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'''Editors-in-Chief:''' [[C. Michael Gibson, M.S., M.D.]] '''Associate Editor-In-Chief''': [[User:Ujjwal Rastogi|Ujjwal Rastogi, MBBS]] [mailto:urastogi@perfuse.org]
 
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'''Editor(s)-In-Chief:''' {{ATI}}, [[C. Michael Gibson, M.S., M.D.]] [mailto:charlesmichaelgibson@gmail.com]; '''Associate Editor(s)-In-Chief:''' {{CZ}} ;[[User:Kashish Goel|Kashish Goel, M.D.]]; '''Assistant Editor(s)-In-Chief:''' [[User:Justine Cadet|Justine Cadet]]


{{Deep vein thrombosis}}
{{Deep vein thrombosis}}


==Overview==
==Overview==
'''Deep-vein thrombosis''' (also known as '''deep-venous thrombosis''' or '''DVT''' and colloquially as '''economy class syndrome''') is the formation of a [[blood clot]] ("thrombus") in a [[deep vein]].   
Deep vein thrombosis (also known as deep venous thrombosis or DVT and colloquially referred to as economy class syndrome) is the formation of a [[blood clot]] ("thrombus") in a [[deep vein]]. The risk is significantly increased if the thrombus embolizes to the lungs, causing [[pulmonary embolism]]. Occasionally, veins in the arm are also affected (known as ''[[Paget-Schrötter disease]]''). Upper extremity DVT is less common but also may lead to [[PE]], especially in the presence of a venous catheter.<ref name="pmid15222648">{{cite journal| author=Ramzi DW, Leeper KV| title=DVT and pulmonary embolism: Part I. Diagnosis. | journal=Am Fam Physician | year= 2004 | volume= 69 | issue= 12 | pages= 2829-36 | pmid=15222648 | doi= | pmc= | url= }} </ref> [[Thrombophlebitis]] is swelling (inflammation) of a vein caused by a blood clot. Venous thromboembolism (VTE) is a hypernym which includes [[Deep venous thrombosis]] (DVT) and [[pulmonary embolism]] (PE). It is a major public health problem and one of the most common cause of preventable cause of death in hospital patients. It is the third most common cardiovascular disorder after [[coronary artery disease]] and [[stroke]]. It is frequently underestimated and misdiagnosed and failure to provide adequate prophylaxis and therapy can be fatal for the patient.


DVT of the lower extremity is subdivided into two categories:
==Classification==
*'''Distal (calf) vein''' thrombosis, in which thrombi remain confined to the deep calf veins
Deep vein thrombosis (DVT) is classified based on the site of occlusion or clot formation. Symptom presentation and complication is largely influenced by location of the embolus.
*'''Proximal vein''' thrombosis, in which thrombosis involves the popliteal, femoral, or iliac veins
==Pathophysiology==
Venous thrombosis is composed of three mechanisms, collectively described as the [[Virchow's triad]]: 1. Alterations in blood flow ([[stasis]]): Venous stasis is a major risk factor for the development of thrombosis. It occurs in certain pathological conditions (as in [[Congestive heart failure|heart failure]]) wherein it causes an increase in platelet to endothelium contact and decreases the dilution of clotting factors. This increases the risk of clot formation, and it forms microthrombi, which further grow and propagate. 2. Injury to the vascular endothelium ([[Endothelial dysfunction]]): Intrinsic or secondary to external trauma, such as [[catheterization]], can cause [[Tunica intima|intimal]] damage and [[coagulation|stimulate clot formation]]. 3. Alterations in the constitution of blood ([[Hypercoagulability]]): Abnormal changes in coagulation can increase the propensity to develop thrombosis.
==Differentiating Deep Vein Thrombosis from Other Diseases==
Only 25% of the patient evaluated for [[deep vein thrombosis]] (DVT) have the disease.<ref name="pmid3951515">{{cite journal| author=Huisman MV, Büller HR, ten Cate JW, Vreeken J| title=Serial impedance plethysmography for suspected deep venous thrombosis in outpatients. The Amsterdam General Practitioner Study. | journal=N Engl J Med | year= 1986 | volume= 314 | issue= 13 | pages= 823-8 | pmid=3951515 | doi=10.1056/NEJM198603273141305 | pmc= | url= }} </ref> DVT is characterized by pain and swelling of the limb, which is not specific. Numerous patients with DVT are asymptomatic.
==Epidemiology and Demographics==
In the United States, approximately 350,000 to 600,000 new cases of [[venous thromboembolism]] are diagnosed each year. The incidence of deep vein thrombosis is estimated to be 100 cases per 100,000 persons per year. Deep vein thrombosis accounts for two-thirds of all venous thromboembolism cases. Mortality and complications from deep vein thrombosis are high: one-third of the patients develop [[post-thrombotic syndrome]] and another 30% have recurrent DVT within 10 years. In the United States, deep vein thrombosis accounts for approximately 100,000 deaths each year.
==Risk Factors==
The identification and minimization of risk factors is important in the management of DVT.  The duration of [[anticoagulation]] is guided by the presence of [[Thrombophilia#Treatment|thrombophilic risk factors]].
==Natural History, Complications and Prognosis==
Thrombus formation typically begins in the calf veins and naturally progresses to the proximal veins and ultimately, breaks free from the site formation and travels to the pulmonary artery where it is called a [[pulmonary embolism]]. In many cases, patients with a thrombus can be asymptomatic until it progresses into the proximal veins.


