Thrombophilia natural history, complications and prognosis: Difference between revisions

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{{Thrombophilia}}
{{Thrombophilia}}
{{CMG}}; {{AE}} {{asiri}}
{{CMG}}; {{AE}} {{asiri}} {{JK}}


==Overview==
==Overview==
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==Natural History==
==Natural History==
*If left untreated, the annual incidence of incident thrombosis in asymptomatic patients with [[Factor V Leiden]] and [[Prothrombin G20210A]] is low (<0.06%).<ref name="pmid15254285">{{cite journal| author=Bates SM, Ginsberg JS| title=Clinical practice. Treatment of deep-vein thrombosis. | journal=N Engl J Med | year= 2004 | volume= 351 | issue= 3 | pages= 268-77 | pmid=15254285 | doi=10.1056/NEJMcp031676 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15254285  }} </ref> The risk is approximately equivalent to treatment with [[oral contraceptive]]s.
*[[Factor V Leiden]] and [[Prothrombin G20210A]]: If left untreated, the annual incidence of incident thrombosis in asymptomatic patients is low (<0.06%). However, the occurrence of recurrent thrombosis can not be predicted in such inherited thrombophilias. <ref name="pmid15254285">{{cite journal| author=Bates SM, Ginsberg JS| title=Clinical practice. Treatment of deep-vein thrombosis. | journal=N Engl J Med | year= 2004 | volume= 351 | issue= 3 | pages= 268-77 | pmid=15254285 | doi=10.1056/NEJMcp031676 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15254285  }} </ref><ref name="pmid15900005">{{cite journal| author=Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR| title=Thrombophilia, clinical factors, and recurrent venous thrombotic events. | journal=JAMA | year= 2005 | volume= 293 | issue= 19 | pages= 2352-61 | pmid=15900005 | doi=10.1001/jama.293.19.2352 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15900005  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17213089 Review in: Evid Based Med. 2006 Apr;11(2):59] </ref><ref name="pmid12932383">{{cite journal| author=Baglin T, Luddington R, Brown K, Baglin C| title=Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. | journal=Lancet | year= 2003 | volume= 362 | issue= 9383 | pages= 523-6 | pmid=12932383 | doi=10.1016/S0140-6736(03)14111-6 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12932383  }} </ref>  
*In patients on oral anticoagulant therapy for venous thromboembolism, the annual incidence of significant bleeds is approximately 2-3%.<ref name="pmid14644891">{{cite journal| author=Linkins LA, Choi PT, Douketis JD| title=Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. | journal=Ann Intern Med | year= 2003 | volume= 139 | issue= 11 | pages= 893-900 | pmid=14644891 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14644891  }} </ref> 
*[[Protein_C|Protein C]], [[Protein_S|Protein S]], and [[Antithrombin]] deficiencies: These conditions carries an increased risk for recurrent thrombosis in untreated patients. <ref name="pmid15900005">{{cite journal| author=Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR| title=Thrombophilia, clinical factors, and recurrent venous thrombotic events. | journal=JAMA | year= 2005 | volume= 293 | issue= 19 | pages= 2352-61 | pmid=15900005 | doi=10.1001/jama.293.19.2352 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15900005  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17213089 Review in: Evid Based Med. 2006 Apr;11(2):59] </ref><ref name="pmid16670075">{{cite journal| author=De Stefano V, Simioni P, Rossi E, Tormene D, Za T, Pagnan A et al.| title=The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S. | journal=Haematologica | year= 2006 | volume= 91 | issue= 5 | pages= 695-8 | pmid=16670075 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16670075  }} </ref>  
*Inherited thrombophilia from [[Factor V Leiden]] and [[Prothrombin G20210A]] did not predict for recurrent thrombosis.<ref name="pmid15900005">{{cite journal| author=Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR| title=Thrombophilia, clinical factors, and recurrent venous thrombotic events. | journal=JAMA | year= 2005 | volume= 293 | issue= 19 | pages= 2352-61 | pmid=15900005 | doi=10.1001/jama.293.19.2352 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15900005  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17213089 Review in: Evid Based Med. 2006 Apr;11(2):59] </ref><ref name="pmid12932383">{{cite journal| author=Baglin T, Luddington R, Brown K, Baglin C| title=Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. | journal=Lancet | year= 2003 | volume= 362 | issue= 9383 | pages= 523-6 | pmid=12932383 | doi=10.1016/S0140-6736(03)14111-6 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12932383  }} </ref>  
*[[Oral contraceptives]], [[hormone replacement therapy]], and [[pregnancy]] can significantly increase thrombotic risk in patients with underlying thrombophilia.<ref name="pmid18501222">{{cite journal| author=Dalen JE| title=Should patients with venous thromboembolism be screened for thrombophilia? | journal=Am J Med | year= 2008 | volume= 121 | issue= 6 | pages= 458-63 | pmid=18501222 | doi=10.1016/j.amjmed.2007.10.042 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18501222  }} </ref>  
*In untreated patients with [[Protein_C|protein C]], [[Protein_S|protein S]], and [[antithrombin]] deficiencies, there is an increased risk for recurrent thrombosis.<ref name="pmid15900005">{{cite journal| author=Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR| title=Thrombophilia, clinical factors, and recurrent venous thrombotic events. | journal=JAMA | year= 2005 | volume= 293 | issue= 19 | pages= 2352-61 | pmid=15900005 | doi=10.1001/jama.293.19.2352 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15900005  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17213089 Review in: Evid Based Med. 2006 Apr;11(2):59] </ref><ref name="pmid16670075">{{cite journal| author=De Stefano V, Simioni P, Rossi E, Tormene D, Za T, Pagnan A et al.| title=The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S. | journal=Haematologica | year= 2006 | volume= 91 | issue= 5 | pages= 695-8 | pmid=16670075 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16670075  }} </ref>
*Certain high risk thrombophilias require indefinite [[anticoagulant|anticoagulation]]. However, such patients on preventive oral anticoagulant therapy for venous thromboembolism still carries the annual incidence of significant bleeds of ~2-3%.<ref name="pmid14644891">{{cite journal| author=Linkins LA, Choi PT, Douketis JD| title=Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. | journal=Ann Intern Med | year= 2003 | volume= 139 | issue= 11 | pages= 893-900 | pmid=14644891 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14644891  }} </ref>
*[[Oral contraceptives]], [[hormone replacement therapy]], and [[pregnancy]] can significantly increase thrombotic risk in patients with thrombophilia.<ref name="pmid18501222">{{cite journal| author=Dalen JE| title=Should patients with venous thromboembolism be screened for thrombophilia? | journal=Am J Med | year= 2008 | volume= 121 | issue= 6 | pages= 458-63 | pmid=18501222 | doi=10.1016/j.amjmed.2007.10.042 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18501222  }} </ref>  
*Certain high risk thrombophilias require indefinite [[anticoagulant|anticoagulation]].  


