Treatment and Management of

Venous Thromboembolism (VTE)

Jaclyn D. Cole, PharmD, BCPS
University of South Florida
College of Pharmacy
Objectives: Pharmacists
• Discuss the pathophysiology of venous thromboembolism (VTE)
• Analyze the epidemiology of VTE
• Evaluate appropriate treatment options for VTE
• Develop clinical recommendations for VTE patient care

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Objectives: Technicians
• Discuss pathophysiology of venous thromboembolism (VTE)
• Analyze the epidemiology of VTE
• Differentiate medications appropriate for the treatment of VTE

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Pathophysiology & epidemiology

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Venous Thromboembolism (VTE)
• Blood clots can form in:
• Arms, legs, lungs
• Venous thromboembolism (VTE)
• Blood clot that forms in a vein
• Deep venous thrombosis (DVT)
• Blood clot in a deep vein
• Pulmonary embolism (PE)
• Blood clot in the lungs

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Epidemiology
• 900,000 VTE incidences annually
• First VTE occurs in 100/100,000 persons annually
• Approximately 1/3 = PE, 2/3 = DVT alone
• Idiopathic condition in 25-50% patients
• Recurrence rate ~7% at 6 months (despite therapy)
• Death ~6% DVT, ~12% PE within 1 month diagnosis

NQF-Endorsed Voluntary Consensus Standards for Hospital Care: VTE-1.

Kaatz, et Al., 2011.
Caprini, et al. 200.
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White RH. Circulation. 2003.
Pathophysiology

• Normal clotting

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Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014.
Pathophysiology

• Coagulation cascade

http://www.coagadex.com/coagulation-cascade
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Pathophysiology

• Thrombus formation

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Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014.
“Triad” Causal Factors
• Blood stasis
• Vessel damage
• Hypercoagulable State

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102004.
Morris, et. al,
http://www.thrombosisadviser.com/en/image.php?image=virchow-triad&category=haemostasis
Risk Factors
• Recent orthopedic/general surgery • Obesity
• Limited physical • > 60 years of age
movement/immobile • Smoker
• Hx stroke, heart attack, heart • Implanted vascular access
failure, paralyzed
• Previous thromboembolism (high
• Broken bone (leg, hip, pelvis) risk)
• Cancer • Anti-phospholipid syndrome (high
• Blood circulation problems risk)
• Personal or family history of blood
clots
• Hormones (birth control, hormone
replacement)

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Caprini, et. al., 2004
VTE Risk Score
• Assess patient specific risk factors
• Scores categorize the risk of that patient having a VTE
• Evidence-based standardized scoring systems
• Caprini VTE Risk Score (surgical)
• Rogers VTE Risk Score (surgical)
• Padua VTE Prediction Score (non-surgical)
• Kucher VTE Risk Score (non-surgical)

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Symptoms
• Depends on location of blood clot
• Deep Venous Thrombosis (DVT)
• Pulmonary Embolism (PE)

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Symptoms of DVT: Leg or Arm
• Unilateral swelling
• Warmth, redness
• Pain
• Worsens when standing or walking

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http://www.elastictherapy.com/problems.html
 Symptoms of PE: Lungs
• Difficulty Breathing
• Shortness of breath (SOB)
• Chest pain
• Worse with deep breaths
• Coughing
• May cough up blood or bloody phlegm
• Rapid HR
• Fainting/Dizziness

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http://www.beltina.org/health-dictionary/pulmonary-embolism-diagnosis-symptoms-treatment.html
 Diagnosis
• Clinical assessment
• Elevated D-dimer*
• Diagnostic studies

VTE Event Diagnostic Study

DVT Venography*
Compression ultrasound
PE Pulmonary angiography*
Computerized tomography
Ventilation-perfusion (V/Q) scan

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Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014.
Prognosis

• Fatality
• DVT: Rarely fatal
• PE: Death can occur within minutes of symptom onset
• Complications
• Postthrombotic syndrome
• Chronic thromboembolic pulmonary hypertension (CTPH)

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Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014.
Treatment of VTE

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• Treatment of venous
thromboembolism (VTE)

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Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014
Non-pharmacologic treatment

