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Professional Reference articles are designed for health professionals to use. They are written by UK doctors and based on research evidence, UK and European Guidelines. You may find the Thrombophilia article more useful, or one of our other health articles.

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What is thrombophilia?

Thrombophilia refers to a predisposition to thromboembolism. In practice, the term is used to describe patients who are at significantly increased long-term risk of venous thromboembolism (VTE). Heritable thrombophilia is an inherited tendency for venous thrombosis.1

How common is thrombophilia? (Epidemiology)2

  • Factor V Leiden thrombophilia is the most common inherited form of thrombophilia. The prevalence in the US and European general populations is 3-8% for one copy of the factor V Leiden mutation, and about 1:5000 people have two copies of the mutation.

  • Moderate protein S deficiency is estimated to affect 1:500 individuals. Severe deficiency is rare and its prevalence is unknown.

  • Moderate protein C deficiency affects about 1:500 individuals. Severe deficiency occurs in about 1:4000000 newborns.

  • Prothrombin-related thrombophilia is the second most common genetic form of thrombophilia, occurring in about 1.7-3% of the European and US general populations.

  • Hereditary antithrombin III deficiency has a prevalence of 1:500-5000 in the general population.

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What are the causes of thrombophilia?1

Thrombophilia may be heritable, acquired or mixed.

Heritable causes3

  • Heritable thrombophilias can be identified in 30-50% of VTE. Factor V Leiden, prothrombin 20210G>A, and deficiencies of antithrombin,protein C and protein S increase the risk of a first VTE.

  • However, an individual's risk is determined by a combination of genetic, acquired and circumstantial risk factors.

  • At least 50% of VTE events in thrombophilic individuals are provoked by predisposing factors such as immobility, surgery, trauma, cancer, hormonal therapy and pregnancy.

  • Non-modifiable risk factors such as advancing age and family history also increase thrombotic risk.

  • Factor V Leiden is the most common heritable thrombophilia in Caucasian populations. It is rare or absent in people of black African, Far East Asian, native Australian and native American origin.4

  • Individuals may have more than one inherited thrombophilia genotype, particularly in populations where the factor V Leiden and prothrombin 20210A alleles are common. Combined thrombophilias can multiply the VTE risk.

Acquired causes5

Mixed or uncertain causes5 9

  • Hyperhomocysteinaemia:

    • May be inherited or acquired (deficiencies of folic acid, vitamins B12 and B6 may contribute).

    • Is a risk factor for VTE.

    • Mild hyperhomocysteinaemia is common in the general population; the severe form is rare.

    • The most common genetic hyperhomocysteinaemia involves the gene for methylene tetrahydrofolate reductase (MTHFR). Homocystinuria is a rare genetic cause.

  • Clotting factor levels:

    • Raised factor VIIIc is now established as a risk factor for VTE.

    • Other clotting factors may be relevant - eg, raised levels of factors VII, IX and XI, or deficiency of factor XII. However, their role is uncertain.

  • Other factors possibly involved in thrombophilia are plasminogen deficiency, plasminogen activator, plasminogen activator inhibitor, heparin cofactor II deficiency and histidine-rich glycoprotein.

Thrombophilia symptoms (presentation)

Possible symptoms of thrombophilia are:

  • A strong family history of VTE.

  • VTE which is spontaneous or with minimal provoking factors.

  • VTE at a young age.

  • Thrombosis in an unusual site (eg, mesenteric, portal vein, sagittal sinus thrombosis) or in multiple sites.

  • Recurrent VTE.

  • Recurrent miscarriage.

  • Neonatal thrombosis (eg, neonatal purpura fulminans - rare).

  • Warfarin-induced skin necrosis (rare).

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Assessment and screening

  • Take a careful personal and family history, including VTE events and whether there were any provoking factors for the VTE event, such as immobility, surgery, oestrogens, etc.

  • Selective screening based on prior VTE history is more cost-effective than universal screening.10

  • There is currently no strong evidence for the benefit(s) of testing for thrombophilia to determine the risk of recurrent VTE:11 12

    • One review found that universal screening of women prior to prescribing hormone replacement therapy (HRT) was the most cost-effective strategy but universal screening of women prior to prescribing combined oral contraceptives was the least cost-effective strategy. Selective thrombophilia screening based on previous personal and/or family history of VTE was more cost-effective than universal screening in all the patient groups evaluated.13

    • It has been recommended that thrombophilia testing should not be performed in most situations and that, when performed, it should be used in a very selective manner and only in circumstances where the information obtained will influence a decision important to the patient and outweigh the potential risks of testing.

    • Testing should not be performed during acute thrombosis or during the initial (three-month) period of anticoagulation.