Occasionally the veins of the '''arm''' are also affected (known as ''[[Paget-Schrötter disease]]''). [[Thrombophlebitis]] is swelling (inflammation) of a vein caused by a blood clot. There is a significant risk, when a thrombus embolize and travel to the lungs, causing [[pulmonary embolism]].  
== Diagnosis ==
=== Pretest Probability ===
In a patient with suspected [[DVT]], establishing pre-test probability helps in early risk stratification and appropriate use of laboratory tests and imaging modalities. Many pretest probability scoring systems are proposed for use in primary care patients, like the Wells score, Hamilton score , and AMUSE score. <ref name="pmid16357403">{{cite journal |author=Subramaniam RM, Chou T, Heath R, Allen R |title=Importance of pretest probability score and D-dimer assay before sonography for lower limb deep venous thrombosis |journal=AJR Am J Roentgenol |volume=186 |issue=1 |pages=206–12 |year=2006 |month=January|pmid=16357403|doi=10.2214/AJR.04.1398 |url=http://www.ajronline.org/cgi/pmidlookup?view=long&pmid=16357403 |accessdate=2011-12-22}}</ref><ref name="pmid21242558">{{cite journal |author=van der Velde EF, Toll DB, Ten Cate-Hoek AJ, Oudega R, Stoffers HE, Bossuyt PM, Büller HR, Prins MH, Hoes AW, Moons KG, van Weert HC|title=Comparing the diagnostic performance of 2 clinical decision rules to rule out deep vein thrombosis in primary care patients|journal=Ann Fam Med|volume=9 |issue=1 |pages=31–6 |year=2011 |pmid=21242558 |pmc=3022042 |doi=10.1370/afm.1198 |url=http://www.annfammed.org/cgi/pmidlookup?view=long&pmid=21242558 |accessdate=2011-12-22}}</ref> When combined with pretest probability, ultrasonography and D-dimer tests are most useful in a diagnosis for DVT.
=== History and Symptoms ===
A proper history and physical exam is very important for establishing an accurate diagnosis of [[DVT]] or [[VTE]]. One of the first steps in the management of [[DVT]] is the determination of the [[Pretest probability of DVT#Wells score|Wells score for DVT]]. Out of the 10 clinical questions in the score, 9 can be ascertained solely on the basis of history and physical exam. This underscores the importance of these variables. A high index of suspicion is also necessary to diagnose [[DVT]].
=== Physical Examination ===
The physical examination may be completely normal in patients with [[DVT]]. A high degree of suspicion is necessary for early identification of venous thrombosis, as sometimes these patients are admitted with a different complaint and a thorough physical exam gives a clue to the diagnosis.
=== Laboratory Findings ===
The lifetime incidence of [[DVT]] ranges from 2-5% in the general population. It accounts for a large number of ER visits and puts the patient at-risk for a life-threatening [[pulmonary embolism]]. The use of D-dimer after assessment of pre-test probability has been widely validated now and has led to a significant reduction in unnecessary procedures in the ER and hospital settings. This chapter will review the role of D-dimer in diagnosis of [[DVT]]. For a detailed discussion on D-dimer, please visit [[D-dimer]].


