Guideline sources The following summarized guidelines for the evaluation and management of factor V Leiden are prepared by our editorial team based on guidelines from the American Society of Hematology (ASH 2023; 2018), the Pathway (Pathway 2023), the British Society for Haematology (BSH 2022), the International Federation of Gynecology and Obstetrics (FIGO 2021), the European Society for Vascular Surgery (ESVS 2021; 2017), the American Association for the Study of Liver Diseases (AASLD 2021), the American College of Gastroenterology (ACG 2020), the European Stroke Organisation (ESO 2017), the Anticoagulation Forum (AF 2016), the European Society for Trauma and Emergency Surgery (ESTES 2016), the European Association for the Study of the Liver (EASL 2016), the Society of Obstetricians and Gynaecologists of Canada (SOGC 2014), the Society for Vascular Surgery (SVS 2014), the Central European Vascular Forum (CEVF/IUA/IUP 2012), the British Committee for Standards In Haematology (BCSH 2012), the American College of Chest Physicians (ACCP 2012), and the American Heart Association (AHA/ASA 2011). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Calculator Calculator Calculat Caprini Score for venous thromb Geneva Risk Score for venous th IMPROV Guidelines https://web.pathway.md/diseases/rec908OQ43qB7Tngk 1/7 6/29/23, 4:01 AM Factor V Leiden Pathway 1. Screening and diagnosis Indications for screening, general principles: As per BSH 2022 guidelines, do not obtain routine thrombophilia testing in first-degree relatives of patients with a history of VTE. D As per AF 2016 guidelines, do not obtain testing for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia, including when contemplating pregnancy or estrogen therapy. D Indications for screening (minor provoking risk factors): avoid obtaining testing for factor V Leiden to guide thromboprophylaxis in patients with a family history of factor V Leiden (with or without VTE) and having a minor provoking risk factor for VTE, such as immobility or minor injury, illness, or infection. D Indications for screening (before combined oral contraceptives): do not obtain thrombophilia testing to guide the use of combined oral contraceptives in females in the general population. D Show 2 more Indications for screening (before hormonal therapy): avoid obtaining thrombophilia testing to guide the use of hormone-replacement therapy in patients from the general population. D Show 2 more Indications for screening (pregnancy): consider obtaining testing for the known familial thrombophilia in females with a family history of VTE and known homozygous factor V Leiden or a combination of factor V Leiden and prothrombin G20210A in the family. Consider administering antepartum thromboprophylaxis in patients with the same familial thrombophilia. C Show 2 more Indications for testing, first episode of thrombosis: As per BSH 2022 guidelines: Do not obtain genetic testing for FVL mutation to predict a first episode of venous thrombosis. D Do not obtain routine testing for heritable thrombophilic traits after a venous thrombotic event to guide management decisions. D As per AF 2016 guidelines, do not obtain thrombophilia testing following an episode of provoked or unprovoked VTE. D Show 2 more Indications for testing (deep vein thrombosis): do not obtain thrombophilia testing in patients with provoked deep vein thrombosis. D Show 2 more Indications for testing, cerebral vein thrombosis: As per ESO 2017 guidelines: Avoid obtaining thrombophilia testing in patients with cerebral venous thrombosis to reduce death, improve functional outcomes, or prevent recurrent venous thrombosis. D Consider obtaining thrombophilia testing in patients with a high pre-test probability of carrying severe thrombophilia (a personal and/or family history of venous thrombosis, https://web.pathway.md/diseases/rec908OQ43qB7Tngk 2/7 6/29/23, 4:01 AM Factor V Leiden Pathway young age at cerebral venous thrombosis, cerebral venous thrombosis without a transient or permanent risk factor) to prevent recurrent venous thrombotic events. E As per AHA/ASA 2011 guidelines: Consider obtaining testing for prothrombotic conditions, including FVL mutation, in patients with cerebral venous thrombosis. C Consider obtaining thrombophilia testing to identify underlying coagulation defects in pediatric patients with cerebral venous thrombosis. C Indications for testing, mesenteric vein thrombosis: As per ESVS 2017 guidelines, consider obtaining genetic testing for thrombophilia in patients with mesenteric vein thrombosis. C As per ESTES 2016 guidelines, obtain testing for thrombophilia in patients with mesenteric vein thrombosis. B Indications for testing (portal vein thrombosis): obtain testing for inherited thrombophilias, including FVL mutation, in patients with portal vein thrombosis. A Indications for testing, Budd-Chiari syndrome: As per AASLD 2021 guidelines, obtain a full thrombophilia workup at the time of hepatic vein thrombosis/Budd-Chiari syndrome diagnosis. Evaluate additional factors even when one causal factor