Who should be investigated for heritable thrombophilia?1

It is important that patients are counselled in advance of any decision on whether or not to undertake testing. This should include discussion of the aims of testing and how it might alter management decisions.

Identifying a heritable thrombophilic trait in a patient who has had a venous thrombotic event:

  • Testing for heritable thrombophilic traits after a venous thrombotic event is not recommended as a routine to guide management decisions.

  • Routine thrombophilia testing to first‐degree relatives of people with a history of VTE is not recommended.

  • Selective testing of asymptomatic first‐degree relatives of probands with protein C, protein S and antithrombin deficiency may be considered where this may influence the management and life choices depending on personal circumstances.

  • Genetic testing for variants in genes (eg MTHFR, SERPINE1 variants (PAI‐1plasma level)) without a clinically significant link to thrombosis is not recommended.

Thrombosis in unusual sites:

  • Testing for heritable thrombophilia in patients with thrombosis is not recommended if the only indication is thrombosis at an unusual site because the association is weak, and management would not be changed by their presence.

  • Testing in patients with thrombosis at unusual sites with full blood count abnormalities suggestive of a myeloproliferative neoplasm is recommended.

  • Genetic testing with JAK2 mutation is recommended in patients with splanchnic vein thrombosis or cavernous sinus thrombosis in the absence of clear provoking factors and a normal FBC.

  • Testing for antiphospholipid antibodies in patients with thrombosis at unusual sites in the absence of clear provoking factors is recommended, as the type and duration of anticoagulation are affected by the presence of these antibodies.

  • Testing for paroxysmal nocturnal haemoglobinuria is recommended in patients with thrombosis at unusual sites and abnormal haematological parameters (cytopenia and abnormal red cell indices) or evidence of haemolysis (raised lactate dehydrogenase, bilirubin and reticulocyte count).

  • Testing for antiphospholipid antibodies may be considered in patients with retinal vein occlusion (RVO) in the absence of any other risk factors associated with RVO.

Arterial thrombosis except stroke:

  • Testing for heritable thrombophilia is not recommended in patients with arterial thrombosis as the association between heritable thrombophilia and arterial thrombosis in adults is weak and does not alter the management.

  • Testing for antiphospholipid antibodies in patients with arterial thrombosis in the absence of other vascular risk factors is recommended.

Ischaemic stroke-all types except cerebral venous sinus thrombosis:

  • Testing for heritable thrombophilia is not recommended in patients with stroke, regardless of age.

  • Testing for antiphospholipid antibodies should be considered in young (under 50 years of age) patients in the absence of identifiable risk factors for cardiovascular disease because this may alter management including choice of antithrombotic therapy.

  • In patients with stroke, an abnormal full blood count should prompt consideration for testing for myeloproliferative neoplasm and for paroxysmal nocturnal haemoglobinuria.

  • The presence of a patent foramen ovale in patients with a stroke is not an indication for thrombophilia testing.

Paediatric thrombosis, neonatal thrombosis, purpura fulminans and stroke in children:

  • Neonates and children with purpura fulminans should be tested urgently for protein C and S deficiency.

  • Thrombophilia screening is not routinely recommended for neonatal stroke.

  • In neonates with multiple unexplained thrombosis, especially with clinical evidence suggestive of catastrophic antiphospholipid syndrome, testing for antiphospholipid antibodies and heritable thrombophilia should be considered.

Thrombophilia testing in relation to pregnancy:

  • Testing for antithrombin deficiency may be considered in pregnant women with a known family history of this deficiency or evidence of heparin resistance.

  • In women with a history of unprovoked VTE, testing for antiphospholipid antibodies should be performed outside pregnancy. Antiphospholipid antibody testing should be avoided during pregnancy as the results may not be reliable.

Women with pregnancy complications:

  • Heritable thrombophilia screening in women with pregnancy complications, such as recurrent miscarriage or adverse pregnancy outcomes, is not recommended.

  • For women with recurrent or late pregnancy loss, screening for antiphospholipid antibodies can be considered as the results aid risk stratification and treatment decisions.


Important points

  • Do not test for heritable thrombophilia at the time of acute VTE - because the results will not influence initial treatment, the usefulness of the test needs considering and patient counselling is needed.

  • No single method of testing can detect all thrombophilic defects.

  • Interpretation of the test results is complex; false positives and false negatives are common.

  • The tests require supervision by experienced laboratory staff. The results require interpretation by an experienced clinician who is aware of all relevant factors of the individual case.

  • Pre-test patient counselling and a physician with specialist knowledge are recommended.

The initial tests

  • FBC and film - looking for myeloproliferative disorders, paroxysmal nocturnal haemoglobinuria, thrombocytosis, polycythaemia.

