Deep vein thrombosis natural history, complications and prognosis: Difference between revisions

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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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| [[File:Siren.gif|30px|link=Deep vein thrombosis resident survival guide]]|| <br> || <br>
| [[Deep vein thrombosis resident survival guide|'''Resident'''<br>'''Survival'''<br>'''Guide''']]
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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}}
 
==Overview==
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.
 
==Natural History==
* Many patients with a [[deep vein thrombosis]] (DVT) originating in the calf veins are asymptomatic until proximal vein involvement.<ref name="pmid12814982">{{cite journal |author=Kearon C |title=Natural history of venous thromboembolism |journal=[[Circulation]] |volume=107 |issue=23 Suppl 1 |pages=I22–30 |year=2003 |month=June |pmid=12814982 |doi=10.1161/01.CIR.0000078464.82671.78 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12814982 |issn=}}</ref> However, even assymptomatic DVTs are associated with increased risk of death<ref name="pmid30419597">{{cite journal| author=Kalayci A, Gibson CM, Chi G, Yee MK, Korjian S, Datta S et al.| title=Asymptomatic Deep Vein Thrombosis is Associated with an Increased Risk of Death: Insights from the APEX Trial. | journal=Thromb Haemost | year= 2018 | volume= 118 | issue= 12 | pages= 2046-2052 | pmid=30419597 | doi=10.1055/s-0038-1675606 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30419597  }} </ref>.
* About half of all calf DVTs resolve spontaneously, without intervention.<ref name="pmid12814982">{{cite journal |author=Kearon C |title=Natural history of venous thromboembolism |journal=[[Circulation]] |volume=107 |issue=23 Suppl 1 |pages=I22–30 |year=2003 |month=June |pmid=12814982 |doi=10.1161/01.CIR.0000078464.82671.78 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12814982 |issn=}}</ref>
* One-sixth of all calf DVTs progress to involvement with the proximal veins.<ref name="pmid12814982">{{cite journal |author=Kearon C |title=Natural history of venous thromboembolism |journal=[[Circulation]] |volume=107 |issue=23 Suppl 1 |pages=I22–30 |year=2003 |month=June |pmid=12814982 |doi=10.1161/01.CIR.0000078464.82671.78 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12814982 |issn=}}</ref>
* Typical onset of thrombus formation may occur during the intraoperative period though there is a potential latent onset up to many months after the initial surgery.<ref name="pmid12814982">{{cite journal |author=Kearon C |title=Natural history of venous thromboembolism |journal=[[Circulation]] |volume=107 |issue=23 Suppl 1 |pages=I22–30 |year=2003 |month=June |pmid=12814982 |doi=10.1161/01.CIR.0000078464.82671.78 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12814982 |issn=}}</ref>
* Surgeries characteristically responsible for thrombus formation include:
** [[Hip replacement]]
** [[Knee replacement]]
* Knee replacement surgery is associated with twice the frequency of asymptomatic onset.<ref name="pmid12814982">{{cite journal |author=Kearon C |title=Natural history of venous thromboembolism |journal=[[Circulation]] |volume=107 |issue=23 Suppl 1 |pages=I22–30 |year=2003 |month=June |pmid=12814982 |doi=10.1161/01.CIR.0000078464.82671.78 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12814982 |issn=}}</ref>
* Without treatment, one-fourth to one-third of symptomatic, isolated distal thrombi in the deep veins involve proximal veins.<ref name="pmid12814982">{{cite journal |author=Kearon C |title=Natural history of venous thromboembolism |journal=[[Circulation]] |volume=107 |issue=23 Suppl 1 |pages=I22–30 |year=2003 |month=June |pmid=12814982 |doi=10.1161/01.CIR.0000078464.82671.78 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12814982 |issn=}}</ref>
** Patients with isolated calf DVT treated with five days of heparin therapy without a tandem oral anticoagulant therapy were at highest risk for recurrent or extension of DVT within three months of follow-up.<ref name="pmid12814982">{{cite journal |author=Kearon C |title=Natural history of venous thromboembolism |journal=[[Circulation]] |volume=107 |issue=23 Suppl 1 |pages=I22–30 |year=2003 |month=June |pmid=12814982 |doi=10.1161/01.CIR.0000078464.82671.78 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12814982 |issn=}}</ref>
*Patients with untreated DVT have the potential to develop:
** [[Post-thrombotic syndrome|Post-phlebitic syndrome]] (occurs in 10-30% of all DVT cases)
** Pain
** [[Edema]]
** Skin discoloration
** Venous ulcers (10% of the cases)
** [[Chronic venous insufficiency]]
* Mortality rates associated with venous thrombosis can be very high.
** In one study, 6% of patients with DVT died within one month of diagnosis.<ref name="pmid12814979">{{cite journal| author=White RH| title=The epidemiology of venous thromboembolism. | journal=Circulation | year= 2003 | volume= 107 | issue= 23 Suppl 1 | pages= I4-8 | pmid=12814979 | doi=10.1161/01.CIR.0000078468.11849.66 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12814979  }} </ref>
** Other research suggests that approximately one-fourth of all patients die within one year of venous thrombosis onset.<ref name="pmid12814982">{{cite journal |author=Kearon C |title=Natural history of venous thromboembolism |journal=[[Circulation]] |volume=107 |issue=23 Suppl 1 |pages=I22–30 |year=2003 |month=June |pmid=12814982 |doi=10.1161/01.CIR.0000078464.82671.78 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12814982 |issn=}}</ref>
** Patients presenting with a venous thrombosis consistently have higher in-hospital mortality rates.<ref name="pmid12814982">{{cite journal |author=Kearon C |title=Natural history of venous thromboembolism |journal=[[Circulation]] |volume=107 |issue=23 Suppl 1 |pages=I22–30 |year=2003 |month=June |pmid=12814982 |doi=10.1161/01.CIR.0000078464.82671.78 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12814982 |issn=}}</ref>
'''Rule of 30's'''
* 30% will die in 30 days.
* 30% will have recurrence in 10 years. The actual number at 10 years has been reported to be 36%<ref name="pmid31340984">{{cite journal| author=Khan F, Rahman A, Carrier M, Kearon C, Weitz JI, Schulman S et al.| title=Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis. | journal=BMJ | year= 2019 | volume= 366 | issue=  | pages= l4363 | pmid=31340984 | doi=10.1136/bmj.l4363 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31340984  }} </ref>
* 30% will develop [[post phlebitic syndrome]].
 