is identified, and consult with a hematologist. E As per EASL 2016 guidelines, obtain testing for inherited thrombophilias, including FVL mutation, in patients with Budd-Chari syndrome. A Indications for testing, superficial vein thrombosis: As per BCSH 2012 guidelines, do not obtain routine testing for underlying thrombophilia in patients with superficial venous thrombosis. D As per CEVF/IUP/IUA 2012 guidelines, obtain testing for thrombophilia in patients with spontaneous nonvaricose superficial venous thrombosis or recurrent varicose superficial venous thrombosis. E Indications for testing (unusual site venous thrombosis): do not obtain testing for inherited thrombophilias in patients with thrombosis at an unusual site. D Indications for testing (recurrent thrombosis): consider obtaining thrombophilia testing in patients with a history of recurrent venous thrombosis and chronic recurrent venous leg ulcers. C Indications for testing (arterial thrombosis): do not obtain testing for inherited thrombophilias in patients with arterial thrombosis D or acute ischemic stroke, D including neonatal stroke. D 2. Medical management Management of venous thromboembolism (general principles): manage VTE in FVL mutation carriers according to current published guidelines on VTE (including deep vein thrombosis, PE, cerebral venous thrombosis, as well as thrombosis in unusual sites). E https://web.pathway.md/diseases/rec908OQ43qB7Tngk 3/7 6/29/23, 4:01 AM Factor V Leiden Pathway Management of venous thromboembolism (deep vein thrombosis): initiate full-dose extended anticoagulant therapy with periodic reevaluations in patients with deep vein thrombosis and high risk thrombophilia, including homozygous FVL mutation. B Management of venous thromboembolism (cerebral vein thrombosis): consider initiating indefinite anticoagulation with a target INR of 2.0-3.0 in patients with cerebral venous thrombosis with severe thrombophilia, including homozygous FVL mutation. C Management of venous thromboembolism, mesenteric vein thrombosis: As per ACG 2020 guidelines, initiate indefinite anticoagulation in patients with mesenteric vein thrombosis and thrombophilia. B As per ESVS 2017 guidelines, initiate lifelong anticoagulation in patients with mesenteric vein thrombosis with proven thrombophilia. B As per ESTES 2016 guidelines, initiate anticoagulation for a minimum of 6 months in patients with mesenteric vein thrombosis and thrombophilia. B Management of venous thromboembolism (portal vein thrombosis): consider initiating anticoagulation in patients with chronic portal vein thrombosis with evidence of inherited thrombophilia. Consider continuing anticoagulation indefinitely in patients with thrombophilia. C 3. Specific circumstances Pregnant patients, screening: As per BSH 2022 guidelines, do not obtain screening for heritable thrombophilias in patients with pregnancy complications, such as recurrent miscarriage or adverse pregnancy outcomes. D As per FIGO 2021 guidelines, do not obtain screening for hereditary thrombophilias in patients with a history of fetal growth restriction. D As per SOGC 2014 guidelines: Do not obtain universal screening for thrombophilias in patients experiencing adverse pregnancy outcomes (severe preeclampsia, IUGR, stillbirth). D Do not obtain routine screening for all inherited thrombophilias in patients with a first episode of VTE during in pregnancy. D Pregnant patients, antepartum: As per ASH 2018 guidelines: Avoid initiating antepartum thromboprophylaxis to prevent a first venous thromboembolic event in patients with heterozygous FVL mutation, regardless of family history of VTE. D Consider initiating antepartum thromboprophylaxis to prevent a first venous thromboembolic event in patients with homozygous FVL mutation or combined thrombophilias, regardless of family history of VTE. C As per SOGC 2014 guidelines, initiate prophylactic-dose thromboprophylaxis during pregnancy in patients with any of the following: personal history of provoked VTE and low-risk thrombophilia A https://web.pathway.md/diseases/rec908OQ43qB7Tngk 4/7 6/29/23, 4:01 AM Factor V Leiden Pathway asymptomatic homozygous FVL mutation B asymptomatic combined thrombophilia. B As per ACCP 2012 guidelines: Consider initiating antepartum thromboprophylaxis with prophylactic- or intermediate-dose LMWH in patients with homozygous FVL mutation, no personal history of VTE, and a positive family history of VTE. C Consider obtaining antepartum clinical vigilance in patients with homozygous FVL mutation, no personal history of VTE, and no family history of VTE. C Pregnant patients, postpartum: As per ASH 2018 guidelines: Avoid initiating postpartum thromboprophylaxis to prevent a first venous thromboembolic event in patients with heterozygous FVL mutation, regardless of family history of VTE. D Consider initiating postpartum thromboprophylaxis to prevent a first venous thromboembolic event in patients with homozygous FVL mutation or combined thrombophilias, regardless of family history. C As per SOGC 2014 guidelines: Initiate postpartum