BỘ GIÁO DỤC VÀ ĐÀO TẠO

ĐẠI HỌC HUẾ

TRƯỜNG ĐẠI HỌC Y DƯỢC

TRẦN VIỆT HƯNG

Venous Thromboembolism
(VTE)

Cao học Ngoại : 2017-2019

Hướng dẫn Khoa học

PGS.TS LÊ QUANG THỨU
 Venous Thromboembolism (VTE)
 Overview
 Practice Essentials
 Background
 Pathophysiology
 Etiology
 Epidemiology
 Prognosis
 Patient Education

 Presentation
 History
 Physical Examination

 DDx

 Workup
 Laboratory Studies
 Chest Radiography
 Helical (Spiral) Computed Tomography
 Doppler Ultrasonography
 Echocardiography
 Pulmonary Angiography
 Venography
 Ventilation-Perfusion Scanning
 Plethysmography
 Electrocardiography

 Treatment
 Approach Considerations
 Anticoagulant Therapy
 Thrombolytic Therapy
 Thrombectomy, Embolectomy, IVC Filter, and Ligation
 Inpatient Care
 Outpatient Care
 Complications
 Diet
 Activity
 Prevention
 Consultations

 Guidelines
 ASH Guidelines for Optimal Management of Anticoagulation Therapy for VTE
 ESA Guidelines for VTE Prophylaxis in Elderly Surgical Patients
 ACCP Guidelines for Prevention and Treatment of Thrombosis
 AAOS Guidelines for Prevention of VTE in Hip and Knee Arthroplasty
 International Guidelines for Prevention and Treatment of VTE in Cancer
Patients
 ASCO Guidelines for Prevention and Treatment of VTE in Cancer Patients

 Medication
 Medication Summary
 Anticoagulants, Hematologic
 Thrombolytic Agents
 Factor Xa Inhibitors
 Thrombin Inhibitors

 Questions & Answers
 Media Gallery
 References

Prognosis
Thromboembolic disease accounts for approximately a quarter of a million
hospitalizations in the United States annually and for about 5-10% of all
deaths.
About one third of PE cases are fatal. Of these, 67% are not diagnosed ante
mortem, and 34% occur rapidly. A high rate of clinically unsuspected DVT and
PE leads to significant diagnostic and therapeutic delays, and this accounts
for substantial morbidity and mortality.
Studies demonstrate a 95% risk reduction with treatment of thromboembolic
disease. There is, however, a risk of recurrence following the discontinuance
of treatment that is related to the type and number of risk factors the patient
has and whether they persist following completion of treatment. Some 5-7% of
all recurrences are fatal.

Patient Education
For the success and ease of outpatient treatment, patients on oral warfarin
anticoagulation should be instructed on the impact of dietary choices on
treatment goals and the need for frequent monitoring. Instruction on the
avoidance of reversible risk factors would be helpful in preventing disease
recurrence.
The best approach to patient education is one that starts with open
communication with the patient and family, reviewing not only the procedure
or planned surgical intervention, but also potential complications.
For patient education information, see the Lung Disease and Respiratory
Health Center, as well as Pulmonary Embolism and Deep Vein Thrombosis
(Blood Clot in the Leg, DVT).

Presentation
History
With pulmonary embolism (PE), the patient often experiences acute onset of
shortness of breath; sometimes the patient even pinpoints the moment of
distress. Complaints related to signs of deep vein thrombosis (DVT), lower-
extremity swelling, and warmth to touch or tenderness may be present.
Dyspnea is the most frequent symptom of PE.
With a smaller PE near the pleura, the patient may complain of pleuritic chest
pain, cough, or hemoptysis. Sometimes, massive PE can present with
syncope. The patient may have a sense of impending doom, with
apprehension and anxiety. History may reveal the presence of one or more
causes or risk factors.
Physical Examination
Some patients have signs of DVT, lower-extremity swelling, and tenderness
and warmth to touch. Clinical signs of pulmonary thromboembolism also
include the following:
 Tachypnea (respiratory rate exceeding 18 breaths/min) is the most
common sign of PE
 Tachycardia often is present
 The second heart sound can be accentuated
 Fever may be present
 Lung examination findings frequently are normal
 Cyanosis may be present
In the appropriate clinical setting, when shortness of breath, hypoxemia, and
tachycardia are present, there should be a high clinical suspicion of PE until it
is ruled out. Timely anticoagulation is important; 5-7% of recurrences are fatal.
The likelihood of PE in a patient in whom it is suspected may be assessed by
the Wells clinical decision rule. The criteria are scored as follows:
 Clinical symptoms of DVT (3 points)
 Other diagnoses less likely than PE (3 points)
 Heart rate higher than 100 beats/min (1.5 points)
 Immobilization for at least 3 days or surgery in previous 4 weeks (1.5
points)
 Previous DVT/PE (1.5 points)
 Hemoptysis (1 point)
 Malignancy (1 point)
In the modified Wells criteria, PE is likely when the score is greater than 4 and
unlikely when the score is less than 4. Highly sensitive D-dimer is coupled into
the decision algorithm. [19]
DDx
Diagnostic Considerations
Conditions that should be differentiated from deep vein thrombosis (DVT)
include the following:
 Cellulitis
 Ruptured Baker cyst
 Arterial insufficiency
 Hematoma
 Trauma
 Muscle strain
 Arthritis
 Tendonitis
 Iliac vein compression
 Lymphedema
 Sciatic nerve compression
Congestive heart failure (CHF), acute respiratory distress syndrome (ARDS),
pulmonary infection, acute pulmonary hypertension, myocardial infarction
(MI), cardiac tamponade, and right-side heart failure should be included in the
differential diagnoses of shortness of breath and hypoxemia and should be
differentiated from pulmonary embolism (PE).

Workup
Laboratory Studies
The arterial blood gas on room air demonstrates hypoxemia (arterial oxygen
tension [PaO2] < 80 mm Hg) and an elevated alveolar-arterial oxygen
gradient. Acid-base status may demonstrate a respiratory alkalosis.
Enzyme-linked immunoassay (ELISA) can be used to quantify the presence of
D-dimer, which is a specific degradation product of cross-linked fibrin. [20] This
is an important marker of the activation of fibrinolysis. It can be elevated in
pneumonia, cancer, sepsis, and surgery.
A plasma D-dimer level higher than 500 ng/mL has been shown to have a
sensitivity of 97% and a specificity of 45%. The value of D-dimer is in its
negative predictive value. A plasma D-dimer level lower than 500 ng/mL in
those with low pretest probability essentially excludes pulmonary embolism
(PE).
This study is less helpful in older patients, in that the D-dimer level tends to
increase with age. In a study by Righini et al, an age-adjusted D-dimer cutoff
combined with a probability assessment was shown to rule out the diagnosis
of PE in emergency department (ED) patients with suspected PE and was
associated with a low likelihood of subsequent symptomatic VTE, thus
increasing the proportion of patients in whom the diagnosis could be
excluded. [21]
Elevated troponins are associated with an adverse prognosis in acute
PE. [22]Elevated natriuretic peptides, brain natriuretic peptide (BNP), and N-
terminal pro-BNP have been shown to be predictive of adverse short-term
outcomes in acute PE and can be predictive of mortality. [23, 24] Measurement
of both troponin and BNP are important for risk stratification in patients with
PE.
Chest Radiography
Chest radiographic findings most often are normal. Radiographs may,
however, reveal an enlarged right descending pulmonary artery, decreased
pulmonary vascularity (Westermark sign), a wedge-shaped infiltrate, or an
elevation of the hemidiaphragm (Hampton hump). If infarction occurs, a
pleural effusion may be present.
Helical (Spiral) Computed Tomography
Helical (spiral) computed tomography (CT) allows for the imaging of
pulmonary vessels by way of intravenous (IV) contrast material as the patient
moves through a gantry at a constant rate and the radiography source rotates.
PE is diagnosed by identifying filling defects, which are either central or
adherent to the wall (see the image below).
 Helical CT scan of the
pulmonary arteries. A filling defect in the right pulmonary artery is present,
consistent with a pulmonary embolism.