==Complications==
==Complications==
*The primary complication of thrombophilia is the development of [[Thrombus|blood clots]]
*The primary complication of thrombophilia is the development of [[Thrombus|blood clots]], also known as '''thrombus formation'''.
*Common complications of thrombophilia include [[deep vein thrombosis]] and [[pulmonary embolism]]  
*The most common complications of thrombophilia are as follows: <ref name="pmid11529700">{{cite journal| author=Bauer KA| title=The thrombophilias: well-defined risk factors with uncertain therapeutic implications. | journal=Ann Intern Med | year= 2001 | volume= 135 | issue= 5 | pages= 367-73 | pmid=11529700 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11529700  }} </ref><ref name="pmid15254285">{{cite journal| author=Bates SM, Ginsberg JS| title=Clinical practice. Treatment of deep-vein thrombosis. | journal=N Engl J Med | year= 2004 | volume= 351 | issue= 3 | pages= 268-77 | pmid=15254285 | doi=10.1056/NEJMcp031676 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15254285  }} </ref><ref name="pmid18501222">{{cite journal| author=Dalen JE| title=Should patients with venous thromboembolism be screened for thrombophilia? | journal=Am J Med | year= 2008 | volume= 121 | issue= 6 | pages= 458-63 | pmid=18501222 | doi=10.1016/j.amjmed.2007.10.042 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18501222  }} </ref>
**[[Deep vein thrombosis]]  
**[[Pulmonary embolism]]
** Postthrombotic syndrome (PTS) with chronic venous ulceration (CVU) <ref name="pmid23762560">{{cite journal| author=Rabinovich A, Kahn SR| title=Association between Thrombophilia and the Post-Thrombotic Syndrome. | journal=Int J Vasc Med | year= 2013 | volume= 2013 | issue=  | pages= 643036 | pmid=23762560 | doi=10.1155/2013/643036 | pmc=3665186 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23762560  }} </ref>


