Chapter 10:
Venous Thromboembolism
Part I of II
Jon Wietholter, PharmD, BCPS
Clinical Assistant Professor
West Virginia University School of Pharmacy
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Venous Thromboembolism (VTE)
• VTE: thrombosis formation in the venous circulation.
Usually in deep and major veins
• Manifested as:
– Deep vein thrombosis (DVT)
– Pulmonary embolism (PE)
• Often provoked by:
– Prolonged immobility
– Vascular injury
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Venous Circulation (Fig. 10-1)
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Virchow’s Triad
• Three major elements leading to VTE
• Consists of:
– Stasis in blood flow
– Vascular endothelial injury
– Hypercoagulable state
• Activated Protein C resistance most common
• Protein C and/or S deficiency
• Malignancy
• These risk factors are additive!
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Pathophysiology
• Vessel injury
– Hemostatic plug seals the vessel wall
– Inappropriate response can lead to clot
• Endothelial cells inside blood vessels
– Create substances that:
• Inhibit platelet adherence
• Prevent activation of coagulation cascade
• Facilitate fibrinolysis
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
VTE
• Most frequently seen in:
– Hospitalized patients
– Trauma
– Major surgery
• Often has few or no symptoms
– First manifestation often sudden death
• Long-term sequelae
– Post-thrombotic syndrome (PTS)
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Epidemiology and Etiology
• True incidence is unknown
– >50% have no overt symptoms
– Incidence doubles every decade after 50
– Incidence is slightly higher in men
• Estimated 2 million VTE’s in US/year
– 600,000 hospitalized
– 60,000 die
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
VTE Risk Factors (see Table 10-1)
• Age
• Prior history of VTE
• Major surgery
– i.e. Orthopedic procedures of leg(s)/hip(s)
• Trauma
• Malignancy
• Pregnancy
• estrogen use Drug Therapy: Estrogen-containing
medications, SERMs, Chemotherapy.
• Hypercoagulable states
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
CLINICAL PRESENTATION
AND DIAGNOSIS
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
VTE
• Majority of VTE’s begin in lower extremity
• Can either:
– Remain asymptomatic
– Spontaneously lyse
– Obstruct the venous circulation
– Propagate into proximal veins
– Embolize
– Slowly incorporate into the endothelium
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
VTE Symptoms
• Symptoms are very nonspecific
– Unilateral leg pain/warmth/swelling
– Shortness of breath and/or cough
– Tachypnea and/or tachycardia
– Hemoptysis
• Objective tests used to confirm VTE
– Radiographic studies (Gold standard)
– D-dimer test
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
VTE PREVENTION
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
ACCP Guidelines
• Low Risk
– i.e. Minor surgery in mobile patients
– Risk of VTE: <10%
• Moderate Risk
– i.e. Major surgery but no risk factors, acutely ill
– Risk of VTE: 10-40%
• High Risk
– i.e. Major trauma or hip fracture
– Risk of VTE: 40-80%
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
ACCP Guidelines
• Low Risk Prophylaxis:
– Early, aggressive ambulation
• Moderate Risk Prophylaxis:
– UFH every 8-12h
– LWMH daily
– Fondaparinux daily
• High Risk Prophylaxis:
– LMWH every 12-24 hours
– Fondaparinux daily
– Warfarin with INR of 2-3
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Pharmacologic Options
• Aspirin is NOT appropriate therapy
• Appropriate therapies:
– UFH
– LMWHs
• Dalteparin
• Enoxaparin
• Tinzaparin
– Fondaparinux
– Warfarin
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
UFH
• Less effective than LMWHs or fondaparinux
– Hip or knee replacement
– Other high-risk populations
• Effective, cost-conscious option in:
– General surgical procedures
– Following MI or stroke
– Moderate risk patients
• Dose: 5000 units subcutaneously (SQ) every 8 or 12 hrs
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
LMWHs & Fondaparinux
• Best choice for high-risk populations
– i.e. Hip and/or knee replacement
• Dosing is indication specific
• No evidence that a specific LMWH is better than others
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Warfarin
• As effective as LMWHs in highest-risk
• Dose: Adjusted to keep INR 2-3
• Advantages: cost and oral dosing
• Main disadvantages:
– Full antithrombotic effect not seen for several days
– Many drug and food interactions
– Frequent monitoring & dosing changes
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Pharmacologic Options
• Choice of medication/dose based on:
– Patient’s risk of thrombosis
– Patient’s risk of bleeding
– Cost
– Availability of medication
• Duration of therapy not well defined
– Given throughout the period of risk
• Typically, can be stopped once patient is ambulating regularly and
other risk factors are no longer present.
