Venous Thromboembolism

11 Venous Thromboembolism
James C. Lee, Bryan Zobeck, and Edith A. Nutescu
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Identify risk factors and signs and symptoms of deep vein thrombosis (DVT) and pulmonary
embolism (PE).
2. Describe the processes of hemostasis and thrombosis.
3. Determine a patient’s risk of developing venous thrombosis.
4. Formulate an appropriate prevention strategy for a patient at risk for DVT.
5. Select and interpret laboratory test(s) to monitor antithrombotic medications for safety and efficacy.
6. Identify factors that place a patient at high risk of bleeding while receiving antithrombotic medications.
7. State at least two potential advantages of newer anticoagulants (ie, low-molecular-weight heparins
[LMWHs], fondaparinux, oral direct thrombin inhibitors [DTIs], and oral direct factor Xa inhibitors) over
traditional anticoagulants (ie, unfractionated heparin and warfarin).
8. Manage a patient with toxicity secondary to an anticoagulant with or without bleeding.
9. Identify relevant factors such as drug–drug and drug–food interactions to optimize anticoagulant
medication selection.
10. Formulate an appropriate treatment plan, including duration and monitoring, for a patient who develops
a DVT or PE.
INTRODUCTION as well as ongoing patient assessment and education.4,9,10 Well-

organized anticoagulation management services improve quality
V
enous thromboembolism (VTE) is one of the most com-
of care and reduce overall cost. A systematic approach to drug
mon cardiovascular disorders in the United States. VTE is
therapy management reduces risks, but bleeding remains a com-
manifested as deep vein thrombosis (DVT; ie, thrombus
mon and serious complication.10,11 Therefore, preventing VTE
causing obstruction of a deep vein in the leg, pelvis, or abdomen)
is paramount to improving outcomes. When VTE is suspected,
and pulmonary embolism (PE; ie, thrombus causing obstruction
a rapid and accurate diagnosis is critical to making appropriate
of a pulmonary artery or one of its branches and resulting in pul-
treatment decisions. The optimal use of antithrombotic drugs
monary infarction) (Figure 11–1).1,2 A thrombus is a blood clot
requires not only an in-depth knowledge of their pharmacol-
attached to the vessel wall composed of platelets, fibrin, and clot-
ogy and pharmacokinetic properties but also a comprehensive
ting factors that may partially or completely occlude the lumen of
approach to patient management.3,12
a blood vessel and compromise blood flow and oxygen delivery
to distal tissue. It is often provoked by prolonged immobility or
vascular injury and most frequently seen in patients hospitalized EPIDEMIOLOGY AND ETIOLOGY
for a serious medical illness, trauma, or major surgery. VTE can The true incidence of VTE in the general population is unknown
also occur with little or no provocation in patients who have an because many patients, perhaps more than 50%, have no overt
underlying hypercoagulable disorder. symptoms or go undiagnosed.1,12,13 An estimated 2 million people
Although VTE may initially cause few or no symptoms, the in the United States develop VTE each year, of whom 600,000 are
first overt manifestation of the disease may be sudden death from hospitalized and 60,000 die. The estimated annual direct medical
PE which can occur within minutes, before effective treatment costs of managing the disease are well over $1 billion. The inci-
can be given.2,3 A history of VTE is a significant risk factor for dence of VTE nearly doubles in each decade of life older than
recurrent thromboembolic events.4-7 Postthrombotic syndrome 50 years of age and is slightly higher in men. As the population
(PTS) is a complication of VTE that occurs due to damage to the ages, the total number of DVT and PE cases continues to rise.1,2,13,14
vein caused by a blood clot and leads to development of symp- The risk of VTE is related to several factors includ-
tomatic venous insufficiency such as chronic lower extremity ing age, history of VTE, major surgery (particularly orthopedic
swelling, pain, tenderness, skin discoloration, and ulceration.2 procedures of the lower extremities), trauma, malignancy, preg-
The treatment of VTE is fraught with substantial risks.8 nancy, estrogen use, and hypercoagulable states (Table 11–1).5-7
Antithrombotic therapies (thrombolytics and anti- VTE risk factors can be categorized into one of the three elements
coagulants) require precise dosing and meticulous monitoring, of Virchow triad: stasis in blood flow, vascular endothelial injury,
213
214 SECTION 1 | CARDIOVASCULAR DISORDERS
JJugular
Jug u vein
Subclavian vein
Superior vena cava
ava
a Cephalic vein
Basilic vein
Inferior vena cava

a
Iliac vein
Femoral vein
Great saphenous vein
Popliteal vein
Small saphenous vein
Anterior tibial vein
Dorsal venous arch
FIGURE 11–1. Venous circulation. (From Witt DM, Clark NP, Vazquez SR. Venous thromboembolism. In: DiPiro JT, Yee GC, Posey LM,
et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 11th ed. New York, NY: McGraw-Hill. Available from: https://accesspharmacy.
mhmedical.com/content.aspx?bookid=2577&sectionid=219316417. Accessed July 15, 2020.)
and inherited or acquired changes in blood constituents resulting disorders like polycythemia vera, may also contribute to slowed
in hypercoagulable states.15-17 These risk factors are additive, and blood flow and thrombus formation.5-7,16,17
some can be easily identified in clinical practice.1,3 A prior history While a normal endothelium is antithrombotic, damage to
of venous thrombosis (in which blood changes from a liquid to the endothelium creates a substrate for platelet binding and acti-
a solid state and produces a blood clot) is perhaps the strongest vation that ultimately leads to clot formation. Major surgery,
risk factor for recurrent VTE, presumably because of damage to trauma, and indwelling central catheters can cause endothelial
venous valves and obstruction of blood flow caused by the ini- damage. Smoking and hypertension can also lead to endothelial
tial event.5-7 Rapid blood flow (as in arteries) has an inhibitory dysfunction by shifting the balance between clot formation and
effect on thrombus formation, but a slow rate of blood flow (as clot breakdown toward thrombosis.5-7,16,17
in veins) reduces the clearance of activated clotting factors in A growing list of hereditary deficiencies, gene mutations,
the zone of injury and slows the influx of regulatory substances. and acquired diseases has been linked to hypercoagulability
Stasis tips the delicate balance of procoagulation and antico- (Table 11–1).18,19 Some patients may have multiple genetic defects.
agulation in favor of thrombogenesis. The rate of blood flow Hereditary deficiencies include activated protein C resistance also
in the venous circulation, particularly in the deep veins of the known as factor V Leiden, the prothrombin G20210A gene muta-
lower extremities, is relatively slow. Valves in the deep veins of tion, deficiencies of the natural anticoagulants protein C, protein
the legs, as well as contraction of the calf and thigh muscles, S, and antithrombin (AT), and high concentrations of factors
facilitate the flow of blood back to the heart and lungs. Damage VIII, IX, and XI. Acquired disorders of hypercoagulability include
to the venous valves and periods of prolonged immobility result malignancy, antiphospholipid antibodies, obesity, estrogen use,
in venous stasis. Vessel obstruction, either from a thrombus and pregnancy.20,21 Estrogen-containing contraceptives, estrogen
or external compression, promotes clot propagation. Numer- replacement therapy, and many of the selective estrogen receptor
ous medical conditions and surgical procedures are associated modulators (SERMs) increase the risk of venous thrombosis.20,22
with reduced venous blood flow and increase the risk of VTE. Although the mechanisms are not clearly understood, estro-
Greater than normal blood viscosity, seen in myeloproliferative gens increase serum clotting factor concentrations and induce
CHAPTER 11 | VENOUS THROMBOEMBOLISM 215
to become activated, releasing a number of procoagulant sub-

Table 11–1 stances that stimulate circulating platelets to expose GP IIb and
Risk Factors for Venous Thromboembolism (VTE) IIIa surface receptors subsequently allowing platelets to adhere to
one another, resulting in platelet aggregation (Figure 11–2). The
Risk Factor Considerations and Examples damaged vascular tissue releases tissue factor that activates the
Age Risk doubles with each decade after age 50 extrinsic pathway of the coagulation cascade (Figure 11–3).23
History of VTE Strongest known risk factor The clotting cascade is a stepwise series of enzymatic reactions
Venous stasis Major medical illness (eg, heart failure, acute that results in the formation of a fibrin mesh.12 Clotting factors
myocardial infarction, ischemic stroke, circulate in the blood in inactive forms. Once a precursor is acti-
acute infection) vated by specific stimuli, it activates the next clotting factor in
Major surgery (eg, general anesthesia for the sequence. The final steps in the cascade are the conversion of
> 30 minutes) prothrombin (factor II) to thrombin (factor IIa) and fibrinogen
Paralysis (eg, due to stroke or spinal cord to fibrin. Thrombin plays a key role in the coagulation cascade;
injury)
Polycythemia vera it is responsible not only for the activation of fibrin but also for
Obesity the activation of factors V and VIII, creating a positive feedback
Varicose veins loop that greatly accelerates the entire cascade. Thrombin also
Immobility (eg, bed rest for ≥ 3 days during enhances platelet aggregation.
hospital admission) Traditionally, the coagulation cascade has been divided into
Vascular injury Major orthopedic surgery (eg, knee and hip three distinct parts: the intrinsic, the extrinsic, and the common
replacement) pathways. This artificial division is misleading because there
Trauma (especially fractures of the pelvis, hip, are numerous interactions between the three pathways.16,17,23
or leg)
A number of tempering mechanisms modulate coagulation
Indwelling venous catheters
Hypercoagulable Malignancy, diagnosed or occult (Figure 11–2).23,24 Without effective self-regulation, the coagula-
states Activated protein C resistance/factor V Leiden tion cascade would proceed unabated until all clotting factors and
Prothrombin G20210A gene mutation platelets are consumed.
Protein C deficiency
Protein S deficiency
Antithrombin deficiency CLINICAL PRESENTATION AND DIAGNOSIS
Factor VIII excess (> 90th percentile) Although a thrombus can form in any part of the venous circula-
Factor XI excess (> 90th percentile)
tion, most begin in the lower extremities. Once formed, a venous
Antiphospholipid antibodies
Dysfibrinogenemia thrombus may (a) remain asymptomatic, (b) spontaneously lyse,
Plasminogen activator inhibitor-1 (PAI-1) (c) obstruct the venous circulation, (d) propagate into more prox-
excess imal veins, (e) embolize, and/or (f) slowly incorporate into the
Pregnancy/postpartum endothelial layer of the vessel.1,3,16 Most patients with VTE never
Drug therapy Estrogen-containing oral contraceptive pills develop symptoms.3,25 However, even those who initially experi-
Estrogen replacement therapy ence no symptoms may suffer long-term consequences, such as
Selective estrogen receptor modulators (SERMs) PTS and recurrent VTE.
Heparin
Given that VTE can be debilitating or fatal, it is important
Chemotherapy
to treat it quickly and aggressively.1,2,12 However, because major
bleeding induced by antithrombotic drugs can be equally harm-
ful, it is also important to avoid treatment when the diagnosis
activated protein C resistance. Increased serum estrogen concen-
is not reasonably certain. Assessment should focus on patient-
trations may explain, in part, the increased risk of VTE during
specific risk factors during the medical history (Table 11–1).1,2,12
pregnancy and the postpartum period.22
Venous thrombosis is uncommon in the absence of risk factors,
and the effects of these risk factors are additive. If a patient has
PATHOPHYSIOLOGY multiple risk factors, VTE should be strongly suspected even
Hemostasis, the arrest of bleeding following vascular injury, is when the symptoms are very subtle.
essential to life.23 Within the vascular system, blood remains in a The symptoms of DVT or PE are nonspecific, and
fluid state, transporting oxygen, nutrients, plasma proteins, and it is extremely difficult to distinguish VTE from other disorders
waste. When a vessel is injured, a dynamic interplay between on clinical symptoms alone.1-3,25 Therefore, objective tests are
thrombogenic (activating) and antithrombotic (inhibiting) forces required to confirm or rule out the diagnosis. Patients with DVT
results in the local formation of a hemostatic plug that seals the frequently present with unilateral leg pain on the affected leg,
vessel wall and prevents further blood loss (Figures 11–2 and swelling that can persist after a night’s sleep, and cyanosis of the
11–3). A disruption of this delicate system of checks and balances skin in the affected leg (Table 11–2). Similarly, PTS, a long-term
may lead to inappropriate clot formation within the blood vessel complication of DVT caused by damage to the venous valves, pro-
that can obstruct blood flow or embolize to a distant vascular bed. duces chronic lower extremity swelling, pain, and tenderness that
Under normal circumstances, endothelial cells lining the inside lead to skin discoloration and ulceration. To distinguish acute
of blood vessels maintain blood flow by producing a number of DVT from PTS and other possible diagnoses, a clinical predic-
substances that inhibit platelet adherence, prevent activation of tion rule that incorporates signs, symptoms, and risk factors can
the coagulation cascade, and facilitate fibrinolysis.16,17,23 Vascular be used to categorize the patient as at low, intermediate, or high
injury exposes the subendothelium. Platelets adhere to the suben- probability of having acute DVT. This model, known as the Wells
dothelium with their glycoprotein (GP) Ib surface receptors and criteria, is summarized in Table 11–2.2,3,12 If the clinical probabil-
facilitated by von Willebrand factor (vWF). This causes platelets ity of DVT is low, the D-dimer test can be used to confirm the
Activators Inhibitors
Vessel wall injury
Endothelium
von Willebrand factor
Collagen
Tissue factor
Platelet thrombus
Tissue factor Coagulation

cascade activated Antithrombin
Factor VIIa
Heparin
Factor VIIIa
Thrombomodulin
Factor IXa
Protein C
Factor Va
Protein S
Factor Xa
Thrombin Tissue factor pathway inhibitor
Fibrin formation
Factor XIIIa
Stabilized fibrin clot
Fibrinolysis and
clot degradation
Tissue plasminogen Plasminogen activator
activator inhibitor-1
α2-antiplasmin
Recanalization
and healing
FIGURE 11–2. Hemostasis and thrombosis. (From Witt DM, Clark NP, Vazquez SR. Venous thromboembolism. In: DiPiro JT, Yee GC,
Posey LM, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 11th ed. New York, NY: McGraw-Hill. Available from: https://
accesspharmacy.mhmedical.com/content.aspx?bookid=2577&sectionid=21931641. Accessed July 15, 2020.)
patient does not have DVT. The D-dimer test is a quantitative ruled out if D-dimer testing is negative. If D-dimer testing is posi-
measure of fibrin breakdown in the serum and a marker of acute tive, or if the patient has a moderate or high clinical probability of
thrombotic activity. D-dimer assays are sensitive but not specific PE, diagnostic imaging studies should be performed. Pulmonary
markers for VTE, so a negative D-dimer test can be used to rule angiography allows visualization of the pulmonary arteries and is
out the diagnosis of DVT. the gold standard for diagnosing PE but is an extremely invasive
If the D-dimer test is positive in a low-probability patient, or procedure. Diagnosis of VTE can be made if there is a persistent
if the patient has a moderate or high probability of DVT, then an intraluminal filling defect observed on multiple X-ray films. How-
objective radiographic test is used to confirm the diagnosis of DVT. ever, as with DVT, a noninvasive test is preferred, such as computed
Contrast venography allows visualization of the entire venous sys- tomographic pulmonary angiography, magnetic resonance imag-
tem in the lower extremities. This radiographic contrast study is ing (MRI), and ventilation/perfusion (V/Q) scans.
the most accurate and reliable method for diagnosis of DVT and
considered the gold standard in clinical trials.3,25,26 However, venog-
raphy is an expensive, invasive procedure that is technically diffi- PREVENTION
cult to perform and evaluate. Severely ill patients may be unable to Given that VTE is often clinically silent and potentially fatal, pre-
tolerate the procedure, and many develop hypotension and cardiac vention strategies have the greatest potential to improve patient
arrhythmias. Furthermore, the contrast material is irritating to ves- outcomes.5-7 The goal of an effective VTE prophylaxis program
sel walls and toxic to the kidneys. For these reasons, noninvasive is to identify all patients at risk, determine each patient’s level of
testing using duplex ultrasonography is preferred. risk, and select and implement regimens that provide sufficient
Like DVT, the nonspecific nature of the signs and symptoms protection for the level of risk.5-7 At the time of hospital
of PE requires further evaluation. Table 11–3 describes the Wells admission, transition of care, and prior to discharge, all patients
criteria, a validated prediction model that can be used to stratify should be evaluated for risk of VTE, and appropriate prophylaxis
patients into high, moderate, and low probability of PE.3,25-27 In strategies should be routinely used. Prophylaxis should be contin-
patients with a low clinical probability of PE, diagnosis of PE can be ued throughout the period of risk.
XII
PK
XI HK
TF
XIa
XI
VII VIIa Ca2+
VIIa/TF XIa
PL/Ca2+ IXa
Activated
platelets
X Xa
VIIIa VIII
PL/Ca2+
Va V
Prothrombin Thrombin
Fibrinogen Fibrin
FIGURE 11–3. Summary of coagulation pathways. Specific coagulation factors (“a” indicates activated form) are responsible for
the conversion of soluble plasma fibrinogen into insoluble fibrin. This process occurs via a series of linked reactions in which the
enzymatically active product subsequently converts the downstream inactive protein into an active serine protease. The activation
of thrombin leads to additional stimulation of platelets. (Ca2+, calcium; HK, high-molecular-weight kininogen; PK, prekallikrein; PL,
phospholipid surface; TF, tissue factor.) (From Freedman JE, Loscalzo J. Arterial and venous thrombosis. In: Longo DL, Fauci AS, Kasper DL,
et al., eds. Harrison’s Principles of Internal Medicine, 20th ed. New York, NY: McGraw-Hill; 2018.)
Table 11–2
Clinical Model/Modified Wells Criteria for Evaluating the Pretest Probability of Deep Vein Thrombosis (DVT)
Clinical Characteristic Score