Upper extremity DVT is less common but also may lead to PE, especially in the presence of a venous catheter<ref name="pmid15222648">{{cite journal| author=Ramzi DW, Leeper KV| title=DVT and pulmonary embolism: Part I. Diagnosis. | journal=Am Fam Physician | year= 2004 | volume= 69 | issue= 12 | pages= 2829-36 | pmid=15222648 | doi= | pmc= | url= }} </ref>.  
=== Ultrasound ===
Venous ultrasound is the confirmatory test for diagnosis of [[DVT]]. The most common form is compression ultrasonography, which assesses the compressibility of femoral and popliteal veins. Diagnosis of [[DVT]] is established if the vein can not be collapsed under gentle ultrasound probe pressure. In most cases, it is performed in the proximal veins, as the risk of [[pulmonary embolism]] is much higher with that. Whole-leg ultrasound examines the deep veins of the proximal leg and calf, and it is used in cases where distal [[DVT]] is suspected. Iliac vein ultrasound may be performed, if thrombosis is suspected (e.g.: Pregnant women with swelling of the whole leg).
=== Venography ===
Venography is the "[[gold standard]]" to diagnose venous thrombosis, however it is not the preferred test in clinical settings. It includes injection of contrast into the dorsal foot vein and checking for a intraluminal filling defect that is present in more than one view.
=== CT ===
Venous thrombosis in the proximal deep veins is responsible for more than 90% of the [[pulmonary embolism]]s. Some of the investigators have suggested combined use of CT PE protocol and CT scan venography in cases of suspected [[DVT]] and [[PE]].<ref name="pmid15051664">{{cite journal| author=Kanne JP, Lalani TA| title=Role of computed tomography and magnetic resonance imaging for deep venous thrombosis and pulmonary embolism. | journal=Circulation | year= 2004 | volume= 109 | issue= 12 Suppl 1 | pages= I15-21 | pmid=15051664 | doi=10.1161/01.CIR.0000122871.86662.72 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15051664  }} </ref>
=== MRI ===
[[Magnetic Resonance Imaging|MRI]] can also be used for the diagnosis of venous thrombosis, however it is usually not applied as a first test because of cost and inaccessibility.
=== Other Imaging Findings ===
A number of invasive and non-invasive approaches are possible.<ref name="pmid17261857">{{cite journal| author=Snow V, Qaseem A, Barry P, Hornbake ER, Rodnick JE, Tobolic T et al.| title=Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. | journal=Ann Intern Med | year= 2007 | volume= 146 | issue= 3 | pages= 204-10 | pmid=17261857 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17261857  }} </ref>
=== Specific Situations ===
The approach to diagnosis of [[DVT]] may be modified in certain situations, where the suspicion is high or there is a recurrent episode. This chapter will discuss these modifications that have been recommended to the American College of Chest Physicians.<ref name="pmid22315267">{{cite journal |author=Bates SM, Jaeschke R, Stevens SM, ''et al.'' |title=Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines |journal=Chest |volume=141 |issue=2 Suppl |pages=e351S–418S |year=2012 |month=February |pmid=22315267 |doi=10.1378/chest.11-2299 |url=}}</ref>
== Treatment ==
=== Medical Therapy ===
An approach to the treatment of [[DVT]] has been described [[Deep vein thrombosis treatment algorithm|here]]. The primary purpose of treatment is to prevent the
further clot extension, acute [[pulmonary embolism]], recurrence of [[thrombosis]], prevention of late complications such as [[post-thrombotic syndrome]] and chronic thromboembolic [[pulmonary hypertension]].
=== Primary Prevention ===
Primary prevention includes the strategies that help to avoid the development of disease. Awareness of Deep venous thrombosis is the best way to prevent this condition.
=== Secondary Prevention ===
The U.S. Preventive Services Task Forces describes secondary prevention measures as those that identify and treat asymptomatic persons who have already developed risk factors or preclinical disease but in whom the condition is not clinically apparent. [[Clinical practice guidelines]] by the American College of Chest Physicians (ACCP) provide recommendations on DVT prophylaxis in hospitalized patients.<ref name="pmid15383478">Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
Chest. 2004 Sep;126 (3 Suppl):338S-400S. http://www.chestjournal.org/cgi/content/full/126/3_suppl/338S PMID 15383478</ref>
=== Landmark Trials ===
Landmark trials have compared different formulations and routes of antithrombin administration to treat and prevent deep vein thrombosis.