View Media Gallery

The advantage of helical CT is that it is minimally invasive and allows

concurrent visualization of the parenchyma, pleura, and mediastinum. When
looking at the main, lobar, and segmental veins, helical CT has a sensitivity of
about 93%. Its positive predictive value is approximately 95%.
The limitations of helical CT include the need for contrast and the requirement
for a higher dose of radiation than is used with some other diagnostic
modalities. Obliquely or horizontally oriented vessels (eg, those of the
segmental branches of the right middle lobe and lingula) are poorly visualized.
The scan is technically inadequate or inconclusive in approximately 1-10% of
cases.
Doppler Ultrasonography
Results from Doppler ultrasonography (US) can indicate the presence of
thrombus within a vein. A normal vein is free of internal echoes and can be
compressed. In acute deep vein thrombosis (DVT), however, internal echoes
are present and the vessel is not compressible.
Duplex scanning of the venous system uses Doppler flow assessment
combined with B-mode US. The advantage of color flow Doppler US is the
ability to determine motion and the direction of flow.
Echocardiography
Echocardiography can demonstrate signs of right-side heart strain. Right
ventricular dilatation, right ventricular hypokinesis, or tricuspid regurgitation
may be present. Interventricular septum bulging into the left ventricle may be
present, and the size of the left ventricle may be reduced. Echocardiography
can also be used to identify signs of impending heart failure.
Pulmonary Angiography
Pulmonary angiography has long been the diagnostic criterion standard.
Angiography allows for the visualization of the pulmonary vasculature with
contrast agents, and in the event of PE, it evidences the cutoff of a vein and a
lack of flow to the affected area.
It is an invasive procedure that requires the administration of IV contrast
material, and it is more expensive than other procedures.
Pulmonary angiography leads to increased morbidity in approximately 2-5% of
patients; this is related to bleeding and to complications from the use of IV
contrast agents. Mortality occurs in fewer than 1% of patients in whom this
procedure is performed.
Venography
Contrast venography is an invasive technique that can provide direct proof of
thrombus by demonstrating a filling defect with the aid of contrast medium
through the deep venous system. However, it can cause iatrogenic venous
thrombosis, tissue sloughing from contrast extravasation, and an allergic
contrast reaction.
Ventilation-Perfusion Scanning
Ventilation-perfusion scanning is a common screening technique. This
modality provides a probability estimate for PE by evaluation of the size and
the number of defects in the perfusion of the lung compared with the areas of
ventilation.
The diagnosis of PE is easily made with this modality when the probability
estimate is high for PE. With a normal scan finding, the possibility of PE is
excluded. However, the test results are nondiagnostic in about 66% of cases.
The image below compares normal ventilation findings with a perfusion
defect.

Ventilation-perfusion scan.
Left image: Posterior view of normal findings on ventilation scan. Right image:
Posterior view of a perfusion scan that reveals a perfusion defect in the left
upper quadrant. The defect in the middle of the image is due to the position of
the heart.

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Plethysmography
Impedance plethysmography may detect impaired venous emptying of the leg
by assessing the volume response to temporary occlusion of the venous
system. Emptying is assessed by the rapidity of volume decrease. Slow
emptying indicates obstruction.
Impedance plethysmography is a noninvasive method of assessment.
Sensitivity and specificity have been reported to be between 92% and 95%.
However, it is of limited value when DVT is asymptomatic or distal or when
findings are nonocclusive.
Conditions leading to poor forward blood flow, hypotension, or vein
compression can be responsible for false-positive results.
Electrocardiography
Electrocardiography is of greatest value in ruling out myocardial infarction.
Sinus tachycardia often is present, and right axis deviation, right bundle
branch block, and deeply inverted T waves in V1-V3 may be found. An
S1Q3T3 pattern may be seen.

Treatment
Approach Considerations
Anticoagulant and thrombolytic therapy options are available for the treatment
of venous thromboembolism (VTE). Anticoagulant therapy prevents further
clot deposition and allows the patient’s natural fibrinolytic mechanisms to lyse
the existing clot. [25] Guidelines have been developed for optimal management
of anticoagulation therapy in patients with VTE. [26] (See Guidelines.)
Anticoagulant inpatient medications should include heparin or a low-
molecular-weight heparin (LMWH), followed by the initiation of an oral
coumarin derivative. The predominant coumarin derivative in clinical use in
North America is warfarin sodium.
The anticoagulant properties of unfractionated heparin (UFH), LMWH, and
warfarin sodium stem from their effects on the factors and cofactors of the
coagulation cascade.
Patients with acute, massive pulmonary embolism (PE) causing hemodynamic
instability may be treated initially with a thrombolytic agent (eg, streptokinase
or tissue plasminogen activator [t-PA]). t-PA has increasingly been used as
the first-choice thrombolytic agent. Antibodies to streptokinase may be
developed, limiting its use.
Surgical interventions for venous thromboembolic disorders include
thrombectomy and venous interruption.
Special considerations
Pregnancy
In pregnancy, establishing a clear guideline for the treatment of
thromboembolic disease is difficult from an evidence-based perspective.
Heparin is the anticoagulant of choice, given its relative safety for the fetus.
Heparin therapy should be discontinued immediately before delivery, and then
both heparin and warfarin therapy can be started post partum.
Pregnant women with a history of previous thromboembolic disease probably
should receive some prophylaxis, as the estimated range of recurrence is 0-
15%.
Cancer
International clinical practice guidelines for the treatment and prophylaxis of
VTE in patients with cancer were issued in early 2013. [27] Guidelines have
also been published by the American Society of Clinical Oncology
(ASCO). [28, 29] (See Guidelines.)
Anticoagulant Therapy
The results of a Cochrane review indicated that the use of heparin in patients
with cancer but with no therapeutic or prophylactic indication for it was related
to a significant reduction in death at 24 months but not at 12 months. [30] A
statistically and clinically important reduction in VTE was also noted. It had no
effect on bleeding or quality of life. Future studies are needed to investigate
the survival benefit of different types of anticoagulants in patients with different
types and stages of cancer.
No significant reduction in mortality at 6 months, 1 year, 2 years, or 5 years
was found in another, similar Cochrane review comparing the use of oral
anticoagulants with either placebo or no intervention in patients with cancer
who had no therapeutic or prophylactic indication for anticoagulation. In
addition, the oral anticoagulant warfarin was found to increase major and
minor bleeding. [31]
In a study of patients with a first VTE who did not have cancer and who
received different durations of anticoagulant treatment, the results indicated a
similar risk of recurrent VTE whether anticoagulation therapy was stopped
after 3 months or a longer period of treatment was provided. The study
evaluated data from seven randomized trials that included 2925 men or
women. Proximal deep vein thrombosis (DVT) and PE showed a higher risk of
recurrence whenever treatment was stopped. [32]
Results from phase II/III studies, according to a report by Merli et al,
suggested that newer oral anticoagulants may provide an efficacious
alternative for prevention of VTE in orthopedic surgery and have had a good
overall safety profile, with no evidence of increased hepatotoxicity.
Comparison with large observational registries, however, revealed differences
between real-life patient populations; differences in endpoint definitions also
prevented indirect comparison of agents. [33]
The study’s authors stated that specific compliance and postmarketing safety
issues (especially liver enzyme monitoring requirements) need to be clarified
before these agents can be widely accepted in routine clinical practice.
Heparin

