DVT) and/or pulmonary embolism (PE).

Warfarin = Vitamin K antagonist, used mainly for VTE (treatment and prevention) and stroke prevention in AFib Direct-acting oral anticoagulants (DOACs) = Preferred over warfarin for most conditions Unfractionated heparin (UFH), low molecular weight heparins (LMWHs) and fondaparinux = Work by binding to Antithrombin (AT) and causing a conformational change which increases AT activity 1,000-fold Dabigatran (Pradaxa) = An oral Direct thrombin inhibitor (DTI)

Stroke prophylaxis in AFib = DOACs Moderate-to-severe mitral stenosis or a mechanical heart valve = Warfarin Cancer = LMWH Antiphospholipid syndrome = Warfarin

Warfarin = Vitamin K antagonist Direct-acting oral anticoagulants (DOACs) = Less drug-drug interactions, less or comparable bleeding and a shorter half-life compared to warfarin Unfractionated heparin (UFH), low molecular weight heparins (LMWHs) and fondaparinux = Inhibit factor Xa more specifically than unfractionated heparin Dabigatran (Pradaxa) = Blocks thrombin directly, decreasing the amount of fibrin available for clot formation

Anticoagulant = A substance that prevents the coagulation of blood Vitamin K antagonism = Warfarin is a vitamin K antagonist, which is required for the carboxylation (activation) of clotting factors Factor Xa inhibition = Unfractionated heparin (UFH), low molecular weight heparins (LMWHs) and fondaparinux work by binding to Antithrombin (AT) and causing a conformational change which increases AT activity 1,000-fold Thrombin inhibition = Direct thrombin inhibitors (DTIs) block thrombin directly, decreasing the amount of fibrin available for clot formation

They do not break down clots = Anticoagulants The most common side effect is bleeding = Anticoagulants Coagulation involves activation of platelets and the clotting cascade = Blood Clots The clotting cascade has two pathways which lead to fibrin formation = Coagulation Cascade

Embolus = A clot (or a piece of it) that travels to another location Blood Stasis = Stopping or slowing of blood flow Thrombolytics = Break down clots Venous Thromboembolism = Refers to deep vein thrombosis (DVT) and/or pulmonary embolism (PE)

VTE treatment in patients with cancer = LMWH Moderate-to-severe mitral stenosis or a mechanical heart valve = Warfarin VTE treatment in patients with antiphospholipid syndrome = Warfarin Heparin-induced thrombocytopenia (HIT) = Argatroban

Malnutrition

Bleeding in the upper GI tract

Infection

True

True

True

New or worse than usual I from gingivitis, drugs

From drugs, on abdomen from LMWH injection that was rubbed (do not rub.) or an epidural or spinal hematoma in a patient using a LMWH or DOAC who is given neuraxial anesthesia or a spinal puncture

Coffee-ground emesis (vomit) - from bleeding in upper GI tract Esophageal - From varices (bleeding veins, with liver cirrhosis), chronic reflux (esophagitis, Barrett's) Stomach - From ulcer (e.g., NSAID-induced) Duodenal- From ulcer (e.g., H. pylori-induced)

Epistaxis = Dry nasal mucosa Gums = Gingivitis Hematoma = Rubbing an LMWH injection Blood from the anus = Hemorrhoids

Blood in emesis = Bleeding in upper GI tract Bloody diarrhea = Infection Hematuria = UTIs Bruising = Chronic steroids

Esophageal bleeding = Varices Stomach bleeding = Ulcer Duodenal bleeding = Ulcer Rectal bleeding = Hemorrhoids

1.5-2.5 times that of the control

Gingivai

Protamine

5,000 units SC every 8-12 hours

Immediate when given intravenously (IV)

All of the above

True

True

True

True

True

True

osteoporosis, alopecia

0.3-0.7 units/mL

protamine

UFH binds to antithrombin (AT), which then inactivates thrombin (factor Ila) and factor Xa (as well as factors IXa, XIa, Xlla and plasmin) and prevents the conversion of fibrinogen to fibrin.

Prophylaxis of VTE: 5,000 units SC Q8-12H

IV: immediate, SC: 20-30 min

aPTT = Measured 6 hours after initiation and every 6 hrs until therapeutic, then every 24 hrs and with every dosage change anti-Xa = Typically monitored 6 hours after initiation and every 6 hrs until therapeutic, then every 24 hrs and with every dosage change Platelets, Hgb, Hct = Monitored at baseline and daily aPTT therapeutic range = 1.5-2.5 times that of the control

Hyperkalemia = Can occur with long-term use of heparin Osteoporosis = Can occur with long-term use of heparin Alopecia = Can occur with long-term use of heparin Bruising = Can occur with heparin therapy