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 IVC Filter
• Implanted in inferior vena cava
• Captures an embolism on its way to
heart/lungs
• Allows blood flow around trapped clots
• Option when unable to take
anticoagulants:
• Contraindicated
• Previous failure on therapy

https://www.drugwatch.com/ivc-filters/

Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014.21
http://www.uofmmedicalcenter.org/HealthLibrary/Article/41273 21
Pharmacologic treatment options

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Drugs & the Clotting Cascade

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http://www.nature.com/nrcardio/journal/v10/n7/fig_tab/nrcardio.2013.73_F1.html
Treatment of VTE
• Heparin
• Low Molecular Weight Heparins (LMWH)
• Lovenox®, Fragmin®
• Factor Xa Inhibitors
• Arixtra®, Xarelto®, Eliquis®, Savaysa®
• Vitamin K Antagonist (VKA)
• Coumadin®
• Direct Thrombin Inhibitor
• Pradaxa®
• Thrombolytic therapy
• Surgical removal

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Heparin
• MOA: acts on multiple sites of the normal
coagulation system
• Combines with antithrombin III to inactivate Factor Xa, which inhibits
conversion of prothrombin thrombin
• Dose: adjust to target aPTT (60-85 sec) per nomogram
• IV: 80 U/kg (or 5000 U) x 1, then 1000 U/Hr
• SQ: 333 U/kg x1, then 250 U/kg Q12H
• Caution: check dosage strength before administration
• Side Effects: bleeding, heparin-induced
thrombocytopenia (HIT)

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Heparin sodium® [package insert].
http://fdb.rxlist.com/drugs/search.aspx?simprint=&scolor=4&sshape=&pagenumber=47
Low Molecular Weight Heparin
(LMWH)
• Lovenox® (enoxaparin)
• Fragmin® (dalteparin)

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http://www.rxzone.us/product.cfm/rx/Lovenox-40Mg-Prefill-Syringes-10X4-Ml-471771.html
https://healthy.kaiserpermanente.org/health/care/
 Low Molecular Weight Heparin
(LMWH)
• MOA: higher activity with anti-factor Xa than anti-thrombin compared to
heparin
• Dose:
• Enoxaparin: 1 mg/kg SQ Q12H <or> 1.5 mg/kg SQ Q24H
• Dalteparin: 100 units/kg SQ Q12H <or> 200 mg/kg SQ Q24H
• Dose adjust
• CrCl <30 ml/min
• Anti-factor Xa level: 0.5-1 units/mL
• Side Effects: bleeding, anemia, diarrhea, nausea, thrombocytopenia

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Lovenox® [package insert], Fragmin® [package insert]. Leyvraz, et.al. 1991, CHEST 2012
Factor Xa Inhibitors
• Injectable
• Arixtra® (fondaparinux)
• Oral tablet
• Xarelto® (rivaroxaban)
• Eliquis® (apixaban)
• Savaysa® (edoxaban)
• Future: betrixaban

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 Factor Xa Inhibitors
• MOA: selectively inhibits active binding site for factor Xa
on the coagulation cascade
• Side Effects: hemorrhage, anemia, thrombocytopenia

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Arixtra® [package insert]. , Xarelto® [package insert], Eliquis® [Package Insert].
Factor Xa Inhibitors
• Fondaparinux (Arixtra®)
• Dose:
• 5 mg SQ Q24H (<50 kg)
• 7.5 mg SQ Q24H (50-100 kg)
• 10 mg SQ Q24H (>100 kg)
• Caution:
• Bleeding risk increased in renal impairment and BW < 50 kg
• Needle guard may cause allergic reaction in latex sensitive individuals

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Arixtra® [package insert].
 Factor Xa Inhibitors
• Rivaroxaban
• 15 mg PO BID x 21 days, then 20 mg PO Daily
• CrCl < 30: Avoid use
• Patient Counseling
• Take with food
• Missed dose
• If miss dose and taking BID- may take 2 doses at once! (max 2 tablets
in one day, 30 mg/24 hours)
• If miss dose and taking once daily- take as soon as remember on that
day, do NOT double dose

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Xarelto® [package insert]
 Factor Xa Inhibitors
• Apixaban (Eliqius®)
• 10 mg PO BID x 7 days, then 5 mg PO BID
• Patient counseling:
• With or without food

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Eliquis® [Package Insert].
Factor Xa Inhibitors

