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'''Editor(s)-In-Chief:''' [[C. Michael Gibson, M.S., M.D.]] [mailto:charlesmichaelgibson@gmail.com], {{ATI}}; {{AE}}
'''Editor(s)-In-Chief:''' [[C. Michael Gibson, M.S., M.D.]] [mailto:charlesmichaelgibson@gmail.com], {{ATI}}; {{AE}}
==Overview==
==Overview==
The most common sources of pulmonary emboli are proximal leg [[deep venous thrombosis|deep venous thromboses]] ([[DVT]]s) or pelvic vein thromboses. Any risk factor for [[DVT]] also increases the risk of pulmonary embolism, and therefore DVT and PE are considered to be a continuum termed [[venous thromboembolism]] ([[VTE]]). Approximately 15% of patients with a DVT will develop a pulmonary embolus.  Smoking, estrogen-containing hormonal contraceptives, and immobilization (including long distance travel) are common risk factors.
The most common sources of pulmonary emboli are proximal leg [[deep venous thrombosis|deep venous thromboses]] ([[DVT]]s) or pelvic vein thromboses. Any risk factor for [[DVT]] also increases the risk of pulmonary embolism, and therefore DVT and PE are considered to be a continuum termed [[venous thromboembolism]] ([[VTE]]). Approximately 15% of patients with a DVT will develop a pulmonary embolus.  In these chapters on VTE, the word risk factors refers to those epidemiologic and genetic variables that expose someone to a higher risk of developing [[venous thrombosis]].  The word triggers refer to those factors in the patients immediate history or environment that may have lead to the occurrence of the [[venous thrombosis]].  The risk factors for VTE are a constellation of predisposing conditions which stem from the three principles of [[Virchow's triad]]: stasis of the blood flow, damage to the vascular [[endothelial cell]]s, and [[hypercoagulability]].  The risk factors for VTE can be classified as temporary, modifiable and non-modifiable.  It is suggested that [[venous thrombosis]] also shares risk factors with [[arterial thrombosis]], such as [[obesity]], [[hypertension]], [[smoking]], and [[diabetes mellitus]].<ref name="pmid20620709">{{cite journal| author=Goldhaber SZ| title=Risk factors for venous thromboembolism. | journal=J Am Coll Cardiol | year= 2010 | volume= 56 | issue= 1 | pages= 1-7 | pmid=20620709 | doi=10.1016/j.jacc.2010.01.057 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20620709  }} </ref>


==Risk Factors==
==Risk Factors==
The development of thrombosis is classically due to a group of causes referred to as [[Virchow's triad]]. Virchow's triad includes alterations in [[blood flow]], factors in the vessel wall, and factors affecting the properties of the [[blood]]. It is common for more than one risk factor to be present.


[[File:VTE Pathophysisology Virchow's triad.JPG|300x400px]]
Shown below is a list of predisposing factors to [[VTE]].<ref name="pmid12814980">{{cite journal| author=Anderson FA, Spencer FA| title=Risk factors for venous thromboembolism. | journal=Circulation | year= 2003 | volume= 107 | issue= 23 Suppl 1 | pages= I9-16 | pmid=12814980 | doi=10.1161/01.CIR.0000078469.07362.E6 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12814980  }} </ref><ref name="pmid18757870">{{cite journal| author=Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P et al.| title=Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). | journal=Eur Heart J | year= 2008 | volume= 29 | issue= 18 | pages= 2276-315 | pmid=18757870 | doi=10.1093/eurheartj/ehn310 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18757870  }} </ref> The risk factors are classified as moderate or weak depending on how strongly they predispose for a VTE.


'''Figure''': Virchow's triad encompasses three broad categories of factors that are thought to contribute to venous thrombosis.
{| style="cellpadding=0; cellspacing= 0; width: 600px;"
|-
| style="padding: 0 5px; font-size: 100%; background: #F5F5F5;" align=center |'''Moderate risk factors''' || style="padding: 0 5px; font-size: 100%; background: #F5F5F5;" align=center |'''Weak risk factors'''
|-
|  style="font-size: 90%; padding: 0 5px; background: #DCDCDC" align=left |❑ [[Chemotherapy]]<br>
❑ [[Chronic heart failure]]<br>
❑ [[Respiratory failure]]<br>
❑ [[Hormone replacement therapy]]<br>
❑ [[Cancer]]<br>
❑ [[Oral contraceptive pills]] <br>
❑ [[Stroke]] <br>
❑ [[Pregnancy]] <br>
❑ [[Postpartum]] <br>
❑ Prior history of [[VTE]] <br>
❑ [[Thrombophilia]] <br>
| style="font-size: 90%; padding: 0 5px; background: #DCDCDC" align=left |❑ Advanced [[age]] <br>
❑ [[Laparoscopic surgery]] <br>
❑ Prepartum <br>
❑ [[Obesity]] <br>
❑ [[Varicose veins]]
|}