Unpredictable anticoagulant response = Due to variable and extensive binding to plasma proteins and cells Continuous IV infusions are common for treating VTE and ACS = Because heparin has a very short half-life Do not give IM = Due to hematoma risk Heparin lock-flushes (HepFlush) = Used to keep IV lines open

Prophylaxis ofVTE = $5,000$ units SC $Q8-12H$ Treatment ofVTE = $80$ units/kg IV bolus; $18$ units/ kg/ hr infusion or $5,000$ units IV bolus; $1,000$ units/hr infusion Treatment of ACS/STEMI = $60$ units/kg IV bolus (max $4,000$ units); infuse $12$ units/kg/hr (max $1,000$ units/hr) Outpatient Treatment ofVTE = $333$ units/kg x $1$ dose SC; $250$ units/kg SC $Q12H$

Prophylaxis ofVTE = Unfractionated Heparin Treatment ofVTE = Unfractionated Heparin Treatment of ACS/STEMI = Unfractionated Heparin Outpatient Treatment ofVTE = Unfractionated Heparin

Treatment ofVTE = $80$ units/kg IV bolus or $5,000$ units IV bolus Outpatient Treatment ofVTE = $333$ units/kg x $1$ dose SC

Decreased platelet count

Hemoglobin

LMWH has a shorter half-life than UFH

Factor Xa

30 mg IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg SC Q12H

120 units/kg (max 10,000 units) SC Q12H

True

True

True

True

False

False

The potential side effects of LMWH include bleeding, bruising, and hematoma formation. Monitoring parameters for LMWH include platelet count, hemoglobin, hematocrit, and serum creatinine.

LMWH has a more predictable anticoagulant response than UFH and does not require anti-Xa level monitoring in most cases. However, anti-Xa level monitoring is recommended in pregnancy and may be done in obesity, low body weight, pediatrics, elderly, or renal insufficiency. Unlike UFH, LMWH is not monitored using aPTT. LMWH is administered subcutaneously and should not be administered via the IM route.

The potential drug interactions of UFH and LMWH are primarily due to additive effects with other drugs that can increase bleeding risk, such as other anticoagulants, antiplatelet drugs, some herbal supplements, NSAIDs, SSRIs, SNRIs, and thrombolytics.

Dose 0.75 mg/kg SC Q12H (no bolus - max 75 mg for the first two SC doses only). If CrCI < 30 ml/min - dose 1 mg/kg SC daily (no bolus).

120 units/kg (max 10,000 units) SC Q12H

History of HIT, active major bleed, hypersensitivity to pork

Anti-Xa level monitoring = Recommended in pregnancy aPTT monitoring = Not used Peak anti-Xa levels = Obtained 4 hours post SC dose Drug level monitoring = Does not require in most cases

Expelling air bubble from syringe = Can cause loss of drug Administration route = Not via IM Storage condition = Room temperature Antidote = Protamine

Anticoagulant response = More predictable than UFH Monitoring requirement = May be done in obesity, low body weight, pediatrics, elderly or renal insufficiency Platelet count = Decreased in some cases Monitoring parameter = SCr

Enoxaparin = Patients less than 75 years: Dose 30 mg IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg SC Q12H (max 100 mg for the first two SC doses only). If CrCI < 30 ml/min - dose 30 mg IV bolus plus a 1mg/kg SC dose, followed by 1 mg/kg SC daily. For Patients greater than or equal to 75 years: Dose 0.75 mg/kg SC Q12H (no bolus - max 75 mg for the first two SC doses only). If CrCI < 30 ml/min - dose 1 mg/kg SC daily (no bolus). For Patients managed with percutaneous coronary intervention (PCI): if the last SC dose was given 8-12 hours before balloon inflation, give 0.3 mg/kg IV bolus. Dalteparin = Dose 0.75 mg/kg SC Q12H (no bolus - max 75 mg for the first two SC doses only). If CrCI < 30 ml/min - dose 1 mg/kg SC daily (no bolus). For Patients managed with percutaneous coronary intervention (PCI): if the last SC dose was given 8-12 hours before balloon inflation, give 0.3 mg/kg IV bolus. Unfractionated Heparin = Dose 60 units/kg IV bolus (max 4000 units), then 12 units/kg/hr IV infusion (max 1000 units/hr) - adjust infusion rate based on aPTT. Bivalirudin = Dose 0.1 mg/kg IV bolus followed by 0.25 mg/kg/hr IV infusion (max 4 mg/min) - adjust infusion rate based on aPTT or ACT.

