(Circulation. 1997;95:1749-1751.)
© 1997 American Heart Association, Inc.
Articles |
Interrelated Risk Factors for Venous Thromboembolism
the Division of Hematology, University of Texas–Houston.
Correspondence to Martin D. Phillips, MD, Division of Hematology, University of Texas–Houston, 6431 Fannin St, Room 5.278 MSB, Houston, TX 77030. E-mail martinp{at}heart.med.uth.tmc.edu
Key Words: Editorials • homocysteine • risk factors • thrombosis, venous • activated protein C resistance
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Introduction |
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 Top Introduction References |
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The concept of multiple risk factors interacting to cause arterial thrombotic disease is well established. Conversely, venous thrombotic events are often described as discrete events, even though many of the known risk factors for venous thrombosis are lifelong. In most cases, it remains enigmatic why any particular thrombosis occurs. Unanswered questions include why there is often a 30- or 40-year lag before the first thrombosis in many patients with documented congenital hypercoagulable states. Why do first-degree relatives of affected patients who share the defective gene generally have only a 50% lifetime risk of developing thrombosis?
In part, the answers to these questions are that several factors, congenital and acquired, must operate in concert to defeat the redundancy of antithrombotic mechanisms. An article in this issue of Circulation1 demonstrates an interaction of two such risk factors: activated protein C resistance and moderate hyperhomocyst(e)inemia. Alone, each factor carries a modest risk of thrombosis. Together, they exponentially increase the probability of thrombosis. In addition, unlike the previously described risk factors, homocyst(e)inemia is potentially treatable.
Both of these mechanisms that contribute to the development of venous thrombosis have been described recently. The first is factor V Leiden, the cause of most cases of resistance to activated protein C.2 This point mutation in the factor V molecule greatly decreases the rate of inactivation of factor Va by activated protein C.3 The factor V Leiden point mutation does not alter the plasma concentration or coagulant activity of factor V but only stabilizes it against proteolytic inactivation. Factor Va and factor Xa together form the "prothrombinase complex" that generates thrombin from prothrombin. The downregulation of this complex by activated protein C and protein S appears to be a very important step in the control of a prothrombotic response, demonstrated by the propensity to venous thrombosis of individuals who are deficient in either protein C or protein S or resistant to their action. Furthermore, inhibition of this complex is the primary mode of action of low-molecular-weight heparin and a lesser target of standard heparin.
Factor V Leiden is a very common mutation. About 4% of Caucasians are heterozygous and <0.1% are homozygous for this mutation, with some known racial and ethnic differences.4 Heterozygotes have a 3-fold and homozygotes an 80-fold lifetime relative risk of venous thrombosis. There is no association with myocardial infarction or stroke,5 although resistance to activated protein C by a mechanism other than factor V Leiden may predispose to stroke.6 The observation that heterozygosity of factor V Leiden is very common but the relative risk of thrombosis it confers is modest infers that there must be additional factors contributing to the development of thrombosis.
The other recent development is the understanding that moderately elevated plasma levels of homocysteine are associated with both venous7 and arterial thrombosis (reviewed by Mayer et al8 ). The observation began with individuals with the rare disorder of homozygous homocystinuria, in which there are extremely high plasma levels of homocysteine and related metabolites. This inborn error of metabolism is associated with profound premature atherosclerosis and venous thrombosis. Subsequently, the investigation of apparently normal patients with otherwise unexplained venous thrombosis demonstrated a greater-than-expected number of individuals with blood homocysteine levels above the 95th percentile. These patients have "moderate homocyst(e)inemia," that is, levels statistically above the population norm but not the extreme elevations of the rare homozygous patients with homocystinuria. It remains unproved whether the moderate elevation of homocysteine directly or indirectly causes the thrombotic tendency or if it is only a marker of another, perhaps intracellular, disorder. A point mutation in the enzyme methylenetetrahydrofolate reductase has been associated with some cases of moderate hyperhomocyst(e)inemia.9 Other known causes include a dietary deficiency of folate or vitamin B12,10 cigarette smoking,11 chronic renal dialysis,12 and organ transplantation.13
Overall, a moderately elevated homocysteine level is a weak risk factor for venous thrombosis. Many studies have examined the relationship between moderate homocyst(e)inemia and venous thrombosis. A recent case-control analysis demonstrated the risk well.7 Although both sexes and all age groups demonstrated a trend toward an association of elevated homocysteine and venous thrombosis, only in women >50 years old was the association statistically significant. Smaller studies have not observed any association.14
It is becoming apparent that the development of venous thrombosis is multifactorial. Despite the capacity to measure plasma levels of natural anticoagulant proteins and homocysteine and the wide availability of a polymerase chain reaction assay for factor V Leiden, the causes of many cases of venous thrombosis remain unknown. The mechanisms by which these entities cause thrombosis are similarly unclear. Other acquired influences, including trauma, malignancy, and immobility, contribute to the development of venous thrombosis.