==Complications==
Venous thrombosis may lead to any of the following major complications:
* Recurrence may occur unevenly across the sexes; with men being almost four times more likely than women for a venous thrombosis recurrence.<ref name="pmid15201412">{{cite journal| author=Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S| title=The risk of recurrent venous thromboembolism in men and women. | journal=N Engl J Med | year= 2004 | volume= 350 | issue= 25 | pages= 2558-63 | pmid=15201412 | doi=10.1056/NEJMoa032959 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15201412  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15518462 Review in: ACP J Club. 2004 Nov-Dec;141(3):78] </ref>
* Major bleeding due to [[anticoagulation]]
* Death - Proximal vein thrombosis is responsible for more than ninety percent of [[Pulmonary embolism|acute pulmonary emboli]]. Acute PE is ultimately associated with a high mortality if not treated promptly. <ref name="pmid19718469">{{cite journal |author=Galanaud JP, Sevestre-Pietri MA, Bosson JL, Laroche JP, Righini M, Brisot D, Boge G, van Kien AK, Gattolliat O, Bettarel-Binon C, Gris JC, Genty C, Quere I |title=Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study |journal=Thromb. Haemost. |volume=102 |issue=3 |pages=493–500 |year=2009 |month=September|pmid=19718469 |doi=10.1160/TH09-01-0053 |url=http://www.schattauer.de/index.php?id=1268&L=1&pii=th09-01-0053&no_cache=1|accessdate=2011-12-14}}</ref>
 
Other complications include:
* [[Post-thrombotic syndrome]]
* [[Phlegmasia alba dolens]]
* [[Phlegmasia cerulea dolens]]
* [[Lemierre syndrome]]
* Septic pelvic thrombophlebitis
 
* Impairment of the quality of life might occur especially when [[post-thrombotic syndrome]] occurs.<ref name="pmid15911732">{{cite journal| author=Kahn SR, Ducruet T, Lamping DL, Arsenault L, Miron MJ, Roussin A et al.| title=Prospective evaluation of health-related quality of life in patients with deep venous thrombosis. | journal=Arch Intern Med | year= 2005 | volume= 165 | issue= 10 | pages= 1173-8 | pmid=15911732 | doi=10.1001/archinte.165.10.1173 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15911732  }} </ref>
 
The rate of complications in lower extremity DVT is higher from that in upper extremity DVT.  Shown below is a table summarizing the differences in the rate of occurrence of complications.<ref name="pmid21366477">{{cite journal| author=Kucher N| title=Clinical practice. Deep-vein thrombosis of the upper extremities. | journal=N Engl J Med | year= 2011 | volume= 364 | issue= 9 | pages= 861-9 | pmid=21366477 | doi=10.1056/NEJMcp1008740 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21366477  }} </ref>
 
{|
|-
| style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF;" align=center | '''Complications''' ||style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF;" align=center | '''Upper extremity DVT'''|| style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF;" align=center |'''Lower extremity DVT'''
|-
|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |[[Pulmonary embolism]] || style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |6% || style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |15-32%
|-
|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |Recurrence of DVT ||style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left | 2-5% || style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |10%
|-
| style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |Post thrombotic syndrome || style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |5% || style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |56%
|}
 