Active cancer (cancer treatment within previous 6 months or currently on palliative treatment) +1
Paralysis, paresis, or recent plaster immobilization of the lower extremities +1
Recently bedridden for 3 days or more, or major surgery within the previous 12 weeks requiring general or regional +1
anesthesia
Localized tenderness along the distribution of the deep venous system +1
Entire leg swollen +1
Calf swelling at least 3 cm larger than that on the asymptomatic side (measured 10 cm below tibial tuberosity) +1
Pitting edema confined to the symptomatic leg +1
Collateral superficial veins (nonvaricose) +1
Previously documented DVT +1
Alternative diagnosis at least as likely as DVT –2
Assess the patient for the presence of any of the 9 clinical characteristics listed above
Assign a score of “+1” for each characteristic that is present.
Tally the total score.
If an alternative diagnosis is at least as likely as DVT, then subtract 2 points from the total points tallied above.
In patients with symptoms in both legs, the more symptomatic leg is used.
Risk Score Interpretation
Total Risk Score Clinical Probability of DVT

0 Low
1 Moderate
2 Moderate
3 or higher High
Clinical Presentation and Diagnosis of DVT

General Laboratory Tests
Most commonly develops in patients with identifiable risk t Initial laboratory evaluation should include complete blood
factors (Table 11–1) during or following a hospitalization. Many count (CBC) with differential, coagulation studies (such as
patients have asymptomatic disease. prothrombin time [PT]/international normalized ratio
[INR], activated partial thromboplastin time [aPTT]), serum
Symptoms
chemistries with renal and liver function, and urinalysis.
Patient may complain of persistent unilateral leg swelling, pain,
t Serum concentrations of D-dimer, a by-product of thrombin
warmth, and/or skin discoloration. Symptoms are nonspecific, and
generation, will be elevated in an acute event. A negative
objective testing must be performed to establish the diagnosis.
D-dimer in a patient with low clinical probability of DVT can
Signs be used to rule out DVT.
t Superficial veins may be dilated, and a “palpable cord” may t Patient may have an elevated erythrocyte sedimentation rate
be felt in the affected leg. (ESR) and white blood cell (WBC) count.
t May experience unilateral leg edema with measurable Diagnostic Tests
difference in leg circumference compared to the unaffected
t Duplex ultrasonography is the most commonly used test to
leg, erythema, increase in warmth, and tenderness with
diagnose DVT. It is a noninvasive test that can measure the
palpation of calf muscles.
rate and direction of blood flow and visualize clot formation
t May experience pain in the popliteal or calf region in the in proximal veins of the legs. It cannot reliably detect small
affected leg when the examiner dorsiflexes the foot while the blood clots in distal veins. Coupled with a careful clinical
knee is flexed/slightly bent (Homans sign). assessment, it can confirm or rule out (exclude) the diagnosis
t Note: Physical examination signs can be unreliable. Homans in most cases. Repeat testing may be necessary if the first test
sign can also be unreliable. is negative and the patient is still symptomatic.
Clinical Probability t Venography (also known as phlebography) is the gold standard
for diagnosis of DVT. However, it is an invasive test that involves
Apply the Wells criteria to determine the probability that the injection of radiopaque contrast dye into a foot vein. It is
patient’s signs, symptoms, and risk factors are the result of DVT expensive and can cause anaphylaxis and nephrotoxicity.
(Table 11–2).
There are several risk assessment models available for esti-

mating VTE risk specific to hospitalized medical and surgical Table 11–4
patients.5-7,12 While none of these models have been extensively Risk Factors for Predicting Venous Thromboembolism (VTE)
validated, the Padua prediction score is recommended for assess- in Hospitalized Medical Patients (Padua Prediction Score)
ment of medical patients (Table 11–4), and the Caprini score
is recommended for assessment of general surgical patients Risk Factor Points
(Table 11–5). Bleeding risk should also be assessed to help iden-
Active cancera 3
tify patients in whom the risk of bleeding may outweigh benefits Previous VTE (with the exclusion of superficial vein 3
of pharmacologic prophylaxis.5-7 Table 11–6 lists general and thrombosis)
Reduced mobilityb 3
Already known thrombophilic conditionc 3
Table 11–3 Recent (≤ 1 month) trauma and/or surgery 2
Elderly age (≥ 70 years) 1
Clinical Model/Wells Criteria for Evaluating the Pretest Heart and/or respiratory failure 1
Probability of Pulmonary Embolism (PE) Acute myocardial infarction or ischemic stroke 1
Acute infection and/or rheumatologic disorder 1
Clinical Characteristic Score Obesity (body mass index ≥ 30) 1
Ongoing hormonal treatment 1
Cancer +1 Cumulative score of ≥ 4 points indicates high risk of VTE
Hemoptysis +1
Previous PE or DVT +1.5 a
Patients with local or distant metastases and/or in whom
Heart rate > 100 beats/min +1.5 chemotherapy or radiotherapy had been performed in the previous
Recent surgery or immobilization +1.5 6 months.
Clinical signs of DVT +3 b
Alternative diagnosis less likely than PE +3 Anticipated bed rest with bathroom privileges (either because of
patient’s limitations or on physician’s order) for at least 3 days.
Risk Score Interpretation c
Carriage of defects of antithrombin, protein C or S, factor V Leiden,
Total Risk Score Clinical Probability of PE G20210A prothrombin mutation, antiphospholipid syndrome.
0–1 Low Adapted with permission from Kahn SR, Lim W, Dunn AS, et al.
2–6 Moderate Prevention of VTE in nonsurgical patients: Antithrombotic Therapy
7 or higher High and Prevention of Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest.
DVT, deep vein thrombosis. 2012;141(2 suppl):e195S–e226S.
Clinical Presentation and Diagnosis of PE

General Laboratory Tests
Most commonly develops in patients with risk factors for VTE t Serum concentrations of D-dimer, a by-product of
(Table 11–1) during or following a hospitalization. Although thrombin generation, will be elevated. A negative D-dimer
many patients will have symptoms of DVT prior to developing in a patient with low clinical probability of PE can be used
a PE, many will not, and some patients can be asymptomatic. to rule out PE.
Patients may die suddenly before effective treatment can be t In patients with a low probability for PE, the PE rule-out
initiated. criterion (“PERC rule”) is an alternative to D-dimer testing. In
Symptoms patients who meet all following eight criteria, the likelihood
of PE is low, and no further testing is required: age less than
t May complain of cough, pleuritic chest pain, chest tightness,
50 years; heart rate less than 100 beats/min; oxyhemoglobin
shortness of breath with or without exertion, wheezing,
saturation at or above 95% (0.95); no hemoptysis; no
orthopnea, or palpitations.
estrogen use; no prior DVT or PE; no unilateral leg swelling;
t May present with hemoptysis (spit or cough up blood). and no surgery/trauma requiring hospitalization within the
t May complain of dizziness or experience syncope. prior 4 weeks.
t May be misdiagnosed as a myocardial infarction (MI) or t May have an elevated ESR and WBC count.
pneumonia, and objective testing must be performed to t May have elevated serum lactate dehydrogenase (LDH) or
establish the diagnosis. aspartate aminotransferase (AST; serum glutamic-oxaloacetic
Signs transaminase [SGOT]) with normal bilirubin.
t May have tachypnea (increased respiratory rate) and t Serum troponin I, troponin T, and B-type natriuretic peptide
tachycardia (increased heart rate). can be elevated in a large PE. These typically resolve within
40 hours if due to PE but persist longer after acute MI.
t May appear diaphoretic (sweaty) and may have fever.
t Electrocardiogram may show nonspecific ST-segment and
t Neck veins (external jugular veins) may be distended reflecting T-wave changes and tachycardia. Arterial blood gases may
increased jugular venous pressure and increased heart pressure. show acute respiratory alkalosis from hyperventilation.
t The examiner may see use of accessory respiratory muscles
and may hear diminished breath sounds, crackles, wheezes, Diagnostic Imaging Tests
or pleural friction rub during auscultation of the lungs. A t A computed tomography (CT) pulmonary angiography with
parasternal lift or right ventricular S3, S4 may be found on the radiocontrast is the most commonly used test to diagnose
heart examination. PE, but some institutions still use a V/Q scan. Spiral (or helical)
t In massive PE, the patient may appear cyanotic and CT scans can detect emboli in the proximal pulmonary
hypotensive and may appear to have signs of right-sided heart arteries. A V/Q scan measures the distribution of blood
failure. In such cases, oxygen saturation by pulse oximetry or and air flow in the lungs. When there is a large mismatch
arterial blood gas will likely indicate the patient is hypoxic. between blood and air flow in one area of the lung, there is a
high probability the patient has a PE.
t In the worst cases, the patient may go into circulatory shock
and die within minutes. t Pulmonary angiography is the gold standard for diagnosis
of PE. However, it is an invasive test that involves injection
Clinical Probability of radiopaque contrast dye into the pulmonary artery. The
Apply the Wells criteria to determine the probability that the test is expensive and associated with significant risk of
patient’s signs, symptoms, and risk factors are the result of PE mortality.
(Table 11–3).
procedure-specific risk factors for major bleeding complica- blood flow and promotes the flow of natural antithrombotic fac-
tions. Patients with moderate to high risk of VTE should receive tors into the lower extremities. All hospitalized patients should
pharmacologic prophylaxis. If pharmacologic prophylaxis is be encouraged to ambulate as early as possible, and as frequently
contraindicated, such as in patients actively bleeding or at high as possible.
risk of bleeding, nonpharmacologic prophylaxis should be used Graduated compression stockings (GCS) are specialized
(Table 11–7). hosiery that provide graduated pressure on the lower legs and
Several pharmacologic and nonpharmacologic methods are feet to help prevent thrombosis. Compared with anticoagulant
effective for preventing VTE, and these can be used alone or drugs, GCS are relatively inexpensive and safe; however, they are
in combination (Table 11–7).5-7 Nonpharmacologic methods less effective and not recommended in moderate-to-higher-risk
improve venous blood flow by mechanical means; drug ther- patients.2 They offer an alternate in low-to moderate-risk patients
apy prevents thrombus formation by inhibiting the coagulation when pharmacologic interventions are contraindicated. When
cascade. combined with pharmacologic interventions, GCS have an addi-
tive effect. However, some patients are unable to wear compres-
Nonpharmacologic Therapy sion stockings because of the size or shape of their legs, and some
Ambulation as soon as possible following surgery lowers the inci- patients may find them hot, confining, and very difficult to put
dence of VTE in low-risk patients.5-7 Walking increases venous on and remove.
Table 11–5
Risk Factors for Predicting Venous Thromboembolism (VTE) in General Surgical Patients (Modified Caprini Risk
Assessment Model for VTE in General Surgical Patients)
Risk Score
1 Point 2 Points 3 Points 5 Points

Age 41–60 years Age 61–74 years Age ≥ 75 years Stroke (< 1 month)
Minor surgery Arthroscopic surgery History of VTE Elective arthroplasty
BMI > 25 kg/m2 Major open surgery Family history of VTE Acute spinal cord
Swollen legs (> 45 minutes) Factor V Leiden injury (< 1 month)
Varicose veins Laparoscopic surgery Prothrombin G20210A
Pregnancy or postpartum (> 45 minutes) Lupus anticoagulant
History of unexplained or recurrent spontaneous abortion Malignancy Anticardiolipin antibodies
Oral contraceptives or hormone replacement Confined to bed (> 72 hours) Elevated serum
Sepsis (< 1 month) Immobilizing plaster cast homocysteine
Serious lung disease, including pneumonia (< 1 month) Central venous access Heparin-induced
Abnormal pulmonary function thrombocytopenia
Acute myocardial infarction Other congenital or
Heart failure (< 1 month) acquired thrombophilia
History of inflammatory bowel disease
Medical patient at bed rest
Risk Score Interpretation
Total Risk Score Risk of VTE

0 Very low (< 0.5%)
1–2 Low (1.5%)
3–4 Moderate (3%)
≥5 High (6%)
BMI, body mass index.

Adapted with permission from Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic
Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest.
2012;141(2 suppl):e227S–e277S.
Table 11–6
Risk Factors for Major Bleeding Complications
Procedures in Which
Bleeding Complications
May Have Especially
General Risk Factors Procedure-Specific Risk Factors Severe Consequences
Active bleeding Abdominal Surgery Craniotomy
Previous major bleeding Male sex, preoperative hemoglobin level < 13 g/dL (130 g/L; 8.07 mmol/L), Spinal surgery
Known, untreated bleeding malignancy, and complex surgery defined as two or more procedures, Spinal trauma
disorder difficult dissection, or more than one anastomosis Reconstructive
Severe renal or hepatic failure Pancreaticoduodenectomy procedures involving
Thrombocytopenia Sepsis, pancreatic leak, sentinel bleed free flap
Acute stroke Hepatic Resection
Uncontrolled systemic Number of segments, concomitant extrahepatic organ resection, primary
hypertension liver malignancy, lower preoperative hemoglobin level, and platelet counts
Lumbar puncture, epidural, or Cardiac Surgery
spinal anesthesia within previous Use of aspirin, use of clopidogrel within 3 days before surgery
4 hours or next 12 hours BMI > 25 kg/m2, nonelective surgery, placement of five or more grafts, older
Concomitant use of anticoagulants, age, renal insufficiency, operation other than CABG, longer bypass time
antiplatelet therapy, or Thoracic Surgery
thrombolytic drugs Pneumonectomy or extended resection
BMI, body mass index; CABG, coronary artery bypass graft.

