Importance of Family History as a Risk Factor for Venous Thromboembolism
Venous thromboembolism (VTE) is a multifactorial disease with many known genetic and acquired risk factors.1 A positive family history is an independent risk factor for VTE that may reflect the presence of a hereditary thrombophilic disorder. However, the predictive value of a positive family history for detection of known heritable causes of VTE is low,2,3 suggesting that there are as-yet undiscovered genetic or environmental risk factors that account for the familial clustering of this disorder.
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In the current edition of Circulation, Zöller and colleagues4 present the results of their database linkage study that explored the role of family history as a risk factor for VTE. Using unique individual national identifiers to link data from the national Swedish Multigenerational Registry (a family data set that links second-generation Swedes born since 1932 with their siblings) with information from the Swedish Hospital Discharge Register (which contains complete data on all hospital discharge diagnoses since 1986), they identified 45 362 patients hospitalized for deep vein thrombosis, pulmonary embolism, thrombophlebitis (including superficial phlebitis), or thrombosis in unusual sites over a 21-year period. On the basis of results from other population-based epidemiological studies, the reported VTE incidence rates of 32.5 per 100 000 in male and 36.2 per 100 000 in female individuals are somewhat lower than expected,5,6 likely reflecting the high rate of out-of-hospital VTE management in Sweden.7 However, the exponential rise in incidence rates with increasing age is consistent with prior work. As previously reported,5 there is a spike in incidence rates among female individuals 10 to 40 years of age, reflecting the reproductive period; a male predominance then emerges after 50 years of age.
The most striking findings of the study by Zöller and colleagues were the increased incidence rates and standardized incidence ratios for VTE in patients with a history of VTE in ≥1 siblings and the effect of age on the standardized incidence ratios. The overall standardized incidence ratios ranged from 2 to 3, which is consistent with prior reports,3 but the ratios were >20-fold higher among those with ≥2 affected proband siblings than those with a single affected proband sibling, making this one of the strongest risk factors for VTE identified to date (the Table).8 The highest incidence rates among patients with a familial sibling history were observed in those ≥70 years of age (386.5 per 100 000 in male and 374.3 per 100 000 in female individuals), whereas the highest familial standardized incidence ratios occurred at much younger ages (ratio of 4.34 among male individuals 20 to 29 years of age and 5.49 among female individuals 10 to 19 years of age). Familial standardized incidence ratios declined with increasing age, reflecting the diminishing impact of family history as a risk factor for VTE at older ages. Environmental sharing appeared to have little effect on the risk of VTE, a finding that suggests that genetic factors explain most of the increased familial risk.
The study by Zöller et al was rigorously conducted and is the largest population-based study to date that explores the importance of family history as a risk factor for VTE. The study provides robust evidence of the strength of the association and the influence of age and sex on this association. A potential limitation of the study is that it was restricted to hospitalized cases of VTE, thereby excluding information on siblings who were treated as outpatients. One method to explore the impact of excluding outpatients would be to examine the consistency of the results over the 21-year study period because the shift from inpatient to outpatient management of VTE gained increasing popularity over the years. Although this was not done, outpatient management of VTE is unlikely to have had much impact on the standardized incidence ratios because there is no reason to suspect that patients with a familial sibling VTE history would be affected differently by outpatient treatment than those without such a history. Another potential limitation of this study is the lack of information about known risk factors for VTE. The absence of this information precludes exploration into the extent to which genetic and environmental VTE risk factors contribute to the familial clustering of cases.
The findings of this study have implications for clinical practice. Family history is a powerful risk factor for VTE, particularly in those who have >1 sibling with a history of VTE. Known genetic thrombophilic disorders account for only a fraction of the risk conferred by a positive family history,3 indicating that testing family members does little to improve risk prediction. In families in which >1 sibling has a history of VTE, the high risk of VTE mandates vigilance for early detection of recurrent disease, avoidance of recognized environmental risk factors such as estrogen-containing compounds, and vigorous thromboprophylaxis during periods of risk such as surgery or immobilization for medical illness. For young women with a strong family history of VTE, thromboprophylaxis during pregnancy and the puerperium may also be a consideration.
What are the implications of this study for further research? Although thrombophilic disorders are found in 30% to 50% of young patients with VTE, many patients have none of the known defects. The study by Zöller and colleagues suggests that searches for new genetic determinants of VTE should focus on young patients with >1 sibling with a history of VTE.
The pathogenesis of VTE reflects a complex interplay between inherited and acquired risk factors.9 The study by Zöller et al highlights the importance of a family history of VTE over the life cycle. For younger patients, a positive family history is a major risk factor for VTE that trumps known thrombophilic disorders. What are the genetic defects responsible for this association? This is an area that deserves further study.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
- © 2011 American Heart Association, Inc.
- Bezemer ID,
- van der Meer FJ,
- Eikenboom JC,
- Rosendaal FR,
- Doggen CJ
- Zöller B,
- Li X,
- Sundquist J,
- Sundquist K
- Heit JA
- Lindmarker P,
- Holmstrom M
- Anderson FA Jr.,
- Spencer FA
- Varga EA,
- Kujovich JL