thromboprophylaxis in patients with homozygous FVL mutation or combined thrombophilia. B Consider initiating postpartum thromboprophylaxis in patients with heterozygous FVL mutation with any of the following clinical or pregnancy-related risk factors: Situation Guidance BMI 30 kg/m at first antepartum visit Maternal risk factors Smoking > 10 cigarettes/day antepartum Cardiac disease Maternal comorbidity Systemic lupus erythematous Sickle cell disease IBD Varicose veins Gestational diabetes Gestational comorbidity Preeclampsia IUGR Placenta previa Preterm delivery Delivery-related factors Emergency C-section Peripartum or postpartum blood loss of > 1 L or blood product replacement Stillbirth C https://web.pathway.md/diseases/rec908OQ43qB7Tngk 5/7 6/29/23, 4:01 AM Factor V Leiden Pathway As per ACCP 2012 guidelines, consider initiating postpartum thromboprophylaxis for 6 weeks with prophylactic- or intermediate-dose LMWH or vitamin K antagonists targeted at INR of 2.0-3.0 in patients with homozygous FVL mutation and no personal history of VTE, regardless of family history of VTE. C Clinical findings Past medical history Past obstetric history Acute ischemic stroke IUGR Budd-chiari syndrome Miscarriage Cerebral venous thrombosis Placental abruption DVT Preeclampsia Mesenteric vein thrombosis Stillbirth Portal vein thrombosis Lab findings Prothrombin G20210A mutation Splanchnic vein thrombosis Activated protein C resistance Superficial vein thrombosis Prolonged PTT Family history VTE Genetic testing F5 gene mutation References 1. Nir Melamed, Ahmet Baschat, Yoav Yinon et al. FIGO International Federation of Gynecology and Obstetrics) initiative on fetal growth: best practice advice for screening, diagnosis, and management of fetal growth restriction. Int J Gynaecol Obstet. 2021 Mar;152 Suppl 1 Suppl 1 3 57. Open 2. Scott M Stevens, Scott C Woller, Kenneth A Bauer et al. Guidance for the evaluation and treatment of hereditary and acquired thrombophilia. J Thromb Thrombolysis. 2016 Jan;41 1 154 64. Open 3. Saskia Middeldorp, Robby Nieuwlaat, Lisa Baumann Kreuziger et al. American Society of Hematology 2023 Guidelines for Management of Venous Thromboembolism: Thrombophilia Testing. Blood Adv. 2023 May 17;bloodadvances.2023010177. Open 4. Tilsed JV, Casamassima A, Kurihara H et al. ESTES guidelines: acute mesenteric ischaemia. Eur J Trauma Emerg Surg. 2016 Apr;42 2 253 70. Open 5. Deepa J Arachchillage, Lucy Mackillop, Arvind Chandratheva et al. Guidelines for thrombophilia testing: A British Society for Haematology guideline. Br J Haematol. 2022 May 29. Open 6. E Kalodiki, V Stvrtinova, C Allegra et al. Superficial vein thrombosis: a consensus statement. Int Angiol. 2012 Jun;31 3 203 16. Open 7. Karapetyan H, Grigoryan A, Mullie L. Recommendations & Algorithms. Pathway Editors. Open https://web.pathway.md/diseases/rec908OQ43qB7Tngk 6/7 6/29/23, 4:01 AM Factor V Leiden Pathway 8. Stavros K Kakkos, Manjit Gohel, Niels Baekgaard et al. Editor's Choice European Society for Vascular Surgery ESVS 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis. Eur J Vasc Endovasc Surg. 2021 Jan;61 1 9 82. Open 9. Chan WS, Rey E, Kent NE et al. Venous thromboembolism and antithrombotic therapy in pregnancy. J Obstet Gynaecol Can. 2014 Jun;36 6 527 53. Open 10. Patrick G Northup, Juan Carlos Garcia-Pagan, Guadalupe Garcia-Tsao et al. Vascular Liver Disorders, Portal Vein Thrombosis, and Procedural Bleeding in Patients With Liver Disease: 2020 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 366 413. Open 11. Bates SM, Rajasekhar A, Middeldorp S et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv. 2018 Nov 27;2 22 3317 3359. Open 12. Gustavo Saposnik, Fernando Barinagarrementeria, Robert D Brown Jr et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011 Apr;42 4 1158 92. Open 13. Douglas A Simonetto, Ashwani K Singal, Guadalupe Garcia-Tsao et al. ACG Clinical Guideline: Disorders of the Hepatic and Mesenteric Circulation. Am J Gastroenterol. 2020 Jan;115 1 18 40. Open 14. M Bj rck, M Koelemay, S Acosta et al. Editor's Choice Management of the Diseases of Mesenteric Arteries and Veins: Clinical Practice Guidelines of the European Society of Vascular Surgery ESVS . Eur J Vasc Endovasc Surg. 2017 Apr;53 4 460 510. Open 15. Campbell Tait, Trevor Baglin, Henry Watson et al. Guidelines on the investigation and management of venous thrombosis at unusual sites. Br J Haematol. 2012 Oct;159 1 28 38. Open 16. Shannon M Bates, Ian A Greer, Saskia Middeldorp et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141 2 Suppl):e691S- e736S. Open 17. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatol. 2016 Jan;64 1 179 202. Open 18. J M Ferro, M G Bousser, P Canh o et al. European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis - endorsed by the European Academy of Neurology. Eur J Neurol. 2017 Oct;24 10 1203 1213. Open 19. O'Donnell TF Jr, Passman MA, Marston WA et al. Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg. 2014 Aug;60 2 Suppl):3S 59S. Open https://web.pathway.md/diseases/rec908OQ43qB7Tngk 7/7