Heparin is the first line of therapy. It is administered by bolus dosing, followed

by a continuous infusion. Adequacy of therapy is determined by an activated
partial thromboplastin time (aPTT) of 1.5-2 times baseline. Progression or
recurrence of thromboembolism is 15 times more likely when a therapeutic
aPTT is not achieved within the first 48 hours.
A weight-based nomogram has been employed to determine adequate
dosing, using heparin at 80 mg/kg for the bolus and 18 mg/kg/hr for the
infusion. A short course of heparin is followed by a longer course of oral
anticoagulant (warfarin sodium). It should be started only after effective
anticoagulation has been achieved; there can be an increase in coagulability
and thrombogenesis during the first few days of oral anticoagulant
administration.
The goal is to achieve an international normalized ratio (INR) of 2.0-3.0. The
optimum duration of treatment depends on several factors (eg, first episode or
recurrent event, other underlying risk factors). [34] A minimum of 3 months of
oral therapy has been suggested following a first episode of DVT or PE.
Low-molecular-weight heparin

Several studies have shown that LMWH, which is a fractionated heparin, is as

effective as UFH in treating DVT. Minimal requirements for outpatient therapy
with LMWH regimens include the following:
 Stable PE or DVT
 Low risk for bleeding
 Absence of severe renal insufficiency
 Availability of systems for administration and monitoring of LMWH and
warfarin, as well as surveillance and treatment of recurrent
thromboembolic disease
A Cochrane review found that LMWH, in a comparison with oral
anticoagulants (eg, a vitamin K antagonist [VKA] or ximelagatran), reduced
VTE events but not death in patients with cancer. [35]
Factor Xa and direct thrombin inhibitors

Apixaban, dabigatran, rivaroxaban, edoxaban, and betrixaban are alternatives

to warfarin for prophylaxis or treatment of DVT and PE. Apixaban, edoxaban,
rivaroxaban, and betrixaban all inhibit factor Xa, whereas dabigatran is a
direct thrombin inhibitor.
Rivaroxaban
Rivaroxaban is an oral factor Xa inhibitor approved by the US Food and Drug
Administration (FDA) in November 2012 for the treatment of DVT or PE and
for reduction of the risk of recurrent DVT and PE following initial treatment.
Approval for this indication was based on studies totaling 9478 patients with
DVT or PE. Participants were randomly assigned to receive rivaroxaban, a
combination of enoxaparin and a VKA (eg, warfarin), or a placebo. Study
endpoints were designed to measure the number of patients who experienced
recurrent symptoms of DVT, PE, or death after receiving treatment.
Results showed that rivaroxaban was as effective as the enoxaparin-VKA
combination for treating DVT and PE. Approximately 2.1% of patients treated
with rivaroxaban experienced a recurrent DVT or PE, compared with 1.8-3%
treated with the enoxaparin-VKA combination. [36, 37] Additionally, results from
extended treatment demonstrated a reduced risk of recurrent DVT and PE.
Approximately 1.3% in the rivaroxaban group experienced recurrent DVT or
PE compared with 7.1% in the placebo group. [38, 39]
In October 2017, the FDA approved rivaroxaban in a dosage of 10 mg once
daily for reducing the ongoing risk of recurrent VTE after at least 6 months of
initial anticoagulation therapy. [40] In the new prescribing information, the drug
may be initiated at 15 mg twice daily for the first 21 days after VTE, then
reduced to 20 mg once daily from day 22 through at least day 180. After at
least 180 days, the once-daily 10-mg regimen may now be prescribed for
patients at continued risk for VTE.
Apixaban
In August 2014, apixaban was approved by the FDA for treatment of DVT and
PE. The approval for treatment of PE and prevention of recurrence was based
on the outcome of the AMPLIFY (Apixaban for the Initial Management of
Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) and
AMPLIFY-EXT studies, in which apixaban therapy was compared with
enoxaparin and warfarin treatment.
The AMPLIFY study showed that, in comparison with the standard
anticoagulant regimen, apixaban therapy resulted in a 16% reduction in the
risk of a composite endpoint that included recurrent symptomatic VTE or VTE-
associated death. [41]
Dabigatran
Dabigatran inhibits free and clot-bound thrombin and thrombin-induced
platelet aggregation. It was approved in 2010 to reduce the risk of stroke in
patients with nonvalvular atrial fibrillation. In April 2014, it was approved for
the treatment of DVT and PE in patients who have been treated with a
parenteral anticoagulant for 5-10 days. Additionally, it was approved to reduce
the risk of DVT and PE recurrence in patients who have been previously
treated. Approval was based on results from 4 global phase III trials.
The RE-COVER and RE-COVER II trials included patients with DVT and PE
who were treated with parenteral anticoagulant therapy for 5-10 days. Results
showed dabigatran was noninferior to warfarin in reducing DVT and PE after a
median of 174 days of treatment with a lower risk of bleeding compared with
warfarin. [42, 43]
The RE-SONATE trial and RE-MEDY trials included 2856 patients with acute
DVT and PE who had completed at least 3 months of anticoagulant therapy.
Results showed that dabigatran was noninferior to warfarin in the extended
treatment of VTE and carried a lower risk of major or clinically relevant
bleeding than warfarin did. [44]
Edoxaban
Edoxaban was approved by the FDA in January 2015 for treatment of DVT
and PE in patients who have been initially treated with a parenteral
anticoagulant for 5-10 days. Approval was based on the Hokusai-VTE study
that included 4921 patients with DVT and 3,319 patients with PE.
Among patients with PE, 938 had right ventricular dysfunction, as assessed
by measurement of N-terminal pro-brain natriuretic peptide (BNP)
levels. [45] The rate of recurrent VTE in this subgroup was 3.3% in the
edoxaban group and 6.2% in the warfarin group. Edoxaban was noninferior to
high-quality standard warfarin therapy and caused significantly less bleeding
in a broad spectrum of patients with VTE, including those with severe PE.
In a study of edoxaban for the treatment of cancer-associated VTE, 1050
patients were randomized to receive LMWH for at least 5 days followed by
oral edoxaban (60 mg daily) or subcutaneous (SC) dalteparin (200 IU/kg body
weight daily). Treatment was for 6 to 12 months. Edoxaban was noninferior to
SC dalteparin for the composite outcome of recurrent VTE or major bleeding.
The rate of recurrent VTE was lower, but the rate of major bleeding was
higher with edoxaban. [46]
Betrixaban
Betrixaban, an FXa inhibitor, was approved by the FDA in June 2017. It is
indicated for prophylaxis of VTE in adults hospitalized for acute medical illness
who are at risk for thromboembolic complications owing to moderate or severe
restricted mobility and other risk factors that may cause VTE.
Approval of betrixaban was based on data from the phase 3 APEX
studies. [47, 48]These randomized, double-blind, multinational clinical trials
compared extended-duration betrixaban (35-42 days) with short-duration
enoxaparin (6-14 days) for VTE in 7513 acutely medically ill hospitalized
patients with VTE risk factors.
Patients in the betrixaban group took an initial dose of 160 mg orally on day 1,
followed by 80 mg once daily for 35-42 days, and received a placebo injection
once daily for 6-14 days. Patients in the enoxaparin group received 40 mg SC
once daily for 6-4 days and took an oral placebo once daily for 35-42 days.
Efficacy was measured in 7441 patients by using a composite outcome score
composed of the occurrence of asymptomatic or symptomatic proximal DVT,
nonfatal PE, stroke, or VTE-related death. Betrixaban showed significant
decreases in VTE events as compared with enoxaparin.
Thrombolytic Therapy
Thrombolytic therapy dissolves recent clots promptly by activating a plasma
proenzyme, plasminogen, to its active form, plasmin. Plasmin degrades fibrin
to soluble peptides. Thrombolytic therapy speeds pulmonary tissue
reperfusion and rapidly reverses right heart failure. It also improves pulmonary
capillary blood flow and more rapidly improves hemodynamic parameters.
The recombinant t-PAs (rt-PAs) tenecteplase, alteplase, and reteplase are
thrombolytic agents that the Food and Drug Administration (FDA) has
approved for thrombolytic use in PE. In head-to-head studies by Goldhaber et
al between rt-PA and heparin, there was a higher incidence of recurrent PE
and death in the group receiving heparin. Patients in both groups had
bleeding complications requiring transfusion therapy. [49]
Indications