Medical conditions included in the triad are:
The risk factors of VTE can be further classified into modifiable, non-modifiable and temporary.
* '''Alterations in Blood Flow''': Alterations in blood flow can be caused by some of the following conditions:
**[[Pregnancy]] which is a [[pro-coagulant]]
**[[Obesity]] which is also a [[pro-coagulant]]
**Being immobile for long periods of time. The immobilizations include:
***After a [[surgery]]
***[[Physical trauma|Injury]]
***[[Economy class syndrome|Long-distance air travel]]
* '''Factors in the Vessel Wall''':
** This is of limited direct relevance in VTE
* '''Factors Affecting the Properties of the Blood''' (pro-coagulant state):
** [[Estrogen]]-containing [[hormonal contraception]]
** Genetic [[thrombophilias]] which include:
***[[Factor V Leiden]]
***[[Prothrombin]] mutation G20210A
***[[Protein C deficiency]]
***[[protein S deficiency]]
***[[Antithrombin]] deficiency
***[[Hyperhomocysteinemia]]
***[[Plasminogen]]/[[Fibrinolysis]] disorders
** Acquired thrombophilias which include:
***[[Antiphospholipid syndrome]]
***[[Nephrotic syndrome]]
***[[Paroxysmal nocturnal hemoglobinuria]]


=== Risk Factors Identified in the PIOPED Study<ref name="pmid8523135">{{cite journal| author=Worsley DF, Alavi A| title=Comprehensive analysis of the results of the PIOPED Study. Prospective Investigation of Pulmonary Embolism Diagnosis Study. | journal=J Nucl Med | year= 1995 | volume= 36 | issue= 12 | pages= 2380-7 | pmid=8523135 | doi= | pmc= | url= }} </ref> ===
===Modifiable Risk Factors===
Modifiable risk factors are reversible based upon lifestyle/behavior modification.
* Obesity: [[Obesity]] is defined as a body-mass index (BMI) above 30 kg/m2.<ref name="pmid20404252">{{cite journal| author=Holst AG, Jensen G, Prescott E| title=Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study. | journal=Circulation | year= 2010 | volume= 121 | issue= 17 | pages= 1896-903 | pmid=20404252 | doi=10.1161/CIRCULATIONAHA.109.921460 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20404252  }} </ref> <ref name="pmid21352080">{{cite journal| author=Vayá A, Martínez-Triguero ML, España F, Todolí JA, Bonet E, Corella D| title=The metabolic syndrome and its individual components: its association with venous thromboembolism in a Mediterranean population. | journal=Metab Syndr Relat Disord | year= 2011 | volume= 9 | issue= 3 | pages= 197-201 | pmid=21352080 | doi=10.1089/met.2010.0117 | pmc= | url= }} </ref> <ref name="pmid18695082">{{cite journal| author=Eichinger S, Hron G, Bialonczyk C, Hirschl M, Minar E, Wagner O et al.| title=Overweight, obesity, and the risk of recurrent venous thromboembolism. | journal=Arch Intern Med | year= 2008 | volume= 168 | issue= 15 | pages= 1678-83 | pmid=18695082 | doi=10.1001/archinte.168.15.1678 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18695082  }} </ref>


Independent risk factors identified in ''prospective investigation of pulmonary embolism diagnosis'' (PIOPED) include:
* [[Smoking]]:<ref name="pmid20404252">{{cite journal| author=Holst AG, Jensen G, Prescott E| title=Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study. | journal=Circulation | year= 2010 | volume= 121 | issue= 17 | pages= 1896-903 | pmid=20404252 | doi=10.1161/CIRCULATIONAHA.109.921460 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20404252  }} </ref> Smoking significantly increases the risk of [[DVT]], particularly among women who are taking [[oral contraceptive pills]] as well as among obese people.
* Immobilization, [[paresis]], or [[paralysis]]
 
**Travel of 4 hours or more in the past month would be considered an immobilization.
* Use of [[oral contraceptives]]<ref name="pmid17726684">{{cite journal| author=Pomp ER, Rosendaal FR, Doggen CJ| title=Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use. | journal=Am J Hematol | year= 2008 | volume= 83 | issue= 2 | pages= 97-102 | pmid=17726684 | doi=10.1002/ajh.21059 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17726684  }} </ref>
* Surgery within the last 3 months or having suffered a [[stroke]].
 