Adapted with permission from Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic
Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest.
2012;141(2 suppl):e227S–e277S.
Table 11–7
Thrombosis Risk Classification and Recommended Venous Thromboembolism Prevention Strategies5-7
Indication and Level of Risk Prevention Strategies

Hospitalized Medical Patients
Low thrombosis risk Early ambulation
High thrombosis riska (Padua score > 4) LMWH, LDUH, fondaparinux, betrixaban
Critically Ill Patients
High thrombosis riska LMWH, LDUH
General Surgical Patients
Very low thrombosis risk (Caprini Score 0) Early ambulation
Low thrombosis risk (Caprini Score 1–2) IPC
Moderate thrombosis riskb (Caprini Score 3–4) LMWH, LDUH, IPC
High thrombosis riskb (Caprini Score ≥ 5) LMWH, LDUH, plus GCS or IPC
Cancer Surgery LMWH, rivaroxaban, apixaban
Major Orthopedic Surgery
Hip fracture surgeryb LMWH, fondaparinux, LDUH, adjusted dose warfarin, aspirin
Hip and knee arthroplastyb LMWH, fondaparinux, LDUH, warfarin, aspirin, apixaban, dabigatran, rivaroxaban
a
Mechanical methods of prophylaxis with IPC or GCS should be used in patients actively bleeding or those at high risk of bleeding complications
(see Table 11–6 for risk factors for major bleeding).
b
Mechanical methods of prophylaxis with IPC should be used in patients actively bleeding or those at high risk of bleeding complications
(see Table 11–6 for risk factors for major bleeding).
GCS, graduated compression stockings; IPC, intermittent pneumatic compression; LDUH, low-dose unfractionated heparin; LMWH, low-
molecular-weight heparin.
Similar to GCS, intermittent pneumatic compression Pharmacologic Therapy

(IPC) devices increase the velocity of blood flow in the lower Appropriately selected drug therapies can dramatically reduce the
extremities.5-7 These devices sequentially inflate a series of cuffs incidence of VTE in medical and surgical patients (Table 11–7).
wrapped around the patient’s legs from the ankles to the thighs Choice of medication and dose to use for VTE prevention must
and then deflate in 1- to 2-minute cycles. Although IPC has been be based on the patient’s level of risk for thrombosis and bleed-
shown to reduce the risk of VTE in surgical patients, most stud- ing risk, as well as the cost and availability of an adequate drug
ies failed to define the type of device used. IPC was frequently therapy monitoring system.5-7
used in combination with other prophylaxis methods, making it The most extensively studied drugs for the prevention of VTE
difficult to quantify their efficacy. Although IPC is safe to use in are unfractionated heparin (UFH), the low-molecular-weight hep-
patients who have contraindications to pharmacologic therapies, arins (LMWHs; dalteparin and enoxaparin), fondaparinux, and
it does have a few drawbacks: it is more expensive than GCS; it is warfarin.5-7 Generally, the LMWHs provide improved protection
a relatively cumbersome technique; some patients may have dif- against VTE when compared with low-dose UFH in most medi-
ficulty sleeping while using it, and some patients find the devices cal and surgical patients and when compared to low-dose UFH
hot and uncomfortable. To be effective, IPC needs to be used and warfarin in major orthopedic surgery patients. Fondaparinux
throughout the day. In practice, this is difficult to achieve, and is more effective than LMWH in patients undergoing high-risk
special efforts should be made to ensure the devices are worn and orthopedic surgery, but it has a heightened risk of bleeding.
operational for most of the day. For hospitalized general surgical and medical patients, the
Inferior vena cava (IVC) filters, also known as Greenfield fil- available evidence supports the use of UFH 5000 units subcu-
ters, provide short-term protection against PE in very high-risk taneously (SC) every 8 to 12 hours, enoxaparin 40 mg SC daily,
patients by preventing the embolization of a thrombus formed in dalteparin 2500 to 5000 units SC daily, or fondaparinux 2.5 mg
the lower extremities into the pulmonary circulation.5-7 Insertion of SC daily. Betrixaban is also approved for extended VTE prophy-
a filter into the IVC is a minimally invasive procedure. Despite the laxis in hospitalized adult patients with acute medical illnesses
widespread use of IVC filters, there are very limited data regarding and was found noninferior to prophylactic-dose enoxaparin with
their effectiveness and long-term safety. The evidence suggests that no differences in major bleeding. Betrixaban is given as an ini-
IVC filters, particularly in the absence of effective antithrombotic tial 160-mg dose followed by 80 mg daily, with the dose halved
therapy, are thrombogenic themselves and increase the long-term in the setting of severe renal impairment (creatinine clearance
risk of recurrent DVT and of filter thrombosis. Although IVC fil- [CrCl] 15–30 mL/min [0.25–0.5 mL/s]) or concomitant use of
ters can reduce the short-term risk of PE in patients at highest risk, P-glycoprotein (P-gp) inhibitors.28
they should be reserved for patients in whom other prophylactic For the prevention of VTE following major orthopedic surgery,
strategies cannot be used. To further reduce the long-term risk of current evidence supports the use of UFH, LMWH, fondaparinux,
VTE in association with IVC filters, pharmacologic prophylaxis adjusted dose warfarin, aspirin, and the direct oral anticoagulants
is necessary in patients with IVC filters in place, and warfarin (DOACs; apixaban, dabigatran, edoxaban, and rivaroxaban). The
therapy should begin as soon as the patient is able to tolerate it.2 If role of aspirin for VTE prevention is controversial as it produces
used, retrievable filters are preferred, which can be removed once a very modest reduction in VTE following orthopedic surgeries
pharmacologic prophylaxis can be safely administered or once the of the lower extremities.5
patient is no longer at risk for VTE.
The effectiveness of UFH, aspirin, and warfarin is lower than surgery and in high-risk cancer patients and offer a convenient
LMWH, and long-term safety data are lacking for apixaban, alternative to traditional anticoagulants.5,29-31 Both agents have
dabigatran, and rivaroxaban; thus the American College of Chest shown superior efficacy compared to LMWH with a similar rate
Physicians (ACCP) guidelines recommend the use of LMWH or of bleeding complications in orthopedic surgery patients. Riva-
fondaparinux preferentially over other pharmacologic options in roxaban is given at a fixed dose of 10 mg once daily, and apixa-
major orthopedic surgery patients.5 The appropriate prophylactic ban is given at a fixed dose of 2.5 mg twice daily. Both are given
dose for each LMWH product in orthopedic surgery is indication without the need for routine laboratory monitoring and dosing
specific; however, enoxaparin 30 mg SC twice daily or 40 mg SC adjustments (as with warfarin) and without the inconvenience of
daily, and dalteparin 5000 units SC daily are the most commonly administration by injection (as with LMWH and fondaparinux).
used regimens. The dose of fondaparinux is 2.5 mg SC daily. The oral direct thrombin inhibitor (DTI) dabigatran is another
The dose of warfarin, another commonly used option for pre- option for VTE prevention following orthopedic surgery but is
vention of VTE following orthopedic surgery, must be adjusted only approved for use following hip replacement surgery. Dabiga-
to maintain an INR between 2 and 3.5 Oral administration and tran is given as an initial 110-mg dose, followed by 220 mg once
low drug acquisition cost give warfarin some advantages over the daily. Dabigatran should not be used in those with CrCl less than
LMWHs and fondaparinux. However, warfarin does not achieve 30 mL/min (0.50 mL/s) or concomitantly with P-gp inhibitors.
its full antithrombotic effect for several days and requires frequent Optimal duration for VTE prophylaxis is not well established
monitoring and periodic dosage adjustments, making therapy but should be given throughout the period of risk. For patients
cumbersome. Warfarin should only be used when a systematic who have undergone total knee replacement, total hip replace-
patient monitoring system is available. ment, or hip fracture repair, prophylaxis is recommended for a
The oral factor Xa inhibitors rivaroxaban and apixaban are also minimum of 10 to 14 days; however, extending it up to 35 days
options for VTE prevention following hip and knee replacement is recommended due to continued VTE risk up to 1 month
postsurgery.5-7
TREATMENT
Patient Encounter 1 Desired Therapeutic Outcomes
The goal of VTE treatment is to prevent short- and long-term
A 32-year-old woman (BMI 23 kg/m2) with a recent history complications of the disease. The aim of initial therapy is to
of 3-day hospitalization due to traumatic injuries sustained prevent propagation or local extension of the clot, emboliza-
from a motor vehicle crash is readmitted to the hospital with tion, hemodynamic collapse, and death. The goal of long-term
increasing left leg pain and redness, fever, and fatigue. She and extended therapy is to prevent complications such as PTS,
is diagnosed with osteomyelitis and started on antibiotic pulmonary hypertension, and recurrent VTE.2,12
therapy.
PMH: Left leg type II fracture status post reduction and General Treatment Principles
immobilization. Anticoagulant drugs are considered the mainstay of therapy for
FH: Father died at 55 years due to PE; mother died at 63 years patients with VTE, and the therapeutic strategies for DVT and
due to breast cancer; sister with history of DVT at 37 years. PE are similar.2,12 Management decisions are guided by balanc-
ing the risks and benefits of various treatment options. Treatment
SH: Occasional alcohol use. Employed in county government.
of VTE can be divided into three phases: acute (first 5–10 days),
Lives at home with spouse and pets.
long term (first 3 months), and extended (beyond 3 months).12
Home Meds: Norethindrone/ethinyl estradiol 0.5 m/0.035 mg The acute treatment phase of VTE is typically accomplished by
daily, hydrocodone-acetaminophen 10 mg/325 mg every administering a fast-acting parenteral anticoagulant or a DOAC
4 hours as needed, ibuprofen 600 mg twice daily as (Table 11–8). The long-term and extended phase treatments of
needed. VTE are usually accomplished using oral anticoagulant agents
Allergies: amoxicillin (anaphylaxis) such as warfarin, or one of the DOACs.2,12 In certain populations,
such as patients with cancer and women who are pregnant, the
VS: BP 135/70 mm Hg, HR 72 beats/min, RR 16 breaths/min,
LMWHs are the preferred agents during long-term and extended
T 38.7°C (101.7°F), Wt 67 kg (147 lb).
treatment phases due to better safety or efficacy.2,31 The etiol-
Labs: WBC 22.4 × 103/mm3 (22.4 × 109/L); estimated ogy of VTE will guide the duration of therapy. VTE can be pro-
glomerular filtration rate (eGFR) 80 mL/min/1.73 m2; CrCl voked (by transient or persistent risk factors), unprovoked (or
78 mL/min (1.30 mL/s). idiopathic), and cancer associated. Patients with unprovoked or
Hospital Treatment: cefazolin 2 g IV every 7 hours, cancer-associated VTE have a significantly higher risk of recur-
hydrocodone-acetaminophen 10/325 mg PO every 4 to rence compared to patients with provoked VTE.2,12,31
6 hours as needed, ibuprofen 400 mg PO every 4 to 6 hours In the absence of contraindications, treatment of
as needed. VTE should initially include a rapidly acting DOAC (eg, apixa-
Which risk factor(s) predispose this patient to VTE? ban, rivaroxaban, edoxaban) or a rapid-acting injectable anti-
coagulant (eg, UFH, LMWH, fondaparinux). If warfarin is used
What is her estimated risk for developing VTE? for oral anticoagulation, it should be initiated on the same day
Given her presentation and history, create an appropriate VTE as the parenteral anticoagulant, and the parenteral agent should
prophylaxis plan including the pharmacologic agent, dose, be overlapped for a minimum of 5 days and until the INR is
route and frequency of administration, duration of therapy, greater than or equal to 2 for at least 24 to 48 hours. If dabiga-
and monitoring parameters. tran or edoxaban is used for oral anticoagulation, they should be
initiated after 5 to 10 days of initial treatment with a parenteral
and prevent destruction of the venous valves. While they may

Table 11–8 decrease the incidence and severity of PTS, clinical trials have
Pharmacologic Options for the Acute Phase Treatment of failed to show reduction in recurrent DVT, PE, or death32; there-
Venous Thromboembolism (VTE) fore, their use in most patients is not recommended.2,12 In a select
group of high-risk patients with massive iliofemoral DVT who
Parenteral Anticoagulants are at risk of venous gangrene and limb loss, thrombolysis may be
UFH considered. See Table 11–9.
IV administration:a use weight-based dosing nomogram In patients with acute PE, use of thrombolytics provides short-
(Table 11–10) term benefits such as restoring pulmonary artery patency and
Or
SC administration: 17,500 units (250 units/kg) given every 12 hours
hemodynamic stability.2,12,32 However, systemic thrombolysis
(an initial 5000-unit IV bolus dose is recommended to obtain does not reduce mortality and is associated with a greater risk
rapid anticoagulation) of major bleeding.12 Given the relative lack of data to support
Adjust subsequent doses to attain a goal aPTT based on the their routine use, thrombolytics should be reserved for select
institution-specific therapeutic range high-risk circumstances. Candidates for thrombolytic therapy are
Or patients with acute massive embolism who are hemodynamically
SC administration: 333 units/kg followed by 250 units/kg given
every 12 hours (fixed-dose unmonitored dosing regimen)
LMWHs
Dalteparin: 200 units/kg SC once daily or 100 units/kg SC twice daily Table 11–9
Enoxaparin: 1.5 mg/kg SC once daily or 1 mg/kg SC twice daily; if
CrCl < 30 mL/min (0.50 mL/s): 1 mg/kg SC once daily Thrombolysis for the Treatment of Venous
Thromboembolism
Factor Xa Inhibitor
Fondaparinuxb: t Thrombolytic therapy should be reserved for patients who
For body weight ≤ 50 kg (110 lb), use 5 mg SC once daily present with PE with shock, hypotension, or massive DVT with
For body weight 50–100 kg (110–220 lb), use 7.5 mg SC once daily limb gangrene
For body weight ≥ 100 kg (220 lb), use 10 mg SC once daily t Diagnosis must be objectively confirmed before initiating
Direct Oral Anticoagulants (DOACs) thrombolytic therapy
Apixaban: 10 mg PO twice daily for the initial 7 days, then 5 mg PO t Thrombolytic therapy is most effective when administered as
twice dailyc soon as possible after PE diagnosis, but benefit may extend up
Dabigatran: 150 mg PO twice daily after 5–10 days of parenteral to 14 days after symptom onset
anticoagulationd FDA-Approved PE Thrombolytic Regimens
Edoxaban: 60 mg PO once daily or 30 mge PO once daily after t Streptokinase 250,000 units IV bolus over 30 minutes followed
5–10 days of parenteral anticoagulation by 100,000 units/hour for 12–24 hoursa
Rivaroxaban: 15 mg PO twice daily for the initial 21 days, then 20 mg t Urokinase 4400 units/kg IV bolus over 10 minutes followed by
PO dailyd,f 4400 units/kg/hour for 12–24 hoursa
a
t Alteplase (rt-PA) 100 mg IV over 2 hours
IV administration preferred due to improved dosing precision. Non–FDA-Approved Thrombolytic Regimens
b
Contraindicated in patients with CrCl < 30 mL/min (0.50 mL/s). t Reteplase two 10-unit IV boluses given 30 minutes apart
c
After the initial 6 months of therapy, the dose is reduced to 2.5 mg t Tenecteplase weight-adjusted IV bolus over 5 seconds
PO twice daily. (30–50 mg with a 5-mg step every 10 kg from < 60 to > 90 kg)
d t Factors that increase the risk of bleeding must be evaluated
Avoid in patients with CrCl < 30 mL/min (0.50 mL/s).
before thrombolytic therapy is initiated (ie, recent surgery,
e
Reduced dose for CrCl 15–50 mL/min (0.25–0.83 mL/s), body weight trauma or internal bleeding, uncontrolled hypertension, recent
≤ 60 kg (132 lb), or concomitant use of P-glycoprotein inhibitors. stroke, or intracranial hemorrhage)
f
In cancer patients, rivaroxaban and edoxaban are the only DOACs t Baseline laboratories should include CBC and blood typing in
recommended for VTE treatment. Rivaroxaban is recommended for case transfusion is needed
both initial and long-term treatment. Edoxaban is recommended t IV UFH should not be used during IV thrombolytic therapy.
only for long-term treatment. Neither the aPTT nor any other anticoagulation parameter
aPTT, activated partial thromboplastin time; CrCl, creatinine should be monitored during the thrombolytic infusion
clearance; IV, intravenous; LMWHs, low-molecular-weight heparins; t aPTT should be measured following the completion of
SC, subcutaneous; UFH, unfractionated heparin. thrombolytic therapy:
t If aPTT < 2.5 times the control value, UFH infusion should be
started and adjusted to maintain aPTT in therapeutic range
t If aPTT > 2.5 times the control value, remeasure every 2–4
anticoagulant. Anticoagulation therapy should be continued for hours and start UFH infusion when aPTT is < 2.5
a minimum of 3 months. However, duration of anticoagulation t Avoid phlebotomy, arterial puncture, and other invasive
therapy should be based on the patient’s risk of VTE recurrence procedures during thrombolytic therapy to minimize the risk of
and major bleeding.2,12 bleeding
Pharmacologic Therapy a
Two-hour infusions of streptokinase and urokinase are as effective
▶
and safe as alteplase; 2-hour infusion times are preferred over longer
Thrombolytics
infusion times.
The role of thrombolysis in the treatment of VTE is aPTT, activated partial thromboplastin time; CBC, complete
controversial.2,12,32 Compared with anticoagulants, thrombolyt- blood count; DVT, deep vein thrombosis; FDA, Food and Drug
ics restore venous patency more quickly; however, the bleeding Administration; IV, intravenous; PE, pulmonary embolism; rt-PA,
risk associated with their use is significantly higher. In patients recombinant tissue plasminogen activator; UFH, unfractionated
with DVT, thrombolytics decrease short-term pain and swelling heparin.
and elevated factor VIII levels are common in pregnant patients.

