Pharmacotherapy of

Venous Thromboembolism

Abera J. (BPharm., MSc in Clinical Pharmacy)

School of Pharmacy, CHMS, HU.

07/08/2022 By; Abera J 1

 Introduction
 Venous thromboembolism (VTE)
 Results from clot formation within the venous
circulation
 Commonly the legs, but clots can form in the arms,
mesenteric and cerebral veins
 Manifested as
Deep vein thrombosis (DVT) and/or
Pulmonary embolism (PE)
 DVT is rarely fatal but death from PE can occur within
minutes after symptom onset
 Epidemiology
 Incidence of symptomatic objectively diagnosed VTE
2 to 3 per 1,000
Increase with age from 0.1 per 1,000 in adolescence to
8 per 1,000 in those over 80 years
 The incidence of VTE increase in Pts with
Multiple traumas, orthopedic procedures of the
lower extremities, a prior history of VTE,
metastatic CA, a history of MI, stroke, and spinal
cord injury or hypercoagulable disease
 Pathophysiology
Virchow’s Triad
Vascular
Wall Injury

Hypercoagulable Circulatory
State Stasis
 Pathophysiology…
Circulatory Stasis
Alteration in blood flow can include turbulence, stasis,
mitral stenosis, and varicose veins
AF, LV dysfunction, immobility or paralysis, venous
obstruction from tumor, obesity, or pregnancy
Vascular Wall Injury
Damage to the veins arising from shear stress or HTN
Trauma/surgery, chemical irritation, heart valve disease
or replacement, atherosclerosis, indwelling catheters
 Pathophysiology…
Hypercoagulability
Hyperviscosity, deficiency of antithrombin-III,
nephrotic syndrome, changes after severe trauma or
burn, disseminated CA, late pregnancy and delivery,
smoking, and obesity.
Estrogen therapy, trauma or surgery of lower
extremity, inflammatory bowel disease, sepsis,
 Factors Regulating Hemostasis and Thrombosis
Thrombogenic Antithrombotic
Vessel wall Exposed subendothelium Heparin sulfate
Tissue factor Dermatan sulfate
Plasminogen activator Thrombomodulin
inhibitor-1 Tissue plasminogen activator
Urokinase-Plasminogen Activator
Circulating Platelets Antithrombin
elements Platelet activating factor Heparin cofactor II
Clotting factors Protein C
Promothrombin (factor II) Protein S
Fibrinogen (factor I) Plasminogen
Von Willebrand factor Tissue factor pathway inhibitor
Proteolytic enzymes
α2-Antiplasmin
Blood flow Slow rate of flow Fast rate of flow
Turbulent flow Laminar flow
 Pathophysiology…
 A thrombus can form in any part of the venous circulation
– The majority begin in the leg(s)
 Once formed, a venous thrombus may;
Remain asymptomatic
Spontaneously lyse
Obstruct the venous circulation
Propagate into more proximal veins
Embolize to the lungs resulting in PE, or
Act in any combination of these ways
 Risk factors
 Age: incidence increases with age
 History of VTE: risk highest during the first 6
months of life
 Venous stasis:
Hospitalization
Surgery (general anesthesia > 30 minutes)
Paralysis (stroke, spinal cord injury)
Immobility
Obesity
 Risk factors…
 Vascular injury: Major orthopedic surgery (Knee or
hip replacement), trauma (fracture of the pelvis, hip or
leg),
 Hyper-coagulable state
factor V Leiden (activated protein C resistance)
 Protein C, protein S, and anti-thrombin deficiency
 High conc. of factors VIII, IX, and XI or fibrinogen
Malignancy
Anti-phospholipid antibodies (SLE, IBD)
 Risk factors…
 Drug therapy

Estrogen containing contraceptives

Estrogen replacement therapy

SERM (tamoxifen, raloxifen)

CA therapy
Heparin induced thrombocytopenia
 Clinical Presentation
Symptoms
DVT PE
 Asymptomatic  Chest pain/tightness
 Pain  SOB
 Unilateral leg swelling  Pain (back, shoulder, upper
 Warmth abdominal)
 Palpitation
 Erythema
 Lightheadedness
 Dizziness, Syncope
 Hemoptysis
 Clinical Presentation….
Signs
DVT PE
 Tachypnea
 Palpable cord
 Tachycardia
 Diaphoresis
 Distended neck veins
 Cyanosis
 Hypotension
 cardiovascular collapse
 New cardiac arrhythmia
 Clinical Presentation…..