**These may have a connection to immobilization.
* [[Hyperhomocysteinemia]]:<ref name="pmid8592549">{{cite journal| author=den Heijer M, Koster T, Blom HJ, Bos GM, Briet E, Reitsma PH et al.| title=Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. | journal=N Engl J Med | year= 1996 | volume= 334 | issue= 12 | pages= 759-62 | pmid=8592549 | doi=10.1056/NEJM199603213341203 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8592549  }} </ref> [[Hyperhomocysteinemia]] can be reduced with vitamin B supplementation.
* History of [[venous thromboembolism]].
 
* Malignancies, especially [[lung cancer]].
===Non-Modifiable Risk Factors===
**Malignancies have been found in up to 17% of patients with an idiopathic [[deep vein thrombosis]] (DVT).
* Advanced age
* Current or past history of [[thrombophlebitis]].
* [[Trauma]] to the lower extremities or pelvis during the past 3 months.
* [[Smoking]]
* [[Central venous instrumentation]] within the past 3 months
* Prior pulmonary embolism
* [[Heart failure]]
* [[Heart failure]]
* [[Chronic obstructive pulmonary disease]]
* [[Thrombophilia]] or [[hypercoagulable state]]
** [[Factor V Leiden]]
** [[Prothrombin G20210A mutation]]
** [[Protein C deficiency]]
** [[Protein S deficiency]]
** [[Antithrombin deficiency]]
** [[Activated protein C resistance]]
** [[Antithrombin III deficiency]]
** [[Factor VIII]] mutation
** [[Antiphospholipid syndrome]]
** [[Heparin induced thrombocytopenia]]
** [[Nephrotic syndrome]]
** [[Paroxysmal nocturnal hemoglobinuria]]
* [[Polycythemia vera]]
 
===Temporary Risk Factors===
* [[Pregnancy]] and the peri-partum period
* Active [[cancer]]
* [[Central venous catheter]]
 
===Other Possible Risk Factors===
Other possible factors associated with VTE include:
* Nutrition low in fish<ref name="pmid20620109">{{cite journal| author=Konofal E, Lecendreux M, Cortese S| title=Sleep and ADHD. | journal=Sleep Med | year= 2010 | volume= 11 | issue= 7 | pages= 652-8 | pmid=20620109 | doi=10.1016/j.sleep.2010.02.012 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20620109  }} </ref>
* [[Psychological stress]]<ref name="pmid20620109">{{cite journal| author=Konofal E, Lecendreux M, Cortese S| title=Sleep and ADHD. | journal=Sleep Med | year= 2010 | volume= 11 | issue= 7 | pages= 652-8 | pmid=20620109 | doi=10.1016/j.sleep.2010.02.012 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20620109  }} </ref>
* Cardiovascular risk factors such as [[diabetes]] and [[hypercholesterolemia]]<ref name="pmid20620109">{{cite journal| author=Konofal E, Lecendreux M, Cortese S| title=Sleep and ADHD. | journal=Sleep Med | year= 2010 | volume= 11 | issue= 7 | pages= 652-8 | pmid=20620109 | doi=10.1016/j.sleep.2010.02.012 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20620109  }} </ref>
* Acute medical illness
* Drug abuse (intravenous [IV] drugs)
*[[Hemolytic anemias]]
*[[Dyslipidemia]]
*[[Inflammatory bowel disease]]
*[[Phenothiazines]]
*[[Thrombocytosis]]
*[[Varicose veins]]
*[[Venography]]
*[[Warfarin]] (first few days of therapy)