Enoxaparin = 1 mg/kg SC Q12H or 1.5 mg/kg SC daily (only for inpatient VTE treatment). If CrCI < 30 ml/min, dose 1 mg/kg SC daily. Dalteparin = 2,500-5,000 units SC daily Unfractionated Heparin = 80 units/kg IV bolus (max 5000 units), then 18 units/kg/hr IV infusion (max 1500 units/hr) - adjust infusion rate based on aPTT. Fondaparinux = 5-10 mg SC daily (CrCl < 50 ml/min: 5 mg)

Enoxaparin = 30 mg SC Q12H or 40 mg SC daily CrCI < 30 ml/min: 30 mg SC daily Dalteparin = 2,500-5,000 units SC daily Unfractionated Heparin = 5,000 units SC BID or TID (if CrCl < 30 ml/min: 5,000 units SC daily) Warfarin = 2-5 mg PO daily (target INR 2-3)

Formation of antibodies against heparin and PF4 complex

~3%

5-14 days

Argatroban

Greater than or equal to 150,000/mm^3

5 days

False

True

False

True

True

True

non-heparin anticoagulants (in particular, argatroban)

greater than or equal to 150,000/mm^3

lower doses (5 mg maximum)

Heparin forms a complex with antithrombin III, which inactivates thrombin and other clotting factors.

Untreated HIT can lead to a prothrombotic state causing complications such as heparin-induced thrombocytopenia and thrombosis (HITT), amputations, post-thrombotic syndrome, and death.

A diagnosis of HIT is made by a compatible clinical picture, an unexplained drop in platelet count (defined as > 50% drop from baseline), and laboratory confirmation of antibodies (ELISA test and confirmatory serotonin release assay) or platelet activation by heparin.

Warfarin = $5$ mg maximum Argatroban = Overlap with warfarin for a minimum of five days Bivalirudin = Preferred anticoagulant for urgent cardiac surgery or PCI Heparin = Not recommended in patients with HIT

$<150,000/mm^3$ = Do not start warfarin therapy $>150,000/mm^3$ = Start warfarin therapy $>100,000/mm^3$ = Initiate warfarin at lower doses $<50,000/mm^3$ = High risk of warfarin-induced limb gangrene and necrosis

Heparin = Not recommended LMWH = Not recommended Vitamin K antagonists = Not recommended Argatroban = Recommended

HIT = An immune-mediated IgG drug reaction that has a high risk of venous and arterial thrombosis PF4 = Platelet factor 4, a protein that can bind to heparin Pro-coagulant microparticles = Particles released during platelet activation in HIT that promote blood clotting HITT = Heparin-induced thrombocytopenia and thrombosis, a prothrombotic state that can lead to amputations, post-thrombotic syndrome, and/or death

Thrombocytopenia = The most common sign of HIT Thrombosis = Can come before thrombocytopenia in up to 25% of patients with HIT Prothrombotic state = A condition caused by HIT that can lead to many complications Platelet activation = Occurs when the immune system forms antibodies against heparin bound to PF4, causing platelet activation and release of pro-coagulant microparticles

Suspected or confirmed HIT = Stop all forms of heparin and LMWH including heparin flushes and heparin-coated catheters Patient on warfarin and diagnosed with HIT = Discontinue warfarin and administer vitamin K Patient exposed to heparin within the past three months = Onset of HIT can occur within hours Patient exposed to heparin for more than four days = Estimated incidence of HIT is ~3%

Fondaparinux

2.5 mg PO BID

10 mg PO BID

15 mg PO BID x 21 days, then 20 mg PO daily with food

Patients with a creatinine clearance (CrCl) less than 30 ml/min

Rivaroxaban (Xarelto)

Edoxaban (Savaysa)

False

True

False

True

True

True

True

Apixaban (Eliquis), edoxaban (Savaysa), rivaroxaban (Xarelto)

10 mg PO BID x 7 days, then 5 mg PO BID

2.5 mg BID

20 mg PO daily with evening meal

60 mg daily, start after 5-10 days of parenteral anticoagulation

2.5 mg PO BID

15 ml/min

20 mg PO daily with evening meal = Nonvalvular AFib (CrCI > 50 ml/min) 15 mg PO daily with evening meal = Nonvalvular AFib (CrCI 15-50 ml/min) 10 mg PO daily (for 12 days after knee or 35 days after hip replacement surgery) = Prophylaxis for DVT (after knee/hip replacement) 10 mg PO daily for a duration of 31 to 39 days = Prophylaxis of VTE in Acutely ill Medical Patients

Rivaroxaban = CrCI < 15 ml/min Edoxaban = CrCI > 95 ml/min Apixaban, Edoxaban, Rivaroxaban = Active pathological bleeding All = patients receiving neuraxial anesthesia (epidural, spinal) or undergoing spinal puncture

Rivaroxaban (Xarelto) = Doses greater than or equal to 15 mg must be taken with food Edoxaban (Savaysa) = reduced efficacy in nonvalvular AFib patients with CrCI > 95 ml/min; do not use Apixaban, Edoxaban, Rivaroxaban = premature discontinuation increases risk of thrombotic events