==Prognosis==
Probability of recurrence can be estimated with the HERDOO2 rule:<ref name="pmid28314711">{{cite journal| author=Rodger MA, Le Gal G, Anderson DR, Schmidt J, Pernod G, Kahn SR et al.| title=Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study. | journal=BMJ | year= 2017 | volume= 356 | issue=  | pages= j1065 | pmid=28314711 | doi=10.1136/bmj.j1065 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28314711  }} </ref>


{{Deep vein thrombosis}}
* '''H'''yperpigmentation
===Probability scoring===
* '''E'''dema
In 2006, Scarvelis and Wells overviewed a set of [[clinical prediction rule]]s for DVT,<ref>{{cite journal | author = Scarvelis D, Wells P | title = Diagnosis and treatment of deep-vein thrombosis. | journal = CMAJ | volume = 175 | issue = 9 | pages = 1087-92 | year = 2006 | id = PMID 17060659. [http://www.cmaj.ca/cgi/content/full/175/9/1087 Free Full Text] }}</ref> on the heels of a widely adopted set of clinical criteria for pulmonary embolism.<ref>Neff MJ. ACEP releases clinical policy on evaluation and management of pulmonary embolism. ''American Family Physician''. 2003; '''68'''(4):759-?.  Available at: [http://www.aafp.org/afp/20030815/practice.html http://www.aafp.org/afp/20030815/practice.html]. Accessed on: December 8, 2006.</ref><ref>{{cite journal | author = Wells P, Anderson D, Rodger M, Ginsberg J, Kearon C, Gent M, Turpie A, Bormanis J, Weitz J, Chamberlain M, Bowie D, Barnes D, Hirsh J | title = Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. | journal = Thromb Haemost | volume = 83 | issue = 3 | pages = 416-20 | year = 2000 | id = PMID 10744147}}</ref>
* '''R'''edness in either leg
* '''D'''-dimer level ≥250 μg/L
* '''O'''besity with body mass index ≥30
* '''O'''lder age, ≥65 years


===Wells score or criteria===
Per the authors, "Women with a first unprovoked VTE event and none or one of the HERDOO2 criteria have a low risk of recurrent VTE and can safely discontinue anticoagulants after completing short term treatment."<ref name="pmid28314711"/>
(Possible score -2 to 9)


:1) Active cancer (treatment within last 6 months or palliative) -- 1 point
==References==
:2) Calf swelling >3 cm compared to other calf (measured 10 cm below tibial tuberosity) -- 1 point
{{reflist|2}}
:3) Collateral superficial veins (non-varicose) -- 1 point
:4) Pitting edema (confined to symptomatic leg) -- 1 point
:5) Swelling of entire leg - 1 point
:6) Localized pain along distribution of deep venous system -- 1 point
:7) Paralysis, paresis, or recent cast immobilization of lower extremities -- 1 point
:8) Recently bedridden > 3 days, or major surgery requiring regional or general anesthetic in past 12 weeks -- 1 point
:9) Previously documented DVT -- 1 point
:10) Alternative diagnosis at least as likely -- Subtract 2 points


===Interpretation===
: Score of 2 or higher - deep vein thrombosis is likely. Consider imaging the leg veins.
: Score of less than 2 - deep vein thrombosis is unlikely. Consider blood test such as [[d-dimer]] test to further rule out deep vein thrombosis.


[[Category:Disease]]
[[Category:Cardiology]]
[[Category:Hematology]]
[[Category:Hematology]]
[[Category:Pulmonology]]
[[Category:Angiology]]
[[Category:Cardiology]]
[[Category:Emergency medicine]]
[[Category:Emergency medicine]]
[[Category:Mature chapter]]
[[Category:Vascular surgery]]
[[Category:Up-To-Date]]
[[Category:Cardiovascular diseases]]


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Latest revision as of 12:21, 26 July 2019
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

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Case #1

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Directions to Hospitals Treating Deep vein thrombosis

Risk calculators and risk factors for Deep vein thrombosis natural history, complications and prognosis

Overview

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.