'''The risk of future thrombosis in patients with thrombophilia:'''
'''Table 1: The risk of future thrombosis in patients with thrombophilia:'''
{| class="wikitable"
! style="font-weight: bold;" |Thrombophilic state
! style="font-weight: bold;" |Thrombotic risk<ref name="pmid15254285">{{cite journal| author=Bates SM, Ginsberg JS| title=Clinical practice. Treatment of deep-vein thrombosis. | journal=N Engl J Med | year= 2004 | volume= 351 | issue= 3 | pages= 268-77 | pmid=15254285 | doi=10.1056/NEJMcp031676 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15254285  }} </ref>
|-
| [[Trauma]]/[[General surgery]]
| Modest
|-
| [[Elderly|Age > 60]]
| Modest
|-
| [[Immobilization]]
| Modest
|-
| [[Pregnancy]]
| Modest
|-
| [[Hormone therapy|Hormone therapies]]
| Modest
|-
| [[Factor V Leiden]] heterozygosity
| Modest
|-
| [[Prothrombin]] mutation
| Modest
|-
| Homocysteinemia
| Modest
|-
| Increased factor VIII levels
| Modest
|-
| Increased factor IX levels
| Modest
|-
| Increased factor XI levels
| Modest
|-
| Protein C and S deficiency
| Intermediate
|-
| Dysfibrogenemia
| Intermediate
|-
| [[Malignancy]]
| High
|-
| APLS/[[Lupus anticoagulant]]
| High
|-
| Myeloproliferative disorders/hyperviscosity
| High
|-
| PNH
| High
|-
| [[Orthopedic surgery]]
| High
|-
| [[Antithrombin deficiency]]
| High
|-
| Factor V Leiden homozygosity
| High
|-
|}