Patient Encounter 2 AT deficiency has been linked to higher UFH dose requirements.
The requirement of these higher UFH doses is termed heparin
A 62-year-old woman with a new diagnosis of ovarian cancer
resistance. Factor VIII elevations can result in altered activated
is admitted to the hospital for debulking surgery.
partial thromboplastin time (aPTT) response to UFH, and moni-
PMH: Depression × 19 years; obesity × 25 years, ulcerative toring with antifactor Xa levels is recommended.2,9,10
colitis × 35 years, history of hip fracture 8 years ago with The dose of UFH required to achieve a therapeutic anticoagu-
subsequent lower left extremity DVT, treated with LMWH and lant response is correlated to the patient’s weight.2,9 Weight-based
warfarin for 3 months. dosing regimens should be used to exceed the therapeutic thresh-
FH: Mother died at 72 years due to ovarian cancer; brother old in the first 24 hours after initiating treatment.9,10 Achieving
55 years old with type 2 diabetes; maternal grandmother died a therapeutic aPTT in the first 24 hours after initiating UFH is
at 65 years due to breast cancer. critical because it has been shown to lower the risk of recurrent
SH: Smoked half a pack per day for 25 years, quit 15 years VTE. For nonobese patients, the actual body weight should be
ago; occasional alcohol use. Lives alone and expects to be used to calculate the initial UFH dose (Table 11–10). For obese
discharged to a rehabilitation facility postoperatively before patients, using the actual body weight to calculate the initial dose is
returning home. also generally recommended; however, data are limited in morbidly
obese patients, that is, weight more than 150 kg (330 lb). Some
Home Meds: Sertraline 100 mg by mouth daily; oxycodone experts recommend using an adjusted body weight (ABW) in these
5–10 mg by mouth every 5 hours as needed for pain; St. John’s patients instead. The infusion rate is then adjusted based on labora-
wort 2 capsules daily. tory monitoring of the patient’s response.9,10 (See Table 11–10.)
Allergies: NKDA Due to significant interpatient variability and
VS: BP 110/60 mm Hg, HR 55 beats/min, RR 18 breaths/min, changes in patient response over time, UFH requires close moni-
T 37.0°C (98.6°F), Wt 127 kg (280 lb), BMI 41 kg/m2. toring and periodic dose adjustment. The response to UFH can be
monitored using a variety of laboratory tests including the aPTT,
Labs: Hemoglobin, hematocrit, platelets, and liver function whole blood clotting time, activated clotting time (ACT), antifac-
tests (LFTs) within normal limits; eGFR 96 mL/min/1.73 m2; tor Xa activity, and plasma heparin concentration.9,10 Although it
CrCl 94 mL/min (1.57 mL/s). has several limitations, the aPTT is the most widely used test in
Which risk factor(s) predispose this patient to VTE? clinical practice to monitor UFH. Traditionally, therapeutic aPTT
How should postoperative VTE be prevented? range is defined as 1.5 to 2.5 times the control aPTT value. How-
ever, due to variations in reagents and instruments used to mea-
How long should she receive VTE prophylaxis? sure the aPTT in different laboratories, each institution should
What education about VTE prophylaxis should she receive? establish a therapeutic range for UFH. The institution-specific
therapy range should correlate with a plasma heparin concentra-
tion of 0.2 to 0.4 units/mL (kU/L) by protamine titration or 0.3
unstable (systolic blood pressure [SBP] < 90 mm Hg) and at low risk to 0.7 units/mL (kU/L) by an amidolytic antifactor Xa assay.4,27
for bleeding. Current guidelines recommend a short infusion time An aPTT should be obtained at baseline, 6 hours after initiating
(2 hours) over a prolonged infusion time (24 hours) and administra- the heparin infusion, and 6 hours after each dose change because
tion through a peripheral vein over a pulmonary artery catheter.2,12 this is the time required to reach steady state. UFH dose is then
adjusted based on the aPTT measurement and institutional-
▶ Unfractionated Heparin specific therapeutic range (Table 11–10). In patients with heparin
UFH has traditionally been the drug of choice for indications resistance, antifactor Xa concentrations may be a more accurate
requiring rapid anticoagulation including the acute treatment method of monitoring the patient’s response.9,10
of VTE. Unlike thrombolytics, UFH and other anticoagulants Side effects associated with UFH include bleeding, thrombocy-
will not dissolve a formed clot but prevent its propagation and topenia, hypersensitivity reactions, and with prolonged use, alo-
growth.2,9 Heparin exerts its anticoagulant effect by augmenting pecia, hyperkalemia, and osteoporosis.9,10 Bleeding is
the natural anticoagulant, AT. See Figure 11–4. the most common adverse effect associated with antithrombotic
UFH can be administered via the intravenous (IV) or subcuta- drugs including UFH therapy.8 A patient’s risk of major hemor-
neous (SC) route.2,9 See Table 11–8. When rapid anticoagulation rhage is related to the intensity and stability of therapy, age, con-
is required, UFH should be administered IV, and an initial bolus current drug use, history of gastrointestinal bleeding, risk of falls
dose should be given. For the treatment of VTE, UFH is gener- or trauma, and recent surgery. Several risk factors can increase the
ally given as a continuous IV infusion. The half-life of UFH is risk of UFH-induced bleeding (Table 11–11). The risk of bleeding
dose dependent and ranges from 30 to 90 minutes but may be is related to intensity of anticoagulation. Higher aPTT values are
significantly longer, up to 150 minutes, with high doses. UFH is associated with an increased risk of bleeding. The risk of major
eliminated by two mechanisms: (a) enzymatic degradation via bleeding is 1% to 5% during the first few days of treatment.2,9,10 In
a saturable zero-order process, and (b) renally via a first-order addition to the aPTT, hemoglobin, hematocrit, and blood pres-
process. Lower UFH doses are primarily cleared via enzymatic sure should be monitored. Concurrent use of UFH with other
processes, whereas higher doses are primarily renally eliminated. antithrombotic agents, such as thrombolytics and antiplate-
Clearance of UFH can be impaired in patients with renal and let agents, also increases bleeding risk. Patients receiving UFH
hepatic dysfunction. Patients with active thrombosis may require therapy should be closely monitored for signs and symptoms of
higher UFH doses due to a more rapid elimination or variations bleeding, including epistaxis, hemoptysis, hematuria, hemateme-
in the plasma concentrations of heparin-binding proteins. sis, hematochezia, melena, severe headache, and joint pain. If
Certain patient-specific situations may require UFH higher major bleeding occurs, UFH should be stopped immediately
doses to achieve a therapeutic anticoagulant effect. AT deficiency and the source of bleeding treated.9,10 If necessary, use protamine
Unfractionated heparin (Xa:IIa 1:1)

Thrombin (IIa)
Pentasaccharide Thrombin (IIa) Ternary
complex
Conformational change
Factor Xa Factor Xa
Antithrombin
Low-molecular-weight heparin (Xa:IIa 3-4:1)

Most LMWH
Thrombin (IIa)
chains too short
Pentasaccharide to form ternary
Thrombin (IIa) complex
Factor Xa Factor Xa
Antithrombin
Fondaparinux (100% Xa)

Pentasaccharide
Antithrombin
Factor Xa Factor Xa
FIGURE 11–4. Mechanism of action of unfractionated heparin, low-molecular-weight heparin (LMWH), and fondaparinux. (From
Witt DM, Clark NP. Venous thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic
Approach, 9th ed. New York, NY: McGraw-Hill; 2014:266.)
sulfate as an antidote to reverse the effects of UFH. The usual dose maternal hemorrhage. UFH is not secreted into breast milk and
is 1 mg protamine sulfate per 100 units of UFH, up to a maxi- is safe for use by women who wish to breast-feed.2,9,10,20 For treat-
mum of 50 mg, given as a slow IV infusion over 10 minutes. The ment of VTE in children, the UFH dose is 50 units/kg bolus
effects of UFH are neutralized in 5 minutes, and the effects of followed by an infusion of 20,000 units/m2 per 24 hours. Alter-
protamine persist for 2 hours. If bleeding is not controlled or the natively, a loading dose of 75 units/kg followed by an infusion of
anticoagulant effect rebounds, repeated doses of protamine may 28 units/kg/hour if younger than 12 months and 20 units/kg/hour
be administered.9,10 if older than 1 year may be considered.33
Heparin-induced thrombocytopenia (HIT) is a very serious
adverse effect associated with UFH use. Platelet counts should ▶ Low-Molecular-Weight Heparins
be monitored at baseline and every 2 to 3 days throughout the Compared with UFH, LMWHs have improved pharmacody-
course of UFH therapy.9,10 HIT should be suspected if the platelet namic and pharmacokinetic properties.9,10,12 They exhibit less
count drops by more than 50% from baseline or to below 150 × binding to plasma and cellular proteins, resulting in a more pre-
103/mm3 (150 × 109/L). HIT should also be suspected if throm- dictable anticoagulant response. Consequently, routine moni-
bosis occurs despite UFH use. Immediate discontinuation of all toring of anticoagulation activity and dose adjustments are not
heparin-containing products including the use of LMWHs and required in most patients. LMWHs have longer plasma half-lives,
heparin-based flushes is required. Alternative anticoagulation allowing once- or twice-daily administration, improved SC bio-
with parenteral DTIs should be initiated. In patients with con- availability, and dose-independent renal clearance. In addition,
traindications to anticoagulation therapy, UFH should not be LMWHs have a more favorable side effect profile than UFH. They
administered (Table 11–12). are also associated with a lower incidence of HIT, osteopenia, and
UFH may be used to treat VTE during pregnancy. UFH should osteoporosis. Two LMWHs are currently available in the United
be used with caution in the peripartum period due to risk of States: dalteparin and enoxaparin.
Table 11–10 Table 11–12

a
Weight-Based Dosing for UFH Administered by Contraindications to Anticoagulation Therapy
Continuous IV Infusion for Venous Thromboembolism
General
Initial Loading Dose Initial Infusion Rate t Active bleeding
t Hemophilia or other hemorrhagic tendencies
80 units/kg (maximum = 18 units/kg/hour (maximum = t Severe liver disease with elevated baseline PT/INR
10,000 units) 2300 units/hour) t Severe thrombocytopenia (platelet count < 20 × 103/mm3
Maintenance Infusion Rate [20 × 109/L])
aPTT (seconds) Dose Adjustment t Malignant hypertension
< 37 (or < 12 seconds below 80 units/kg bolus then increase t Inability to meticulously supervise and monitor treatment
institution-specific therapeutic infusion by 4 units/kg/hour Drug-Specific Contraindications
range) UFH
37–47 (or 1–12 seconds below 40 units/kg bolus then increase t Hypersensitivity to UFH
institution-specific therapeutic infusion by 2 units/kg/hour t History of HIT
range) LMWHs
48–71 (within institution-specific No change t Hypersensitivity to LMWH, UFH, pork products, methylparaben,
therapeutic range) or propylparaben
72–93 (or 1–22 seconds above Decrease infusion by t History of HIT or suspected HIT
institution-specific therapeutic 2 units/kg/hour Fondaparinux
range) t Hypersensitivity to fondaparinux
> 93 (or > 22 seconds above Hold infusion for 1 hour then t Severe renal insufficiency (CrCl < 30 mL/min [0.50 mL/s])
institution-specific therapeutic decrease by 3 units/kg/hour t Body weight < 50 kg (110 lb) for prophylaxis
range) t Bacterial endocarditis
t Thrombocytopenia with a positive in vitro test for antiplatelet
a
Use actual body weight for all calculations. Adjusted body weight antibodies in the presence of fondaparinux
(ABW) may be used for morbidly obese patients (> 130% of ideal Lepirudin
body weight [IBW]). t Hypersensitivity to hirudins
Argatroban
ABW = IBW + (Actual body weight – IBW) × 0.7
t Hypersensitivity to argatroban
aPTT, activated partial thromboplastin time; IV, intravenous; UFH, Warfarin
unfractionated heparin. t Hypersensitivity to warfarin
t Pregnancy
t History of warfarin-induced skin necrosis
Like UFH, LMWHs prevent the propagation and growth of t Inability to obtain follow-up PT/INR measurements
formed thrombi.9 The anticoagulant effect is mediated through a t Inappropriate medication use or lifestyle behaviors
Dabigatran
specific pentasaccharide sequence that binds to AT. The primary
t Mechanical prosthetic heart valves
difference in the pharmacologic activity of UFH and LMWH is t Hypersensitivity to dabigatran
their relative inhibition of thrombin (factor IIa) and factor Xa. Apixaban
Smaller heparin fragments (as in LMWHs) cannot bind AT and t Hypersensitivity to apixaban
thrombin simultaneously (Figure 11–4). The SC bioavailability of Rivaroxaban
the LMWHs is greater than 90%. Peak anticoagulant effect of the t Hypersensitivity to rivaroxaban
LMWHs is reached 3 to 5 hours after a SC dose. The elimination
half-life is 3 to 6 hours and is agent-specific. In patients with renal CrCl, creatinine clearance; HIT, heparin-induced thrombocytopenia;
INR, international normalized ratio; LMWHs, low-molecular-weight
impairment, the half-life of LMWHs is prolonged.9,10,12 heparins; PT, prothrombin time; UFH, unfractionated heparin.
Table 11–11 Dose of LMWHs for the treatment of VTE is determined based
Risk Factors for Major Bleeding While on Anticoagulation on the patient’s weight and is administered SC once or twice daily
(Table 11–8). Due to their predictable anticoagulant effect, rou-
Increased anticoagulation intensity (eg, INR > 5, aPTT > 120 seconds) tine monitoring is not necessary in most patients.9 LMWHs have
Initiation of therapy (first few days and weeks) been evaluated in many randomized trials and have been shown
Unstable anticoagulation response (eg, variable INR response) to be at least as safe and effective as UFH for the treatment of
Age older than 65 years
Concurrent antiplatelet drug use VTE.2,12 Indeed, the rate of mortality was lower in patients treated
Concurrent NSAID or aspirin use with an LMWH in clinical trials. This mortality benefit was pri-
History of gastrointestinal bleeding marily seen in patients with cancer.34
Recent surgery or trauma Prior to initiating treatment with an LMWH, baseline labora-
High risk for fall/trauma (eg, elderly, sedentary/bedbound, tory tests should include PT/INR, aPTT, CBC, and serum creati-
high-risk medications) nine (SCr). Monitor the CBC with platelet count every 3 to 5 days
Heavy alcohol use during the first 2 weeks of therapy, and every 2 to 4 weeks with
Renal failure extended use.9,10 Use LMWHs cautiously in patients with renal
Cerebrovascular disease
Active malignancy impairment due to the potential of drug accumulation and risk
of bleeding. Specific dosing recommendations for patients with a
aPTT, activated partial thromboplastin time; INR, international CrCl less than 30 mL/min (0.50 mL/s) are currently available for
normalized ratio; NSAID, nonsteroidal anti-inflammatory drug. enoxaparin but are lacking for other LMWH agents (Table 11–8).
Current guidelines recommend the use of UFH over LMWH 6 weeks to make dose adjustments is recommended.35 LMWHs
in patients with severe renal dysfunction (CrCl < 30 mL/min have also been used to treat VTE in pediatric patients. Chil-
[0.50 mL/s]).2 dren younger than 1 year require higher doses (eg, enoxaparin
Most patients with an uncomplicated DVT and PE 1.5 mg/kg SC every 12 hours). Monitor antifactor Xa activity to
can be managed safely at home.2 LMWHs can be easily adminis- guide dosing in children.33
tered in the outpatient setting, thus enabling treatment of VTE
at home. Several large clinical trials have demonstrated the effi- ▶ Factor Xa Inhibitors
cacy and safety of LMWHs for outpatient treatment of DVT and
PE, and this approach is commonly utilized in clinical practice.2,34 Parenteral Fondaparinux is an indirect inhibitor of factor Xa
Patients with DVT with normal vital signs, low bleeding risk, no and exerts its anticoagulant activity by accelerating AT.9,36 Due to
other comorbid conditions requiring hospitalization, and who its small size, fondaparinux exerts inhibitory activity specifically
are stable may have anticoagulant initiated at home. Although the against factor Xa and has no effect on thrombin (Figure 11–4).
treatment of patients with PE in the outpatient setting is more After SC administration, fondaparinux is completely absorbed,
controversial, patients with submassive PE who are hemody- and peak plasma concentrations are reached within 2 to 3 hours.9,36
namically stable can be safely treated in the outpatient setting as It has a half-life of 17 to 21 hours, permitting once-daily admin-
well.12 Patients considered for outpatient therapy must be reliable istration, but the anticoagulant effects of fondaparinux will per-
or have adequate caregiver support and must be able to strictly sist for 2 to 4 days after stopping the drug. In patients with renal
adhere to the prescribed treatment regimen and recommended impairment, fondaparinux clearance is reduced, and the antico-
follow-up visits. Close patient follow-up is critical to the success agulant effect persists even longer. Fondaparinux does not require
of any outpatient DVT treatment program. Home DVT treatment routine coagulation monitoring or dose adjustments.
results in cost savings and improved patient satisfaction and qual- Fondaparinux is not metabolized in the liver and therefore
ity of life.2,12,34 has few drug interactions.9,36 However, concurrent use with other
Laboratory methods of measuring a patient’s response to antithrombotic agents increases the risk of bleeding. Unlike the
LMWH may be warranted in certain situations.9,35 Although heparins, factor Xa inhibitors do not affect platelet function and
controversial, measurement of antifactor Xa activity has been do not react with the heparin platelet factor (PF)-4 antibod-
the most widely used method in clinical practice. Monitoring of ies seen in patients with HIT. Thus, they have a theoretical role
antifactor Xa activity may be considered in adult patients who in treatment and prevention of HIT. A few small observational
are morbidly obese (weight > 150 kg [330 lb] or body mass index studies report fondaparinux use in the management of patients
[BMI] > 50 kg/m2), weigh less than 50 kg (110 lb), or have signifi- with HIT. Based on these data some centers use fondaparinux in
cant renal impairment (CrCl < 30 mL/min [0.50 mL/s]). Labora- patients with subacute HIT or a history of HIT who require anti-
tory monitoring may also be useful in children, pregnant women, coagulation therapy.9
and those on long-term therapy.35 Fondaparinux is as safe and effective as IV UFH for the treat-
As with UFH, bleeding is the major complication associated ment of PE and SC LMWH for the treatment of DVT.9,35 The
with LMWHs. The incidence of major bleeding reported in clini- recommended dose for fondaparinux in the treatment of VTE
cal trials is less than 3%.8,9 Minor bleeding, especially bruising at is based on the patient’s weight (Table 11–8). Fondaparinux
the injection site, occurs frequently. Protamine sulfate will par- is renally eliminated, and accumulation can occur in patients
tially reverse the anticoagulant effects of the LMWHs and should with renal dysfunction. Due to the lack of specific dosing
be administered in the event of major bleeding. Due to its lim- guidelines, fondaparinux is contraindicated in patients with
ited binding to LMWH chains, protamine only neutralizes 60% severe renal impairment (CrCl < 30 mL/min [0.50 mL/s]).
of their antithrombotic activity. If the LMWH was administered Baseline renal function should be measured and monitored
within the previous 8 hours, give 1 mg protamine sulfate per 1 mg closely throughout therapy. Based on limited data, monitor-
of enoxaparin or 100 antifactor Xa units of dalteparin. If bleeding antifactor Xa activity to guide fondaparinux dosing is not
ing is not controlled, give another 0.5 mg of protamine sulfate for recommended.9,36
every antifactor Xa 100 units of LMWH. Give smaller protamine As with other anticoagulants, the major side effect associated
doses if more than 8 hours have lapsed since the last LMWH dose. with fondaparinux is bleeding. Fondaparinux should be used cau-
The incidence of HIT is lower with LMWHs than with UFH.9,10 tiously in elderly patients because their risk of bleeding is higher.
However, LMWHs cross-react with heparin antibodies in vitro Patients receiving fondaparinux should be carefully monitored
and should not be given as an alternative anticoagulant in patients for signs and symptoms of bleeding. A CBC should be obtained
with a diagnosis or history of HIT. Monitor platelet counts every at baseline and monitored periodically to detect the possibility
few days during the first 2 weeks and periodically thereafter. of occult bleeding. In the event of major bleeding, fresh-frozen
In patients undergoing spinal and epidural anesthesia or spi- plasma and factor concentrates should be given. Fondaparinux
nal puncture, spinal and epidural hematomas have been linked is not reversed by protamine.9,36 Data are limited regarding the
to the use of LMWHs. In patients with indwelling epidural cath- use of fondaparinux during pregnancy, and its use in pediatric
eters, concurrent use of LMWHs and all other agents that impact patients has not been studied.36
hemostasis should be avoided. When inserting and removing the Oral Apixaban, rivaroxaban, edoxaban, and betrixaban are direct
indwelling epidural catheters, the timing of LMWH administra- inhibitors of factor Xa, part of a newer generation of oral anti-
tion around catheter manipulation should be carefully coordi- coagulants also referred to as direct-acting oral anticoagulants
nated. Catheter manipulation should only occur at minimal or (DOACs).29,30,37,38 Apixaban and rivaroxaban have been evaluated
trough anticoagulant levels.9,10 and approved by the Food and Drug Administration (FDA) for
LMWHs are a convenient alternative to UFH for the treatment the treatment of VTE (DVT and PE) and reduction in the risk of
of VTE in pregnant women.9,20 The LMWHs do not cross the recurrence of DVT and PE. Edoxaban is also approved for VTE
placenta. Because the pharmacokinetics of LMWHs may change treatment. Rivaroxaban had similar efficacy and safety when
during pregnancy, monitoring of antifactor Xa activity every 4 to compared to traditional therapy with LMWH and a vitamin K
Table 11–13
Dosing of the Direct Oral Anticoagulants in the Treatment of Venous Thromboembolism (VTE) and Their Reversal Agents
Dabigatran Rivaroxaban Apixaban Edoxaban