Natural History

  • Many patients with a deep vein thrombosis (DVT) originating in the calf veins are asymptomatic until proximal vein involvement.[1] However, even assymptomatic DVTs are associated with increased risk of death[2].
  • About half of all calf DVTs resolve spontaneously, without intervention.[1]
  • One-sixth of all calf DVTs progress to involvement with the proximal veins.[1]
  • Typical onset of thrombus formation may occur during the intraoperative period though there is a potential latent onset up to many months after the initial surgery.[1]
  • Surgeries characteristically responsible for thrombus formation include:
  • Knee replacement surgery is associated with twice the frequency of asymptomatic onset.[1]
  • Without treatment, one-fourth to one-third of symptomatic, isolated distal thrombi in the deep veins involve proximal veins.[1]
    • Patients with isolated calf DVT treated with five days of heparin therapy without a tandem oral anticoagulant therapy were at highest risk for recurrent or extension of DVT within three months of follow-up.[1]
  • Patients with untreated DVT have the potential to develop:
  • Mortality rates associated with venous thrombosis can be very high.
    • In one study, 6% of patients with DVT died within one month of diagnosis.[3]
    • Other research suggests that approximately one-fourth of all patients die within one year of venous thrombosis onset.[1]
    • Patients presenting with a venous thrombosis consistently have higher in-hospital mortality rates.[1]

Rule of 30's

  • 30% will die in 30 days.
  • 30% will have recurrence in 10 years. The actual number at 10 years has been reported to be 36%[4]
  • 30% will develop post phlebitic syndrome.

Complications

Venous thrombosis may lead to any of the following major complications:

  • Recurrence may occur unevenly across the sexes; with men being almost four times more likely than women for a venous thrombosis recurrence.[5]
  • Major bleeding due to anticoagulation
  • Death - Proximal vein thrombosis is responsible for more than ninety percent of acute pulmonary emboli. Acute PE is ultimately associated with a high mortality if not treated promptly. [6]

Other complications include:

The rate of complications in lower extremity DVT is higher from that in upper extremity DVT. Shown below is a table summarizing the differences in the rate of occurrence of complications.[8]

Complications Upper extremity DVT Lower extremity DVT
Pulmonary embolism 6% 15-32%
Recurrence of DVT 2-5% 10%
Post thrombotic syndrome 5% 56%

Prognosis

Probability of recurrence can be estimated with the HERDOO2 rule:[9]

  • Hyperpigmentation
  • Edema
  • Redness in either leg
  • D-dimer level ≥250 μg/L
  • Obesity with body mass index ≥30
  • Older age, ≥65 years

Per the authors, "Women with a first unprovoked VTE event and none or one of the HERDOO2 criteria have a low risk of recurrent VTE and can safely discontinue anticoagulants after completing short term treatment."[9]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Kearon C (2003). "Natural history of venous thromboembolism". Circulation. 107 (23 Suppl 1): I22–30. doi:10.1161/01.CIR.0000078464.82671.78. PMID 12814982. Unknown parameter |month= ignored (help)
  2. ↑ Kalayci A, Gibson CM, Chi G, Yee MK, Korjian S, Datta S; et al. (2018). "Asymptomatic Deep Vein Thrombosis is Associated with an Increased Risk of Death: Insights from the APEX Trial". Thromb Haemost. 118 (12): 2046–2052. doi:10.1055/s-0038-1675606. PMID 30419597.
  3. ↑ White RH (2003). "The epidemiology of venous thromboembolism". Circulation. 107 (23 Suppl 1): I4–8. doi:10.1161/01.CIR.0000078468.11849.66. PMID 12814979.
  4. ↑ Khan F, Rahman A, Carrier M, Kearon C, Weitz JI, Schulman S; et al. (2019). "Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis". BMJ. 366: l4363. doi:10.1136/bmj.l4363. PMID 31340984.
  5. ↑ Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S (2004). "The risk of recurrent venous thromboembolism in men and women". N Engl J Med. 350 (25): 2558–63. doi:10.1056/NEJMoa032959. PMID 15201412. Review in: ACP J Club. 2004 Nov-Dec;141(3):78
  6. ↑ Galanaud JP, Sevestre-Pietri MA, Bosson JL, Laroche JP, Righini M, Brisot D, Boge G, van Kien AK, Gattolliat O, Bettarel-Binon C, Gris JC, Genty C, Quere I (2009). "Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study". Thromb. Haemost. 102 (3): 493–500. doi:10.1160/TH09-01-0053. PMID 19718469. Retrieved 2011-12-14. Unknown parameter |month= ignored (help)
  7. ↑ Kahn SR, Ducruet T, Lamping DL, Arsenault L, Miron MJ, Roussin A; et al. (2005). "Prospective evaluation of health-related quality of life in patients with deep venous thrombosis". Arch Intern Med. 165 (10): 1173–8. doi:10.1001/archinte.165.10.1173. PMID 15911732.
  8. ↑ Kucher N (2011). "Clinical practice. Deep-vein thrombosis of the upper extremities". N Engl J Med. 364 (9): 861–9. doi:10.1056/NEJMcp1008740. PMID 21366477.
  9. ↑ 9.0 9.1 Rodger MA, Le Gal G, Anderson DR, Schmidt J, Pernod G, Kahn SR; et al. (2017). "Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study". BMJ. 356: j1065. doi:10.1136/bmj.j1065. PMID 28314711.

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