Definition^1,2

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.³

Epidemiology^1,2,3

Thrombophilia may be heritable, acquired or mixed.

Heritable causes⁴

The following genetic factors are established as contributing to thrombophilia, and carry a ≥2 x risk of venous thromboembolism (VTE):

• Factor V Leiden is the most common heritable thrombophilia in Caucasian populations (see table). It is rare or absent in people of black African, Far East Asian, native Australian and native American origin.⁷
• 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 causes⁸

• Antiphospholipid syndrome:
  • Associated with both venous and arterial thrombosis.
  • May be primary (venous or arterial thrombosis, or recurrent first trimester abortions) or secondary (linked to other conditions, e.g. systemic lupus erythematosus, collagenosis).
• Acquired antithrombin deficiency:
  • Due to liver disease, nephrotic syndrome, disseminated intravascular coagulation or pregnancy.
• Myeloproliferative disorders, thrombocytosis or polycythaemia.
• Cancer.
• Certain inflammatory conditions, e.g. inflammatory bowel disease.
• Haemolytic anaemias, including paroxysmal nocturnal haemoglobinuria.⁹
• Behçet's disease.
• Nephrotic syndrome.
• Heart failure, recent myocardial infarction or stroke.
• Possibly, HIV infection.¹⁰

Mixed or uncertain causes^4,8

• 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, e.g. raised levels of factors VII, IX and XI, or deficiency of factor XII. However, their role is uncertain.^4,11
• Other factors possibly involved in thrombophilia are plasminogen deficiency, plasminogen activator, plasminogen activator inhibitor, heparin cofactor II deficiency, and histidine-rich glycoprotein.

Presentation

Possible presentations are:

• A strong family history of venous thromboembolism (VTE).
• VTE which is spontaneous or with minimal provoking factors.
• VTE at a young age.
• Thrombosis in an unusual site (e.g. mesenteric, portal vein, sagittal sinus thrombosis) or in multiple sites.
• Recurrent VTE.
• Recurrent miscarriage.
• Neonatal thrombosis (e.g. neonatal purpura fulminans - rare).
• Warfarin-induced skin necrosis (rare) - see separate Protein C deficiency article.

Assessment²

History

Take a careful personal and family history:

• Specifically ask about venous thromboembolism (VTE) events.
• Enquire whether the VTE diagnosis was confirmed - if not, is the history plausible? Was the patient anticoagulated?
• Were there any provoking factors for the VTE event (immobility, surgery, oestrogens, etc.)?

Who should be investigated for heritable thrombophilia?³

• In the 1980s -1990s thrombophilia testing became common in unselected patients and their relatives. However, it is now recognised that this approach is not clinically useful. It is reasonable to test where clinical management will be influenced by the results. For example, consider testing where the results will affect decisions about the duration of anticoagulation in VTE patients, or VTE prophylaxis during high-risk periods.
• Targeted case-finding of relatives of patients with 'severe' or 'high-risk' thrombophilia has been suggested, such as deficiency of antithrombin, protein C or protein S, although this remains an area of contention.
• There is no accepted definition of thrombosis-prone families. It is important to consider the circumstances of the VTE history; for example, the age of the patient and any provoking factors such as immobility, surgery or pregnancy.
• Before testing, patients should be counselled about the implications of a positive result.

Investigation^2,3

Important points

• Do not test for heritable thrombophilia at the time of acute venous thromboembolism (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 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.
• Pretest patient counselling and a physician with specialist knowledge are recommended.

The initial tests

• Full blood count and film - looking for 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.^2,14

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.
  • Should be considered when there is a severe familial thrombotic tendency in the absence of the other heritable thrombophilias mentioned above.
  • Test details are given in recent guidelines.³

Management of thrombophilia^1,2

See also Pregnancy and postnatal section, below.

Management of acute venous thromboembolism (VTE)³

• For an acute VTE, use standard treatment, i.e. heparin initially, followed (if not pregnant) by warfarin.²
• Decisions regarding duration of anticoagulation (lifelong or not) in unselected patients should be made with reference to whether or not a first episode of venous thrombosis was provoked or not, other risk factors, and risk of anticoagulant therapy-related bleeding, regardless of whether a heritable thrombophilia is known.

Minimising VTE risk

• 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, e.g. surgery, immobility, pregnancy and postnatal.
• 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.
  • World Health Organization (WHO) guidelines state that known thrombogenic mutations, or a history of VTE, are absolute contra-indications to the combined contraceptive preparations.¹⁵
  • Progestogen-only contraceptives can be used.
• Preconception advice.¹⁶

Consider thromboprophylaxis²

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 (e.g. 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 postnatal¹⁶

Background

• 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).

Recent Royal College of Obstetricians and Gynaecologists (RCOG) Green Top Guidelines¹⁶ give detailed guidance for reducing venous thromboembolism (VTE) risk in all pregnant and postnatal women, including those with known or suspected thrombophilia or a past/family history of VTE. See prevention section in separate article Venous Thromboembolism in Pregnancy.