{| class="wikitable"
{| class="wikitable"
Line 97: Line 33:
|}
|}


'''The effect of concurrent hormone exposure on incident thrombosis and thrombotic risk in patients with thrombophilia:'''
'''Table 2: The effect of concurrent hormone exposure on incident thrombosis and thrombotic risk in patients with underlying thrombophilia:'''
{| class="wikitable"
{| class="wikitable"
! style="font-weight: bold;" | Thrombophilic state
! style="font-weight: bold;" | Thrombophilic state
Line 123: Line 59:
| 4
| 4
|-
|-
| style="font-style: italic;" | OCP and factor V leiden heterozygous
| OCP and factor V leiden heterozygous
| style="font-style: italic;" | 0.3
| 0.3
| style="font-style: italic;" | 35
| 35
|-
|-
| style="font-style: italic;" | OCP and factor V leiden homozygous
| OCP and factor V leiden homozygous
| style="font-style: italic;" |  
|  
| style="font-style: italic;" | 100
| 100
|-
|-
| style="font-style: italic;" | OCP and prothrombin G20210A
| OCP and prothrombin G20210A
| style="font-style: italic;" |  
|
| style="font-style: italic;" | 16
| 16
|-
|-
| style="font-style: italic;" | OCP and protein C/S, or antithrombin III deficiency
| OCP and protein C/S, or antithrombin III deficiency
| style="font-style: italic;" |  
|  
| style="font-style: italic;" | 9.7
| 9.7
|-
|-
| [[Pregnancy]]
| [[Pregnancy]]
Line 143: Line 79:
| 7
| 7
|-
|-
| style="font-style: italic;" | Pregnancy and factor V leiden heterozygous
| Pregnancy and factor V leiden heterozygous
| style="font-style: italic;" |
|
| style="font-style: italic;" | 35
| 35
|-
|-
| [[Cancer]]
| [[Cancer]]
Line 155: Line 91:
| 50
| 50
|}
|}
Data were extracted from multiple sources.<ref name="pmid11529700">{{cite journal| author=Bauer KA| title=The thrombophilias: well-defined risk factors with uncertain therapeutic implications. | journal=Ann Intern Med | year= 2001 | volume= 135 | issue= 5 | pages= 367-73 | pmid=11529700 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11529700  }} </ref><ref name="pmid15254285">{{cite journal| author=Bates SM, Ginsberg JS| title=Clinical practice. Treatment of deep-vein thrombosis. | journal=N Engl J Med | year= 2004 | volume= 351 | issue= 3 | pages= 268-77 | pmid=15254285 | doi=10.1056/NEJMcp031676 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15254285  }} </ref><ref name="pmid18501222">{{cite journal| author=Dalen JE| title=Should patients with venous thromboembolism be screened for thrombophilia? | journal=Am J Med | year= 2008 | volume= 121 | issue= 6 | pages= 458-63 | pmid=18501222 | doi=10.1016/j.amjmed.2007.10.042 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18501222  }} </ref>
*Deep venous thrombosis has two major complications: pulmonary embolism, which is acute and life-threatening, and postthrombotic syndrome (PTS) with chronic venous ulceration (CVU).


==Prognosis==
==Prognosis==
The prognosis depends on the underlying thrombophilia as each form has a different associated thrombotic risk. Patients who develop multiple or atypical clots, arterial thrombosis, or life-threatening thrombosis have worse prognosis.
*The prognosis depends on the underlying thrombophilia as each disorder has a different associated thrombotic risk (Table 1 and 2).  
 
*Thrombophilias associated with the development of multiple or atypical clots, arterial thrombosis, or life-threatening thrombosis carries '''worse prognosis''' which are as follows:  
Thrombophilias generally associated with worse prognosis include:
**[[Antiphospholipid Syndrome]]
*[[Antiphospholipid Syndrome]]
**[[Paroxysmal nocturnal hemoglobinuria]]
*[[Paroxysmal nocturnal hemoglobinuria]]
**[[Antithrombin III deficiency]]
*[[Antithrombin III deficiency]]
**[[Factor V Leiden]] homozygosity
*[[Factor V Leiden]] homozygosity
*High risk thrombophilic conditions require consideration for '''lifelong [[anticoagulation]]''' under the supervision of an expert consultant.
 
**[[Antiphospholipid Syndrome]]
Certain thrombophilic conditions are high risk and require consideration for lifelong [[anticoagulation]]. In these cases, expert consultation is recommended.
**[[Paroxysmal nocturnal hemoglobinuria]]
 
**Recurrent thrombosis regardless of underlying thrombophilia
{| class="wikitable"
**History of life-threatening thrombosis or atypical locations
! style="font-weight: bold;" | Possible indications for lifelong/prophylactic anticoagulation
**Malignancy with history of thrombosis
|-
| Antiphospholipid syndrome
|-
| Paroxysmal nocturnal hemoglobinuria
|-
| Recurrent thrombosis regardless of underlying thrombophilia
|-
| History of life-threatening thrombosis or atypical locations
|-
| Malignancy with history of thrombosis
|}


==References==
==References==

Latest revision as of 20:14, 12 March 2021

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2] Jaspinder Kaur, MBBS[3]

Overview

The annual thrombotic risks are variable and depend on the underlying thrombophilia.[1]