=== Risk Factors from the Nurse's Health Study<ref name="pmid9039882">{{cite journal| author=Goldhaber SZ, Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Speizer FE et al.| title=A prospective study of risk factors for pulmonary embolism in women. | journal=JAMA | year= 1997 | volume= 277 | issue= 8 | pages= 642-5 | pmid=9039882 | doi= | pmc= | url= }} </ref> ===
== Risk Factors from the Nurse's Health Study<ref name="pmid9039882">{{cite journal| author=Goldhaber SZ, Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Speizer FE et al.| title=A prospective study of risk factors for pulmonary embolism in women. | journal=JAMA | year= 1997 | volume= 277 | issue= 8 | pages= 642-5 | pmid=9039882 | doi= | pmc= | url= }} </ref> ==
* [[Obesity]]: RR (relative risk) 2.9
* [[Obesity]]: RR (relative risk) 2.9
* [[Smoking]]:
* [[Smoking]]:
Line 64: Line 91:
* [[Hormone replacement therapy]]: RR approximately 2
* [[Hormone replacement therapy]]: RR approximately 2


=== Risk Factors from the Physician's Health Study<ref name="pmid7877648">{{cite journal| author=Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP| title=Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. | journal=N Engl J Med | year= 1995 | volume= 332 | issue= 14 | pages= 912-7 | pmid=7877648 | doi=10.1056/NEJM199504063321403 | pmc= | url= }} </ref> ===
== Risk Factors from the Physician's Health Study<ref name="pmid7877648">{{cite journal| author=Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP| title=Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. | journal=N Engl J Med | year= 1995 | volume= 332 | issue= 14 | pages= 912-7 | pmid=7877648 | doi=10.1056/NEJM199504063321403 | pmc= | url= }} </ref> ==
* [[Anticardiolipin antibody]] level above the 95th percentile. <ref name="pmid1443986">{{cite journal| author=Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Schur PH, Hennekens CH et al.| title=Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. | journal=Ann Intern Med | year= 1992 | volume= 117 | issue= 12 | pages= 997-1002 | pmid=1443986 | doi= | pmc= | url= }} </ref>.
* [[Anticardiolipin antibody]] level above the 95th percentile. <ref name="pmid1443986">{{cite journal| author=Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Schur PH, Hennekens CH et al.| title=Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. | journal=Ann Intern Med | year= 1992 | volume= 117 | issue= 12 | pages= 997-1002 | pmid=1443986 | doi= | pmc= | url= }} </ref>.
* [[Factor V Leiden]]
* [[Factor V Leiden]]
Line 72: Line 99:
* Hyperhomocysteinemia in association with Factor V increases the risk of a DVT by about 10 times.
* Hyperhomocysteinemia in association with Factor V increases the risk of a DVT by about 10 times.
* [[Lupus anticoagulant]] was found in 8.5% of patients with idiopathic DVT.
* [[Lupus anticoagulant]] was found in 8.5% of patients with idiopathic DVT.
=== Other Risk Factors Include: ===
*[[Acute medical illness]]
*Drug abuse (intravenous [IV] drugs)
*[[Hemolytic anemias]]
*[[Homocystinuria]]
*[[Hypercoagulable states]], which can be caused by hereditary factors.
*[[Hyperlipidemias]]
*[[Inflammatory bowel disease]]
*[[Phenothiazines]]
*[[Pregnancy]]
*[[Thrombocytosis]]
*[[Varicose veins]]
*[[Venography]]
*[[Venous pacemakers]]
*[[Venous stasis]]
*[[Warfarin]] (first few days of therapy)


==References==
==References==

Revision as of 16:05, 2 June 2014

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Editor(s)-In-Chief: C. Michael Gibson, M.S., M.D. [1], The APEX Trial Investigators; Associate Editor(s)-in-Chief:

Overview

The most common sources of pulmonary emboli are proximal leg deep venous thromboses (DVTs) or pelvic vein thromboses. Any risk factor for DVT also increases the risk of pulmonary embolism, and therefore DVT and PE are considered to be a continuum termed venous thromboembolism (VTE). Approximately 15% of patients with a DVT will develop a pulmonary embolus. In these chapters on VTE, the word risk factors refers to those epidemiologic and genetic variables that expose someone to a higher risk of developing venous thrombosis. The word triggers refer to those factors in the patients immediate history or environment that may have lead to the occurrence of the venous thrombosis. The risk factors for VTE are a constellation of predisposing conditions which stem from the three principles of Virchow's triad: stasis of the blood flow, damage to the vascular endothelial cells, and hypercoagulability. The risk factors for VTE can be classified as temporary, modifiable and non-modifiable. It is suggested that venous thrombosis also shares risk factors with arterial thrombosis, such as obesity, hypertension, smoking, and diabetes mellitus.[1]

Risk Factors

Shown below is a list of predisposing factors to VTE.[2][3] The risk factors are classified as moderate or weak depending on how strongly they predispose for a VTE.