Thrombolytic treatment may be administered in acute PE associated with

hemodynamic instability in patients who do not seem prone to bleeding, on
the basis of the American College of Chest Physicians (ACCP) evidence-
based guidelines regarding antithrombotic therapy and prevention of
thrombosis. [34]
Contraindications
Absolute contraindications for thrombolysis include the following:
 Gastrointestinal (GI) bleeding within the past 6 months
 Active or recent internal bleeding
 History of hemorrhagic stroke
 Intracranial or intraspinal disease
  Recent cranial surgery or head trauma
 Pregnancy
Relative contraindications include the following:
 Major surgery or trauma within the past 2 weeks
 Biopsy within 10 days
 Other invasive procedures
 Procedures in a location inaccessible to external compression
 Uncontrolled coagulation defects such as thrombocytopenia
 Nonhemorrhagic stroke
Thrombectomy, Embolectomy, IVC Filter, and Ligation
Thrombectomy for venous embolism is performed less frequently, in view of
the relatively high incidence of rethrombosis, unless heparin infusion is added
to the therapeutic regimen.
Pulmonary embolectomy remains a therapeutic option, but mortality is
extremely high. It is reserved for cases of massive PE in which an absolute
contraindication for thrombolysis is present or when all other treatment
modalities have failed. It is only effective when the clot is in the large central
vessels.
Catheter pulmonary embolectomy is performed by inserting a cup-tipped,
steerable catheter into the central venous system, with access gained through
the jugular vein or through the right common femoral vein. When the cup
reaches the thrombus, suction is applied and the thrombus is extracted.
The inferior vena cava (IVC) filter is designed to trap potentially lethal emboli
while maintaining vena caval patency. It has been used in cases where
anticoagulation is contraindicated, where there has been a complication of
anticoagulation, where anticoagulation has failed, or in the case of pulmonary
embolectomy. [50]
Although IVC filters are frequently placed in adults who have experienced
acute PE or VTE to prevent a subsequent event, evidence for the safety and
efficacy of the practice is limited. In a study published in late 2018, Bikdeli et
al found that for older adults with PE, the use of IVC filters appears to offer no
mortality benefit and may in fact confer a mortality risk. [51, 52]
Ligation of venous tributaries is an option that is rarely practiced today. Its use
has been limited by a high mortality and the need for continuous
anticoagulation. It essentially has been replaced by the percutaneous
insertion of the IVC filter.
Inpatient Care
In general, inpatient care requires the administration and continuation of
intravenous (IV) or SC anticoagulants, with an oral anticoagulant (the
coumarin derivative warfarin sodium) started within 72 hours of the SC
anticoagulant or, if IV heparin is being given, once the aPTT is therapeutic
(1.5-2 times baseline).
The reason that the oral administration of warfarin sodium is started after
anticoagulation with SC or IV anticoagulants has been achieved is because
warfarin can have an initial procoagulant effect, particularly in patients with
protein C or protein S deficiencies, potentially causing fat necrosis.
For patients whose treatment has included thrombolysis for acute, massive
PE causing hemodynamic instability, heparin infusion should be started once
the thrombin time (TT) or aPTT is less than twice the baseline value.
Treatment with an oral coumarin derivative should begin after 24-48 hours of
consistent anticoagulation.
Appropriate anticoagulation with the oral medication has been accomplished
when the INR is between 2.0 and 3.0.
Once the INR is consistently within the desired range, treatment can continue
in the outpatient setting as long as no other concomitant conditions are
present that require continued inpatient treatment.
Outpatient Care
Prolongation of the prothrombin time (PT) should be monitored in the
outpatient setting by the routine measurement of the INR, with adjustments
made to maintain its level between 2.0 and 3.0. In the outpatient setting, the
oral anticoagulant, warfarin sodium, is continued; oral anticoagulation
treatment should be continued for at least 3 months.
In patients with recurrent venous thrombosis or with a continuing risk factor,
such as a hematologic factor or a malignancy, prolonged or even indefinite
anticoagulation treatment should be considered.
The results of one study suggested that outpatient care may be a safe and
effective alternative to inpatient care in selected hemodynamically stable
patients with PE. [53]The study evaluated data from 344 patients with a low risk
of death at 19 emergency departments internationally. Patients in the inpatient
group experienced no recurrent VTE events within 90 days and no major
bleeding within 14 days or at 90 days.
Whereas a few members of the outpatient group developed recurrent VTE
within 90 days (1/171) and major bleeding within 14 days or at 90 days (2/171
and 3/171, respectively), patients in the outpatient group experienced less
mean length of stay than did those in the inpatient group (0-5 days and 3-9
days, respectively). One inpatient and one outpatient died within 90 days. [53]
Complications
Postthrombotic syndrome

The most common long-term complication of treated DVT is postthrombotic

syndrome (postphlebitic syndrome), which is a chronic complication of VTE
characterized by pain and swelling. [54] Chronic deep venous insufficiency,
recurrent cellulitis, venous stasis, and ulceration of the skin can develop in as
many as 50% of patients treated with full anticoagulation.
The results from an open-label, randomized, controlled trial suggested that
additional treatment with catheter-directed thrombolysis using alteplase (an rt-
PA) reduces the development of postthrombotic syndrome, prompting the
authors to suggest that it be considered for patients at low risk of bleeding
who have high proximal DVT. [55]
Bleeding

The most feared complication of the treatment of PE is severe and fatal

bleeding. Major risk factors for bleeding include intensity and duration of
therapy, increased age, and significant hepatic or renal dysfunction.
Comparison studies of the incidence of severe and fatal bleeding
complications between heparin and rt-PA have demonstrated no significant
differences. When significant bleeding does occur, it may be necessary to
treat with agent-specific strategies. [56]
Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) and thrombosis [57] may develop in 3-

4% of patients receiving heparin. It is an immune-mediated process that
typically presents within 5-10 days of therapy. It can result in bleeding or
thrombosis and should be suspected when the platelet count falls
precipitously to less than 50% below its baseline or to less than 100,000/µL. In
such cases, heparin therapy should be stopped immediately.
LMWH cross-reacts with the antibody in vitro in 90% of cases. Therefore, it
should not be substituted in the acute setting. Danaparoid, a heparinoid, has
less than 10% cross-reactivity with the antibody.
Fondaparinux has been used in suspected HIT. A study by Kang et al found
that fondaparinux was shown had an effectiveness and safety profile similar to
those of argatroban and danaparoid. [58]
Recombinant hirudin is also been approved for HIT and thrombosis.
Plasmapheresis and immunoglobulin G (IgG) infusion may be effective in
cases with thrombosis.
Heparin-induced osteopenia

