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Table 1: Acquired and Inherited Causes of VTE †
Acquired	Inherited
Neoplastic Conditions Pregnancy Oral Contraceptive Use Surgery /Trauma (prolonged immoblization) Antiphospholipid antibodies Prior VTE Advancing Age	Factor V Leiden mutation Prothrombin mutation MTHFR mutations Protein C or S deficiency Antithrombin III deficiency Dysfibrinogenemia
†: This list is not intended to be exhaustive

History of Inherited Thrombophilia

Hemostasis is a critical function for complex organisms and involves a delicate balance between procoagulant and anticoagulant factors (Figure 1). The involved proteins in this system are encoded for by a number of genes in the DNA. Historically, genetic factors were felt to be only rare contributors to the risk of developing VTE. Deficiencies in proteins C and S along with antithrombin III deficiency were among the first genetic conditions to be implicated in VTE. They are characterized by autosomal dominant inheritance (present in each generation with 50% risk of transmission to offspring) and may be implicated in only about 5-7% of cases of VTE. In these rare instances, recognition that a genetic cause of VTE was present typically occurred in the setting of recurrent VTE and/or a family history of VTE in close relatives. The documentation of low levels of the various factors confirmed the diagnoses in these cases.

Increased Recognition of Genetic Factors

From a genetic standpoint, the clinical landscape began to change when, in the early 1990s, researchers began to collect and study families that contained multiple members affected by VTE or recurrent VTE (suggesting a genetic mechanism) but who did not have detectable deficiencies in certain factors. The discovery that a proportion of these patients were resistant to the action of activated protein C was foundation for the discovery, in 1994, of the factor V Leiden mutation (described below). A year later a prothrombin mutation was discovered as another VTE risk factor. These findings, merged with new understanding of the genetic basis of mildly elevated homocysteine levels, elevated genetic considerations into a position of importance in evaluating VTE. Although the absolute risks of VTE in patients with these mutations are modest compared with those in the cases of protein C/S and antithrombin III deficiencies, the impact on VTE is noteworthy as the mutations are relatively common. When the effects of factor V, prothrombin, and homocysteine are considered, a genetic component to the development of VTE can now be identified in 30-45% of unselected thrombotic episodes (Table 2).

Table 2: Prevalence of genetic mutations in healthy individuals and persons with VTE
Inherited Risk for VTE	Healthy Persons (%)	Persons with VTE (%)	Odds Ratio
Protein S	?	2.3	?
Protein C	0.2-0.4	3.7	9.3-18.5
Antithrombin III deficiency	0.02	1.9	95
Prothrombin mutation	2.7	7.1	2.6
Factor V Leiden mutation	4.8	20	4.2
From: Seligsohn 2001 and Rosendaal 1999

The Genetic Basis of Factor V Leiden and Prothrombin Mutation

The factor V Leiden and prothrombin gene mutations are the two most common genetic risk factors for VTE, being present in approximately 25% of cases of VTE [Seligsohn 2001]. A detailed explanation of the molecular genetic aspects of these two important mutations is beyond the scope of this review. A familiarity with the fundamental concepts behind these mutations, however, is of value in understanding these mutations in a clinical context. In the 1990s it was recognized that a proportion of VTE patients demonstrated resistance to activated protein C (APC). Protein C functions as an anticoagulant, in part by inactivating factor V (which has procoagulant activity). In the APC resistant patients the anticoagulant activity of APC on factor V is attenuated ("the factor V is resistant to the actions of APC").

In approximately 80% of the APC-resistant patients, an explanation for the "resistance" lies in a mutation in the gene for factor V. The mutation, a single nucleotide change, alters the amino acid sequence of factor V and is called the factor V Leiden mutation (Leiden is the city where the mutation was first detected). The alteration occurs exactly at one of the sites of action for APC, rendering APC less efficient at inactivating the factor V. With effectively more factor V (a procoagulant), an increased tendency to VTE is present.

