Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study) [see comments]

Abstract

A deficiency of protein C (PC), antithrombin, or protein S is strongly associated with deep-vein thrombosis in selected patients and their families. However, the strength of the association with venous thrombosis in the general population is unknown. This study was a population-based, patient-control study of 474 consecutive outpatients, aged less than 70 years, with a first, objectively diagnosed, episode of venous thrombosis and without an underlying malignant disease, and 474 healthy controls who matched for age and sex. Relative risks were estimated as matched odds ratios. Based on a single measurement, there were 22 (4.6%) patients with a PC deficiency (PC activity, less than 0.67 U/mL or PC antigen, less than 0.33 U/mL when using coumarins). Among the controls, the frequency was 1.5% (seven subjects). Thus, there is a threefold increase in risk of thrombosis in subjects with PC levels below 0.67 or 0.33 U/mL [matched odds ratio, 3.1; 95% confidence interval (CI), 1.4 to 7.0]. When a PC deficiency was based on two repeated measurements, the relative risk for thrombosis increased to 3.8 (95% CI, 1.3 to 10); when it was based on DNA-confirmation, the relative risk increased further to 6.5 (95% CI, 1.8 to 24). In addition, there was a gradient in thrombosis risk, according to PC levels. The results for antithrombin are similar to those for PC, although less pronounced (relative risk, 2.2; 95% CI, 1.0 to 4.7). We could not find an association between reduced total protein S (relative risk, 0.7; 95% CI, 0.3 to 1.8) or free protein S levels (relative risk, 1.6; 95% CI, 0.6 to 4.0) and thrombosis risk. Although not very frequent, PC and antithrombin deficiency are clearly associated with an increase in thrombosis risk.

Familial thrombophilia: genetic risk factors and management

“…Family members with protein C deficiency have an 8-1 0-fold increased risk of venous thrombosis and by the age of 40. half of them will have experienced at least one thrombotic event [ 16,1 7]. This risk is similar to that observed in a population based study [10].…”

“…In a population-based control study the relative risk for APC resistance was 7 whereas for protein C deficiency it was 6. 5 suggesting that the two abnormalities do not differ in severity [10,26].…”

“…Antithrombin deficiency appears to be more clinically severe than deficiencies of protein C and protein S. The prevalence of anti-thrombin deficiency has been reported to be 4% amongst thrombophilic patients [9]. I% in patients presenting with a first DVT [10] and 0.02% in blood donors [II]. The 50-fold difference in the prevalence among patients with a first event DVT and that in the 'healthy' population of blood donors.…”

The factor VR506Q mutation causing APC resistance is highly prevalent amongst unselected outpatients with clinically suspected deep venous thrombosis

“…Our study demonstrated the FV : R506Q mutation to be an important risk factor in outpatients with DVT. This is in marked contrast to other congenital prothrombotic disorders, which are only rarely found in thrombosis patients [19][20][21][22][23][24]. More than a quarter of the outpatients with venous thrombosis verified by phlebography were found to be carriers of the FV : R506Q mutation, a strikingly high proportion, even larger than figures reported for selected series of thrombosis patients from other countries [2,4,9,12].…”

Genetic Markers Associated With Plasma Protein C Level in African Americans: The Atherosclerosis Risk in Communities (ARIC) Study

“…In the general population, a low level of circulating protein C as well as common variants in the protein C gene is associated with increased risk of venous thromboembolism [Folsom et al, Supporting Information is available in the online issue at wileyonlinelibrary.com. * Correspondence to: Weihong Tang Koster et al, 1995;Smith et al, 2007]. Activated protein C has other physiologic effects including anti-inflammatory and antiapoptotic activities and endothelial barrier stabilization [Jackson and Xue, 2008].…”