• Laboratory tests:

Serum D-dimer concentration elevated

Elevated erythrocyte sedimentation rate

White blood cell count elevation

 Clinical Presentation…
• Diagnostic tests:
Duplex ultrasonography (most common) (DVT)
Venography or phlebography (gold standard)
(DVT)
Ventilation-perfusion & CT scans (PE)

Pulmonary angiography (gold standard) (PE)

 Diagnosis
 Important to treat VTE quickly & aggressively
 Assessment of Pt's status should focus on search for risk factors

Venous thrombosis uncommon in absence of risk factors

 VTE should be strongly suspected in Pts with multiple risk

factors
 Treatment of VTE
General Approach
 Mainstay of treatment for VTE…….Anticoagulation
therapies
 DVT and PE are treated similarly
 VTE treatment is divided into three phases
1. Acute phase:
From diagnosis to 7 days
Requires rapidly acting anticoagulants to prevent
thrombus extension and embolization
Treatment of choice includes: UFH, LMWH,
fondaparinux, or rivaroxaban
 Treatment of VTE…
2. Early maintenance phase
 From the 7th day to 3 months
 Continued therapeutic anticoagulation
 To reduce the risk of long-term sequelae
postthrombotic syndrome
 Allow formed clot to be slowly dissolved by endogenous
thrombolytic processes
3. Long term anticoagulation
 Anticoagulation therapy extending beyond 3 months
 Aimed at long-term secondary prevention of recurrent VTE
 Treatment of VTE…