==References==
==References==
{{reflist|2}}
{{reflist|2}}


[[Category:Disease]]
[[Category:Cardiology]]
[[Category:Hematology]]
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[[Category:Cardiology]]
[[Category:Emergency medicine]]
[[Category:Emergency medicine]]
[[Category:Mature chapter]]
[[Category:Vascular surgery]]
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[[Category:Cardiovascular diseases]]


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Latest revision as of 16:45, 14 July 2017

https://https://www.youtube.com/watch?v=mMEdNCdUeAE%7C350}}


Resident
Survival
Guide

Editor(s)-In-Chief: The APEX Trial Investigators, C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] ;Kashish Goel, M.D.; Assistant Editor(s)-In-Chief: Justine Cadet

Deep Vein Thrombosis Microchapters

Home

Patient Information

Overview

Classification

Pathophysiology

Causes

Differentiating Deep vein thrombosis from other Diseases

Epidemiology and Demographics

Risk Factors

Triggers

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Approach

Assessment of Clinical Probability and Risk Scores

Assessment of Probability of Subsequent VTE and Risk Scores

History and Symptoms

Physical Examination

Laboratory Findings

Ultrasound

Venography

CT

MRI

Other Imaging Findings

Treatment

Treatment Approach

Medical Therapy

IVC Filter

Invasive Therapy

Surgery

Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Special Scenario

Upper extremity DVT

Recurrence

Pregnancy

Trials

Landmark Trials

Case Studies

Case #1

Deep vein thrombosis overview On the Web

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Most cited articles

Review articles

CME Programs

Powerpoint slides

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Ongoing Trials at Clinical Trials.gov

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NICE Guidance

FDA on Deep vein thrombosis overview

CDC on Deep vein thrombosis overview

Deep vein thrombosis overview in the news

Blogs on Deep vein thrombosis overview

Directions to Hospitals Treating Deep vein thrombosis

Risk calculators and risk factors for Deep vein thrombosis overview

Overview

Deep vein thrombosis (also known as deep venous thrombosis or DVT and colloquially referred to as economy class syndrome) is the formation of a blood clot ("thrombus") in a deep vein. The risk is significantly increased if the thrombus embolizes to the lungs, causing pulmonary embolism. Occasionally, veins in the arm are also affected (known as Paget-Schrötter disease). Upper extremity DVT is less common but also may lead to PE, especially in the presence of a venous catheter.[1] Thrombophlebitis is swelling (inflammation) of a vein caused by a blood clot. Venous thromboembolism (VTE) is a hypernym which includes Deep venous thrombosis (DVT) and pulmonary embolism (PE). It is a major public health problem and one of the most common cause of preventable cause of death in hospital patients. It is the third most common cardiovascular disorder after coronary artery disease and stroke. It is frequently underestimated and misdiagnosed and failure to provide adequate prophylaxis and therapy can be fatal for the patient.

Classification

Deep vein thrombosis (DVT) is classified based on the site of occlusion or clot formation. Symptom presentation and complication is largely influenced by location of the embolus.

