The clinical link between arterial and venous thrombotic disorders was identified in a case–control study of patients with deep vein thrombosis (DVT) and subclinical atherosclerosis.¹ Subsequently, the first prospective study evaluating the incidence of cardiovascular events after an episode of acute venous thromboembolism (VTE) was conducted and findings indicated a significant association between the incidence of cardiovascular events and acute pulmonary embolism (PE).² It was then suggested that venous and arterial thromboses might be part of a continuous spectrum of the same disease,³ a hypothesis supported by the concept that inflammation and coagulation are interrelated.⁴ Further studies have reported a positive association between DVT or PE, or both, and symptomatic atherosclerosis,^5-7 or markers for risk of arterial thrombosis.⁸ There is inconsistent evidence, however, that arterial disease is a risk factor for VTE^9,10 or that venous thrombosis is a risk factor for arterial disease.^9,11

Atherosclerotic disease and VTE potentially share a common pathogenesis and clinical manifestations and additionally might have overlapping risk factors.^9,10,12 Mechanisms implicated in both arterial and venous thrombosis include endothelial injury, platelet activation, elevated levels of intrinsic clotting factors and inflammatory markers, increased fibrinogen, and impaired fibrinolysis, resulting in thrombus formation in both arteries and veins.⁹ Other environmental factors associated with arterial and venous thromboses include older age, obesity, smoking, diabetes mellitus, arterial hypertension, dyslipidemia, and hormonal determinants.^9,13,14 There is strong evidence that inflammation and thrombosis are implicated in the complications of diabetes and play a role in the development of its vascular complications.^4,15 Studies have shown that high plasma fibrinogen levels are associated with insulin resistance, a condition characterized by impaired glucose tolerance, and might be risk factors for developing type 2 diabetes in individuals.^16,17

Family history of VTE is an established risk factor for VTE among blacks and whites.^18-21 To investigate the effects of traditional cardiovascular risk factors and family history of myocardial infarction (MI) on the incidence of VTE, Braekkan et al²² conducted a prospective, population-based study involving 21 330 adults residing in Tromso, Norway. Their findings indicated that a family history of MI in one or more first-degree relatives with a history of MI before the age of 60 was a risk factor for both MI and VTE. These findings provide evidence of a link between arterial and venous thromboses. Two other prospective studies have investigated the effects of family history of MI on the risk of VTE, one conducted in Norway²³ and one in Sweden.²⁴ In both studies, there was a slightly increased risk of VTE associated with a family history of MI either among first-degree relatives before the age of 60²³ or among parents.²⁴ Furthermore, in a recent report describing findings from a case– control study, Mili et al²¹ found that certain comorbid conditions could further increase the risk of VTE associated with a positive family history of VTE. In addition, it is known that a family history of MI is a risk factor for future MI.^25,26

To examine the association between VTE and a family history of MI among whites and blacks and to confirm the Northern European studies' findings among whites,^22-24 we analyzed data from the Genetic Attributes and Thrombosis Epidemiology (GATE) study.^21,27,28 The GATE study is a matched case–control study of VTE designed to evaluate the roles of genetic polymorphisms and environmental factors and their interaction in the etiology of VTE; the study also compares risk factors for VTE between blacks and whites. The objectives of our report were to evaluate a family history of MI as a risk factor for VTE among blacks and whites and to assess whether such an association would be modified by other risk factors for VTE.

The median age of case patients was 50.0 years (5th percentile, 25 years old; 95th percentile, 68 years old), and the median age of control patients was 50.5 years (5th percentile, 27 years old; 95th percentile, 68 years old). The distribution differences between the 2 ethnic groups and between males and females were not statistically significant (Table 1). While case patients with VTE were less educated than were control patients, a family history of MI, obesity, diabetes, hypertension, cancer, and plasma fibrinogen levels ≥ 3 g/L were risk factors for VTE in unadjusted analyses.

Overall results from our case–control study provided evidence that a family history of MI was a risk factor for DVT or PE, or both, among certain subgroups. Specifically, a family history of MI was associated with VTE among whites but not among blacks. In addition, a family history of MI in a relative younger than 50 years was a stronger risk factor for VTE among whites than among blacks. A family history of MI was also associated with VTE among whites who had diabetes and plasma fibrinogen levels ≥3 g/L. When we assessed the risk of DVT only or PE only among whites, we found a difference in the pattern of a family history of MI between these 2 conditions compared with those without a family history of MI; the risk of DVT only was almost 4-fold increased among whites with diabetes and a history of MI in any relative, whereas for PE only, the risk was 2.5-fold increased among whites with a history of MI in a first-degree relative younger than 50 years. Obesity, hypertension, or cancer did not further increase the magnitude of the association between VTE and a family history of MI among whites or blacks.