Persons carrying a factor V mutation are at an increased risk of developing VTE (approximately 20% by mid-adulthood) [Zoller 1997], which represents a 4- to 7-fold risk over non-carriers. This risk is not particularly striking, except for the observation that roughly 5% of the general population carries a single factor V mutation (as high as 15% in Northern Europe). It is the presence of a "modest" VTE risk spread over a large number of individuals that accounts for the importance of this mutation. Homozygotes (individuals with two factor V mutations) have a greatly increased risk of VTE, estimated to be roughly 80-fold over the general population.

Other Genetic Risk Factors for VTE

Table 3* "High Priority" Tests for VTE

Factor V Leiden Variant†

Prothrombin Variant†

Serum Homocysteine

Factor VIII (elevated)

Lupus Anticoagulant

*Adapted from Seligsohn 2001 † DNA based test

The list of other genetic contributors to VTE continues to grow. The genetic basis of protein C and S deficiency and antithrombin III deficiency are now reasonably well established. More recently, attention has focused on mutations in the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) as leading to modest increased levels of homocysteine which is a risk factor for VTE and arterial events. A general algorithm for determining which genetic tests to pursue (and in what order) based on the prevalence of the individual mutations has recently been suggested [Seligsohn 2001]. In this clinically oriented review, Seligsohn and Lubetsky suggest a diagnostic workup based on tests that should be given "high priority" (more common contributors to VTE), "intermediate priority," and "low priority" (rarely contributing to VTE). The "high priority" tests suggested are listed in Table 3.

Multiple Risk Factors for VTE

As more is learned about genetic contributors to VTE it has become increasingly clear that in many cases more than one risk factor may be present. This finding fits well with the concept that the genetic mutations are best thought of as being risk factors for VTE, rather than causative of VTE. As suggested previously, referring to these genetic changes as "variants" highlights their roles as risk factors rather than powerful mutations that inevitably cause disease. In the case of factor V Leiden mutations, for instance, 20% of mutation carriers develop VTE by mid-adulthood, implying that 80% of the carriers do not develop VTE by this age. The interaction of multiple risk factors justifies the approach suggested by Table 3 where a panel of VTE risk factor testing is performed.

Clinical Application of Genetic Evaluation for VTE

The genetic thrombophilia field continues to evolve and the relatively novelty of these discoveries means that long-term prospective data on the use of this information to promote health and prevent disease is clearly lacking. Not surprisingly an overall consensus on how best to integrate this knowledge into clinical practice has proven to be elusive. The American College of Medical Genetics has addressed the uncertainties in this area with a published statement outlining the reasonable use of factor V Leiden testing (Table 4). These guidelines are intended to assist clinicians in evaluating patients with venous thromboembolism. In many cases the involvement of a geneticist and/or hematologist familiar with the thombophilias is entirely appropriate.

Thrombophilia and Oral Contraceptive Use

As the factor V mutations and prothrombin gene mutations are relatively common, a consideration of these disorders in women who take oral contraceptives (OCPs) is warranted. There has been (and continues to be) some debate over whether women taking OCPs should undergo counseling and screening for common prothrombotic states. Based on case-control studies it appears that the factor V Leiden mutation greatly increases the risk of thrombosis in women taking OCPs. Estimates of as high as a 35-fold risk of thrombosis is found in women who are both factor V Leiden mutation carriers and taking OCPs [Andersen 1998]. Furthermore, female carriers of factor V mutations who begin OCPs appear to develop thromboembolic disease sooner than non-carriers who initiate OCPs [Bloemenkamp 2000]. These strikingly elevated risks have led some to suggest that universal screening for factor V mutations should be done for all women prior to initiation of OCPs. However, for women with a negative personal or family history of thromboembolic events, this strategy proves to be relatively costly and inefficient. It is estimated that perhaps as many as 500,000 women would need to be screened for factor V mutations to prevent a single excess death from pulmonary embolism [Vandenbroucke 1996].