Potential complications of thrombophilia

• Complications of venous thromboembolism (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.² However, this remains an area of debate.^17,18
• Warfarin-induced skin necrosis in patients with protein C or S deficiency:
  • This is extremely rare, and may be due to rapid initiation of warfarin in the absence of heparin.³For details, see Protein C deficiency separate article.
• Possible association with arterial thrombosis:
  • There may be a link between thrombophilia and arterial thrombosis,¹⁹ although the evidence is limited. As a contributor to arterial disease, thrombophilia is probably less important than the established cardiovascular risk factors.³
• Anxiety resulting from thrombophilia testing and results.²⁰

Prognosis^2,7

Venous thromboembolism (VTE) is a multifactorial disease. The VTE risk depends not only on the specific thrombophilia (see table above), 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, but this increases to 35-50 when taking oestrogen-containing contraception, and 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.

Document references

1. Thrombophilia, British Heart Foundation (Factfile), 2002.
2. Investigation and management of heritable thrombophilia, British Committee for Standards in Haematology (2001)
3. Clinical guidelines for testing for heritable thrombophilia, British Committee for Standards in Haematology (December 2009)
4. Khan S, Dickerman JD; Hereditary thrombophilia. Thromb J. 2006 Sep 12;4:15. [abstract]
5. Tait RC, Walker ID, Reitsma PH, et al; Prevalence of protein C deficiency in the healthy population. Thromb Haemost. 1995 Jan;73(1):87-93. [abstract]
6. Dykes AC, Walker ID, McMahon AD, et al; A study of Protein S antigen levels in 3788 healthy volunteers: influence of age, Br J Haematol. 2001 Jun;113(3):636-41. [abstract]
7. Dahlback B; Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood. 2008 Jul 1;112(1):19-27. [abstract]
8. Dutta TK, Venugopal V; Venous thromboembolism: the intricacies. J Postgrad Med. 2009 Jan-Mar;55(1):55-64. [abstract]
9. Ataga KI; Hypercoagulability and thrombotic complications in hemolytic anemias. Haematologica. 2009 Nov;94(11):1481-4.
10. Jong E, Louw S, Meijers JC, et al; The hemostatic balance in HIV-infected patients with and without antiretroviral AIDS Patient Care STDS. 2009 Dec;23(12):1001-7. [abstract]
11. Bertina RM; Elevated clotting factor levels and venous thrombosis. Pathophysiol Haemost Thromb. 2003 Sep-2004 Dec;33(5-6):395-400. [abstract]
12. Cuker A, Pollak EC, Protein C deficiency, eMedicine, Jun 2009
13. Venous thromboembolism - reducing the risk, NICE Clinical Guideline (January 2010); Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital
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. [abstract]
15. Medical eligibility criteria for contraceptive use. World Health Organization, 2004
16. Reducing the Risk of Thrombosis and Embolism during Pregnancy and the Puerperium, Royal College of Obstetricians and Gynaecologists (November 2009)
17. Pabinger I; Thrombophilia and its impact on pregnancy. Thromb Res. 2009;123 Suppl 3:S16-21. [abstract]
18. Said JM, Higgins JR, Moses EK, et al; Inherited thrombophilia polymorphisms and pregnancy outcomes in nulliparous Obstet Gynecol. 2010 Jan;115(1):5-13. [abstract]
19. Martinelli I, Bucciarelli P, Mannucci PM; Thrombotic risk factors: basic pathophysiology. Crit Care Med. 2010 Feb;38(2 Suppl):S3-9. [abstract]
20. 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. [abstract]

Internet and further reading

• Esmon CT; Basic mechanisms and pathogenesis of venous thrombosis. Blood Rev. 2009 Sep;23(5):225-9. [abstract]
• Raffini L; Thrombophilia in children: who to test, how, when, and why? Hematology Am Soc Hematol Educ Program. 2008:228-35. [abstract]
• Varga EA, Kerlin BA, Wurster MW; Social and ethical controversies in thrombophilia testing and update on genetic Semin Thromb Hemost. 2008 Sep;34(6):549-61. Epub 2008 Nov 28. [abstract]
• Tsiolakidou G, Koutroubakis IE; Thrombosis and inflammatory bowel disease-the role of genetic risk factors. World J Gastroenterol. 2008 Jul 28;14(28):4440-4. [abstract]
• Freeman HJ; Venous thromboembolism with inflammatory bowel disease. World J Gastroenterol. 2008 Feb 21;14(7):991-3. [abstract]
• Wu O, Robertson L, Langhorne P, et al; Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost. 2005 Jul;94(1):17-25. [abstract]
• Cohn D, Vansenne F, de Borgie C, et al; Thrombophilia testing for prevention of recurrent venous thromboembolism. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD007069. [abstract]
• Simpson EL, Stevenson MD, Rawdin A, et al; Thrombophilia testing in people with venous thromboembolism: systematic review Health Technol Assess. 2009 Jan;13(2):iii, ix-x, 1-91. [abstract]

Acknowledgements