Heparin-induced osteopenia has been reported following UFH treatment of

more than 1 month's duration.
Skin necrosis

Coumarin derivatives can cause skin necrosis as a consequence of

widespread subcutaneous microthrombosis. This can occur in individuals who
are protein C–deficient, either genetically or owing to large loading doses of a
coumarin derivative. Areas usually affected include the breasts, abdominal
wall, and lower extremities. [59]
Recurrence
Recurrence of thromboembolism had been documented following
discontinuance of therapy. After a 3- to 6-month course of anticoagulant
therapy, the risk of recurrent thromboembolism is lower in patients who have
reversible risk factors. The recurrence rate is higher in patients with previous
proximal vein thrombosis than in those with calf vein thrombosis.
After a 3-month course of anticoagulant therapy, the risk of secondary
thrombosis is 2-4% in the first year. The recurrence risk is dependent on the
precipitating risk factor: Risk is low if VTE is provoked by surgery,
intermediate if it is related to a nonsurgical risk factor, and high if it is
unprovoked and occurs in the setting of the patient with a disease-related risk
factor. [60]
Two studies indicated that aspirin reduces by one third the rate of VTE
recurrence and the rate of major vascular events (a composite outcome made
up of stroke, myocardial infarction, and cardiovascular death, in addition to
VTE). [61, 62] It also reduces arterial thrombotic events.
Diet
No special dietary requirements or restrictions exist. Diet should be as
tolerated.
An exception, however, applies to patients on oral warfarin therapy, who must
avoid vitamin supplements that contain vitamin K and must limit foods that are
high in vitamin K (eg, broccoli, cabbage, red and green lettuce, onion,
peppers, spinach, oils, mayonnaise, black and green leaf teas). For the
patient on oral warfarin therapy, the diet should remain steady, with no drastic
changes in content, in order to facilitate accurate, regular monitoring of the
INR. Drastic changes in vitamin K–containing foods or supplements can affect
the INR.
Activity
Activity in patients with thromboembolism should be limited until
anticoagulation has been achieved and the patient is on oral anticoagulant
medication. Patients on oral warfarin therapy should avoid activities that could
cause trauma.
Prevention
Thromboprophylaxis has been reported to reduce the incidence of DVT and
fatal PE. Prophylaxis may be achieved with medication or with mechanical
devices. Medical prophylaxis should begin either 12 hours before surgery or
immediately after surgery and should be continued for 7-10
days. [63, 64, 65, 66, 67, 68, 69, 70, 71]
UFH given SC can reduce the incidence of thromboembolism. It must be
administered two or three times daily, and bleeding can be a complication.
LMWHs have a longer half-life and greater bioavailability than UFH does. The
requirement for monitoring is less.
Data from an international, multicenter, randomized, controlled study found
that a short-term course of thromboprophylaxis with the anticoagulant
enoxaparin was more effective than an extended course of another
anticoagulant, apixaban, with significantly fewer major bleeding events. [72]
Apixaban was approved by the FDA in December 2012 to reduce risk of
stroke and systemic embolism associated with nonvalvular atrial fibrillation.
Danaparoid, a low-molecular-weight glycosaminoglycan, has been shown to
be effective in preventing DVT and PE. It also has been used in patients
whose treatment course has been complicated by HIT.
Warfarin is effective for thromboprophylaxis; it causes the depletion of vitamin
K–dependent factors in the coagulation cascade. Warfarin requires close
monitoring, and bleeding can be a complication. Dose-adjusted therapy
should be monitored, keeping the INR in the range of 2.0-3.0.
A randomized, controlled trial comparing dalteparin with aspirin for VTE
prophylaxis in total hip arthroplasty patients found aspirin to be as effective
and safe as dalteparin. [73]
The EPCAT II (Extended Venous Thromboembolism Prophylaxis Comparing
Rivaroxaban to Aspirin Following Total Hip and Knee Arthroplasty II) trial
randomly assigned patients to receive either aspirin 81 mg/day or rivaroxaban
10 mg/day on postoperative day 6 after an initial 5 days of rivaroxaban 10
mg/day. [74] Patients who underwent knee arthroplasty continued prophylaxis
for an additional 9 days, and those who underwent hip arthroplasty continued
for an additional 30 days. All patients were followed for 90 days.
The trial showed aspirin to be noninferior to rivaroxaban for VTE prophylaxis
after hip or knee arthroplasty. [74] Eleven (0.64%) patients in the aspirin group
developed symptomatic proximal DVT or PE during follow-up, compared with
12 (0.70%) in the rivaroxaban group. The combination of major bleeding and
clinically relevant nonmajor bleeding occurred in 22 (1.29%) in the aspirin
group and 17 (0.99%) in the rivaroxaban group; however, the rate of major
bleeding alone was higher in the aspirin group (0.47%) than in the rivaroxaban
group (0.29%).
In November 2015, the FDA approved dabigatran for prophylaxis of DVT and
PE after hip replacement surgery. [75]
Nonpharmacologic prophylaxis

External pneumatic compression has been shown to be capable of

temporarily preventing the reduction in fibrinolytic activity that normally follows
surgical operations. Studies have found compression devices to be effective
only in patients with head trauma or spinal fracture. In total hip replacement,
studies have shown them to be efficacious in preventing distal DVT but not in
preventing proximal DVT.
Another method of nonpharmacologic prophylaxis is early ambulation, unless
the patient has an absolute contraindication. Studies have demonstrated that
both symptomatic and ultrasonographically diagnosed DVT are significantly
less common with early ambulation following hip arthroplasty.
A prospective cohort study including 69,950 female nurses found an
association between physical inactivity and the incidence of PE in women.
The data found that the risk of PE was more than twofold greater in women
who spent more time sitting than it was in women who spent less time sitting.
Activities that decrease the amount of time sitting may lower the risk of PE in
women. [76]
In a randomized, controlled study of 90 patients undergoing total knee
arthroplasty, Izumi et al found that intraoperative transcutaneous electrical
nerve stimulation (TENS) had a significant effect with regard to prevention of
DVT prophylaxis, preventing both venous stasis and blood
hypercoagulability. [77]
Postoperative risk

The results of one study suggested that routine postdischarge prophylaxis

should be considered for high-risk patients. The study evaluated the risk of
postdischarge VTE in patients who had undergone cancer surgery. Using data
from 44,656 patients who underwent surgery for nine cancers, the results
showed that VTE occurred post discharge at an overall rate of 33.4%. VTE
was significantly more likely after gastrointestinal, lung, prostate, and
ovarian/uterine operations. [78]
For patients undergoing major orthopedic surgery, the ACCP evidence-based
guidelines recommended the use of either LMWH; fondaparinux; dabigatran,
apixaban, and rivaroxaban (for total hip arthroplasty or total knee arthroplasty
but not for hip fracture surgery); low-dose UFH; adjusted-dose VKA; aspirin
(all grade 1B evidence); or an intermittent pneumatic compression device
(grade 1C evidence) for a minimum of 10-14 days rather than no
antithrombotic prophylaxis. [79]
Elderly surgical patients are at increased risk for VTE. In September 2017, the
European Society of Anesthesiology published guidelines for VTE prophylaxis
in this population (see Guidelines). [80]
Prophylactic practice