Acute VTE 150 mg BID after 15 mg BID × 3 weeks then 10 mg BID for 7 days, then 5 mg BID 60 mg once daily
5–10 days of parenteral 20 mg once daily with food
anticoagulation
Prevention of 150 mg BID 10 mg once daily with food 2.5 mg BID (after 6 months of acute n/a
VTE recurrence (after 6 months of acute treatment)
treatment)
Dosage Any P-gp inducer: avoid CrCl 30–50 mL/min (0.50–0.83 Dual strong CYP3A4 and P-gp inhibitors: CrCl 15–50 mL/min
adjustments concurrent use mL/s): use with caution If dose > 2.5 mg BID, decrease by 50% (0.25–0.83 mL/s)
and/or Any P-gp inhibitor with CrCl < 30 mL/min (0.50 mL/s): If already taking 2.5 mg BID and dual or body weight
thresholds for CrCl < 50 mL/min avoid use strong CYP3A4 and P-gp inhibitor: ≤ 60 kg (132 lb),
avoidance (0.83 mL/s): avoid avoid use or concurrent use
concurrent use No dose adjustment in renal impairment with certain P-gp
CrCl < 30 mL/min or end-stage renal disease required inhibitors: 30 mg
(0.50 mL/s): avoid use once daily
FDA-approved Idarucizumab Recombinant inactivated Recombinant inactivated coagulation n/a
reversal agent 5 g IV by infusion or coagulation Factor Xa Factor Xa
bolus High dose: 800 mg IV bolus + High dose: 800 mg IV bolus + 960 mg IV
960 mg IV infusion infusion
Low dose: 400 mg IV bolus + Low dose: 400 mg IV bolus + 480 mg IV
480 mg IV infusion infusion
CrCl, creatinine clearance; CYP, cytochrome P-450; FDA, Food and Drug Administration; IV, intravenous; P-gp, P-glycoprotein.
antagonist in the treatment of patients with VTE. One study The DOACs inhibit a serine protease single target within the
suggests rivaroxaban may be inferior to warfarin in patients common pathway of the coagulation cascade during the final
with triple positive antiphospholipid antibody syndrome.39 stages of clot formation. See Figure 11–5. This specificity pro-
Apixaban was noninferior in preventing recurrent VTE or VTE- vides a linear dose response and wider therapeutic index that
related death but resulted in lower major bleeding events when allows for fixed dosing and precludes the need for routine coagula-
compared to LMWH and warfarin therapy. Rivaroxaban and tion monitoring.4,12,29,30,37,38 Apixaban, rivaroxaban, edoxaban, and
apixaban can be used as monotherapy without parenteral anti- betrixaban are competitive, selective, and potent direct inhibitors of
coagulation overlap, allowing for a single oral regimen approach factor Xa that bind in a reversible manner to the active site of both
for treating and preventing recurrent VTE. Edoxaban was non- free-floating factor Xa and factor Xa within the prothrombinase
inferior to warfarin in recurrent VTE and associated with less complex, thereby attenuating thrombin generation. These agents
major or clinically relevant nonmajor bleeding. Unlike the other have intrinsic anticoagulant activity and do not require a cofactor
oral factor Xa inhibitors, edoxaban is initiated after completing to exert their effect as with UFH and the LMWHs.4,12,29,30,37,38
5 to 10 days of initial treatment with a parenteral anticoagulant. The pharmacokinetic and pharmacodynamic properties of
See Table 11–13. DOACs are significantly different than those of warfarin. See
TF/VIIa Initiation
X IX
Warfarin
IXa
VIIIa
Va
Apixaban
Betrixaban Xa Amplification
Edoxaban
Rivaroxaban
II
Dabigatran IIa Propagation
Fibrinogen Fibrin
FIGURE 11–5. Mechanism of action of the oral anticoagulants and their targets of inhibition in relationship to other oral
anticoagulants. (TF, tissue factor.) (Adapted from Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost. 2005;3:1843–1853.)
Table 11–14. They have a more rapid onset and offset of action plasma, factor concentrates, or recombinant factor VIIa may be
and shorter half-lives compared to warfarin. However, missed given in the event of a major life-threatening bleed.
doses may be more prone to result in therapeutic complications Apixaban has dual pathways of elimination, with approxi-
than longer half-life therapies such as warfarin. DOACs are all mately 27% being cleared renally and the remainder eliminated
eliminated renally to varying degrees (see Table 11–14), and dose via the fecal route. Elderly, low weight (< 50 kg [110 lb]), and
adjustment or avoidance in patients with renal impairment may patients with renal impairment can have increased exposure to
be needed.4,12,29,30,37,38 See Table 11–13. All DOACs are substrates apixaban, while gender and race do not appear to have clinically
of the P-gp transport system, and the Xa inhibitors are also sub- relevant influence. Pharmacokinetic modeling suggests apixaban
strates of the hepatic cytochrome P-450 (CYP) isoenzyme system. does not accumulate significantly or require dose adjustment in
Any inhibition or induction of these metabolic systems will alter patients with CrCl below 25 mL/min/1.73 m2 (0.24 mL/s/m2),
their absorption.29,30,37,38 There are currently no universally avail- but clinical data in this patient population are limited. Apixaban
able standardized laboratory assays to measure the anticoagulant pharmacokinetics are not significantly altered in patients with
effect of DOACs. This can create challenges in situations where mild- (Child-Pugh A) -to-moderate (Child-Pugh B) hepatic
reversal of anticoagulation is required such as in cases of major impairment. However, apixaban has not been studied in patients
bleeding or need for emergency surgery.12,29,30,37-39 Fresh-frozen with severe hepatic impairment and is not recommended for
Table 11–14
Pharmacologic and Pharmacokinetic Characteristics of Direct Oral Anticoagulants
Property Apixaban Dabigatran Rivaroxaban Edoxaban Betrixaban

Mechanism of Factor Xa inhibitor Direct thrombin Factor Xa inhibitor Factor Xa inhibitor Factor Xa inhibitor
action inhibitor
Bioavailability 50% 3%–7% 80%–100% for 10-mg dose 62% 34%
(%) 66% for 20-mg dosea
Tmax (hours) 1–3 1–3 2–4 1–2 3–4
Onset of effect Within 3 hours Within 3 hours Within 4 hours Within 2 hours n/a
Half-life (hours) 8–15 12–17 5–13 10–14 19–27
Renal excretion 27% 80% 36% 50% 11%
CYP-mediated 25% No 30% CYP3A4 Minor: CYP1A1, 1A2,
metabolism CYP3A4/5, CYP2J2 CYP3A4/5, CYP2J2 (equal) 2B6, 2C9, 2C19,
(minor), CYP1A2 (minor) 2D6, 3A4
Drug P-gp, BCRP P-gp P-gp, BCRP P-gp P-gp
transporter
Drug–drug Potent CYP3A4 and P-gp Potent P-gp Potent CYP3A4 and P-gp P-gp inducers (eg, P-gp inhibitors:
interactions inhibitors; affecting inhibitors; inhibitors; affecting rifampin): affecting affecting
absorption, metabolism, affecting absorption, metabolism, absorption absorption
and excretion absorption and excretion
Food effect No effect reported Delayed Delayed absorption with No effect reported Reduced absorption
absorption with food with increased by 61%–70%
food but no (+39%) bioavailability (low-fat meal) and
influence on Take with largest meal of 48%–50% (high-
bioavailability the day (usually dinner) fat meal)
Age Lower clearance as age Lower clearance No effect reported No effect reported No effect reported
increases as age increases
Body weight Higher exposure with low No effect reported No effect reported 13% higher exposure n/a
body weight (< 50 kg with median low body
[110 lb]) weight (55 kg [121 lb])
compared to high
body weight (84 kg
[185 lb])
Sex Lower clearance in Lower clearance in No effect reported No effect reported No effect reported
women women
Ethnicity No effect reported No effect reported Lower dose in Japanese No effect reported n/a
patients
Gastrointestinal No effect reported Dyspepsia No effect reported No effect reported No effect reported
tolerability 5%–10%
Coagulation Anti-FXa ECT > dTT Anti-Fxa Anti-Fxa Anti-Fxa
measurement
a
Bioavailability is dependent on food intake for doses > 10 mg. Rivaroxaban doses > 10 mg should be administered with food.
BCRP, breast cancer resistance protein; CYP, cytochrome P-450; dTT, diluted thrombin time; ECT, ecarin clotting time; FXa, factor Xa; P-gp,
P-glycoprotein; Tmax, time to maximum plasma concentration.
Table 11–15
Drug Interactions and Monitoring Recommendations for Direct Oral Anticoagulants
Apixaban Rivaroxaban Dabigatran Edoxaban Betrixaban