– Anticoagulation therapy

• Initiated with an injectable anticoagulant

• Transitioned to warfarin maintenance therapy

– Rivaroxaban- as a substitute to the bridge therapy

 Non-pharmacologic Therapy
Mechanical Prevention and Treatment Strategies
• Graduated compression stockings
 Increase the velocity of venous blood flow through the
application of graded pressure
 Should be worn for at least two years
• Intermittent pneumatic compression (IPC)
 Utilize sequential inflation of a series of cuffs……increase the
velocity of blood flow
 Inferior venacava filter: PE
 Can be used together with pharmacologic therapy
 Risk: skin breakdown and ulceration
 Pharmacologic therapy of VTE
Acute treatment of VTE
 Agents: LMWH, fondaparinux, IV UFH, or adjusted-dose SC
UFH
• Unfractionated heparin (UFH)
– 5000 units SC bolus followed by 250units/kg SC BID or
– SC bolus of 333 units/kg, followed by 250 units/kg SC BID
– Moderate IV bolus 80 units/kg followed by IV infusion of 18
units/kg
– Monitor aPTT
 Pharmacologic therapy of VTE…
Acute treatment of VTE…
 LMWH
– Enoxaparin
1mg/kg SC Q12H or
1.5mg/kg SC QD (with warfarin)
 Fondapirinux
<50kg: 5mg SC QD
50-100kg: 7.5mg SC QD
>100 kg: 10mg SC QD
 Pharmacologic therapy of VTE…
Acute treatment of VTE…
 Warfarin: 5-10mg
– Initially bridged with fast acting anticoagulants
For at least 5 days and until an INR ≥2 has been achieved
for at least 24 hours
Adjust dose to maintain an INR between 2 and 3
– Geriatrics: initiate dose <5mg and adjust according to INR
response
 Monotherapy: unacceptable during the acute phase
No rapid anticoagulation effect
high incidence of recurrent thromboembolism
 Pharmacologic therapy of VTE…
Duration of treatment
 Treatment with UFH, LMWH, or fondaparinux should be
overlapped with warfarin for at least 5 days
 UFH, LMWH, or fondaparinux can be stopped when the INR
is >2.0
 Pts with CA should be treated with a LMWH for at least 6
months
 A longer period of heparin therapy (approximately 10 days) is
recommended for massive PE or severe iliofemoral
thrombosis
 Pharmacologic therapy of VTE…
Long term anticoagulation
 Oral anticoagulation therapy (target INR 2.5, range: 2.0 to
3.0)…………for at least 3 months
 Idiopathic VTE, inherited disorder of hypercoagulability, or
antiphospholipid antibodies……..indefinitely (at least 2.5
years)
 Pts with continuing risk factors (e.g., malignancy,
immobility)……….treat for at least 12 months 
 VTE: Special Populations
Pregnancy
– UFH and LMWH preferred during pregnancy
• LMWH recommended over UFH
– Does not cross the placenta
– Use cautiously during 3rd trimester & peripartum period
– Not excreted in breast milk
• Considered safe while breast-feeding
• Avoid warfarin
• crosses placenta
• can produce fetal bleeding, CNS abnormalities, embryopathy
 VTE: Special Populations…
Pediatrics
– UFH & warfarin used most frequently in pediatrics
– LMWH can also be used
 monitor antifactor Xa levels
• Acute thrombosis treatment in children: UFH
– Loading dose:
 75 to 100 units/kg over 10 min
– Maintenance dose:
 28 units/kg/hr: infants up to 12 months of age
 20 units/kg/hr: children > 1 year
 VTE: Special Populations…
• CA Pts
 VTE frequent complication of malignancy
Rate of recurrent VTE and risk of bleeding is much
higher
 Warfarin: often complicated by drug interactions &
interruptions due to procedures
 LMWH: lower incidence of bleeding
 Continue anticoagulation as long as the CA is “active” & Pt
is receiving antitumor therapy
Thrombolysis for the Treatment of VTE
Thrombolysis for the Treatment of VTE…
Thrombolysis for the Treatment of VTE…
 Prevention of VTE
General Approach
 VTE is potentially fatal and costly
 Strategies to prevent DVT in at-risk populations
positively impact patient outcomes
 Effective prophylaxis can reduce the risk of fatal PE in
high-risk surgical and medical populations
 Prevention of VTE…
 Graduated compression stockings
 Intermittent pneumatic compression
 Quit smoking
 Anti-coagulation therapy
 Within 8 hours after surgery
 Mobilizing patients as soon as possible after surgery
 Moving legs during long trips
 Risk Classification for VTE Prevention
Level of Risk Calf Vein Symptomati Fatal PE Prevention Strategies
Thrombosi c PE (%) (%)
s (%)

Low        
• Minor surgery, age <40 years, and 2 0.2 0.002 Ambulation
no clinical risk factors

Moderate 10–20 1–2 0.1–0.4 UFH 5,000 units SC q 12 h

•  Major or minor surgery, age 40–60 Dalteparin 2,500 units SC q 24
years, and no clinical risk factors h
•  Major surgery, age <40 years, and Enoxaparin 40 mg SC q 24 h
no clinic risk factors Tinzaparin 3,500 units SC q 24
•  Minor surgery, with clinical risk h
factor(s) IPC
•  Acutely ill (e.g., MI, ischemic Graduated compression
stroke, CHF exacerbation), and no stockings
clinical risk factors
 Risk Classification for VTE Prevention…
Level of Risk Calf Vein Symptomatic PE Fatal PE Prevention Strategies
Thrombosis (%) (%)
(%)
High        
•  Major surgery, age >60 years, and 20–40 2–4 0.4–1.0 UFH 5,000 units SC q 8 h
no clinical risk factors Dalteparin 5,000 units SC q 24 h
•  Major surgery, age 40–60 years, Enoxaparin 40 mg SC q 24 h
with clinical risk factor(s) Fondaparinux 2.5 mg SC q 24 h
•  Acutely ill (e.g., MI, ischemic Tinzaparin 75 units/kg SC q 24 h
stroke, CHF exacerbation), with IPC
risk factor(s)