In a survey of members of the American Association of Hip and Knee

Surgeons, more than 70% of survey participants reported that their primary
hospital now mandates prophylaxis for VTE. The survey looked at VTE
protocols for lower-extremity total joint surgery. LMWH was considered to be
the most efficacious for prophylaxis, but aspirin was considered to be the
easiest to use, with the lowest risks of bleeding and wound drainage. Warfarin
was the most used agent in hospital prophylaxis, and 90% of respondents
targeted an INR of 1.6-2.5. [81]
A randomized, double-blind phase III study comparing rivaroxaban with SC
enoxaparin found that the primary outcome of composite of any DVT, nonfatal
PE, or death from any cause up to day 17 after surgery occurred in 67 (6.9%)
of 965 patients who received oral rivaroxaban 10 mg/day as compared with 97
(10.1%) of 959 patients who were given enoxaparin 30 mg SC every 12 hours
for the prevention of VTE after total knee arthroplasty. [82]
Pooled data from four phase III studies comparing rivaroxaban (10 mg/day)
with SC enoxaparin (either 40 mg once daily or 30 mg every 12 hours) for
VTE after total hip or knee arthroplasty showed that the composite of
symptomatic VTE and all-cause mortality was lower in the rivaroxaban group
(29/6183 rivaroxaban patients [0.5%] vs 60/6200 enoxaparin patients [1.0%]).
This reduction in symptomatic VTE plus all-cause mortality was consistent
across all prespecified subgroups. There were no statistically significant
differences in major bleeding or nonmajor clinically relevant bleeding. [83]
After reviewing the published literature, the American College of Physicians
(ACP) determined that it would not support the use of measures for universal
VTE prophylaxis in patients if such measures were performed without regard
to risk. [84] It was reported in the study that in nonsurgical patients, heparin
prophylaxis had no significant effect on mortality and led to more bleeding and
bleeding events, which suggested that it was of little or no benefit overall. In
addition, no improvements in clinical outcomes were found with mechanical
prophylaxis, which also resulted in an increase in lower-extremity skin
damage in stroke patients.
Consultations
When PE is suspected, consultation with a pulmonologist may be useful to aid
in the diagnosis or to guide therapy. When the intravascular filling defect is so
severe that it causes cardiac dysfunction or hypotension, the patient can be
best served by transfer to an intensive care setting. Consultation with an
intensive care specialist or pulmonologist would be helpful in decision-making
regarding thrombolysis and in following the effectiveness of treatment.
If cancer or a hematologic disorder is one of the contributing risk factors,
consultation with a hematologist or oncologist may be appropriate.

Guidelines
ASH Guidelines for Optimal Management of Anticoagulation
Therapy for VTE
In November 2018, the American Society of Hematology (ASH) released the
following guidelines on optimal management of anticoagulation therapy for
venous thromboembolism (VTE). [26]
Initial anticoagulant dose selection

In obese patients receiving low-molecular-weight heparin (LMWH) for

treatment of acute VTE, it is suggested that initial LMWH dose selection be
based on actual body weight rather than on a fixed maximum daily dose (ie,
capped dose).
Drug-interaction management

For patients requiring administration of inhibitors or inducers of P-glycoprotein

(P-gp) or strong inhibitors or inducers of cytochrome P450 (CYP) enzymes, it
is suggested to use an alternative anticoagulant (eg, a vitamin K antagonist
[VKA] or LMWH) rather than a direct oral anticoagulant (DOAC) to treat VTE.
Point-of-care INR testing

For patients receiving maintenance VKA therapy for VTE, home point-of-care
international normalized ratio (INR) testing (patient self-testing [PST]) is
suggested in preference to any other INR testing approach except patient self-
management (PSM) in suitable patients (those who have demonstrated
competency to perform PST and who can afford this option).
For patients receiving maintenance VKA therapy for VTE, point-of-care INR
testing by the patient at home with self-adjustment of VKA dose (PSM) is
suggested in preference to any other management approach, including PST in
suitable patients (those who have demonstrated competency to perform PSM
and who can afford this option).
Selection of timing between INR measurements (INR recall interval)

For patients receiving VKA therapy for VTE, an INR recall interval of 4 weeks
or less is suggested rather than an interval longer than 4 weeks after VKA
dose adjustment due to an out-of-target-range INR.
For patients receiving maintenance VKA therapy for VTE, a longer (6-12
weeks) INR recall interval is suggested rather than a shorter (4 weeks)
interval during periods of stable INR control.
Laboratory monitoring of anticoagulant response

For patients with renal dysfunction (creatinine clearance, < 30 mL/min) or

obesity receiving LMWH therapy for VTE, it is suggested not to use anti–factor
Xa concentration monitoring to guide LMWH dose adjustment.
For patients receiving DOAC therapy for VTE, it is suggested not to measure
the DOAC anticoagulant effect during management of bleeding.
Transitions between anticoagulants

For patients transitioning from DOAC to VKA, overlapping DOAC and VKA
therapy until the INR is within the therapeutic range is suggested in
preference to LMWH or UFH “bridging therapy.”
Use of specialized AMS

For patients receiving anticoagulation therapy for VTE, specialized

anticoagulation-management service (AMS) care is suggested in preference
to care provided by the patient’s usual healthcare provider.
Structured patient education

For patients receiving oral anticoagulation therapy for VTE, supplementary

patient education is suggested in addition to basic education.
Efforts to improve adherence to anticoagulant regimen

For patients receiving anticoagulation therapy for VTE, it is suggested not to

use a daily lottery, electronic reminders, or a combination of the two to
improve medication adherence. It is also suggested not to use visual
medication schedules (provided to patients at each visit, along with brief
counseling) to improve medication adherence.
Invasive procedure management

For patients at low-to-moderate risk for recurrent VTE who require interruption
of VKA therapy for invasive procedures, VKA interruption alone is
recommended in preference to periprocedural bridging with LMWH or UHF.
For patients interrupting DOAC therapy for scheduled invasive procedures, it
is suggested not to perform laboratory testing for DOAC effect before
procedures.
Excessive anticoagulation and bleeding management

For patients receiving VKA therapy for VTE with INR >4.5 but < 10 and
without clinically relevant bleeding, temporary cessation of VKA alone is
suggested, without the addition of vitamin K.
For patients with life-threatening bleeding during VKA therapy for VTE and an
elevated INR, use of four-factor prothrombin complex concentrates (PCCs) is
suggested in preference to fresh frozen plasma (FFP) as an addition to
cessation of VKA and IV vitamin K.
For patients with life-threatening bleeding during oral direct Xa inhibitor
therapy for VTE, it is suggested to use either four-factor PCC administration
as an addition to cessation of oral direct Xa inhibitor or cessation of oral direct
Xa inhibitor alone.
For patients with life-threatening bleeding during oral direct Xa inhibitor
therapy for VTE, it is suggested to use coagulation factor Xa (recombinant),
inactivated-zhzo in addition to cessation of oral direct Xa inhibitor rather than
no coagulation factor Xa (recombinant), inactivated-zhzo.
For patients with life-threatening bleeding during dabigatran therapy for VTE,
it is suggested to use idarucizumab in addition to cessation of dabigatran
rather than no idarucizumab.
For patients with life-threatening bleeding during LMWH or unfractionated
heparin (UFH) therapy for VTE, it is suggested to use protamine in addition to
LMWH/UFH cessation rather than no protamine.
Anticoagulant resumption following bleeding

