Normal ranges and genetic variants of antithrombin, protein C and protein S in the general Chinese population. Results of the Chinese Hemostasis Investigation on Natural Anticoagulants Study I Group

Abstract

The online version of this article has a Supplementary Appendix. BackgroundInherited deficiency of antithrombin, protein C and protein S, three important, naturally occurring coagulation inhibitors, might play a major role in the occurrence of venous thromboembolism in Chinese. The establishment of age-and gender-related normal ranges of these inhibitors is crucial for an accurate diagnosis of these deficiencies. Design and MethodsWe designed a prospective cross-sectional study recruiting healthy adults from four universityaffiliated hospitals in China. Antithrombin, protein C and protein S were studied by measuring their activity. Gene analysis was performed when natural anticoagulant deficiency was suspected. Polymorphisms of the factor V gene were searched for among subjects who were positive for activated protein C resistance. ResultsIn 3493 healthy Chinese adults (1734 men, 1759 women; age 17-83 years), we found higher age-adjusted activities for protein C and protein S in men than in women but no sex difference for antithrombin. In women, mean protein C and protein S activities increased with age. In men, mean protein C levels increased with age up to the age of 49 but decreased after 50 years old; mean protein S levels decreased after 50 years of age. Antithrombin levels remained stable over time in women but decreased significantly after 50 years of age in men. Reference values according to age and sex allowed the identification of 15 genetic variants (protein C: 10, antithrombin: 3, protein S: 2) in subjects with protein activity below the 1 st percentile. ConclusionsThis is the largest survey ever conducted in the healthy general Chinese population. These normal ranges provide the essential basis for the diagnosis and treatment of thrombosis in Chinese.Key words: antithrombin, protein C, protein S, normal ranges, genetics, Chinese. Citation: Zhu T, Ding

Protein C Thr315Ala variant results in gain of function but manifests as type II deficiency in diagnostic assays

“…In both types of assays, PC in patient's plasma is activated with an activator derived from the venom of a specific snake (Protac) followed by evaluation of APC activity employing either a plasma-based activated partial thromboplastin time (aPTT) assay or a synthetic peptide-based chromogenic assay. 14,15 In a recent study aimed at establishing the normal range of PC in the healthy population, we identified a healthy subject whose PC:Ag and PC:A levels were 65%, 50% (chromogenic assay), and 36% (clotting assay) of the normal range, respectively. 15 Noting a lack of family history of VTE for the proband, we decided to determine whether a mutation in the PC gene (PROC) was responsible for this apparent type II PC deficiency.…”

“…14,15 In a recent study aimed at establishing the normal range of PC in the healthy population, we identified a healthy subject whose PC:Ag and PC:A levels were 65%, 50% (chromogenic assay), and 36% (clotting assay) of the normal range, respectively. 15 Noting a lack of family history of VTE for the proband, we decided to determine whether a mutation in the PC gene (PROC) was responsible for this apparent type II PC deficiency. Genetic analysis revealed that the proband has a heterozygous missense mutation in PROC leading to substitution of Thr-315 of the PC heavy chain with Ala. 15 In this study, we expressed this PC mutant in HEK-293 cells and purified it to homogeneity.…”

“…15 Noting a lack of family history of VTE for the proband, we decided to determine whether a mutation in the PC gene (PROC) was responsible for this apparent type II PC deficiency. Genetic analysis revealed that the proband has a heterozygous missense mutation in PROC leading to substitution of Thr-315 of the PC heavy chain with Ala. 15 In this study, we expressed this PC mutant in HEK-293 cells and purified it to homogeneity. Following activation, we characterized the anticoagulant and anti-inflammatory properties of the APC mutant in purified, plasma-based, and cell-based assay systems.…”

Molecular basis of protein S deficiency in China

“…The prevalence of heterozygous ProS deficiency is 2-8% in thrombosis patients in Caucasian populations [15], whereas the prevalence in the general population is estimated to be 0.03-0.13% in Caucasians and 0.06-1.12% in Southeast Asians [16][17][18]. Familial and case-control studies suggest that PSD is associated with a 2.5-to 11-fold increased risk of venous thrombosis [15,19,20].…”

Different impact of two mutations of a novel compound heterozygous protein C deficiency with late onset thrombosis

“…An estimated prevalence of the heritable PC deficiency is reported ranging from 0.2 to 0.5% (Esmon, 1987;Miletich et al, 1987). Many individuals affected with PC deficiency from a heterozygous mutation remain asymptomatic for life (Miletich et al, 1987;Zhu et al, 2011). The prevalence of symptomatic hereditary PC deficiency in the population is estimated between 1:16,000 and 1:36,000 (Formstone et al, 1996).…”