• Edoxaban
• 60 mg PO Daily after 5-10 days parenteral anticoag
• Decrease dose to 30 mg PO Daily if: CrCL 15-50 mL/min, ≤ 60
kg, or certain P-gp inhibitors
• Not Recommended (not studied)
• Mechanical heart valves
• Moderate to severe mitral stenosis

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Savaysa® [Package Insert].
Vitamin K Antagonist (VKA)
• Coumadin® (warfarin)
• Jantoven® (warfarin)

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http://drugline.org/drug/medicament/24873/
Vitamin K Antagonist (VKA)
• MOA: inhibits vitamin K-dependent clotting factors (factors II, VII, IX,
X) and anticoagulant proteins C and S
• Dose (patient specific):
• Start with 5 mg PO daily (alt: 10 mg load x 2 days)
• Adjust to INR 2-3 (goal 2.5) for VTE
• Side Effects: hemorrhage, skin necrosis, systemic atheroemboli,
hypersensitivity

Coumadin® [package insert].

CHEST, 2012 35
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Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014
Bridge Therapy
• Heparin or LMWH given with warfarin
• Start warfarin on day 1 or 2 of UFH or LMWH
• At least 5 days and with 2 consecutive
therapeutic INR readings
Factor Half-Life

Protein C 8 hours

Protein S 8 hours

S Factor VII 4-6 hours

N Factor IX 21-30 hours

O Factor X 27-48 hours

T Factor II 42-72 hours

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CHEST, 2012
Vitamin K Antagonist (VKA)
• Dietary Considerations
• Consistent intake of Vitamin K foods
• Drug Interactions (lots!)
• CYP2C9, CYP1A2, CYP3A4
• Antibiotics, antifungals, NSAIDS
• Amiodarone
• Decrease warfarin dose 30-50%
when starting amiodarone! http://www.healthclaps.com/images/Drugs/Vitamins/Health
-Benefits-of-VitaminK-Highest-Foods-and-Deficiency-
• Frequent monitoring and dose adjustments Symptoms.jpg

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Vitamin K Antagonist (VKA)
• Atheroembolism (Purple Toe Syndrome)
• Cholesterol embolization syndrome
• Multiple small emboli move to hands and feet obstruct small arteries
• Occurs within first 3-8 weeks of therapy

http://www.medscape.com/viewarticle/724274_5 38
Vitamin K Antagonist (VKA)
• Genomic Considerations
• VKORC1 (where warfarin works)
• CYP2C9 (warfarin elimination)

Polymorphisms Effect Observed

CYP2C9*2 or *3 allele Require significantly lower doses of warfarin

CYP2C9*1/*1 (wild type)
VKORC1 haplotype group A
VKORC1 haplotype group B
Higher risk sub therapeutic INR, longer to stabilize dosing,
increased bleed risk
Low-dose haplotype group
*more common in Asian Americans
High-dose haplotype group
*more common in African Americans

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Lee. Clinical Medicine and Research.2005.
Direct Thrombin Inhibitor
• Pradaxa® (dabigatran)

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http://www.healthcareglobal.com/news_archive/sectors/pharmaceuticals/pradaxa-be-available-us-says-boehringer,
http://www.drugs.com/pradaxa.html, http://www.drugs.com/pradaxa.html
Direct Thrombin Inhibitor
• MOA: directly inhibits thrombin, which prevents
conversion of fibrinogen  fibrin
• Dose:
• 150 mg PO BID after 5-10 days of parenteral anticoagulation
• Adjust if CrCl < 30 ml/min or acute renal failure
• Side Effects: bleeding, GI effects, hypersensitivity
• Counseling Points
• Keep in original container
• Bottle is only good for 4 months after opening
• Swallow whole with full glass of water

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Pradaxa® [package insert]
Drug VTE Treatment Dose Renal Dosing
Heparin IV: 80 U/kg (or 5000 U) x 1, then 1000 U/Hr None
SQ: 333 U/kg x1, then 250 U/kg Q12H
Enoxaparin 1 mg/kg SQ Q12H CrCl< 30: 1 mg/kg SQ Daily
1.5 mg/kg SQ Q24H
Dalteparin 100 units/kg SQ Q12H Not defined
200 mg/kg SQ Q24H
Fondaparinux 7.5 mg SQ Q24H CrCl 30-50: Caution
*5 mg if <50 kg, 10 mg if >100 kg CrCl < 30: Contraindicated
Warfarin 2-10 mg PO Daily, adjusted to INR (bridge None
therapy required)
Rivaroxaban 15 mg PO BID x 21 days, then 20 mg PO CrCl < 30: Avoid use
Daily