Drug Avoid concomitant use with Avoid concomitant Avoid concomitant use with Avoid concomitant For concomitant
interactions strong dual inhibitors of use with strong P-gp inducers (eg, rifampin) use with P-gp use of P-gp
CYP3A4 and P-gp (eg, dual inhibitors of P-gp inhibitors and impaired inducers (eg, inhibitors (eg,
ketoconazole, ritonavir, CYP3A4 and P-gp renal function can lead rifampin) amiodarone,
erythromycin) or reduce (eg, ketoconazole, to increased exposure Concomitant use azithromycin,
apixaban dose ritonavir, to dabigatran: Avoid with coagulants, verapamil,
Avoid concomitant use erythromycin) concomitant use with antiplatelet drugs, ketoconazole,
with strong dual inducers Avoid concomitant severe renal impairment and thrombolytics clarithromycin):
of CYP3A4 and P-gp (eg, use with strong (CrCl < 30 mL/min may increase the reduce dose to
rifampin, phenytoin, dual inducers of [0.50 mL/s]) risk of bleeding 80 mg × 1 then
carbamazepine) CYP3A4 and P-gp For moderate renal 40 mg daily
Concomitant use with (eg, rifampin, impairment, reduce dose Concomitant use
antiplatelet agents, phenytoin, to 75 mg twice daily when of anticoagulants,
fibrinolytics, heparin, carbamazepine) used concomitantly with antiplatelet drugs,
aspirin, and chronic NSAID Avoid concomitant dronedarone or systemic and thrombolytics
increases bleeding risk use with other ketoconazole or avoid may increase the
anticoagulants concomitant use risk of bleeding.
Monitoring Baseline laboratory assessment: Hemoglobin/hematocrit, liver function, renal function, PT/INR
At every visit: Adherence, signs/symptoms of bleeding or thromboembolism, side effects, concomitant medications
(including over-the-counter)
Annual laboratory assessment: Hemoglobin/hematocrit, renal function, liver function
If CrCl 30–60 mL/min (0.50–1.0 mL/s), > 75 years, or fragile: renal function every 6 months
If CrCl 15–30 mL/min (0.25–0.50 mL/s): renal function every 3 months
If condition changes that might impact anticoagulation therapy: check renal and/or liver function
CrCl, creatinine clearance; CYP, cytochrome P-450; INR, international normalized ratio; NSAID, nonsteroidal anti-inflammatory drug; P-gp,
P-glycoprotein; PT, prothrombin time.
use in these patients. There are no adequate studies in pregnant Medications that are substrates for the P-gp transport system may
women, and its use during pregnancy is likely to increase bleed- impact plasma concentrations of rivaroxaban.30,41
ing risk. Use in pediatric patients has not been studied.29Apixaban While patients with renal impairment can have increased
is a substrate of both the CYP 3A4/5 and P-gp systems, and it may exposure to rivaroxaban, gender, race, age, and extremes of
be subject to a number of drug interactions (Table 11–15).29 See weight (< 50 kg [110 lb] or > 120 kg [265 lb]) have not been
Tables 11–13, 11–14, and 11–15 for pertinent drug interactions, shown to significantly impact its pharmacokinetics or pharmaco-
monitoring, and dosing recommendations. dynamics. Rivaroxaban should be avoided in patients with CrCl
While routine anticoagulation monitoring is not required, less than 30 mL/min (0.50 mL/s) when used for VTE treatment.30
there may be clinical scenarios where knowing the patient’s See Table 11–13. Mild hepatic impairment has minimal impact
degree of anticoagulation may be necessary.40 A drug-specific on the pharmacokinetics and pharmacodynamics of rivaroxaban.
chromogenic anti-Xa assay may be used to measure apixaban Patients with moderate hepatic impairment (Child-Pugh B) have
plasma concentrations; however, this assay is not readily avail- significantly increased exposure to rivaroxaban, and its use in
able in most laboratories. Other tests such as the PT, aPTT, and patients with severe liver disease has not been studied.30 There
INR are not recommended to assess the anticoagulant effects of are no well-controlled studies in pregnant women and pediatric
apixaban.29,40 Baseline and periodic patient assessment including patients, and dosing of rivaroxaban in these patients has not been
adherence, side effects, and renal and liver function should be established.
conducted (Table 11–15).41 Rivaroxaban should not be used concomitantly with medi-
Rivaroxaban’s bioavailability is dose dependent.30 At a dose of cations that are dual P-gp and strong CYP3A4 inhibitors or
10 mg, bioavailability is 80% to 100% and may be taken without inducers.30,41 See Table 11–15. Use with weaker combined P-gp
regard for food. At higher doses, bioavailability is approximately and CYP3A4 substrates should be undertaken with caution and
66% in the fasted state, which is increased to greater than 80% by only if benefit of use outweighs risk. Concomitant use of riva-
food intake. Thus, rivaroxaban 15- and 20-mg tablets should be roxaban with antiplatelet and nonsteroidal anti-inflammatory
taken with the largest meal of the day. See Table 11–14. Like apix- agents should be done with extreme caution due to the additive
aban, rivaroxaban does not induce or inhibit CYP isoenzymes, antithrombotic effects and heightened risk of bleeding. As with
but may be affected by medications that are substrates for this apixaban, a drug-specific chromogenic anti-Xa assay may be used
enzymatic pathway.30 Rivaroxaban has a dual mode of elimina- to measure rivaroxaban activity. Rivaroxaban prolongs the aPTT
tion, with approximately 35% excreted unchanged in the urine and PT in a dose-dependent manner, but the PT is more sensitive
and the remaining two-thirds (in the form of inactive metabo- to rivaroxaban than the aPTT.29,40,41 Because it is widely available
lites) excreted fairly equally between the renal and hepatobiliary and has a low level of complexity, the PT may be used in a quali-
route.30 Rivaroxaban is a P-gp substrate, not only at the level of tative manner to quickly determine the presence of rivaroxaban.
gut absorption, but also at the level of elimination in the kidney. A normal result with most PT reagents would exclude clinically
significant anticoagulant activity. The PT and INR are not suit- Substrate
able for measurement of rivaroxaban activity. recognition site
Edoxaban is 62% orally bioavailable and dose dependent and
is 55% bound to plasma protein. Edoxaban undergoes minimal
CYP3A4 metabolism, hydrolysis, and conjugation, although an Thrombin
Catalytic Thrombin
active primary metabolite is formed via hydrolysis with renal site (IIa)
(IIa)
elimination accounting for approximately half of edoxaban elimi-
nation. Edoxaban should not be used in those with moderate or
severe hepatic impairment (Child-Pugh B and C). Individuals
weighing 60 kg (132 lb) or less should receive a reduced dose of Fibrin-binding Lepirudin
site
30 mg daily. Similar to apixaban and rivaroxaban, chromogenic
antifactor Xa can be considered to evaluate the presence of edox-
aban. Edoxaban may affect PT and aPTT, but these measures
should not be considered reliable measures of serum concen-
trations or anticoagulation intensity. Similar to other DOACs, Thrombin
concomitant use of edoxaban with P-gp inducers, particularly Thrombin
(IIa)
(IIa)
rifampin, should be avoided.37,40,41
Betrixaban is 34% orally bioavailable and, unlike rivaroxaban,
administration with a low- or high-fat meal leads to reduced
Argatroban
betrixaban exposure. Betrixaban should thus be administered or
Bivalirudin
with food. Betrixaban is mainly excreted through feces (85%), Dabigatran
11% through urine, and 1% metabolized via CYP1A1, 1A2, 2B6,
2C9, 2C19, 2D6, and 3A4. A reduced dose is recommended if FIGURE 11–6. Mechanism of action of intravenous direct
severe renal impairment (CrCl 15–30 mL/min [0.25–0.50 mL/s]) thrombin inhibitors, their binding sites, and relative inhibition of
or concomitant use of P-gp inhibitors is present. Betrixaban has the thrombin catalytic and fibrin-binding sites. (From Witt DM,
not been evaluated in the setting of hepatic impairment, and its Nutescu EA, Haines S. Venous thromboembolism. In: DiPiro JT,
use in this patient population should be avoided. Recommended Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A
duration of treatment for betrixaban is 35 to 42 days.38 Pathophysiologic Approach, 8th ed. New York, NY: McGraw-Hill;
Inactivated recombinant coagulation factor Xa is a recom- 2011:326.)
binant modified human factor Xa decoy protein that binds to
the active site of factor Xa inhibitors with high affinity, thereby
preventing DOAC-mediated factor Xa inhibition. This agent is was found to be as effective and safe as warfarin in the treatment
administered intravenously and has been approved for reversal of and prevention of recurrent VTE.12,45 Like edoxaban, patients
rivaroxaban and apixaban.42 A high or low dose is administered should be anticoagulated with UFH or LMWH for the initial 5 to
based on the DOAC used, DOAC dose taken, and time elapsed 10 days of therapy and then transitioned to dabigatran for VTE
since last DOAC dose. treatment.2,12,45 See Table 11–13. Similar to other DOACs, dabi-
gatran can be given in fixed doses without the need for routine
▶ Direct Thrombin Inhibitors coagulation monitoring and has a fast onset and offset of action,
offering more convenient anticoagulation options for patients
Given that thrombin is the central mediator of coagulation and
and providers.45
amplifies its own production, it is a natural target for pharmaco-
Dabigatran is a direct reversible, competitive inhibitor of
logic intervention.9,43,44 DTIs bind thrombin and prevent interac-
thrombin and an oral prodrug of dabigatran etexilate.43-45
tions with their substrates (Figure 11–6).
Dabigatran is converted to its active form dabigatran etexilate by
Parenteral Parenteral DTIs are considered drugs of choice for serum esterases that are independent of CYP pathways. See Table
the treatment of VTE in patients with a diagnosis or history of 11–14. Dabigatran has an oral bioavailability of approximately
HIT.9,43,44 Several injectable DTIs are approved for use in the 3% to 7% and requires an acidic environment for absorption. The
United States including lepirudin, bivalirudin, argatroban, and prodrug is contained in small pellets coated with an acid core.
desirudin. All have been used to treat thrombosis in patients with These pellets are enclosed in a capsule shell. This specific capsule
HIT, but only lepirudin and argatroban are FDA approved for this formulation improves the dissolution and absorption of the pro-
indication. However, as of 2012, lepirudin is no longer commer- drug, independent of gastric pH. Therefore, the capsules should
cially available in the United States. Data with some DTIs (desiru- not be broken, chewed, or opened before administration. Dabiga-
din, bivalirudin) for the treatment of HIT are limited, and there tran demonstrates 35% protein binding and is a substrate of the
are no high-quality studies that directly compare one DTI with efflux transporter P-gp. Although the absence of CYP metabolism
another. DTIs differ in terms of their chemical structure, bind- decreases potential for many drug interactions, coadministration
ing to the thrombin molecule, and pharmacokinetic profiles. See with P-gp substrates, inhibitors, or inducers may affect the effi-
Table 11–16. Unlike heparins, DTIs do not require AT as a cofac- cacy of dabigatran.41,43 See Table 11–15.
tor and do not bind to plasma proteins. Therefore, they produce a Approximately 80% of dabigatran is eliminated in the urine,
more predictable anticoagulant effect. DTIs have a targeted speci- and its use is not recommended for VTE treatment in patients
ficity for thrombin, the ability to inactivate clot-bound thrombin, with a CrCl less than 30 mL/min (0.50 mL/s) due to increased
and an absence of platelet interactions that can lead to HIT.9,43,44 risk of drug exposure and bleeding.45 Subjects with severe liver
Oral Small molecule DTIs have been structurally modified disease were excluded from clinical trials of dabigatran. In those
for oral administration.43 One agent, dabigatran, is currently with moderate hepatic impairment (Child-Pugh B), the pharma-
approved in the United States for treatment of VTE.45 Dabigatran cokinetic profile of dabigatran is not affected. Gender, age, race,
Table 11–16
Pharmacologic and Clinical Properties of Direct Thrombin Inhibitors Used in Treatment of Thrombosis in Patients with
Heparin-Induced Thrombocytopenia (HIT)
Lepirudin Desirudin Bivalirudin Argatroban

Route of administration IV SC IV IV
FDA-approved indication Treatment of VTE prevention Patients with unstable angina undergoing Prophylaxis or treatment
thrombosis in after total hip percutaneous transluminal coronary of thrombosis in adult
patients with arthroplasty angioplasty; PCI with provisional use of patients with HIT;
HIT glycoprotein IIb-IIIa inhibitor; patients with patients with or at risk of
or at risk of HIT or HITTS undergoing PCI HIT undergoing PCI
Binding to thrombin Irreversible Irreversible Partially reversible Reversible
Catalytic site and Catalytic site and Catalytic site and exosite-1 Catalytic site
exosite-1 exosite-1
Half-life in healthy subjects 80 minutes 2–3 hours 25 minutes 40–50 minutes
Monitoring aPTT (IV) aPTT aPTT/ACT aPTT/ACT
SCr/CrCl SCr/CrCl SCr/CrCl Liver function
Elimination Renal Renal Enzymatic (80%) and renal (20%) Hepatobiliary
Antibody development Anti-hirudin Not reported May cross-react with anti-hirudin No
antibodies in up antibodies
to 40%–60% of
patients
Effect on INR + + ++ +++
+ minimal effect
++ moderate effect
+++ significant effect
ACT, activated clotting time; aPTT, activated partial thromboplastin time; CrCl, creatinine clearance; FDA, Food and Drug Administration; HITTS,
heparin-induced thrombocytopenia and thrombosis syndrome; INR, international normalized ratio; IV, intravenous; PCI, percutaneous coronary
intervention; SC, subcutaneous; SCr, serum creatinine; VTE, venous thromboembolism.
or extremes of weight (< 50 kg [110 lb] or > 110 kg [243 lb]) do hypersensitivity reactions, and serious adverse events in those
not significantly impact dabigatran pharmacology. with hereditary fructose intolerance. Fresh-frozen plasma, factor
Dabigatran prolongs the aPTT, PT, thrombin time (TT), and concentrates, or recombinant factor VIIa may also be given in the
ecarin clotting time (ECT) assays in a dose-dependent man- event of a major life-threatening bleed; however, their efficacy for
ner.40,45 Peak values greater than 2.5 times control may indicate this use has not been established. DTIs can increase PT/INR and
supratherapeutic levels. A normal aPTT would indicate a lack of interfere with the accuracy of monitoring and dosing of warfarin
clinically relevant anticoagulant activity. The aPTT may be used therapy. Data on use of DTIs in pregnancy are very limited. Use of
in a qualitative manner to determine the presence of anticoagula- DTIs in pediatric patients has not been established.45
tion with dabigatran. It should not be used to quantitate dabi-
gatran plasma concentrations. The PT is relatively insensitive to ▶ Warfarin
dabigatran, and the INR is not suitable for measurement of dabi- Warfarin had been the primary oral anticoagulant used
gatran due to significant variability. The TT, diluted thrombin in the United States when long-term or extended anticoagulation
time (dTT), and ECT exhibit a linear dose-response with thera- is required, but its use has decreased in favor of DOACs. Warfarin
peutic dabigatran plasma concentrations. Unfortunately, none of is FDA approved for prevention and treatment of VTE.48 Although
these assays are widely available in practice. It is important to note very effective, warfarin has a narrow therapeutic index, requiring
that quantitative thresholds beyond which a patient would be at frequent dose adjustments and careful patient monitoring.4,10,11,48
increased risk of clotting or bleeding have not been established for Warfarin exerts its anticoagulant effect by inhibiting pro-
any of the DOACs.40,43,45 duction of the vitamin K–dependent coagulation factors II
Contraindications to use of DTIs and risk factors for bleeding (prothrombin), VII, IX, and X, as well as the anticoagulant pro-
are similar to those of other antithrombotic agents (Tables 11–11 teins C and S (Figure 11–7). Warfarin has no effect on circulat-
and 11–12). Bleeding is the most common side effect reported. ing coagulation factors that have been previously formed, and
Concurrent use of DTIs with thrombolytics or antiplatelet its therapeutic antithrombotic activity is delayed for 5 to 7 days
agents significantly increases bleeding complications.46 Idaru- (potentially longer in slower metabolizers). This delay is related
cizumab, a humanized monoclonal antibody fragment specific to half-lives of the clotting factors: 60 hours for factor II (pro-
to dabigatran and its acyl glucuronide metabolites, binds free thrombin), 4 to 6 hours for factor VII, 24 hours for factor IX, and
and thrombin-bound dabigatran with 350 times higher affinity 48 to 72 hours for factor X. Proteins C and S, the natural anti-
compared to thrombin and is indicated for dabigatran reversal.47 coagulants, are inhibited more rapidly due to their shorter half-
Idarucizumab is administered as two consecutive 2.5-g infusions lives, 8 to 10 hours and 30 hours, respectively. Reductions in the
or as a single bolus 5-g IV injection. Serious adverse reactions concentration of natural anticoagulants before the clotting fac-
include thromboembolic risk accompanying dabigatran reversal, tors are depleted can lead to a paradoxical hypercoagulable state
Warfarin
Liver cell
CYP1A1
CYP2C9 S R CYP1A2
CYP3A4
Vitamin K
reductase
Reduced vitamin K
Oxidized vitamin K
Vitamin K–dependent Dietary

carboxylase vitamin K
Precursors: Functional:
Factors II, VII, IX, X Factors II, VII, IX, X
Protein C & S Protein C & S
FIGURE 11–7. Pharmacologic activity and metabolism of warfarin and its downstream effects on the vitamin K cycle and clotting
factor production. (CYP, cytochrome P-450 isoenzyme; S, S-warfarin; R, R-warfarin.) (From Witt DM, Nutescu EA, Haines S. Venous
thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 8th ed. New York, NY:
McGraw-Hill; 2011:328.)
during the first few days of warfarin therapy. It is for this reason when compared to clinical algorithms. Based on these data, the
that patients with acute thrombosis should receive a fast-acting FDA recommends incorporating patient’s genotype information
anticoagulant (heparin, LMWH, or fondaparinux) while transi- in guiding warfarin dosing when such information is available.48
tioning to warfarin therapy. Use of DOACs as bridging agents has See Table 11–17.48 Guidelines published by the Clinical Pharma-
not been well evaluated or approved.4,10,11,48 cogenetics Implementation Consortium are available to guide,
Warfarin is metabolized in the liver via several isoen- interpret, and apply genotype information to warfarin dosing.49
zymes including CYP 1A2, 3A4, 2C9, 2C19, 2C8, and 2C18 Although randomized studies to date showed mixed results of
(Figure 11–7).4,10,11,48 Hepatic metabolism of warfarin varies pharmacogenomic-based warfarin dosing on clinical and health
greatly among patients, leading to large interpatient differences utilization outcomes, careful analyses of study design and single-
in dose requirements and genetic variations in these isoenzymes. nucleotide polymorphisms tested in relation to the study patient
Multiple studies have demonstrated that VKORC1 and CYP2C9 population are necessary to appropriately interpret the implica-
genotypes influence the interpatient variability in warfarin dose tions and validity of genotype-guided dosing study outcomes.
requirements, together explaining up to 45% of overall dose vari- Therefore, pharmacogenomic-based dosing has not yet been
ance. Several algorithms that incorporate CYP2C9 genotype and widely adopted in clinical practice, and some guidelines recom-
VKORC1 haplotype with other patient characteristics to predict mend against routine ordering of preemptive genetic testing.2,4
warfarin maintenance dosing requirements have been developed Warfarin displays nonlinear kinetics. Small-dose adjust-
and showed efficacy in better predicting warfarin stable doses ments can lead to large changes in anticoagulant response.4,10,11,48
Table 11–17
Food and Drug Administration Recommended Warfarin Initial Daily Doses Based on CYP2C9 and VKORC1 Genotypes48
CYP2C9
VKORC1 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3

GG 5–7 mg 5–7 mg 3–4 mg 3–4 mg 3–4 mg 0.5–2 mg
AG 5–7 mg 3–4 mg 3–4 mg 3–4 mg 0.5–2 mg 0.5–2 mg
AA 3–4 mg 3–4 mg 0.5–2 mg 0.5–2 mg 0.5–2 mg 0.5–2 mg
CYP, cytochrome P-450.