An additional concern is that a substantial number of women would be identified with factor V Leiden mutations who would not have developed thrombosis on OCPs. Potentially denying this group of women OCPs and exposing them to the risks associated with pregnancy generates concerns about competing risks for these women. Based on these estimates and concerns it seems more prudent to selectively offer screening only to women who are identified as being at elevated risk from family history data.

Summary

Hemostasis is a complex balance between thrombosis and bleeding that is coordinated through a number of interacting proteins. Mutations in a number of the genes encoding these proteins have been identified and it is now clear that hereditary factors contribute significantly to thromboembolic disease. The factor V Leiden and prothrombin gene mutations account for as much as 25% of venous thromboembolic disease and merit consideration in the workup of VTE disease. Universal screening for thrombophilias is not currently recommended. However, testing for factor V Leiden mutations has been recommended for thrombosis characterized by: age<50, recurrent event, in pregnancy, in combination with OCPs, in relatives of individuals who had VTE before age 50, in tobacco-using women with myocardial infarctions before age 50, and in the presence of VTE at "unusual sites." In particular, women with factor V Leiden mutations who use OCPs appear to be at high risk of VTE. With an ever-growing number of available genes/proteins to test, prioritization of "high yield" testing strategies has been recommended. In the near future, the development of inexpensive "thrombophilia panels" may make the evaluation of thrombophilia genes commonplace in clinical practice.

References

Anderson FA, Wheeler HB, Goldberg RJ, et al.. A population based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT study. Archives of Internal Medicine 1991; 151: 933-38.Anderson BS, Olsen J, Neilsen Gl, et al.. Third generation oral contraceptives and heritable thrombophilia as risk factors of non-fatal venous thromboembolism. Thrombosis and Haemostasis 1998; 79:32-31.Bloemenkamp KWM, Rosendaal FR, Helmerhost FJ, Vandenbroucke JP. Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects. Archives of Internal Medicine 2000; 160: 49-52.Grady WW, Griffin JH, Taylor AK, Korf BR, Hier JA. American College of Medical Genetics Consensus Statement on Factor V Leiden Mutation Testing. Genetics in Medicine 2001; 3: 139-148.Hansson PI, Werlin L, Tibblin G, Eriksson H. Deep vein thrombosis and pulmonary embolism in the general population. Archives of Internal Medicine 1997; 148: 1665-70.Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis with a defined urban population. Journal of Internal Medicine 1992; 232: 155-60.Rosendaal FR. Thrombosis in the young: epidemiology and risk factors, a focus on venous thrombosis. Thrombosis and Haemostasis 1997; 78: 1-6.Rosendaal FR. Venous thrombosis: a multicausal disease. The Lancet 1999; 353: 1167-73.Rubinstein I, Murray D, Hoffsein V. Fatal pulmonary emboli in hospitalized patients: an autopsy study. Archives of Internal Medicine 1998; 148: 1425-26.Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. New England Journal of Medicine 2001; 344: 1222-31.Zoller B, Hillarp A, Berntorp E, Dahlback B. Activated protein C resistance due to a common factor V gene mutation is a major risk factor for venous thrombosis. Annual Review of Medicine 1997; 48: 45-58.

Vandenbroucke JP, van der Meer FJM, Helmerhost FM, Rosendaal FR. Factor V Leiden: should we screen oral contraceptive users and pregnant women? BMJ 1996; 313: 1127-30.

Contributed by Matthew Taylor, MD (CO)

The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Regional Genetic Services Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131

Genetic Considerations in Thrombotic Disorders
Table of Contents

Introduction
Adult Thrombotic Disorders
Pediatric Thrombotic Disorders
Fetal and Neonatal Effects of Maternal/Fetal Thrombotic Disorders
Teratogen Hot Topic: Anticoagulants
Heterozygote Counseling for Factor V Leiden mutation