For patients receiving anticoagulation therapy for VTE who survive an episode
of major bleeding, resumption of oral anticoagulation therapy within 90 days is
suggested in preference to discontinuance of oral anticoagulation therapy.
ESA Guidelines for VTE Prophylaxis in Elderly Surgical
Patients
In September 2017, the European Society of Anesthesiology (ESA) issued the
following guidelines regarding prophylaxis for VTE in elderly patients
undergoing surgery [80] :
 The risk for postoperative VTE is increased in patients older than 70
years and in elderly patients presenting with comorbidities, such as
cardiovascular disorders, malignancy, or renal insufficiency; therefore,
risk stratification, correction of modifiable risks, and sustained
perioperative thromboprophylaxis are essential in this patient population
 Timing and dosing of pharmacoprophylaxis may be adopted from the
younger population
 Direct oral anticoagulants are effective and well tolerated in the elderly;
statins may not replace pharmacologic thromboprophylaxis
 Early mobilization and use of nonpharmacologic means of
thromboprophylaxis should be exploited
 In elderly patients, suggest identification of comorbidities increasing the
risk for VTE (eg, congestive heart failure, pulmonary circulation disorder,
 renal failure, lymphoma, metastatic cancer, obesity, arthritis, post-
menopausal estrogen therapy) and correction if present (eg, anemia,
coagulopathy)
 Suggest against bilateral knee replacement in elderly and frail patients
 Suggest timing and dosing of pharmacologic VTE prophylaxis as in the
younger population
 In elderly patients with renal failure, low-dose unfractionated heparin
(UFH) may be used or weight-adjusted dosing of low-molecular-weight
heparin (LMWH)
 In the elderly, recommend careful prescription of postoperative VTE
prophylaxis and early postoperative mobilization
 Recommend multifaceted interventions for VTE prophylaxis in elderly and
frail patients, including pneumatic compression devices, LMWH, and/or
direct oral anticoagulants after knee or hip replacement
ACCP Guidelines for Prevention and Treatment of
Thrombosis
In 2012, the American College of Chest Physicians (ACCP) published the
ninth edition of its guidelines on antithrombotic therapy and prevention of
thrombosis (updated from the eighth edition published in 2009). [34] ACCP
guidelines providing recommendations for the prevention of VTE in orthopedic
surgery patients addressed therapy and prevention. [79] Recommendations
included the following:
 In patients undergoing total hip arthroplasty (THA) or total knee
arthroplasty (TKA), use of one of the following is recommended for a
minimum of 10-14 days rather than no antithrombotic prophylaxis:
LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban, low-dose UFH
(LDUH), adjusted-dose vitamin K antagonist (VKA), aspirin (all grade 1B),
or an intermittent pneumatic compression device (IPCD) (grade 1C)
 In patients undergoing hip fracture surgery (HFS), use of one of the
following is recommended rather than no antithrombotic prophylaxis for a
minimum of 10 to 14 days: LMWH, fondaparinux, LDUH, adjusted-dose
VKA, aspirin (all grade 1B), or an IPCD (grade 1C)
 For patients undergoing major orthopedic surgery (THA, TKA, HFS) and
receiving LMWH as thromboprophylaxis, it is recommended to start either
12 hr or more preoperatively or 12 hr or more postoperatively rather than
within 4 hr or less preoperatively or 4 hr or less postoperatively
(grade 1B)
 In patients undergoing THA or TKA, irrespective of the concomitant use
of an IPCD or length of treatment, LMWH is suggested in preference to
the other agents recommended as alternatives: fondaparinux, apixaban,
 dabigatran, rivaroxaban, LDUH (all grade 2B), adjusted-dose VKA, or
aspirin (all grade 2C)
 In patients undergoing HFS, irrespective of the concomitant use of an
IPCD or length of treatment, LMWH is suggested in preference to the
other agents recommended as alternatives: fondaparinux, LDUH
(grade 2B), adjusted-dose VKA, or aspirin (all grade 2C)
 For patients undergoing major orthopedic surgery, it is suggested to
extend thromboprophylaxis in the outpatient period for up to 35 days from
the day of surgery rather than for only 10-14 days (grade 2B)
 In patients undergoing major orthopedic surgery, dual prophylaxis with an
antithrombotic agent and an IPCD is suggested during the hospital stay
(grade 2C)
 In patients undergoing major orthopedic surgery and increased risk of
bleeding, an IPCD or no prophylaxis is suggested rather than
pharmacologic treatment (grade 2C)
 In patients undergoing major orthopedic surgery and who decline or are
uncooperative with injections or an IPCD, use of apixaban or dabigatran
(alternatively, rivaroxaban or adjusted-dose VKA if apixaban or
dabigatran are unavailable) is recommended rather than alternative forms
of prophylaxis (all grade 1B)
 In patients undergoing major orthopedic surgery, it is suggested not to
use inferior vena cava (IVC) filter placement for primary prevention over
no thromboprophylaxis in patients with an increased bleeding risk or
contraindications to both pharmacologic and mechanical
thromboprophylaxis (grade 2C)
 For asymptomatic patients following major orthopedic surgery, it is
recommended not to perform Doppler (or duplex) ultrasonography (DUS)
screening before hospital discharge (grade 1B)
 No prophylaxis is suggested rather than pharmacologic
thromboprophylaxis in patients with isolated lower-leg injuries requiring
leg immobilization (grade 2C)
 For patients undergoing knee arthroscopy without a history of prior VTE,
no thromboprophylaxis is suggested rather than prophylaxis (grade 2B)
An update in 2016 addressed 12 topics from the ninth edition guidelines, as
well as three new topics. [85]
AAOS Guidelines for Prevention of VTE in Hip and Knee
Arthroplasty
Guidelines from the American Academy of Orthopaedic Surgeons (AAOS) on
preventing venous thromboembolic disease in patients undergoing elective
hip and knee arthroplasty included the following recommendations [86] :
  Recommend against routine postoperative duplex ultrasonography
screening
 Assess risk of previous VTE
 Assess risk for bleeding
 Suggest discontinuance of antiplatelet agents before undergoing elective
hip or knee arthroplasty
 Suggest pharmacologic agents and/or mechanical compressive devices
for prevention of VTE in those undergoing elective hip or knee
arthroplasty who are not at elevated additional risk for VTe or bleeding
 Pharmacologic prophylaxis and mechanical compressive devices for
those who have had previous VTE and are undergoing elective hip or
knee arthroplasty
 Mechanical compressive devices for those who have had known bleeding
disorder and/or active liver disease and are undergoing elective hip or
knee arthroplasty
 Patients should undergo early mobilization following elective hip and knee
arthroplasty
 Use of neuraxial anesthesia for those undergoing elective hip or knee
arthroplasty to help limit blood loss
 Unable to recommend for or against the use of inferior vena cava filters
International Guidelines for Prevention and Treatment of VTE
in Cancer Patients
International clinical practice guidelines for the treatment and prophylaxis of
VTE in patients with cancer were issued in early 2013. [27] Recommendations
included the following:
 For the initial treatment of established VTE, LMWH is recommended, and
fondaparinux and UFH can be also used
 Thrombolysis may only be considered on a case-by-case basis
 Vena cava filters (VCFs) may be considered if there is a contraindication
to anticoagulation or PE recurrence under optimal anticoagulation
 Periodic reassessments of contraindications to anticoagulation are
recommended
 VCFs are not recommended for primary VTE prophylaxis in cancer
patients
 For the early maintenance and long-term treatment of established VTE,
LMWH for a minimum of 3 months is preferred over vitamin K antagonists
(VKAs). Idraparinux is not recommended. After 3-6 months, LMWH or
VKA continuation should be based on individual evaluation of the benefits
and risks, tolerability, patient preference and cancer activity
 For the treatment of VTE recurrence in cancer patients receiving
anticoagulation, there are three options: (i) switch from VKA to LMWH
 when treated with VKA; (ii) increase LMWH dose when treated with
LMWH, and (iii) VCF insertion
 For the prophylaxis of postoperative VTE in surgical cancer patients, use
of LMWH or low-dose UFH is recommended
 Extended prophylaxis (4 weeks) after major laparotomy may be indicated
in patients with a high risk of VTE and low risk of bleeding
 Use of LMWH for VTE prevention in cancer patients undergoing
laparoscopic surgery may be recommended as for laparotomy
 Mechanical methods are not recommended as monotherapy except when
pharmacologic methods are contraindicated
 In hospitalized patients with cancer and reduced mobility, prophylaxis
with LMWH, UFH, or fondaparinux is recommended
 Prophylaxis may be considered in some children and adults with acute
lymphocytic leukemia treated with L-asparaginase, depending on local
policy and patient characteristics
 Routine prophylaxis is not recommended in patients receiving
chemotherapy
 Primary pharmacologic prophylaxis of VTE may be indicated in patients
with locally advanced or metastatic pancreatic or lung cancer treated with
chemotherapy and having a low risk of bleeding
 In patients treated with thalidomide or lenalidomide combined with
steroids and/or chemotherapy, VTE prophylaxis is recommended
ASCO Guidelines for Prevention and Treatment of VTE in
Cancer Patients
In May 2013, the American Society of Clinical Oncology (ASCO) released
revised clinical practice guidelines on VTE prophylaxis and treatment in
patients with cancer.[28] A review of the literature published from December
2007 to December 2012 was completed in MEDLINE and the Cochrane
Collaboration Library, and evidence was assessed to determine which
recommendations required revision. Slight changes were made to existing
recommendations, and two new recommendations were added that focused
on the following:
 The need to assess and periodically reassess the risk for VTE
 The need to educate high-risk patients on how to prevent blood clots and
how to recognize the warning signs of VTE
The recommendation against the routine use of thromboprophylaxis for most
ambulatory patients with cancer remained unchanged. A February 2015
review of 53 publications in MEDLINE and the Cochrane Library by Lyman et
al did not find sufficient evidence to prompt a change in the 2013
guidelines. [29]
Medication
Medication Summary
Anticoagulant inpatient medications should include heparin or a low-
molecular-weight heparin (LMWH), followed by the initiation of an oral
coumarin derivative. Heparin is administered by bolus dosing, followed by a
continuous infusion. The predominant coumarin derivative in clinical use in
North America is warfarin sodium.
Apixaban, dabigatran, rivaroxaban, edoxaban, and betrixaban are alternatives
to warfarin for prophylaxis or treatment of deep venous thrombosis (DVT) and
pulmonary embolism (PE). Apixaban, edoxaban, rivaroxaban, and betrixaban
inhibit factor Xa, whereas dabigatran is a direct thrombin inhibitor.
The US Food and Drug Administration (FDA) has approved the thrombolytic
agents streptokinase and recombinant tissue-type plasminogen activator (rt-
PA) for thrombolytic use in PE. Because antibodies to streptokinase may
develop and rt-PA has increasingly been used as the first-choice thrombolytic
agent.
Anticoagulants, Hematologic
Class Summary
Anticoagulant medications prevent further clot deposition. They allow the
natural fibrinolytic mechanisms to lyse the existing clot.

