American Society of Hematology

Coming of Age and Thrombosis: It's All in the Family

Margaret V. Ragni, MD, MPH

Published on: May 01, 2011

Dr. Ragni indicated no relevant conflicts of interest. 

Zöller B, Li X, Sundquist J, et al. Parental history and venous thromboembolism: a nationwide study of age-specific and sex-specific familial risks in Sweden. J Thromb Haemost. 2011;9:64-70. 

Genetic risks for venous thromboembolism (VTE) are known to include factor V Leiden and prothrombin G20210A mutations, as well as deficiencies of antithrombin, protein C, and protein S. Only 50 percent of the variability in inherited thrombophilia is attributed to familial risk, but even standard VTE risk factors, such as age, immobilization, trauma, malignancy, and estrogen, do not explain the differences in familial VTE risk between children and adults.

Utilizing a nationwide registry, the Swedish Multigeneration Register, linked to hospital discharges, Dr. Zöller and colleagues looked for other determinants of VTE risk among families during the 20-year period of 1987 to 2007. Specifically, they compared cases of VTE (deep venous thrombosis [DVT] and/or pulmonary embolism [PE]), defined by ICD-9 and ICD-10 codes, in offspring of parents hospitalized for VTE and offspring of unaffected parents, specifically calculating the ratio of observed to expected VTE cases, known as standardized incidence ratios (SIR). Linkages were made through individual national identification numbers for each of the 45,362 patients identified on the basis of the first discharge. The ICD codes included DVT, PE, superficial venous thrombosis, and other thromboses, such as portal vein, cerebral vein, and pregnancy-related thromboses.

Parental history of VTE was a strong risk factor for VTE. Of 4,865 children, among whom at least one parent had VTE, the SIR for VTE was 2.00 (95% CI, 1.94-2.05). VTE risk was higher among males, with a SIR of 2.08 (2.00-2.16) and was higher among those in whom both parents were affected, with a SIR of 3.97 (3.40-3.61). Age-specific VTE rates were increased for offspring, with the highest VTE risk in those 10-19 years of age, with a noted SIR of 3.96 (3.13-4.94) and lowest VTE risk in those 70-75 years of age, at a SIR of 1.48 (1.17-1.84). No increase was noted in those under 10 years of age.

There are potential biases in this dataset, which include missing non-hospitalized individuals or those not identified by ICD codes, but these biases are likely to be similar between the groups studied, so the bias is not likely to be selective.

These findings have important implications. First, parental history of VTE is an important risk factor for VTE and should be an important element of clinical history. Second, the contribution of parental VTE to VTE risk decreases with age even though the overall risk of VTE increases, suggesting that familial VTE history is most important at younger ages. Third, children under 10 years of age, even in thrombophilic kindreds, have no increase in VTE risk. Because VTE risk associated with familial VTE is greatest between the ages of 10 and 50, the latter age group should be the primary focus of genome-wide association studies.

Familial Standardized Incidence Rates (SIR) for VTE 

Group Males Females 
With VTE in any parent

2.08 (95% CI: 2.00-2.16) 

1.91 (95% CI: 1.84-1.99) 

With VTE in father

2.09 (95% CI: 1.97-2.22)

2.03 (95% CI: 1.91-2.16)
With VTE in mother

2.03 (95% CI: 1.93-2.13)

1.80 (95% CI: 1.70-1.89)

With VTE in both parents

4.28 (95% CI: 3.44-5.25) 

3.67 (95% CI: 2.91-4.57)
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