Apixaban 10 mg PO BID x 7 days, then 5 mg PO BID None

Edoxaban 60 mg PO Daily after 5-10 days parenteral CrCl 15-50 mL/min: 30 mg PO Daily
anticoagulation
Dabigatran 150 mg PO BID after 5-10 days parenteral CrCl 15-30: 75 mg PO BID
anticoagulation CrCl < 15: Avoid use

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Thrombolytic Therapy
• Not required for most patients
• Patients eligible:
• High-risk patients without hypotension
• Massive PE with evidence of hemodynamic compromise (hypotension,
shock)
• Treatment:
• IV UFH, then Alteplase 100 mg IV over 2 H
• Must assess risk of bleed first

43JT, et al. 2014

Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro
Thrombolytic Administration

• Systemic (preferred)
• Peripheral vein
• Catheter-directed thrombolysis
• CI to thrombolytic therapy
• Failed thrombolytic therapy
• Death is likely before onset of thrombolysis

https://vascular.org/patient-resources/vascular-
treatments/thrombolytic-therapy/catheter-directed- CHEST, 2016.
thrombolytic-therapy 44
Surgical Removal
• Thrombectomy
• Embolectomy
• Reserved for massive PE

http://content.onlinejacc.org/article.aspx?articleid=1902254

45JT, et al. 2014

Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro
Treatment recommendations

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 Initiation of Treatment
• Requires accurate diagnosis
• High probability: parenteral anticoagulation while awaiting results

Phase of treatment Goal

Acute (7 days) Rapid-acting agents (UFH, LMWH, fondaparinux,

rivaroxaban)
Early maintenance (7 days to 3 months) Reduce risk of long-term complications (i.e.
postthrombotic syndrome)
Long-term (> 3 months) Secondary prevention

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Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014
 Duration of Treatment
• “Long-term therapy”
• Minimum duration for DVT or PE: 3 months
• “Extended anticoagulant therapy”
• Usually means therapy continues indefinitely
• Recommended In:
• Second unprovoked VTE with low or moderate
bleeding risk
• VTE and active cancer

CHEST, 2016.
CHEST. 2012.
Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014
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 CHEST 2016 Guidelines
Clinical Presentation
VTE (no cancer) – long term txt
VTE with cancer
VTE treated with anticoagulants
Recurrent VTE on non-LMWH
anticoagulant
Recurrent VTE on LMWH
Treatment (Grade of Recommendation)
Dabigatran, rivaroxaban, apixaban, edoxaban
(2B) > VKA (2C) > LMWH
LMWH > VKA (2B), dabigatran, rivaroxaban,
apixaban, edoxaban (2C)
No IVC filter (1B)
LMWH (2C) for at least 1 month
Increase LMWH dose (2C)
CHEST, 2016
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 Location of DVT
https://www.pinterest.com/pin/574771971165805960/

Location Treatment Notes

Proximal Anticoagulation

Acute isolated distal

• Without severe Serial imaging of deep • No anticoagulation:

symptoms / risks veins for 2 weeks • If thrombus does not extend
• Anticoagulation:
• If thrombus extends but
remains in distain veins
• If thrombus extends into
proximal veins
• With severe symptoms Anticoagulation Same txt as acute proximal DVT
/ risks

Upper extremity (axillary or Anticoagulation >

more proximal veins) thrombolysis
CHEST, 2016.
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CHEST. 2012.
 Location of PE
Clinical Presentation Treatment (Grade of Recommendation)
Subsegmental PE and no proximal DVT (low risk Clinical surveillance > anticoagulation (2C)
recurrence)
Subsegmental PE and no proximal DVT (high risk Anticoagulation > clinical surveillance (2C)
recurrence)
PE with hypotension Thrombolytic therapy (2B)
(SBP < 90 mm Hg for 15 minutes) Systemic therapy > catheter directed
thrombolysis (2C)

CHEST, 2016
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http://www.bodyteen.com/anterms.html
Summary

• VTE is common, deadly, and recurrent

• Confirm diagnosis and location of VTE
• Identify appropriate anticoagulation therapy
• Determine duration of therapy
• Minimize recurrence

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