  • Prothrombin time and activated partial thromboplastin time (aPPT).

  • Assays for antiphospholipid antibodies, factor V Leiden, prothrombin G20210A, protein C, protein S and antithrombin. Details of which assays to use are given in published guidelines.14

Other possible investigations

  • ESR, CRP, antinuclear antibodies - for connective tissue disorders or inflammation.

  • Clotting screen - raised fibrinogen, raised prothrombin, raised factor VIII, plasminogen, factor XII.

  • Homocysteine levels.

  • Investigations for cardiac disease, liver disease, nephrotic syndrome, or other causes of acquired thrombophilia as appropriate.

  • Consider occult malignancy and investigate appropriately.

  • Consider tests for dysfibrinogenaemia:

    • It is very rare.

    • It should be considered when there is a severe familial thrombotic tendency in the absence of the other heritable thrombophilias mentioned above.

Thrombophilia treatment and management

See also 'Pregnancy and postnatal' section, below.

Management of acute VTE

See separate Deep Vein Thrombosis, Pulmonary Embolism and Venous Thromboembolism in Pregnancy articles.

Minimising VTE risk

See also separate Prevention of Venous Thromboembolism article.

  • Patients should be aware of their condition and how to recognise symptoms of VTE.

  • Ensure mobility and adequate hydration.

  • Extra precautions and short-term thromboprophylaxis may be needed at times of increased risk - eg, surgery, immobility, pregnancy and postnatally.

  • Avoid oestrogen-containing contraceptives and HRT:

    • These increase VTE risk (the extent of risk depending on the nature of the thrombophilia) and should generally be avoided.

    • Progestogen-only contraceptives can be used.

  • Pre-pregnancy counselling.15

Consider thromboprophylaxis

The use of short- or long-term anticoagulation should be considered, weighing up the reduction of VTE risk against the risk of serious haemorrhage. This depends on the individual diagnosis and any other medical conditions. Guidelines suggest that, as a general rule:

  • All patients with known thrombophilia or previous VTE - consider short-term thromboprophylaxis at times of increased VTE risk.

  • Patients with a first VTE event - long-term anticoagulation is not indicated (the risks outweigh the benefits).

  • Patients with ≥2 spontaneous VTEs - consider indefinite anticoagulation.

  • Patients with recurrent VTEs linked to a provoking factor (eg, surgery, pregnancy, oestrogen use) may not require long-term anticoagulation but do require prophylaxis during any further high-risk situations.

  • Asymptomatic family members found to have a thrombophilic genotype - the risk of long-term anticoagulation outweighs the benefits. Consider short-term prophylaxis to cover periods of high VTE risk.

Pregnancy and postnatal period15


  • Pregnancy and the puerperium confer increased risk of VTE.

  • Pulmonary embolism is a leading and often preventable cause of maternal mortality in the UK (although the absolute risk is low).

  • The risk begins in the first trimester and is greater postpartum than antenatally, particularly during the first postnatal week.

  • Women with thrombophilia have a further increased risk (the magnitude of increased risk depending on the specific diagnosis).

Royal College of Obstetricians and Gynaecologists (RCOG) Green Top Guidelines give detailed guidance for reducing VTE risk in all pregnant and postnatal women, including those with known or suspected thrombophilia or a past/family history of VTE.15 See the 'Prevention: prophylaxis' section in the separate Venous Thromboembolism in Pregnancy article.

Potential complications of thrombophilia

  • Complications of VTE.

  • Complications of anticoagulation, if used.

  • Pregnancy complications:

    • Antiphospholipid syndrome is associated with pregnancy loss.

    • Heritable thrombophilia may be linked with pregnancy complications, including an increased risk of late fetal loss, pre-eclampsia and intrauterine growth restriction. However, this remains an area of debate.16 17

  • Possible association with arterial thrombosis:

    • There may be a link between thrombophilia and arterial thrombosis, although the evidence is limited.18 As a contributor to arterial disease, thrombophilia is less important than the established cardiovascular risk factors.1

  • Anxiety resulting from thrombophilia testing and results.19


VTE is a multifactorial disease. The VTE risk depends not only on the specific thrombophilia but also on other factors such as:

  • Family history and previous history of VTE.

  • The presence of any additional thrombophilia (heritable or acquired).

  • Other VTE risk factors (age, immobility, surgery, obesity, hormone use and pregnancy/postpartum states).

VTE risks multiply; for example, the relative risk of VTE for women heterozygous for factor V Leiden is 3-8; however, this increases to 35-50 when taking oestrogen-containing contraception and then to several hundred for homozygous factor V Leiden women taking such contraceptives.

