A family with a high incidence of venous thromboembolism was investigated. We performed medical evaluations on 184 of the 411 surviving members of the pedigree, which allowed assignment of individuals into positive, equivocal, or negative categories with respect to their clinical histories of thrombosis. Subjects with antigenic levels of protein C less than 66% of a normal plasma pool were classified as having protein C deficiency. Positive thrombotic histories were found in 13 of the 46 family members determined to be protein-C deficient and in only five of their 138 biochemically unaffected relatives. Statistical analysis of the association between thromboembolic disease and protein-C deficiency was strongly positive chi 2 = 24.95, P less than .0001 with n = 184), indicating that heterozygous protein-C deficiency is an important independent risk factor for the development of thrombotic manifestations in this pedigree. However, the absence of thromboembolic manifestations in many of the protein-C deficient family members to date indicates that other, as yet undefined, factors must play an important role in the clinical expression of this disorder.

See also Almasy L. The complex hunt for genes influencing complex disease. This issue, pp 866-7.Summary. Kindred Vermont II has a high frequency of venous thrombosis, occurring primarily in pedigree members with type I protein C deficiency due to a 3363 inserted (Ins) C mutation in exon 6 of the protein C gene. However, only a subset of 3363 InsC carriers have suffered thrombotic episodes, suggesting that the increased risk of thrombosis results upon the co-occurrence of 3363 InsC with a second, unknown, thrombophilic mutation that segregates independently within the pedigree. To test this hypothesis and to localize the co-occurring gene, we performed a genome scan of venous thrombosis in Kindred Vermont II. Non-parametric linkage statistics identified three potential gene locations, on chromosomes 11q23 (nominal P < 0.0001), 18p11.2-q11.2 (P < 0.0007), and 10p12 (P < 0.0003), supporting the presence of at least one additional thrombophilic mutation in the pedigree. Identification of the unknown mutation(s) promises to reveal a new genetic risk factor for thrombophilia, contribute to our understanding of the blood clotting mechanism, and expand our knowledge of the diversity of oligogenic disease.

Summary.  Background: Clinically silent deep vein thrombosis (DVT) is common and may cause chronic venous disease that resembles post‐thrombotic syndrome. Objective: We evaluated whether peripheral venous disease in a general population shares risk factors with DVT. Methods: In an established cohort of 2404 men and women, the San Diego Population Study, peripheral venous disease was evaluated using physical examination, symptom assessment and venous ultrasound. We performed a case–control study including 308 cases in four hierarchical groups by severity and 346 controls without venous abnormalities, frequency matched to cases by 10‐year age group, race and gender. Cases and controls had no prior history of venous thrombosis. Hemostatic risk factors were measured in cases and controls. Results: Accounting for age, obesity and family history of leg ulcer, odds ratios (ORs) of venous disease for elevated factor VIII, von Willebrand factor (VWF), D‐dimer and for factor V Leiden were 1.4 (95% CI 0.9–2.1), 1.5 (CI 1.0–2.3), 1.7 (CI 1.1–2.8) and 1.1 (CI 0.5–2.4), respectively. These associations were larger for the two most severe case groups; ORs 2.0 (CI 1.0–3.8), 1.7 (CI 0.9–3.3), 2.7 (CI 1.2–6.1) and 2.3 (CI 0.8–7.1). Each hemostatic factor was also associated with severity of venous disease, for example elevated D‐dimer was associated with a 2.2‐fold increased odds of being in one higher severity case group. Prothrombin 20210A was not associated with venous disease. Conclusions: DVT risk factors are associated with presence and severity of peripheral venous disease. Results support a hypothesis that peripheral venous disease may sometimes be post‐thrombotic syndrome as a result of a previous unrecognized DVT.

A family with a high incidence of venous thromboembolism over six generations has been investigated. Medical histories have been obtained on 136 of the 368 members of the kindred which allowed assignment of individuals into positive, equivocal, or negative categories with respect to their thrombotic manifestations. Protein C levels were determined by antigenic assay. Patients with protein C levels less than 66% of normal (mean, minus 2 SD) were classified as having protein C deficiency.The mean age of onset of thrombotic manifestations in the 10 protein C deficient patients with a positive history was 33.8 ± 16.4 years while the mean age of the deficient group with a negative history was 22.0 ± 10.9 years. We conclude that there exists a striking association between thromboembolic disease and protein C deficiency within this large New England kindred.