Natural History

  • Factor V Leiden and Prothrombin G20210A: If left untreated, the annual incidence of incident thrombosis in asymptomatic patients is low (<0.06%). However, the occurrence of recurrent thrombosis can not be predicted in such inherited thrombophilias. [2][3][4]
  • Protein C, Protein S, and Antithrombin deficiencies: These conditions carries an increased risk for recurrent thrombosis in untreated patients. [3][5]
  • Oral contraceptives, hormone replacement therapy, and pregnancy can significantly increase thrombotic risk in patients with underlying thrombophilia.[6]
  • Certain high risk thrombophilias require indefinite anticoagulation. However, such patients on preventive oral anticoagulant therapy for venous thromboembolism still carries the annual incidence of significant bleeds of ~2-3%.[7]

Complications

Table 1: The risk of future thrombosis in patients with thrombophilia:

Thrombotic risk[2] Thrombophilic state
Modest Trauma/General surgery, Age > 60, Immobilization, Pregnancy, Hormone therapies, Factor V Leiden heterozygosity, Prothrombin mutation, Homocysteinemia, Increased factor VIII levels, Increased factor IX levels, Increased factor XI levels
Intermediate Protein C and S deficiency, Dysfibrogenemia
High Malignancy, APLS/Lupus anticoagulant, Myeloproliferative disorders/hyperviscosity, PNH, Orthopedic surgery, Antithrombin deficiency, Factor V Leiden homozygosity

Table 2: The effect of concurrent hormone exposure on incident thrombosis and thrombotic risk in patients with underlying thrombophilia:

Thrombophilic state Annual Incidence (%) Relative Risk
Normal 0.008 1
Factor V Leiden heterozygous 0.06 3-10
Factor V Leiden homozygous 0.5-1 80
Prothrombin G20210A 0.02 1-5
Oral contraceptive (OCP) 0.03 4
OCP and factor V leiden heterozygous 0.3 35
OCP and factor V leiden homozygous 100
OCP and prothrombin G20210A 16
OCP and protein C/S, or antithrombin III deficiency 9.7
Pregnancy 7
Pregnancy and factor V leiden heterozygous 35
Cancer 5
History of venous thrombosis 50

Prognosis

References

  1. 1.0 1.1 Bauer KA (2001). "The thrombophilias: well-defined risk factors with uncertain therapeutic implications". Ann Intern Med. 135 (5): 367–73. PMID 11529700.
  2. 2.0 2.1 2.2 Bates SM, Ginsberg JS (2004). "Clinical practice. Treatment of deep-vein thrombosis". N Engl J Med. 351 (3): 268–77. doi:10.1056/NEJMcp031676. PMID 15254285.
  3. 3.0 3.1 Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR (2005). "Thrombophilia, clinical factors, and recurrent venous thrombotic events". JAMA. 293 (19): 2352–61. doi:10.1001/jama.293.19.2352. PMID 15900005. Review in: Evid Based Med. 2006 Apr;11(2):59
  4. Baglin T, Luddington R, Brown K, Baglin C (2003). "Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study". Lancet. 362 (9383): 523–6. doi:10.1016/S0140-6736(03)14111-6. PMID 12932383.
  5. De Stefano V, Simioni P, Rossi E, Tormene D, Za T, Pagnan A; et al. (2006). "The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S." Haematologica. 91 (5): 695–8. PMID 16670075.
  6. 6.0 6.1 Dalen JE (2008). "Should patients with venous thromboembolism be screened for thrombophilia?". Am J Med. 121 (6): 458–63. doi:10.1016/j.amjmed.2007.10.042. PMID 18501222.
  7. Linkins LA, Choi PT, Douketis JD (2003). "Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis". Ann Intern Med. 139 (11): 893–900. PMID 14644891.
  8. Rabinovich A, Kahn SR (2013). "Association between Thrombophilia and the Post-Thrombotic Syndrome". Int J Vasc Med. 2013: 643036. doi:10.1155/2013/643036. PMC 3665186. PMID 23762560.

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