• Need 21-35 days following hospital discharge in patients who had
total hip/knee replacement.
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
TREATMENT
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Treatment Principles
• Anticoagulants are mainstay of therapy
• Treatment of DVT/PE is identical
• Should include:
– Rapid acting anticoagulant (i.e. UFH/LMWH)
– Overlapped with warfarin for at least 5 days
• Until the INR is greater than 2
• Therapy should be for at least 3 months
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Treatment Timeline (see Fig. 10-5)
Fig 10-5; Page 194
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Anticoagulant Contraindications
• Active bleeding
• Hemophilia
• Severe liver disease with elevated PT
• Severe thrombocytopenia
– Platelet count < 20,000
• Malignant hypertension
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Thrombolytics
• Role is controversial
– Restore venous patency more quickly
– Risk of bleeding is significantly higher
• Clinical trials: no long-term benefit
• May be considered in:
– Patients with massive iliofemoral DVT
– Acute massive PE with hemodynamic instability
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
UFH
• Traditionally the drug of choice
• Does NOT dissolve the clot
– Prevents clot propagation and growth
• Augments antithrombin (AT)
– Heparin molecule binds to AT
– Accelerates AT activity
• Inhibits factors IIa, Xa, IXa, XIa, and XIIa
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
UFH
• Limitations to usage:
– Poor bioavailability when given SQ
• Ranges from 30-70%
• Onset delayed 1-2 hours when compared to IV
– Significant intra/interpatient variability
• Can be given IV and SQ
– Use IV for rapid anticoagulation
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
UFH
• Side effects:
– Bleeding
– Thrombocytopenia
– Hypersensitivity
– Hyperkalemia
– Alopecia
– Osteoporosis
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
UFH
• If major bleeding occurs, use protamine sulfate
– Give 1 mg protamine sulfate per 100 units of UFH
• Max dose of 50 mg
– Given as slow IV infusion over 10 minutes
– Neutralizes the effects of UFH in 5 minutes
– Effects persist for about 2 hours
– Can repeat dose if needed
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
UFH
• Heparin-induced Thrombocytopenia (HIT)
– Serious adverse effect seen with heparin
– Suspected if platelets drop by 50%
– Discontinue all heparin products
– Alternative anticoagulation is needed
• FDA pregnancy category C
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
LMWHs
• Dosing is based on patient’s weight
– Dalteparin
• 200 units/kg SQ daily or 100 units/kg twice daily
– Enoxaparin
• 1.5 mg/kg SQ daily or 1 mg/kg twice daily
• CrCl <30, adjust dose to 1 mg/kg SQ daily
– Tinzaparin
• 175 units/kg SQ daily
- Current guidelines suggest using UFH over LMWH when
CrCl<30.
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
LMWHs
• Can treat uncomplicated DVT at home
– Normal vital signs
– Low-bleeding risk
– No other comorbid conditions
• Submassive PE’s could get outpatient therapy
– If hemodynamically stable
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
LMWHs
• Can measure antifactor Xa activity
– Used in:
• Morbidly obese (> 150 kg or BMI > 50)
• Patients < 50 kg
• Patients with CrCl < 30 mL/min
– Draw levels 4 hours after dose given
– Acceptable level:
• 0.5-1 units/mL with twice daily dosing
• 1-2 units/mL with daily dosing
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
LMWHs
• Common adverse events:
– Bleeding
– Bruising
– HIT
• Incidence lower than with UFH
– Spinal and epidural hematomas
• FDA pregnancy category B
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
LMWHs
• Protamine sulfate used in major bleeds
– Partially reverses effect of LMWHs
– Neutralizes about 60% of activity
– Give 1 mg protamine sulfate per:
• 1 mg enoxaparin or 100 units of dalteparin/tinzaparin
• Smaller dose if LMWH given >8 hours ago
• Give 0.5 mg per 100 units if 2nd dose needed
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Fondaparinux
• Indirect inhibitor of factor Xa
• Accelerates the activity of AT
• Has no effect on thrombin
• Administered SQ only
– Peak plasma concentration in 2-3 hours
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Fondaparinux
• Advantages:
– Predictable dose-response relationship
– Rapid onset of activity
– Long half-life (17-21 hours)
– Does not require routine monitoring
– Not metabolized
• Very few drug interactions
– Does not affect platelet function
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Fondaparinux
• As safe and effective as UFH/LMWHs
• Dosing based on body weight:
– <50 kg: 5 mg SQ daily
– 50-100 kg: 7.5 mg SQ daily
– >100 kg: 10 mg SQ daily
• Renally eliminated
– Contraindicated if CrCl < 30 mL/min
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Fondaparinux
• Bleeding is a common adverse effect