Highest        
•  Major lower-extremity orthopedic 40–80 4–10 0.2–5 Adjusted dose UFH SC q 8 h (aPTT
surgery >36 s)
•  Hip fracture Dalteparin 5,000 units SC q 24 h
•  Multiple trauma Desirudin 15 mg SC q 12 h
•  Major surgery, age >40 years, and Enoxaparin 30 mg SC q 12 h
prior history of VTE Fondaparinux 2.5 mg SC q 24 h
•  Major surgery, age >40 years, and Tinzaparin 75 units/kg SC q 24 h
malignancy Warfarin (INR = 2.0–3.0)
•  Major surgery, age >40 years, and IPC with UFH 5,000 units SC
hypercoagulable state
•  Spinal cord injury or stroke with
limb paralysis
 Prevention of VTE…
Indications Enoxaparin Dalteparin Tinzaparin
Hip-replacement 30 mg SC q 12 h 2,500 units SC given 2 h prior to 75 units/kg SC q
surgery (prophylaxis) initiated 12–24 h after surgery, followed by 2,500 international 24 h initiated the
  surgery units the evening after surgery and at evening prior to
  or  least 6 h after first dose, then 5,000 surgery or 12 h
  40 mg SC q 24 h international units SC q 24 h after surgery
initiated 12 h prior to or or 
surgery 5,000 international units SC q 24 h 4,500 unit SC q
Extended prophylaxis initiated the evening prior to surgery a 24 h initiated 12 h
may be given for up to 3   prior to surgery
weeks

Knee-replacement 30 mg SC q 12 h   75 units/kg SC q
surgery (prophylaxis) initiated 12–24 h prior 24 h initiated the
to surgery evening prior to
surgery or 12 h
after surgery
Trauma (prophylaxis) 30 mg SC q 12 h    
starting 12–36 h after
injury
 Prevention of VTE …
Indications Enoxaparin Dalteparin Tinzaparin
Abdominal surgery 40 mg SC q 24 h 2,500 units SC q 24 h initiated 1–2 h prior to 3,500 unit SC q
(prophylaxis) initiated 2 h prior to surgerya 24 h initiated 1–
surgery Patients with malignancy: 5,000 units SC the 2 h prior to
evening prior surgery then 5,000 units SC q surgery
24 ha
or
2,500 units SC 1–2 h prior to surgery then
2,500 units 12 h after surgery followed by
5,000 units SC q 24 h
Acute medical illness 40 mg SC q 24 h 2,500 units SC q 24 h  
(prophylaxis)
Deep vein thrombosis 1 mg/kg SC q 12 h 100 units/kg SC q 12 h 175 units/kg SC
treatment (with or or  or  q 24 h
without pulmonary 1.5 mg/kg SC q 24 200 units/kg SC q 24 h
embolism) h
Unstable angina or 1 mg/kg SC q 12 h 100 units/kg SC q 12 h (maximum dose
non–Q-wave 10,000 units)
myocardial infarction  
 Heparin-Induced Thrombocytopenia
 Serious adverse effect
 Immunoglobulin mediated response to the heparin molecule 
platelet activation & thrombin generation
 High morbidity & mortality
 Without treatment up to 50% of Pts suffer complications or
die in < 30 days
 Diagnosis based on laboratory findings
 Heparin antibody formation
 Platelet activation
 HIT: Etiology
 HIT……..severe pathologic AE of heparin
 Typically begins at days 5 to 10 but can be delayed up to
20 days
 Rapid -onset HIT occurs within 24 hrs
 Platelets < 150,000 mm3
 Drop in platelet count > 50% from baseline may
indicate HIT
 Frequency related to duration & type of heparin
Increased incidence with IV full dose UFH than low
dose SC UFH or LMWH
 HIT: Clinical Presentation
 Thrombotic complications most common presentation