Moderate risk factors Weak risk factors
❑ Chemotherapy

❑ Chronic heart failure
❑ Respiratory failure
❑ Hormone replacement therapy
❑ Cancer
❑ Oral contraceptive pills
❑ Stroke
❑ Pregnancy
❑ Postpartum
❑ Prior history of VTE
❑ Thrombophilia

❑ Advanced age

❑ Laparoscopic surgery
❑ Prepartum
❑ Obesity
❑ Varicose veins

The risk factors of VTE can be further classified into modifiable, non-modifiable and temporary.

Modifiable Risk Factors

Modifiable risk factors are reversible based upon lifestyle/behavior modification.

  • Obesity: Obesity is defined as a body-mass index (BMI) above 30 kg/m2.[4] [5] [6]

Non-Modifiable Risk Factors

Temporary Risk Factors

Other Possible Risk Factors

Other possible factors associated with VTE include:

Risk Factors from the Nurse's Health Study[10]

Risk Factors from the Physician's Health Study[11]

  • Anticardiolipin antibody level above the 95th percentile. [12].
  • Factor V Leiden
    • RR 2.7, found in 40% of patients with idiopathic DVT.
  • Use of oral contraceptives by a person with the Factor V mutation increases the risk of venous thromboembolism by about 35 times.
  • Hyperhomocysteinemia increases the risk of a DVT by a factor of 3.
  • Hyperhomocysteinemia in association with Factor V increases the risk of a DVT by about 10 times.
  • Lupus anticoagulant was found in 8.5% of patients with idiopathic DVT.

References

  1. ↑ Goldhaber SZ (2010). "Risk factors for venous thromboembolism". J Am Coll Cardiol. 56 (1): 1–7. doi:10.1016/j.jacc.2010.01.057. PMID 20620709.
  2. ↑ Anderson FA, Spencer FA (2003). "Risk factors for venous thromboembolism". Circulation. 107 (23 Suppl 1): I9–16. doi:10.1161/01.CIR.0000078469.07362.E6. PMID 12814980.
  3. ↑ Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P; et al. (2008). "Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)". Eur Heart J. 29 (18): 2276–315. doi:10.1093/eurheartj/ehn310. PMID 18757870.
  4. ↑ 4.0 4.1 Holst AG, Jensen G, Prescott E (2010). "Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study". Circulation. 121 (17): 1896–903. doi:10.1161/CIRCULATIONAHA.109.921460. PMID 20404252.
  5. ↑ Vayá A, Martínez-Triguero ML, España F, Todolí JA, Bonet E, Corella D (2011). "The metabolic syndrome and its individual components: its association with venous thromboembolism in a Mediterranean population". Metab Syndr Relat Disord. 9 (3): 197–201. doi:10.1089/met.2010.0117. PMID 21352080.
  6. ↑ Eichinger S, Hron G, Bialonczyk C, Hirschl M, Minar E, Wagner O; et al. (2008). "Overweight, obesity, and the risk of recurrent venous thromboembolism". Arch Intern Med. 168 (15): 1678–83. doi:10.1001/archinte.168.15.1678. PMID 18695082.
  7. ↑ Pomp ER, Rosendaal FR, Doggen CJ (2008). "Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use". Am J Hematol. 83 (2): 97–102. doi:10.1002/ajh.21059. PMID 17726684.
  8. ↑ den Heijer M, Koster T, Blom HJ, Bos GM, Briet E, Reitsma PH; et al. (1996). "Hyperhomocysteinemia as a risk factor for deep-vein thrombosis". N Engl J Med. 334 (12): 759–62. doi:10.1056/NEJM199603213341203. PMID 8592549.
  9. ↑ 9.0 9.1 9.2 Konofal E, Lecendreux M, Cortese S (2010). "Sleep and ADHD". Sleep Med. 11 (7): 652–8. doi:10.1016/j.sleep.2010.02.012. PMID 20620109.
  10. ↑ Goldhaber SZ, Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Speizer FE; et al. (1997). "A prospective study of risk factors for pulmonary embolism in women". JAMA. 277 (8): 642–5. PMID 9039882.
  11. ↑ Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP (1995). "Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men". N Engl J Med. 332 (14): 912–7. doi:10.1056/NEJM199504063321403. PMID 7877648.
  12. ↑ Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Schur PH, Hennekens CH; et al. (1992). "Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis". Ann Intern Med. 117 (12): 997–1002. PMID 1443986.

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