– NOT reversed by protamine sulfate
– Can give fresh frozen plasma (FFP)
– Factor concentrates in serious bleeding
• i.e. Recombinant factor VIIa
• FDA pregnancy category B
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Mechanism of Action Summary
Fig 10-6; Page 196
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Direct Thrombin Inhibitors (DTIs)
• Act via binding thrombin
– Thrombin is central mediator of coagulation
• Currently 4 parenteral agents on the market
– Lepirudin
– Bivalirudin
– Argatroban
– Desirudin
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
DTIs
• Advantages
– Targeted specificity for thrombin
– Inactivates clot-bound thrombin
– Absence of interactions that cause HIT
• Do not require AT as a cofactor
• Drugs of choice for VTE treatment in HIT
– Predictable anticoagulant effect
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
DTIs
• Lepirudin
– Primarily eliminated renally
– Half-life of 40 min IV and 120 min SQ
– Should raise aPTT 1.5-2.5x baseline
– Up to 40% of patients develop antibodies to drug
– Is a non-reversible DTI
– Used for HIT & HIT-related thrombosis
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
DTIs
• Bivalirudin
– Smaller molecular-weight DTI
– IV only
– Half-life about 25 minutes
– Partially eliminated renally
• Dose adjustments in CrCl <60
– Is a reversible DTI
– Used in HIT patients during angioplasty
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
DTIs
• Argatroban
– Small synthetic molecule
– Reversibly binds to thrombin
– IV only
– Half-life is 40-50 minutes
– Hepatically metabolized
– Used for HIT & HIT-related thrombosis
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
DTIs
• Oral DTIs
– Dabigatran is first to seek FDA approval
– Given 1-2 times daily in fixed doses
– Do not need routine monitoring
– Lower number of drug/food interactions
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
DTIs
• Common adverse events:
– Bleeding
• No antidotes to reverse effects of DTIs
• Would need to give FFP and/or factor concentrates
– Can increase PT/INR
• Data for pregnancy/children lacking
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Warfarin
• Primary oral anticoagulant in US for 60 years
• Drug of choice for long-term anticoagulation
• Has a very narrow therapeutic index
– Requires very close monitoring
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Warfarin
• Inhibits Vitamin K-dependent factors
– Factor II (prothrombin)
– Factor VII
– Factor IX
– Factor X
• Also inhibits protein C and protein S
• No effect on previously formed factors
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Warfarin
• Full activity 5-7 days after 1st dose
– Delay due to half-life of clotting factors
• Can cause hypercoagulable state
– Protein C is a natural anticoagulant
• Its half-life is only 8-10 hours
• Factors II/IX/X have half-lives of ≥ 20 hours
– Must therapeutically “bridge” patients
• i.e. UFH, LMWH, fondaparinux
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Warfarin
• Does not follow linear kinetics
• Doses determined by response
– INR values
• Dose is influenced by:
– Metabolism
– Diet
– Drug interactions
– Health status
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Warfarin
• Most patients start with 5 mg daily
– Higher initial doses OK in young & healthy
– Conservative initial doses used in:
• Elderly
• Heart failure or liver disease patients
• Poor nutritional status
• Patients taking interacting medications
• Loading doses not recommended
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Warfarin
• “Bridging” therapy
– Other anticoagulant overlapped for ≥ 5 days
– Need an INR of at least 2
– 5-7 days needed for full effect of warfarin
• Frequent laboratory monitoring
– PT: measures activity of factors II/VII/X
– INR: corrects PT for differences in reagents
• Duration of therapy: ≥ 3-6 months
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Warfarin
• Goal INR for VTE: 2-3 (Ideally 2.5)
– High-risk patients might need 2.5-3.5
• i.e. Certain mechanical heart valves
• Baseline PT/INR should be obtained
– Followed every 2-3 days for first week
– Factors that can affect INR:
• Adherence and/or interacting medications
• Alcohol and/or vitamin-K rich food
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Warfarin
• Vitamin K used to reverse anticoagulant effects
– Given IV or orally
• IV only in severe overdose/severe bleeding
– Usually reduces INR within 24 hours
– Dose:
• 1-2.5 mg if INR between 5-9
• 5 mg for INR > 9
• Other agents: FFP or clotting factors
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
Warfarin
• Adverse events:
– Bleeding
• Incidence highest in first couple weeks
• Gastrointestinal bleed is most common
• Higher INR’s increase bleeding risk
– Warfarin induced skin necrosis
• FDA pregnancy category X
Copyright @ 2010. The McGraw-Hill Companies. All Rights Reserved.