A very-well-performed study in this issue of Circulation begins to address the multiple risk factors of causation of venous thrombosis. Ridker and colleagues1 evaluated the occurrence of factor V Leiden and moderate elevations of homocysteine in participants of the Physicians' Health Study who had experienced their first venous thrombosis during the study period. Consistent with other studies, there is a weak association of an elevated total homocysteine level with venous thrombosis. Interestingly, the strength of the association only achieves statistical significance in patients without cancer, surgery, or trauma, indicating that these risk factors are not additive with moderate homocyst(e)inemia. Also consistent with other studies is the strong association of factor V Leiden with venous thrombosis. Again, the association is stronger in the absence of acquired risk factors.
The incidence of thrombosis with the presence of both factor V Leiden and modestly elevated total homocysteine is striking. This is a rare occurrence but more frequent in the thrombosis group than the 1 in 400 predicted by chance alone and more frequent than in the control group. It can be extrapolated from the data that all of the cases of thrombosis occurred in the absence of cancer, surgery, or trauma, indicating (contrary to intuition) that factor V Leiden and homocysteine alone or combined do not contribute to venous thrombosis occurring in the setting of these acquired risk factors.
The patients in this study are, on average, older than most patients with first thromboses due to factor V Leiden. This would be an expected finding in those thromboses associated with elevated homocysteine levels because homocysteine levels tend to increase with age. First thrombosis after the fifth decade should suggest an evaluation for malignant disease. It will be important to study other cohorts who are younger at the time of first thrombosis to determine if the strong association of both risk factors holds true in the majority of "idiopathic" thromboses.
A potential weakness of this study is that the activity of other anticoagulant and fibrinolytic proteins is not specifically reported. These defects are rare compared with factor V Leiden, so the results would not be likely to have a major influence on the outcome. This study was only designed to relate these two risk factors. Other studies predict that the simultaneous occurrence of two deficiencies is not common, although when two biochemical defects do occur in the same kindred, they are strongly associated with thrombosis.15 16 17
An interesting observation in this study is that cigarette smoking was, if anything, associated with a lack of thrombosis. This is particularly unusual because of the higher mean homocysteine level in smokers. If smoking is a positive risk factor, it is possible that smokers were self-excluded by experiencing complications before study entry. This is a limitation of case-control studies.
How do these findings impact patient care and research? All patients with venous thrombosis, especially in the absence of proximate causes, should be tested for known hypercoagulable states, including fasting plasma homocysteine. If an abnormality is found, consideration should be given to a longer duration of anticoagulation and education of their first-degree relatives of the potential for thrombosis. Although the causation of thrombosis by homocysteine is not firmly established and pharmacological lowering of homocysteine has not been demonstrated to reduce thrombotic risk, it is prudent to treat moderate hyperhomocyst(e)inemia until the results of prospective trials are known.10 18 19 One milligram daily of folate taken orally may lower homocysteine levels and has almost no side effects.20 If it is ineffective, a higher dose or the addition of vitamin B6 or B12 may be useful. Finally, investigations into the mechanisms of pathological thrombosis and the interrelationships of risk factors in all groups of patients are being pursued actively, so that improvements in prediction and therapy of this severe clinical problem can be identified.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. Ridker PM, Hennekens CH, Selhub J, Miletich JP, Malinow MR, Stampfer MJ. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation. 1997;95:1777-1782.