DVT more common than PE

Arterial thrombosis less frequently
 Atypical manifestations
Skin necrosis

Venous limb gangrene

Anaphylatic-type reactions after UFH IV bolus
 HIT…..Treatment
Goal of therapy
 Reduce thrombosis risk
 by decreasing thrombin generation and platelet activation
 Once HIT diagnosis is established or suspected,
discontinue all sources of heparin
 Initiate alternative anticoagulant
Drugs of choice: agents that rapidly inhibit thrombin
activity & are devoid of significant cross-reactivity
 Warfarin recommended for long-term anticoagulation
 HIT: Treatment…

• DTIs: drug of choice for HIT + thrombosis

– Only lepirudin & argatroban are FDA approved

– Both considered equally suitable for initial treatment

– Administered IV infusion

– Titrated based on aPTT

• LMWHs not recommended

– ~100% cross-reactivity with heparin-antibodies
 HIT: Treatment…
• Warfarin

– CI as monotherapy for initial HIT treatment

• Initial rapid reduction of protein C  increases risk
of thrombosis in Pts with HIT
– can be used for long-term anticoagulation
 HIT: Therapeutic Outcomes
• Duration of treatment based on whether or not a
thrombotic event occurred
• Thrombosis present……alternative anticoagulant
therapy followed by transition to warfarin after platelets
recover to > 150,000 mm3
• Avoid heparin for at least 3 to 6 months
 Unfractionated heparin (UFH)
• MOA: The pentasaccharide sequence of heparin molecule binds
antithrombin, provoking a conformational change that enhance the
activity of antithrombin
• UFH–antithrombin complex is 100 to 1,000 times more potent than
antithrombin alone
– Through its action on thrombin, the UFH–antithrombin complex
inhibits thrombin-induced activation of factors V & VIII
 Factors IIa (thrombin) & Xa most sensitive to inhibition by UFH–
antithrombin complex
 UFH: Pharmacokinetics
• Unreliable PO absorption due to large molecular size &
anionic structure
• Dose dependent subcutaneous bioavailability
 30 to 70%
• Onset of anticoagulant effect: 1 to 2 hours after SQ
injection
 peaks at 3 hours
• Continuous infusion preferred for IV administration
– Intermittent IV boluses produce relatively high peaks
in anticoagulation activity; greater risk of major
bleeding
 UFH: Therapeutic Monitoring
• Close monitoring required: unpredictable patient
response
• Activated partial thromboplastin time (aPTT) used to
monitor therapy
– therapeutic range is institution specific
 UFH: Therapeutic Monitoring
• Antifactor Xa level has replaced aPTT at some facilities
– provides heparin concentration using a calibration
curve
– target concentration: 0.3 to 0.7 U/ml
 UFH: Therapeutic Monitoring
• Measure prior to initiation to determine baseline
• IV infusion: evaluate response 6 hr after initiation or dose
change
• Some acute VTE & MI patients have diminished response to
UFH (“heparin resistance”)
 Suspected in patients who require > 40,000 units of UFH
per 24-hour period
 Adjust dose based on factor Xa concentrations
 UFH: Adverse Effects
• Primary adverse effect: bleeding
– more closely related to underlying risk factors than
high aPTT
• Presence of concomitant bleeding risks increase risk of
UFH-induced hemorrhage
– Thrombocytopenia
– Use of other antithrombotic therapy
– Preexisting source of bleeding
• Risk of bleeding increases with age, recent surgery,
hemostatic defects, heavy alcohol consumption, renal
failure, peptic ulcer disease, neoplasm
 UFH: Adverse Effects
• Thrombocytopenia common (platelet count < 150,000)
 up to 30% of patients have appreciable decline in
platelet count
• Heparin-Induced Thrombocytopenia (HIT)
 serious
 requires immediate intervention
 UFH: Adverse Effects
• Long-term UFH
 alopecia
 priapism
 suppressed aldosterone synthesis with subsequent
hyperkalemia
• UFH doses 20,000 units/day for > 6 months associated with
significant bone loss; may lead to osteoporosis
 especially during pregnancy
 UFH: Management
• Hemorrhage can occur at any site
 monitoring closely for bleeding signs & symptoms
 regular monitoring: hemoglobin, hematocrit, BP
• When major bleeding occurs
 discontinue UFH immediately
 identify and treat underlying source of bleeding
 administer IV protamine sulfate 1 mg per 100 units of
UFH (maximum 50 mg) slow IV infusion over 10 min
 neutralizes UFH in 5 min
 activity persists for 2 hr
 Low Molecular Weight Heparin
• Fragments of UFH produced by chemical or enzymatic
depolymerization
• ~1/3 the molecular weight of UFH
• 3 LMWHs:
 Enoxaparin
 Dalteparin
 Tinzaparin
 Low Molecular Weight
Heparin
• Advantages over UFH:
 Predictable anticoagulation dose response
 Improved subcutaneous bioavailability
 Dose-independent clearance