The dose of warfarin is determined by each patient’s individual based on INR response (Figure 11–8). When initiating therapy,
response to therapy and the desired intensity of anticoagulation. it is difficult to predict the precise warfarin maintenance dose a
In addition to hepatic metabolism and genotype, warfarin dose patient will require. Patients who are younger (< 55 years) and
requirements are influenced by diet, drug–drug interactions, otherwise healthy can safely use higher warfarin “initiation” doses
and health status. Therefore, warfarin dose must be determined (eg, 7.5–10 mg). A more conservative “initiation” dose (eg, 4 mg
by frequent clinical and laboratory monitoring. Although there or less) should be given to patients older than 75 years, patients
are conflicting data regarding the optimal warfarin induction with heart failure, liver disease, or poor nutritional status, and
regimen, when the patient’s genotype is unknown, most patients patients who are taking interacting medications or are at high
can start with 5 mg daily, and subsequent doses are determined risk of bleeding. Loading doses of warfarin (eg, 15–20 mg) are not
Can a PT/INR be obtained

daily?
NO YES
Start warfarin with 5 mg daily Start warfarin with 5 mg daily

Consider 2.5-mg dose if patient Consider 7.5–10-mg dose if patient
age more than 60; concurrent age less than 60; no concurrent use of
use of interacting medications; or interacting medications; and
bleeding risk is high bleeding risk is low
Measure PT/INR on day 3 or 4

Measure PT/INR on day 2
INR less than 1.5—Increase weekly dose 5%–25%
INR less than 1.5—No dose change
INR = 1.5–1.9—No dose change
INR = 1.5–1.9—Decrease dose 25%–50%
INR = 2–2.5—Decrease weekly dose 25%–50%
INR = 2–2.5—Decrease dose 50%–75%
INR greater than 2.5—Decrease
INR greater than 2.5—hold next dose
weekly dose 50% or hold
Measure PT/INR on day 5–7

Measure PT/INR on day 3
INR less than 1.5—Increase weekly dose 10%–25%
INR less than 1.5—Increase dose 0%–25%
INR = 1.5–1.9—Increase weekly dose 0%–20%
INR = 1.5–1.9—No dose change
INR = 2–3—No dose change
INR = 2–2.5—Decrease dose 25%–50%
INR greater than 3—Decrease
INR greater than 2.5—Decrease 50% or hold next dose
weekly dose 10%–25% or hold
Measure PT/INR on day 8–10 Measure PT/INR on day 4

INR less than 1.5—Increase weekly dose 10%–25% INR less than 1.5—Increase dose 0%–25%
INR = 1.4–1.9—Increase weekly dose 5%–20% INR = 1.5–1.9—No dose change or
INR = 2–3—No dose change increase 10%–25%
INR greater than 3—Decrease INR = 2–3—Decrease dose 0%–25%
weekly dose 10%–25% or hold INR greater than 3—Decrease 50% or hold next dose
Measure PT/INR on day 11–14 Measure PT/INR on day 5

INR less than 1.4—Increase weekly dose 10%–20% INR less than 1.5—Increase dose 25%
INR = 1.4–1.9—No dose change INR = 1.5–1.9—Increase dose 0%–25%
INR = 2–3—Decrease weekly dose 10%–20% INR = 2–3—No dose change or
INR greater than 3—Decrease decrease dose 10%–25%
weekly dose 5%–20% or hold INR greater than 3—Decrease 25%–50%
FIGURE 11–8. Initiation of warfarin therapy. (INR, international normalized ratio; PT, prothrombin time.) (From Witt DM, Clark NP,
Vazquez SR. Venous thromboembolism. In: DiPiro JT, Yee GC, Posey LM, et al., eds. Pharmacotherapy: A Pathophysiologic Approach,
11th ed. New York, NY: McGraw-Hill. Available from: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577&sectio
nid=21931641. Accessed July 15, 2020.)
Patient Encounter 3, Part 1

A 48-year-old woman presents to the emergency department Labs: CBC and LFTs within normal limits; eGFR 16 mL/min/
complaining of shortness of breath, chest pain, and dizziness. 1.73 m2; CrCl 12 mL/min (0.2 mL/s)
She started having left calf pain approximately 5 days ago and Procedures/Tests
feeling short of breath and experiencing chest pain (7/10)
last evening. She could not sleep, and her shortness of breath ECG: Normal sinus rhythm; no ischemic changes
has gotten progressively worse in the last several hours. She CXR: Cardiomegaly present without infiltrates
was hospitalized because she was suspected to have a PE. V/Q scan: High probability of PE
Due to the nature of her job, she does not have prescription
insurance during the summer months. What symptoms and findings are consistent with diagnosis of
PE? What are the most likely etiologies for PE in this case?
PMH: Obesity × 20 years, asthma, stage 4 chronic kidney
disease, hypertension; type 2 diabetes mellitus What are appropriate initial acute-phase treatment and
long-term and extended treatment options for PE in this
FH: Mother with history of PE and died of an MI; paternal patient?
grandmother had clots (DVT) in her legs
If UFH is chosen as the initial acute-phase anticoagulation
SH: Full-time bus driver treatment option for this patient’s PE, what is the goal
Current Meds: Albuterol metered-dose inhaler as needed; aPTT?
Ortho-Tri-Cyclen Lo by mouth daily, lisinopril 10 mg daily, insulin What is the patient’s goal INR for warfarin therapy?
glargine 40 units once daily, insulin aspart 15 units before meals,
renal multivitamin daily; ginseng one to two tablets by mouth How long should she remain on anticoagulation therapy?
daily as needed; multivitamin one tablet by mouth daily Given the list of medications the patient took prior to
Allergies: NKDA hospitalization, should any of these be discontinued or
changed? If changed, what alternative therapy would you
PE: recommend?
VS: BP 138/64 mm Hg, HR 102 beats/min, RR 20 breaths/min,
T 38°C (100.4°F), Wt 96 kg (211 lb; BMI 35.3 kg/m2), Ht 65 in (165 cm)
recommended and can create false impressions that a therapeutic corrects for the differences in thromboplastin reagents. Goal or
INR has been achieved in 2 to 3 days and lead to potential future target INR for each patient is based on the indication for warfarin
overdosing.4,10,11,48 Before initiating therapy, screen the patient for therapy. For treatment and prevention of VTE, the INR target is
any contraindications to anticoagulation therapy and risk factors 2.5 with an acceptable range of 2 to 3. Before initiating warfarin
for major bleeding (Tables 11–11 and 11–12). Conduct a thor- therapy, a baseline PT/INR and CBC should be obtained. After
ough medication history including the use of prescription and initiating warfarin therapy, INR should be monitored at least
nonprescription drugs and any herbal supplements to detect every 2 to 3 days during the first week of therapy. Once a stable
interactions that may affect warfarin dosing requirements. response to therapy is achieved, INR monitoring is performed less
In patients with acute VTE, a rapid-acting anticoagulant frequently, weekly for the first 1 to 2 weeks, then every 2 weeks,
(UFH, LMWH, or fondaparinux) should be overlapped with war- and every 4 to 6 weeks thereafter if the warfarin dose and the
farin for a minimum of 5 days and until the INR is greater than patient’s health status are stable.4,10,11,48,50 At each encounter, the
2 and stable. This is important because the full antithrombotic patient should be carefully questioned regarding any factors
effect of warfarin will not be reached until 5 to 7 days or even that may influence the INR result. These factors include adher-
longer after initiating warfarin therapy. Typical maintenance dose ence to therapy, use of interacting medications, consumption
of warfarin for most patients will be between 25 and 55 mg per of vitamin K–rich foods, alcohol use, and general health status.
week, although some patients require higher or lower doses stem- Patients should also be questioned about symptoms related to
ming from their genotype or other clinical factors. Adjustments bleeding and thromboembolic events. Warfarin dose adjustments
in maintenance warfarin dose should be determined based on the should take into account not only the INR result but also patient-
total weekly dose and by reducing or increasing the weekly dose related factors that influence the result. Structured anticoagula-
by increments of 5% to 25%. When adjusting the maintenance tion therapy management services (anticoagulation clinics) have
dose, wait at least 7 days to ensure a steady state has been attained been demonstrated to improve the efficacy and safety of warfarin
on the new dose before checking the INR again. Checking the therapy. Some patients engage in self-testing and self-management
INR too soon can lead to inappropriate dose adjustments and by using a point-of-care PT/INR device approved for home use.
unstable anticoagulation status.4,10,11,48 Highly motivated and well-trained patients are good candidates
Warfarin requires frequent laboratory monitoring for self-testing or self-management.50
to ensure optimal outcomes and minimize complications. PT is Similar to other anticoagulants, warfarin’s primary
the most frequently used test to monitor warfarin’s anticoagulant side effect is bleeding.8 Warfarin can unmask an existing lesion.
effect. PT measures biological activity of factors II, VII, and X. Due Incidence of warfarin-related bleeding appears to be highest dur-
to wide variation in reagent sensitivity, different thromboplastins ing the first few weeks of therapy. The annual incidence of major
will result in different PT results, potentially leading to inappro- bleeding ranges from 1% to 10% depending on the quality of war-
priate dosing decisions.4,10,11,48 To standardize result reporting, the farin therapy management. Bleeding in the gastrointestinal tract is
World Health Organization developed a reference thromboplas- most common. Intracranial hemorrhage (ICH) is one of the most
tin and recommended the INR to monitor warfarin therapy. INR serious complications because it often causes severe disability
patients present with a purplish discoloration of their toes. If these

Patient Encounter 3, Part 2 side effects are suspected, warfarin therapy should be discontinued
immediately, and an alternative anticoagulant should be started.
Following discussion with the patient regarding her
There is a theoretical risk that warfarin may cause accelerated bone
insurance, she is discharged home on warfarin therapy.
loss with long-term use, but to date there is no evidence to support
She was referred to a local area antithrombosis center for
this concern. Warfarin is teratogenic and should be avoided during
monitoring of her oral anticoagulation therapy and has been
pregnancy. Women of childbearing potential should be instructed
maintained on warfarin 6 mg daily for the last 3 months. The
to use an effective form of contraception.
patient presents today for a routine visit for anticoagulation
Warfarin is prone to numerous clinically significant
monitoring and her INR is 5.6. She reports that 3 days ago
drug–drug and drug–food interactions (Tables 11–18, 11–19, and
she was started on a 1-week course of metronidazole, which
11–20).10,11,48 Patients on warfarin should be questioned at every
was prescribed by her primary care physician for bacterial
encounter to assess for any potential interactions with foods, drugs,
vaginosis. She also reports that she is trying to lose weight
and her intake of vitamin K–rich foods (kale, turnip greens,
brussels sprouts) has increased significantly over the last Table 11–18
month. She has no other complaints today and denies any
signs or symptoms of bleeding. Clinically Significant Drug Interactions With Warfarin
What is the most likely explanation for elevated INR? Increase Decrease
Should she be given vitamin K? If yes, discuss the dose, route of Anticoagulation Anticoagulation Increase
administration, and an appropriate patient monitoring plan. Effect (ä INR) Effect (å INR) Bleeding Risk
How will you manage the patient’s warfarin therapy? Outline Acetaminophen Amobarbital Argatroban
a plan including specific dose changes, timing of monitoring, Acute alcohol ingestion Butabarbital Aspirin
and patient education Allopurinol Carbamazepine Clopidogrel
Amiodarone Cholestyramine Danaparoid
Cephalosporins (with Chronic alcohol Dipyridamole
MTT side chain) ingestion Low-molecular-
and death. The intensity of anticoagulation therapy is related to Chloral hydrate Dicloxacillin weight heparins
bleeding risk. Higher INRs result in higher bleeding risk, and Chloramphenicol Griseofulvin Nonsteroidal anti-
risk of ICH increases when the INR exceeds 4.4,10,11 Instability Cimetidine Nafcillin inflammatory
Ciprofloxacin Phenobarbital drugs
and wide fluctuations in the INR are also associated with higher
Clofibrate Phenytoin Ticlopidine
bleeding risk. In cases of warfarin overdose or overanticoagulation, Danazol Primidone Unfractionated
vitamin K may be used to reverse warfarin’s effect. Vitamin K can Disulfiram Rifampin heparin
be given by IV or oral route; the SC route is not recommended as Doxycycline Secobarbital
vitamin K is erratically absorbed and frequently ineffective. The Erythromycin Sucralfate
IV route is reserved for cases requiring urgent reversal and when Fenofibrate Vitamin K
patients have life-threatening bleeding. Anaphylactoid reactions Fluconazole
have been reported with rapid IV administration; therefore, slow Fluorouracil
infusion is recommended. An oral dose of vitamin K will reduce Fluoxetine
INR within 24 hours. If INR is still elevated after 24 hours, another Fluvoxamine
Gemfibrozil
dose of oral vitamin K can be given. The dose of vitamin K should
Influenza vaccine
be based on the degree of INR elevation and whether bleeding Isoniazid
is present. A dose of 2.5 mg orally is recommended when INR is Itraconazole
greater than 10 and there is no active bleeding, while a higher dose Lovastatin
of 10 mg given via slow IV is recommended in cases when life- Metronidazole
threatening bleeding is present. Higher doses (eg, 10 mg) can lead Miconazole
to prolonged warfarin resistance. In cases of life-threatening bleed- Moxalactam
ing, fresh-frozen plasma or clotting factor concentrates should also Neomycin
be administered, in addition to IV vitamin K. In patients in whom Norfloxacin
INR is less than 10, and there is no active bleeding or imminent risk Ofloxacin
Omeprazole
of bleeding, simply withholding warfarin until INR decreases to
Phenylbutazone
within therapeutic range and reducing the weekly dose with more Piroxicam
frequent monitoring is appropriate.4,10,11,48 Propafenone
Nonhemorrhagic side effects related to warfarin are rare but Propoxyphene
can be severe when they occur. Warfarin-induced skin necrosis Quinidine
(incidence < 0.1%) presents as an eggplant-colored skin lesion Sertraline
or a maculopapular rash that can progress to necrotic gangrene. Sulfamethoxazole
It usually manifests in fatty areas such as the abdomen, buttocks, Sulfinpyrazone
and breasts, and generally appears during the first week of ther- Tamoxifen
apy. Patients with protein C or S deficiency or those who receive Testosterone
Vitamin E
large loading doses of warfarin are at greatest risk.48 The mecha-
Zafirlukast
nism is thought to be due to imbalances between procoagulant
and anticoagulant proteins early in the course of warfarin therapy. INR, international normalized ratio; MTT, methyl-tetrazole-
Warfarin-induced purple toe syndrome is another rare side effect; thiomethyl.
to changes in hepatic metabolism or binding to plasma proteins.

Table 11–19 Drugs that affect the CYP2C9, CYP3A4, and CYP1A2 have the
Potential Warfarin Interactions With Herbal and greatest impact on warfarin metabolism. Interactions that impact
Nutritional Products the metabolism of the S-isomer result in greater changes in the INR
than interactions affecting the R-isomer. Pharmacodynamic drug
Decrease interactions enhance or diminish the anticoagulant effect of war-
Increase Anticoagulation Effect Anticoagulation farin, increasing the risk of bleeding or clotting, but may not alter
(Increase Bleeding Risk or ä INR) Effect (å INR) the INR. There are increasing reports regarding dietary supple-
Arnica flower Ginkgo Coenzyme Q10 ments, nutraceuticals, and vitamins that can interact with warfarin.
Angelica root Horse chestnut Ginseng Patients on warfarin may experience changes in the INR due to fluc-
Anise Licorice root Green tea tuating intake of dietary vitamin K. Patients should be instructed to
Asafoetida Lovage root St. John’s wort maintain a consistent diet and avoid large fluctuations in vitamin
Bogbean Meadowsweet K intake rather than strictly avoiding vitamin K–rich foods.4,10,11,48
Borage seed oil Onion
Bromelain Papain
Capsicum Parsley
Nonpharmacologic Therapy
Celery Passionflower herb ▶ Thrombectomy
Chamomile Poplar Most cases of VTE can be successfully treated with anticoagula-
Clove Quassia
tion. In some cases, removal of the occluding thrombus by surgical
Cranberry Red clover
Danshen Rue intervention may be warranted. Surgical or mechanical thrombec-
Devil’s claw Sweet clover tomy can be considered in patients with massive iliofemoral DVT
Dong quai Turmeric when there is a risk of limb gangrene due to venous occlusion.2,12
Fenugreek Vitamin E The procedure can be complicated by recurrence of thrombus
Feverfew Willow bark formation. In patients who present with massive PE, pulmonary
Garlic embolectomy can be performed in patients with contraindications
Ginger to thrombolytic therapy, when thrombolysis has failed clinically, or
INR, international normalized ratio. when thrombolysis will not have sufficient time to take effect. The
usual practice is to administer heparin by IV infusion to achieve
a therapeutic aPTT during the operation, and postoperatively and
herbal products, and nutritional supplements. When an interacting thereafter give warfarin for the usual recommended duration.2,12
drug is initiated or discontinued, more frequent monitoring should
▶ Inferior Vena Cava Filters
be instituted. In addition, the dose of warfarin can be modified
(increased or decreased) in anticipation of the expected impact on An IVC filter is indicated in patients with newly diagnosed proxi-
the INR.10,11,48 Warfarin-related drug interactions can generally be mal DVT or PE who have a contraindication to anticoagulation
divided into two major categories: pharmacokinetic and pharma- therapy.2,12 IVC interruption is accomplished through minimally
codynamic. Pharmacokinetic interactions are most commonly due invasive means by insertion via internal jugular vein or femoral
Table 11–20
Vitamin K Content of Select Foodsa
Very High (> 200 mcg) High (100–200 mcg) Medium (50–100 mcg) Low (< 50 mcg)
Brussels sprouts Basil Apple, green Apple, red
Chickpea Broccoli Asparagus Avocado
Collard greens Canola oil Cabbage Beans
Coriander Chive Cauliflower Breads and grains
Endive Coleslaw Lettuce, green leaf, romaine Carrot
Kale Cucumber (unpeeled) Mayonnaise Celery
Lettuce, red leaf Green onion/scallion Pistachios Cereal
Parsley Lettuce, butterhead Squash, summer Coffee
Spinach Mustard greens Corn
Swiss chard Soybean oil Cucumber (peeled)
Tea, black Dairy products
Tea, green Eggs
Turnip greens Fruit (varies)
Watercress Lettuce, iceberg
Meats, fish, poultry
Pasta
Peanuts
Peas
Potato
Rice
Tomato
a
Approximate amount of vitamin K per 100 g (3.5 oz) serving.
vein access and advancing the filter into the IVC using ultrasound underlying etiology of the VTE, thrombus location, and the
or fluoroscopic guidance. One of the risks associated with IVC patient’s risk factors.2,12 Determining optimal duration of anti-
filters is development of thrombosis on the filter itself. Therefore, coagulation involves weighing the risk of recurrent VTE against
anticoagulation therapy should be resumed as soon as contrain- the risk of bleeding associated with anticoagulation therapy and
dications resolve. Temporary or retrievable filters are frequently determining patient preference regarding treatment duration.
used, and filters should be removed once therapy is completed.15 Patients with provoked VTE by transient risk factors (eg, surgery,
trauma) or an isolated distally located DVT require therapy for
APPROACH TO TREATING PATIENTS WITH VTE 3 months. Patients with unprovoked VTE have a recurrence risk
of at least 10% after 1 year and at least 30% at 5 years, thus most
A treatment algorithm for VTE is presented in Figure 11–9.
such patients require extended if not indefinite anticoagulation,
Note that LMWH or fondaparinux are preferred over UFH for
particularly in those with PE or proximally located DVT and PE,
acute VTE treatment; however, in patients with CrCl less than
and if the patient carries low-to-moderate bleeding risk. Patients
30 mL/min (0.50 mL/s), UFH is the preferred treatment approach.
with low-to-moderate bleeding risk who have a second unpro-
For the long-term and extended treatment phases, DOACs are
voked VTE should receive extended or indefinite anticoagulation
recommended over warfarin to prevent recurrent thrombosis.
and those at high bleeding risk should be treated for 3 months.
In patients with cancer-associated thrombosis, LMWHs are an
Patients who are recommended to receive indefinite anticoagula-
alternative option for the acute, long-term, and extended phases
tion should have periodic visits to assess bleeding risk and patient
of treatment due to efficacy in preventing recurrent thromboem-
preference/quality of life to determine if anticoagulation should
bolic events.2,31,34
continue. Patient preference should always be a strong consider-
Anticoagulation therapy is continued for a minimum
ation when deciding on extended duration anticoagulation.2,12
of 3 months but should be given longer depending on the
Objectively Confirmed VTE
Does the patient have:

Thrombolytic therapy followed by
- PE with severe cardiopulmonary compromise, or Yes
- DVT with high risk of limb loss
anticoagulation with UFH or LMWH
No
- Place IVC filter

Is VTE a lower - Initiate anticoagulation when bleeding or
- Active bleeding, or Yes YYes
extremity DVT? contraindication resolves
- Contraindication to anticoagulation
- Remove IVC filter as soon as clinically acceptable
No
No

UFH x 5 days overlap with
- PE with poor prognosis,1 or Yes Hospitalize for VTE treatment CrCl < 30 mL/ Yes
- DVT unsuitable for outpatient treatment2 min? warfarin and INR > 2
No
Outpatient VTE treatment

No
- Rivaroxaban
- Apixaban
- LMWH/fondaparinux x 5 days THEN dabigatran or edoxaban
- LMWH/fondaparinux x 5 days OVERLAP with warfarin and INR > 2
1–Severe symptoms, renal impairment, inability to obtain or administer appropriate initial anticoagulant therapy, or high bleeding risk.
2–PESI score ≥ 86 points: age (1 pt for each year); male sex (10 pts); cancer (30 pts); heart failure (10 pts); COPD (10 pts); heart rate > 110 bpm
(20 pts); respiratory rate > 30 bpm (20 pts); temperature < 36°C (20 pts); altered mental status (60 pts); O2 sat < 90% (20 pts).
FIGURE 11–9. Acute treatment of VTE. (bpm, beats/min; COPD, chronic obstructive pulmonary disease; CrCl, creatinine clearance
[30 mL/min is equivalent to 0.50 mL/s]; DVT, deep vein thrombosis; INR, international normalized ratio; IVC, inferior vena cava; LMWH,
low-molecular-weight heparin; O2 sat, oxygen saturation [90% is equivalent to 0.90 when expressed as a fraction]; PE, pulmonary
embolism; PESI, pulmonary embolism severity index; UFH, unfractionated heparin; VTE, venous thromboembolism.) (From Witt DM, Clark
NP, Vazquez SR. Venous thromboembolism. In: DiPiro JT, Yee GC, Posey LM, et al., eds. Pharmacotherapy: A Pathophysiologic Approach,
11th ed. New York, NY: McGraw-Hill. Available from: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577&sectio
nid=21931641. Accessed July 15, 2020.)
OUTCOME EVALUATION complications, and (d) reducing the likelihood of long-term

complications including recurrent events.
t Achieve optimal outcomes by (a) preventing
t Given that VTE is often clinically silent and potentially fatal,
the occurrence of VTE in patients who are at risk, (b)
strategies to increase widespread use of prophylaxis have the
administering effective treatments in a timely manner to
greatest potential to improve patient outcomes. Thus, relying
patients who develop VTE, (c) preventing treatment-related
Patient Care Process

Collect Information: t Determine the most appropriate anticoagulant therapy
t Obtain and review from the medical record: past medical and dose options based on patient clinical characteristics,
history, family history, social history, physical assessment insurance coverage, plans for outpatient therapy, complexity
findings, and laboratory and diagnostic testing results. of anticoagulation management, and patient preferences
(Tables 11–8, 11–9, 11–10, and 11–13).
t Complete a medication history of prescription and
nonprescription medication and dietary supplement use. t Determine optimal duration of anticoagulation therapy by
Identify any allergies to medications and other substances. weighing the risk of recurrent VTE against the risk of bleeding
and considering patient preferences regarding treatment
t Interview the patient and review records to identify lifestyle
duration.
habits such as dietary patterns, alcohol and illicit drug use,
smoking status, medication use–related preferences and Implement the Care Plan:
beliefs, and socioeconomic factors that affect access to t Educate the patient on purpose of therapy and importance
medications and health care. of adherence, proper monitoring, potential drug–drug and
Assess the Information: drug–food interactions, dietary consistency with vitamin K–
containing foods if treated with warfarin, taking appropriate
t Based on clinical assessment and physical examination,
birth control measures in females, adherence with
determine whether the patient is experiencing signs or
anticoagulants and with laboratory monitoring, potential
symptoms of VTE (Table 11–1 and Clinical Presentation and
side effects, and procedures to follow in case of emergency.
Diagnosis of DVT and PE).
t Address any patient concerns about anticoagulation
t Apply the Wells criteria to determine the probability that the
treatment and its management.
patient’s signs, symptoms, and risk factors are the result of
DVT and/or PE (Tables 11–2 and 11–3). t Devise a structured plan for long-term monitoring of
anticoagulation therapy; if treated with warfarin, determine
t Review relevant laboratory (eg, D-dimer, PT/INR, aPTT,
if patient is candidate for anticoagulation self-testing.
antifactor Xa activity, SCr, CrCl, blood urea nitrogen [BUN],
serum albumin, liver function tests, CBC with platelets) and t Refer the patient to a specialized anticoagulation monitoring
diagnostic tests (eg, venous ultrasound, V/Q, or CT scan). See service if available or another designated specialized
Clinical Presentation and Diagnosis of DVT and PE. provider.
t Assess pertinent family history (ie, hypercoagulable disorders, t Evaluate patient’s medical insurance status and assess
pregnancy loss, DVT, PE). coverage level for oral and injectable anticoagulant
medications and coverage for follow-up monitoring visits
t Determine if diagnosis of VTE is confirmed based on clinical
and/or anticoagulation self-testing devices and supplies.
criteria and/or diagnostic testing.
t Assess whether the VTE is a new or recurrent event and Follow-up: Monitor and Evaluate:
whether the VTE is an idiopathic or triggered event. t Follow a structured plan for periodic long-term monitoring
t Assess severity of VTE and whether patient is a candidate for of anticoagulation therapy.
outpatient therapy. t Reevaluate risks and benefits of continuing anticoagulation
t Assess risk of bleeding and check for any contraindications to therapy beyond the initial 3 months; patients who are
anticoagulation therapy (Tables 11–6, 11–11, and 11–12). recommended to receive indefinite anticoagulation should
have periodic visits to assess bleeding risk and patient
t Assess dietary and medication profiles, including over-the-
preference/quality of life to determine if anticoagulation
counter medications and herbal therapies used at home
should continue.
for potential drug–drug and drug–food interactions with
anticoagulation therapy (Tables 11–15, 11–18, and 11–19). t Periodically reassess patient adherence, concurrent
medications to screen for drug interactions, dietary habits to
t If the patient is already receiving anticoagulation therapy,
screen for drug–diet interactions, and renal and liver function
assess efficacy, safety, and adherence to therapy.
tests.
Develop a Care Plan: t Monitor the patient to determine if there is worsening or
t Once diagnosis of VTE has been confirmed with an objective new symptoms related to VTE.
test, initiate anticoagulation therapy at full therapeutic doses. t Evaluate the patient to determine if he/she is experiencing
If there is high clinical suspicion of VTE, anticoagulation any side effects such as overt bruising or bleeding, as well as
therapy may be initiated while waiting for results of changes in stool or urine color.
diagnostic tests (Figure 11–9).
on early diagnosis and treatment of VTE is unacceptable DVT Deep vein thrombosis
because many patients will die before treatment can be ECT Ecarin clotting time
initiated. eGFR Estimated glomerular filtration rate
t Effective VTE prophylaxis programs screen all patients ESR Erythrocyte sedimentation rate
admitted to the hospital for VTE risk factors, determine each FDA Food and Drug Administration
FXa Factor Xa
patient’s level of risk, and select and implement prevention GCS Graduated compression stockings
strategies that provide sufficient protection for the level of risk. GP Glycoprotein
t Periodically evaluate patients who are receiving VTE HIT Heparin-induced thrombocytopenia
prophylaxis for signs and symptoms of DVT, such as swelling, HITTS Heparin-induced thrombocytopenia and
pain, warmth, and redness of lower extremities, and for signs thrombosis syndrome
and symptoms of PE, such as chest pain, shortness of breath, IBW Ideal body weight
palpitations, and hemoptysis. ICH Intracranial hemorrhage
INR International normalized ratio
t Providing effective treatment in a timely manner is the IPC Intermittent pneumatic compression (device)
primary goal for patients who develop VTE. Treat DVT IV Intravenous
and PE quickly and aggressively with effective doses of IVC Inferior vena cava
anticoagulant drugs. LDH Lactate dehydrogenase
LDUH Low-dose unfractionated heparin
t Short-term aims of therapy are to prevent propagation or local LFT Liver function test
extension of the clot, embolization, and death. LMWH Low-molecular-weight heparin
t Regularly monitor patients for development of new symptoms MI Myocardial infarction
or worsening of existing symptoms. MRI Magnetic resonance imaging
MTT Methyl-tetrazole-thiomethyl
t All anticoagulant drugs require precise dosing and meticulous NSAID Nonsteroidal anti-inflammatory drug
monitoring. Closely monitor patients receiving anticoagulant PAI-1 Plasminogen activator inhibitor-1
therapy for signs and symptoms of bleeding including PCI Percutaneous coronary intervention
epistaxis, hemoptysis, hematuria, hematemesis, hematochezia, PE Pulmonary embolism
melena, severe headache, and joint pain. If major bleeding PF Platelet factor
occurs, stop therapy immediately and treat the source of P-gp P-glycoprotein
bleeding. In addition, closely monitor patients for potential PT Prothrombin time
drug–drug and drug–food interactions and adherence with PTS Postthrombotic syndrome
rt-PA Recombinant tissue plasminogen activator
the prescribed regimen.
(alteplase)
t Long-term goals of therapy are to prevent complications such SCr Serum creatinine
as PTS, pulmonary hypertension, and recurrent VTE. SBP Systolic blood pressure
t Continue long-term anticoagulation therapy for an SC Subcutaneous
appropriate duration based on etiology of the initial clot and SGOT Serum glutamic-oxaloacetic transaminase
SERM Selective estrogen receptor modulator
presence of ongoing risk factors. TT Thrombin time
UFH Unfractionated heparin
V/Q Ventilation/perfusion (scan)
ACKNOWLEDGMENT VTE Venous thromboembolism
The authors and editors wish to acknowledge and thank Dr. Stuart vWF von Willebrand factor
Haines, an author of this chapter in previous editions of this book. WBC White blood cell
REFERENCES
Abbreviations Introduced 1. Goldhaber SZ, Bounameaux H. Pulmonary embolism and deep
in This Chapter vein thrombosis. Lancet. 2012;379(9828):1835–1846.
2. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for
ABW Adjusted body weight VTE disease: CHEST guideline and expert panel report. Chest.
ACCP American College of Chest Physicians
2016;149(2):315–352.
ACT Activated clotting time
aPTT Activated partial thromboplastin time 3. Bates SM, Jaeschke R, Stevens SM, et al. Diagnosis of DVT:
AST Aspartate aminotransferase Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
AT Antithrombin American College of Chest Physicians Evidence-Based Clinical
BCRP Breast cancer resistance protein Practice Guidelines. Chest. 2012;141(2 suppl):e351S–e418S.
BMI Body mass index 4. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM,
BUN Blood urea nitrogen Palareti G. Oral anticoagulant therapy: Antithrombotic Therapy
CABG Coronary artery bypass graft and Prevention of Thrombosis, 9th ed: American College of
CBC Complete blood count Chest Physicians Evidence-Based Clinical Practice Guidelines.
CrCl Creatinine clearance Chest. 2012;141(2 suppl):e44S–e88S.
CT Computed tomography 5. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of
CYP Cytochrome P-450 VTE in orthopedic surgery patients: Antithrombotic Therapy
DOAC Direct oral anticoagulant and Prevention of Thrombosis, 9th ed: American College of
DTI Direct thrombin inhibitor Chest Physicians Evidence-Based Clinical Practice Guidelines.
dTT Diluted thrombin time Chest. 2012;141(2 suppl):e278S–e325S.

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11 Venous Thromboembolism

James C. Lee, Bryan Zobeck, and Edith A. Nutescu

INTRODUCTION as well as ongoing patient assessment and education.4,9,10 Well-

Inferior vena cava

Great saphenous vein

Small saphenous vein

Anterior tibial vein

Dorsal venous arch

to become activated, releasing a number of procoagulant sub-

Tissue factor Coagulation

Stabilized fibrin clot

Clinical Characteristic Score

Total Risk Score Clinical Probability of DVT

Clinical Presentation and Diagnosis of DVT

There are several risk assessment models available for esti-

Clinical Presentation and Diagnosis of PE

1 Point 2 Points 3 Points 5 Points

Total Risk Score Risk of VTE

BMI, body mass index.

BMI, body mass index; CABG, coronary artery bypass graft.

Indication and Level of Risk Prevention Strategies

Similar to GCS, intermittent pneumatic compression Pharmacologic Therapy

and prevent destruction of the venous valves. While they may

and elevated factor VIII levels are common in pregnant patients.

Unfractionated heparin (Xa:IIa 1:1)

Low-molecular-weight heparin (Xa:IIa 3-4:1)

Fondaparinux (100% Xa)

Table 11–10 Table 11–12

Dabigatran Rivaroxaban Apixaban Edoxaban

Property Apixaban Dabigatran Rivaroxaban Edoxaban Betrixaban

Apixaban Rivaroxaban Dabigatran Edoxaban Betrixaban

Lepirudin Desirudin Bivalirudin Argatroban

Vitamin K–dependent Dietary

VKORC1 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3

CYP, cytochrome P-450.

Can a PT/INR be obtained

Start warfarin with 5 mg daily Start warfarin with 5 mg daily

Measure PT/INR on day 3 or 4

Measure PT/INR on day 5–7

Measure PT/INR on day 8–10 Measure PT/INR on day 4

Measure PT/INR on day 11–14 Measure PT/INR on day 5

Patient Encounter 3, Part 1

patients present with a purplish discoloration of their toes. If these

to changes in hepatic metabolism or binding to plasma proteins.

Objectively Conﬁrmed VTE

Does the patient have:

- Place IVC ﬁlter

Does the patient have:

Outpatient VTE treatment

OUTCOME EVALUATION complications, and (d) reducing the likelihood of long-term

Patient Care Process

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