Heparin

 View full drug information

Heparin augments the activity of antithrombin III and prevents conversion of
fibrinogen to fibrin. It does not actively lyse but is able to inhibit further
thrombogenesis. The drug prevents the reaccumulation of clot after
spontaneous fibrinolysis.

Warfarin (Coumadin, Jantoven)

 View full drug information

Warfarin interferes with the hepatic synthesis of vitamin K–dependent
coagulation factors. It is used for prophylaxis and treatment of venous
thrombosis, PE, and thromboembolic disorders. Tailor the dose to maintain an
international normalized ratio (INR) in the range of 2.0-3.0.
Enoxaparin (Lovenox)

 View full drug information

Enoxaparin prevents DVT, which may lead to PE in patients undergoing
surgery who are at risk for thromboembolic complications. The average
duration of treatment is 7-14 days. Enoxaparin enhances the inhibition of
factor Xa and thrombin by increasing antithrombin III activity. In addition, it
preferentially increases the inhibition of factor Xa. Enoxaparin also has been
approved for the treatment of DVT and PE.

Dalteparin (Fragmin)

 View full drug information

Dalteparin is indicated for the prevention of DVT, which may lead to PE. It
enhances the inhibition of factor Xa and thrombin by increasing antithrombin
III activity. In addition, dalteparin preferentially increases the inhibition of factor
Xa. The average duration of treatment is 7-14 days.

Rivaroxaban (Xarelto)

 View full drug information

Rivaroxaban is an oral factor Xa inhibitor that inhibits platelet activation by
selectively blocking the active site of factor Xa without requiring a cofactor (eg,
antithrombin III) for activity. It is indicated for treatment of DVT or PE, and to
reduce risk of recurrent DVT and PE following initial treatment. It is also
indicated for prophylaxis of DVT in patients undergoing knee or hip
replacement surgery.

Dabigatran (Pradaxa)

 View full drug information

Dabigatran is a direct thrombin inhibitor. Both free and clot-bound thrombin,
and thrombin-induced platelet aggregation is inhibited. It is indicated for the
treatment of DVT and PE in patients who have been treated with a parenteral
anticoagulant for 5-10 days. It is also indicated to reduce the risk of DVT and
PE recurrence in patients who have been previously treated.
Apixaban (Eliquis)

 View full drug information

Apixaban is a factor Xa inhibitor indicated for treatment of DVT and PE. It is
also indicated to reduce the risk of recurrence of DVT and PE in patients who
have been previously treated.

Edoxaban (Savaysa)

 View full drug information

Edoxaban is a factor Xa inhibitor indicated for treatment of DVT and PE in
patients who have been initially treated with a parenteral anticoagulant for 5-
10 days.
Thrombolytic Agents
Class Summary
As stated by the American College of Chest Physicians, [34] thrombolytic
treatment is indicated for acute, massive PE with hemodynamic instability in
patients who do not seem prone to bleeding. These agents dissolve recent
clots promptly by activating a plasma proenzyme, plasminogen, to its active
form, plasmin. Plasmin degrades fibrin to soluble peptides.
Thrombolytic therapy speeds pulmonary tissue reperfusion and rapidly
reverses right heart failure. It improves pulmonary capillary blood flow and
more rapidly improves hemodynamic parameters.

Reteplase; t-PA (Retavase)

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Reteplase is used in the management of PE in hemodynamically unstable
patients. Its safety and efficacy with concomitant administration of heparin or
aspirin during first 24 hours after symptom onset have not been investigated.

Tenecteplase (TNKase)

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Tenecteplase is a modified version of alteplase made by substituting three
amino acids. It has a longer half-life than alteplase and thus can be given as a
single bolus infused over 5 seconds (as opposed to the 90 minutes required
for alteplase). It appears to cause less non–intracranial bleeding than
alteplase but carries a comparable risk of intracranial bleeding and stroke.
Base the dose on the patient's weight. Initiate treatment as soon as possible
after the onset of AMI symptoms. Because tenecteplase contains no
antibacterial preservatives, it must be reconstituted immediately before use.
Factor Xa Inhibitors
Class Summary
Blood coagulation cascade is dependent on the activation of factor X to factor
Xa via the intrinsic and extrinsic pathways.

Apixaban (Eliquis)

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Indicated to reduce risk of stroke and systemic embolism associated with
nonvalvular atrial fibrillation. Also indicated for postoperative prophylaxis of
DVT/PE and for treatment of DVT or PE.

Rivaroxaban (Xarelto)

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Indicated for prophylaxis of DVT, which may lead to PE in patients undergoing
knee or hip replacement surgery. Also indicated to reduce the risk of stroke in
patients with nonvalvular atrial fibrillation. Additionally, it is indicated for
treatment of DVT or PE.

Edoxaban (Savaysa)

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Indicated to reduce risk of stroke and systemic embolism associated with
nonvalvular atrial fibrillation (NVAF).

Betrixaban (Bevyxxa)

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Indicated for prophylaxis of venous thromboembolism (VTE) in adults
hospitalized for acute medical illness who are at risk for thromboembolic
complications owing to moderate or severe restricted mobility and other risk
factors that may cause VTE.
Thrombin Inhibitors
Class Summary
Prevents thrombus development through direct, competitive inhibition of
thrombin. Thrombin enables fibrinogen conversion to fibrin during the
coagulation cascade.

Dabigatran (Pradaxa)

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Inhibits free and clot-bound thrombin and thrombin-induced platelet
aggregation. Indicated for prevention of stroke and systemic embolism
associated with nonvalvular atrial fibrillation. Also indicated for prevention and
treatment of DVT or PE.