 Longer biologic t½
 Lower incidence of thrombocytopenia
 Reduced need for laboratory monitoring
 LMWH: Pharmacology
MOA
• Enhance/accelerate antithrombin activity: bind specific
pentasaccharide sequence
• Cause endothelium to release tissue factor pathway
inhibitor
 Enhances factor Xa & factor VIIa inactivation

• Limited activity against thrombin

 Proportionally greater antifactor Xa activity
 LMWH: Pharmacokinetics
• More predictable anticoagulation response due to reduced
binding to proteins & cells
• Bioavailability ~100% when administered subcutaneously
– Peak anticoagulation effect: 3 to 5 hr
• Predominantly renally eliminated
 LMWH: Dosing &
Administration
• Usually given by SQ injection in abdomen or upper
outer thigh while the patient is supine
• Dosed every 12 to 24 hours
• Larger doses given once daily
– Significantly higher peak plasma concentrations

• CrCl < 30 mL/min
• Reduce enoxaparin dose
• Extend dosing interval to once daily
 LMWH: Therapeutic Monitoring

• Monitoring not necessary due to predictable anticoagulant response

with SQ administration
• Obtain baseline labs
– PT/INR
– aPTT
– complete blood cell count with platelets
– serum creatinine
• Monitor CBC every 5 to 10 days during the first 2 weeks
– every 2 to 4 weeks thereafter
 Low Molecular Weight
Heparin
• Adverse effects:
 most common: bleeding
 epidural & spinal hematomas possible in patients
with epidural catheters
 thrombocytopenia, avoid with HIT history/diagnosis
 Anticoagulant Reversal
Antidote/Dosing

UFH Protamine Sulfate: Binds 100%

1mg/100 units of heparin, cover for the last 3
hours of an IV infusion of heparin

LMWH Protamine Sulfate: Binds 60%

1mg Protamine sulfate per 1mg of enoxaparin
A second dose of 0.5mg proatmine sulfate per
100 anti-Xa units should be administered if
bleeding continues
 Fondaparinux
MOA
• Pentasaccharide specifically but reversibly binds
antithrombin
• Selectively inhibits factor Xa activity
 Prevents thrombus generation & clot formation
• No direct effect on thrombin activity at therapeutic
plasma concentrations
• No effect on platelet function
Fondaparinux: Pharmacokinetics

• Rapidly & completely absorbed following SQ

administration
• Peak plasma concentrations in ~2 hrs after a single dose;
~3 hrs with repeated once-daily dosing
• Elimination t½: 17 to 21 hrs
• Anticoagulant effect persists 2 to 4 days after
discontinuation
• No known drug interactions
 Fondaparinux: Monitoring
• No routine coagulation testing required
• Evaluate baseline CBC then periodically
• Baseline kidney function in patients at risk of developing
renal failure
– Discontinue if CrCl < 30 mL/min
 Fondaparinux
• Safe in elderly patients
– However, major bleeding risk increases with age
• Pregnancy category B
• Not studied in pediatric populations