Pathophysiology

Venous thrombosis is composed of three mechanisms, collectively described as the Virchow's triad: 1. Alterations in blood flow (stasis): Venous stasis is a major risk factor for the development of thrombosis. It occurs in certain pathological conditions (as in heart failure) wherein it causes an increase in platelet to endothelium contact and decreases the dilution of clotting factors. This increases the risk of clot formation, and it forms microthrombi, which further grow and propagate. 2. Injury to the vascular endothelium (Endothelial dysfunction): Intrinsic or secondary to external trauma, such as catheterization, can cause intimal damage and stimulate clot formation. 3. Alterations in the constitution of blood (Hypercoagulability): Abnormal changes in coagulation can increase the propensity to develop thrombosis.

Differentiating Deep Vein Thrombosis from Other Diseases

Only 25% of the patient evaluated for deep vein thrombosis (DVT) have the disease.[2] DVT is characterized by pain and swelling of the limb, which is not specific. Numerous patients with DVT are asymptomatic.

Epidemiology and Demographics

In the United States, approximately 350,000 to 600,000 new cases of venous thromboembolism are diagnosed each year. The incidence of deep vein thrombosis is estimated to be 100 cases per 100,000 persons per year. Deep vein thrombosis accounts for two-thirds of all venous thromboembolism cases. Mortality and complications from deep vein thrombosis are high: one-third of the patients develop post-thrombotic syndrome and another 30% have recurrent DVT within 10 years. In the United States, deep vein thrombosis accounts for approximately 100,000 deaths each year.

Risk Factors

The identification and minimization of risk factors is important in the management of DVT. The duration of anticoagulation is guided by the presence of thrombophilic risk factors.

Natural History, Complications and Prognosis

Thrombus formation typically begins in the calf veins and naturally progresses to the proximal veins and ultimately, breaks free from the site formation and travels to the pulmonary artery where it is called a pulmonary embolism. In many cases, patients with a thrombus can be asymptomatic until it progresses into the proximal veins.

Diagnosis

Pretest Probability

In a patient with suspected DVT, establishing pre-test probability helps in early risk stratification and appropriate use of laboratory tests and imaging modalities. Many pretest probability scoring systems are proposed for use in primary care patients, like the Wells score, Hamilton score , and AMUSE score. [3][4] When combined with pretest probability, ultrasonography and D-dimer tests are most useful in a diagnosis for DVT.

History and Symptoms

A proper history and physical exam is very important for establishing an accurate diagnosis of DVT or VTE. One of the first steps in the management of DVT is the determination of the Wells score for DVT. Out of the 10 clinical questions in the score, 9 can be ascertained solely on the basis of history and physical exam. This underscores the importance of these variables. A high index of suspicion is also necessary to diagnose DVT.

Physical Examination

The physical examination may be completely normal in patients with DVT. A high degree of suspicion is necessary for early identification of venous thrombosis, as sometimes these patients are admitted with a different complaint and a thorough physical exam gives a clue to the diagnosis.

Laboratory Findings

The lifetime incidence of DVT ranges from 2-5% in the general population. It accounts for a large number of ER visits and puts the patient at-risk for a life-threatening pulmonary embolism. The use of D-dimer after assessment of pre-test probability has been widely validated now and has led to a significant reduction in unnecessary procedures in the ER and hospital settings. This chapter will review the role of D-dimer in diagnosis of DVT. For a detailed discussion on D-dimer, please visit D-dimer.

Ultrasound

Venous ultrasound is the confirmatory test for diagnosis of DVT. The most common form is compression ultrasonography, which assesses the compressibility of femoral and popliteal veins. Diagnosis of DVT is established if the vein can not be collapsed under gentle ultrasound probe pressure. In most cases, it is performed in the proximal veins, as the risk of pulmonary embolism is much higher with that. Whole-leg ultrasound examines the deep veins of the proximal leg and calf, and it is used in cases where distal DVT is suspected. Iliac vein ultrasound may be performed, if thrombosis is suspected (e.g.: Pregnant women with swelling of the whole leg).