With thrombophilia testing, interpretation of results and predictions about the prognosis are difficult because:

  • The incidence of thrombosis in those with heritable thrombophilia is variable - from none to recurrent VTE at an early age.

  • Many individuals with heritable thrombophilia diagnosed only by laboratory investigation will not have a thrombotic event.

  • Failure to identify a thrombophilic defect on laboratory testing does not prove that no thrombophilia exists.

  • Clinicians may overestimate the risk of thrombosis and underestimate the risks of anticoagulation.

Further reading and references

  • Mumford AD, Ackroyd S, Alikhan R, et al; Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol. 2014 Nov;167(3):304-26. doi: 10.1111/bjh.13058. Epub 2014 Aug 6.
  • Khider L, Gendron N, Mauge L; Inherited Thrombophilia in the Era of Direct Oral Anticoagulants. Int J Mol Sci. 2022 Feb 5;23(3):1821. doi: 10.3390/ijms23031821.
  • Darlow J, Mould H; Thrombophilia testing in the era of direct oral anticoagulants. Clin Med (Lond). 2021 Sep;21(5):e487-e491. doi: 10.7861/clinmed.2020-1008. Epub 2021 Sep 7.
  1. Arachchillage DJ, Mackillop L, Chandratheva A, et al; Thrombophilia testing: A British Society for Haematology guideline. Br J Haematol. 2022 Aug;198(3):443-458.
  2. Dautaj A, Krasi G, Bushati V, et al; Hereditary thrombophilia. Acta Biomed. 2019 Sep 30;90(10-S):44-46. doi: 10.23750/abm.v90i10-S.8758.
  3. Varga EA, Kujovich JL; Management of inherited thrombophilia: guide for genetics professionals. Clin Genet. 2012 Jan;81(1):7-17. doi: 10.1111/j.1399-0004.2011.01746.x. Epub 2011 Jul 25.
  4. Dahlback B; Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood. 2008 Jul 1;112(1):19-27.
  5. Dutta TK, Venugopal V; Venous thromboembolism: the intricacies. J Postgrad Med. 2009 Jan-Mar;55(1):55-64.
  6. Ataga KI; Hypercoagulability and thrombotic complications in hemolytic anemias. Haematologica. 2009 Nov;94(11):1481-4.
  7. Jong E, Louw S, Meijers JC, et al; The hemostatic balance in HIV-infected patients with and without antiretroviral therapy. AIDS Patient Care STDS. 2009 Dec;23(12):1001-7.
  8. Raffini L; Thrombophilia in children: who to test, how, when, and why? Hematology Am Soc Hematol Educ Program. 2008:228-35.
  9. Khan S, Dickerman JD; Hereditary thrombophilia. Thromb J. 2006 Sep 12;4:15.
  10. Wu O, Robertson L, Twaddle S, et al; Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol Assess. 2006 Apr;10(11):1-110.
  11. Cohn DM, Vansenne F, de Borgie CA, et al; Thrombophilia testing for prevention of recurrent venous thromboembolism. Cochrane Database Syst Rev. 2012 Dec 12;12:CD007069. doi: 10.1002/14651858.CD007069.pub3.
  12. Stevens SM, Woller SC, Bauer KA, et al; Guidance for the evaluation and treatment of hereditary and acquired thrombophilia. J Thromb Thrombolysis. 2016 Jan;41(1):154-64. doi: 10.1007/s11239-015-1316-1.
  13. Wu O, Robertson L, Twaddle S, et al; Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis. Br J Haematol. 2005 Oct;131(1):80-90.
  14. Lyons S, Galloway MJ, Osgerby J, et al; An audit of thrombophilia screens: results from the National Pathology Alliance benchmarking review. J Clin Pathol. 2006 Feb;59(2):156-9.
  15. Thrombosis and Embolism during Pregnancy and the Puerperium, the Acute Management of; Royal College of Obstetricians and Gynaecologists (April 2015)
  16. Pabinger I; Thrombophilia and its impact on pregnancy. Thromb Res. 2009;123 Suppl 3:S16-21.
  17. Said JM, Higgins JR, Moses EK, et al; Inherited thrombophilia polymorphisms and pregnancy outcomes in nulliparous women. Obstet Gynecol. 2010 Jan;115(1):5-13.
  18. Martinelli I, Bucciarelli P, Mannucci PM; Thrombotic risk factors: basic pathophysiology. Crit Care Med. 2010 Feb;38(2 Suppl):S3-9.
  19. Cohn DM, Vansenne F, Kaptein AA, et al; The psychological impact of testing for thrombophilia: a systematic review. J Thromb Haemost. 2008 Jul;6(7):1099-104. Epub 2008 Jul 1.

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