Our case–control study confirmed findings reported previously by Braekken et al²² and Quist-Paulsen et al²³ that a family history of MI in a first-degree relative was a risk factor for VTE among whites. Although both of those studies^22,23, and our study differed in study design (prospective vs retrospective, respectively), the order of magnitude of measures of association between VTE and a family history of MI among whites was very comparable between these studies. On the other hand, in a nationwide family study conducted in Sweden, Zöller et al linked data from the nationwide Swedish Cause of Death Register and hospital discharge records for the period 1964 to 2008 and those from the Swedish Muti-Generation Register.²⁴ They observed positive—although very weak—associations between VTE and a family history of MI among offspring whose parents had a history of MI, as well as between VTE and a history of MI among spouses of those with VTE. The risk of VTE, however, was not statistically significant among individuals who had siblings with a history of MI.

In our study, we found black–white differences in the association between VTE and a family history of MI, with a positive and statistically significant association among whites but not among blacks. These ethnic differences might be explained to some extent by genetic thrombophilia. For example, factor V Leiden and prothrombin gene mutation are much more common among whites than blacks and could account in part for the differences in VTE risk. Black–white differences might also be explained by a higher incidence of MI among whites than among blacks, as reported by Alderman et al³³ when describing results from a cohort study of 3382 male participants enrolled in a work-site hypertension control program. In addition, our study revealed that a family history of MI was a risk factor for DVT among whites with diabetes and plasma fibrinogen levels at ≥3 g/L but not among whites who did not have diabetes. This finding might reflect underlying pathophysiologic mechanisms associated with hyperglycemia, inflammation, and coagulation involved in the development of atherothrombotic disease and venous thrombosis.^4,15

From a public health perspective, we found that the adjusted AF for a family history of MI was 4.5% among blacks versus 11.0% among whites. These proportions can be interpreted as the proportion of all case patients with VTE among the study population who were excess case patients, that is, case patients with VTE who would not have had VTE had a family history of MI been absent.³⁴ As anticipated, the AFs for a family history of MI were smaller than the AFs for a family history of VTE in our study (16.9% among blacks vs 18.3% among whites). We estimated that the AF for the joint effect of a family history of VTE and a family history of MI was 16.4% among blacks versus 22.0% among whites. So, for whites, adding information on family history of MI to a family history of VTE increased the AF by about 4%, whereas for blacks, the increase in the AF was negligible. Because a family history of VTE and MI were correlated, information on either one was predictive of VTE, but the association was stronger for a family history of VTE. Nonetheless, a family history of MI added marginally to the AF, at least among whites.

Strengths and limitations of the GATE study have been described previously.¹² For this report, the strength of our study was that it included a large sample of black study participants and, therefore, had the capability for the first time to report measures of association between VTE and a family history of MI among this ethnic group. Our study, however, had several limitations. First, because a family history of MI was self-reported and many participants might not have had recalled MI in their family members, misclassification of exposure might have occurred. Case patients with VTE might have been more likely than control patients to recall having relatives with MI. In this instance, we would have overestimated the familial risk of VTE. Second, our subset analysis focusing on the effect of plasma fibrinogen included only about half of case patients with VTE. The remaining half was excluded because plasma for the fibrinogen assays was not available for them. We believe, however, that case patients who returned for a blood draw did not differ from those who failed to return with respect to their family history status and plasma fibrinogen levels. Third, we were unable to include a family history of stroke in our analysis because information collected for a blood clot in the brain in family members had a 50% or higher rate of missing data (ie, at least half of participants did not know if their relatives' stroke was caused by a blood clot). Therefore, we were not able to assess the risk of VTE among participants with a family history of arterial thrombosis reflected by both MI and ischemic stroke. Future research could include epidemiologic studies in which a family history of both MI and stroke will be collected in participants to better understand the relationship between arterial and venous thromboses. Finally, our analysis did not include a family history of diabetes because the GATE study was not designed to assess specifically the effects of a family history of diabetes on the risk of VTE and, therefore, a history of diabetes among first-degree relatives was not collected from the study participants during the interviews. Future research could integrate a family history of diabetes to assess the joint effect of a family history of arterial thrombosis and a family history of diabetes on the risk of VTE, especially among whites.

In summary, our study revealed a racial difference in the risk of VTE among participants with a family history of MI. Specifically, a family history of MI appeared to be a risk factor for VTE among whites and diabetes could have further increased the risk of VTE associated with a positive family history of MI, especially among whites with plasma fibrinogen levels ≥3 g/L. Our overall results among whites confirmed those from 2 Norwegian prospective studies,^22,23 providing further evidence of the link between arterial and venous thromboses. In addition, our study was the first report of the association between a family history of MI and the risk of VTE. The white–black differences in the familial risk of VTE observed in our study might in part be due to genetic thrombophilia.

We concluded that a family history of MI might be an instrumental tool to detect at-risk family members of patients with VTE among certain populations when it is used in conjunction with a family history of VTE²¹ and to decrease VTE occurrence among family members of case patients with VTE.