Rivaroxaban, Edoxaban = rash, increases LFTs All = patients receiving neuraxial anesthesia (epidural, spinal) or undergoing spinal puncture are at risk of hematomas and subsequent paralysis Edoxaban = reduced efficacy in nonvalvular AFib patients with CrCI > 95 ml/min; do not use

Apixaban (Eliquis) = 2.5 mg PO BID (for 12 days after knee or 35 days after hip replacement surgery) Rivaroxaban (Xarelto) = 10 mg PO BID x 7 days, then 5 mg PO BID Fondaparinux (Arixtra) = 2.5 mg PO BID (for 12 days after knee or 35 days after hip replacement surgery) Enoxaparin (Lovenox) = 10 mg PO BID x 7 days, then 5 mg PO BID

Apixaban (Eliquis) = Not recommended for HIT Rivaroxaban (Xarelto) = Not recommended for HIT Fondaparinux (Arixtra) = Recommended for HIT Enoxaparin (Lovenox) = Not recommended for HIT

Apixaban (Eliquis) = 10 mg PO BID x 7 days, then 5 mg PO BID Rivaroxaban (Xarelto) = 2.5 mg PO BID Fondaparinux (Arixtra) = 10 mg PO BID x 7 days, then 5 mg PO BID Enoxaparin (Lovenox) = 2.5 mg PO BID

2.5 mg SC daily

Severe renal impairment (CrCI < 30 mL/min)

Epistaxis

True

False

True

Severe renal impairment (CrCI < 30 mL/min)

Bleeding (e.g., epistaxis, bruising, gingival, GI), anemia, local injection site reactions (rash, pruritus, bruising), thrombocytopenia, hypokalemia, hypotension

Do not expel air bubble from syringe prior to injection, Do not administer via IM route

2.5 mg SC daily = Patients < 50 kg 5 mg SC daily = Patients 50-100 kg 7.5 mg SC daily = Patients < 50 kg 10 mg SC daily = Patients > 100 kg

Prophylaxis of VTE = In patients greater than or equal to 50 kg: Give 2.5 mg SC daily Treatment of VTE = Patients 50-100 kg: Give 7.5 mg SC daily

Patients > 100 kg = 10 mg SC daily Patients 50-100 kg = 7.5 mg SC daily Patients < 50 kg = Fondaparinux is contraindicated In patients greater than or equal to 50 kg = 2.5 mg SC daily

Antiplatelet drugs

Clarithromycin

Rifampin

Edoxaban

Stop Xa inhibitor and start parenteral anticoagulant

1-3 days before stopping dabigatran

True

True

True

True

True

True

True

True

True

INR < 3

INR ≤ 2.5

INR < 2

Factor Xa inhibitors can interact with other anticoagulants, drugs that increase bleeding risk, strong dual inducers or inhibitors of CYP3A4 and P-gp, and certain medications that increase exposure to Factor Xa inhibitors.

For patients receiving doses > 2.5 mg BID, the dose of apixaban should be decreased by 50% when coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp. For patients taking 2.5 mg BID, these strong dual inhibitors should be avoided.

Rivaroxaban should be avoided with drugs that are combined P-gp and strong CYP3A4 inducers or inhibitors. Additionally, caution should be exercised when treating patients with CrCl 15-80 mL/min who are receiving combined P-gp and moderate CYP3A4 inhibitors.

Rivaroxaban = INR is less than 3 Edoxaban = INR is less than or equal to 2.5 Apixaban = INR is less than 2 Dabigatran = INR is less than 2

From warfarin to another oral anticoagulant = Stop warfarin and convert when specific INR level is met From oral Xa inhibitors to warfarin = Overlap Xa inhibitor with warfarin until INR therapeutic, then stop Xa inhibitor From dabigatran to warfarin = Start warfarin 1-3 days before stopping dabigatran

Rivaroxaban, Apixaban, Edoxaban = Overlap with warfarin until INR therapeutic, then stop Dabigatran = Start warfarin 1-3 days before stopping

Apixaban = Avoid use with strong dual inducers of CYP3A4 and P-gp Rivaroxaban = Avoid use with drugs that are combined P-gp and strong CYP3A4 inducei's or inhibitors Edoxaban = Avoid use with rifampin Cobicistat = Can increase exposure to the factor Xa inhibitors

Apixaban = CYP450 3A4 and P-gp Rivaroxaban = CYP3A4 and P-gp Edoxaban = P-gp Cobicistat = Not a substrate of Factor Xa

Apixaban = For patients taking 2.5 mg BID, avoid strong dual inhibitors of CYP3A4 and P-gp Rivaroxaban = Benefit must outweigh the potential risks in patients with CrCl 15 - 80 mL/min who are receiving combined P-gp and moderate CYP3A4 inhibitors Edoxaban = When treating DVT/PE, reduce dose to 30 mg daily with verapamil, macrolides and oral itraconazole or ketoconazole Cobicistat = Not recommended to be used with Rivaroxaban