2.
Dahlback B. Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood. 1995;85:607-614.
3.
Kalafatis M, Haley PE, Lu D, Bertina RM, Long GL, Mann KG. Proteolytic events that regulate factor V activity in whole plasma from normal and activated protein C (APC)-resistant individuals during clotting: an insight into the APC-resistance assay. Blood. 1996;87:4695-4707.
4. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet. 1995;346:1133-1134.[Medline] [Order article via Infotrieve]
5.
Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med. 1995;332:912-917.
6.
van der Bom JG, Bots ML, Haverkate F, Slagboom E, Meijer P, de Jong PVTM, Hofman A, Grobbee DE, Kluft C. Reduced response to activated protein C is associated with increased risk for cerebrovascular disease. Ann Intern Med. 1996;125:265-269.
7.
den Heijer M, Koster T, Blom HJ, Bos GM, Briet E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med. 1996;334:759-762.
8. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27:517-527.[Abstract]
9. Kluijtmans LA, van den Heuvel LP, Boers GH, Frosst P, Stevens EM, van Oost BA, den Heijer M, Trijbels FJ, Rozen R, Blom HJ. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;58:35-41.[Medline] [Order article via Infotrieve]
10.
Verhoef P, Stampfer MJ, Buring JE, Gaziano JM, Allen RH, Stabler SP, Reynolds RD, Kok FJ, Hennekens CH, Willett WC. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol. 1996;143:845-859.
11.
Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug JE. Serum total homocysteine and coronary heart disease. Int J Epidemiol. 1995;24:704-709.
12. Bostom AG, Shemin D, Lapane KL, Miller JW, Sutherland P, Nadeau M, Seyoum E, Hartman W, Prior R, Wilson PW, Selhub J. Hyperhomocysteinemia and traditional cardiovascular disease risk factors in end-stage renal disease patients on dialysis: a case-control study. Atherosclerosis. 1995;114:93-103.[Medline] [Order article via Infotrieve]
13. Berger PB, Jones JD, Olson LJ, Edwards BS, Frantz RP, Rodeheffer RJ, Kottke BA, Daly RC, McGregor CGA. Increase in total plasma homocysteine concentration after cardiac transplantation. Mayo Clin Proc. 1995;70:125-131.[Abstract]
14.
Amundsen T, Ueland PM, Waage A. Plasma homocysteine levels in patients with deep venous thrombosis. Arterioscler Thromb Vasc Biol. 1995;15:1321-1323.
15. Koeleman BP, van Rumpt D, Hamulyak K, Reitsma PH, Bertina RM. Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families? Thromb Haemost. 1995;74:580-583.[Medline] [Order article via Infotrieve]
16.
Kalafatis M, Lu D, Bertina RM, Long GL, Mann KG. Biochemical prototype for familial thrombosis: a study combining a functional protein C mutation and factor V Leiden. Arterioscler Thromb Vasc Biol. 1995;15:2181-2187.
17.
Hallam PJ, Millar DS, Krawczak M, Kakkar VV, Cooper DN. Population differences in the frequency of the factor V Leiden variant among people with clinically symptomatic protein C deficiency. J Med Genet. 1995;32:543-545.
18. Ubbink JB, van der Merwe A, Vermaak WJH, Delport R. Hyperhomocysteinemia and the response to vitamin supplementation. Clin Invest. 1993;71:993-998.
19.
Stampfer MJ, Malinow MR. Can lowering homocysteine levels reduce cardiovascular risk? N Engl J Med. 1995;332:328-329.
20.
Campbell NRC. How safe are folic acid supplements? Arch Intern Med. 1996;156:1638-1644.
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