• Most common adverse effect: bleeding

 Risk related to weight
 Use caution with epidurals
 Direct Thrombin Inhibitors
(DTIs)
• Directly interact with thrombin
• Do not require antithrombin (cofactor) for
antithrombotic activity
• Inhibit circulating & clot-bound thrombin
• Do not induce immune-mediated thrombocytopenia

 Used for HIT treatment

• Includes: lepirudin, desirudin, bivalirudin, argatroban
 Warfarin
• Anticoagulant of choice for long-term/extended
anticoagulation
• FDA-approved indications
 VTE prevention & treatment
 Prevention of thromboembolic complications
associated with atrial fibrillation, heart valve
replacement, MI
• Requires continuous monitoring & patient education
 Narrow therapeutic index
 Many food & drug interactions
 Warfarin
• Inhibits enzymes responsible for cyclic interconversion of vitamin
K in the liver
• No direct effect on previously circulating clotting factors or
previously formed thrombi
• Time to pharmacologic effect dependent on the elimination t½’s of
coagulation proteins
– Full antithrombotic effect achieved 8 to 15 days after initiation
of therapy
• Prevents formation & propagation of thrombi by suppressing
clotting factor production
 Warfarin: Pharmacokinetics
• Rapid & extensive GI absorption
 peak plasma concentration ~90 minutes
 PO bioavailability > 90%
• 99% albumin bound

• Metabolized via hepatic cytochrome P450 (CYP) 1A2,

2C9, 2C19, 2C8, 2C18, 3A4
• Large inter-patient differences in dose requirements
 Warfarin: Dosing &
Administration
• Patient-specific dose based on desired intensity of
anticoagulation & patient‘s response
 Regular clinical & laboratory monitoring
• Acute VTE: UFH, LMWH, or fondaparinux should be
overlapped with warfarin for > 5 days
 INR checked every 3 to 5 days until stable
• Dose changes should not be made more than every 3
days
 Adjust by reducing or increasing calculated weekly
dose
 Warfarin: Adverse Effects
• Bleeding/hemorrhagic complications
 GI tract most frequent site
 Intracranial hemorrhage most serious
• Warfarin-induced skin necrosis

• Purple-toe syndrome
 Warfarin Reversal
Supra-therapeutic range Recommendation

INRs above therapeutic range but <4.5 Lower dose or omit a dose, monitor
with no significant bleeding more frequently, and resume therapy at
appropriately adjusted dose when INR
is at therapeutic level

INRs of > 4.5 but <10 and no significant Omit the next one or two doses,
bleeding monitor more frequently and resume
therapy at an appropriately adjusted
dose when INR is at a therapeutic level.

INRs > 10 and no significant bleeding Hold warfarin therapy and administer a
higher dose of vitamin K (2.5 to 5mg)
orally
Patients with warfarin-associated major repletion of coagulation factors, 5 to 10
bleeding mg of vitamin K via slow IV injection
 Warfarin: Interactions
• Vitamin K-containing foods
 Stress dietary consistency, moderation
• Drugs that inhibit or induce CYP2C9, 1A2, 3A4
• Protein-binding displacement interactions
 Transient changes
• Drugs that alter hemostasis, platelet function, or clotting
factor clearance
 Warfarin: Special Populations
• Pregnancy category X
 Fetal hemorrhage
 Teratogenic complications
 CNS abnormalities
– Safe to use while breast-feeding
• Patients undergoing procedures:
– Generally not discontinued for minimally invasive
procedures (dental work)
– higher-risk procedures: stop 4 to 5 days prior
• Start LMWH and give last dose of LMWH 12–24
hours before procedure
 Rivaroxaban
– Dose: 15 mg BID for 3 weeks followed by 20 mg QD

for at least 3 months

– Information on patients with

 creatinine clearance <30 mL/min (<0.5 mL/s)

 cancer

 Thrombolytic therapy limited

– No effective reversal agent

THANK YOU!!

07/08/2022 By; Abera J 80