Venography

Venography is the "gold standard" to diagnose venous thrombosis, however it is not the preferred test in clinical settings. It includes injection of contrast into the dorsal foot vein and checking for a intraluminal filling defect that is present in more than one view.

CT

Venous thrombosis in the proximal deep veins is responsible for more than 90% of the pulmonary embolisms. Some of the investigators have suggested combined use of CT PE protocol and CT scan venography in cases of suspected DVT and PE.[5]

MRI

MRI can also be used for the diagnosis of venous thrombosis, however it is usually not applied as a first test because of cost and inaccessibility.

Other Imaging Findings

A number of invasive and non-invasive approaches are possible.[6]

Specific Situations

The approach to diagnosis of DVT may be modified in certain situations, where the suspicion is high or there is a recurrent episode. This chapter will discuss these modifications that have been recommended to the American College of Chest Physicians.[7]

Treatment

Medical Therapy

An approach to the treatment of DVT has been described here. The primary purpose of treatment is to prevent the further clot extension, acute pulmonary embolism, recurrence of thrombosis, prevention of late complications such as post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension.

Primary Prevention

Primary prevention includes the strategies that help to avoid the development of disease. Awareness of Deep venous thrombosis is the best way to prevent this condition.

Secondary Prevention

The U.S. Preventive Services Task Forces describes secondary prevention measures as those that identify and treat asymptomatic persons who have already developed risk factors or preclinical disease but in whom the condition is not clinically apparent. Clinical practice guidelines by the American College of Chest Physicians (ACCP) provide recommendations on DVT prophylaxis in hospitalized patients.[8]

Landmark Trials

Landmark trials have compared different formulations and routes of antithrombin administration to treat and prevent deep vein thrombosis.

References

  1. Ramzi DW, Leeper KV (2004). "DVT and pulmonary embolism: Part I. Diagnosis". Am Fam Physician. 69 (12): 2829–36. PMID 15222648.
  2. Huisman MV, Büller HR, ten Cate JW, Vreeken J (1986). "Serial impedance plethysmography for suspected deep venous thrombosis in outpatients. The Amsterdam General Practitioner Study". N Engl J Med. 314 (13): 823–8. doi:10.1056/NEJM198603273141305. PMID 3951515.
  3. Subramaniam RM, Chou T, Heath R, Allen R (2006). "Importance of pretest probability score and D-dimer assay before sonography for lower limb deep venous thrombosis". AJR Am J Roentgenol. 186 (1): 206–12. doi:10.2214/AJR.04.1398. PMID 16357403. Retrieved 2011-12-22. Unknown parameter |month= ignored (help)
  4. van der Velde EF, Toll DB, Ten Cate-Hoek AJ, Oudega R, Stoffers HE, Bossuyt PM, Büller HR, Prins MH, Hoes AW, Moons KG, van Weert HC (2011). "Comparing the diagnostic performance of 2 clinical decision rules to rule out deep vein thrombosis in primary care patients". Ann Fam Med. 9 (1): 31–6. doi:10.1370/afm.1198. PMC 3022042. PMID 21242558. Retrieved 2011-12-22.
  5. Kanne JP, Lalani TA (2004). "Role of computed tomography and magnetic resonance imaging for deep venous thrombosis and pulmonary embolism". Circulation. 109 (12 Suppl 1): I15–21. doi:10.1161/01.CIR.0000122871.86662.72. PMID 15051664.
  6. Snow V, Qaseem A, Barry P, Hornbake ER, Rodnick JE, Tobolic T; et al. (2007). "Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians". Ann Intern Med. 146 (3): 204–10. PMID 17261857.
  7. Bates SM, Jaeschke R, Stevens SM; et al. (2012). "Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e351S–418S. doi:10.1378/chest.11-2299. PMID 22315267. Unknown parameter |month= ignored (help)
  8. Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126 (3 Suppl):338S-400S. http://www.chestjournal.org/cgi/content/full/126/3_suppl/338S PMID 15383478

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