PROC c.574_576del polymorphism: a common genetic risk factor for venous thrombosis in the Chinese population

Abstract

See also Hamasaki N. Unmasking Asian thrombophilia: is APC dysfunction the real culprit? This issue, pp 2016–8. Summary. Background: There are ethnic differences in the genetic risk factors for venous thrombosis (VT). The genetic causes of VT in the Chinese population are not fully understood. Objectives: To identify possible common abnormal factors that could contribute to thrombosis susceptibility. Methods/Results: We measured the levels of nine types of plasma coagulation factor, three types of anticoagulation factor and two types of fibrinolytic factor in 310 VT patients. Factor V activity was higher in 32 cases. Eleven of the 32 cases also had low protein C (PC) or protein S (PS) activities, indicating PC or PS deficiency. No other abnormalities were observed in the other 21 cases. All of the samples were sensitive to activated PC inactivation. Therefore, the abnormal factor involved may be FV inactivator or its cofactor rather than FV itself. Resequencing identified a common PROC c.574_576del variant in 10 of the 32 subjects. In a case–control study, this variant was detected in 68 of the 1003 patients and in 25 of the 1031 controls. It had an adjusted odds ratio of 2.71 (95% confidence interval [CI] 1.68–4.36). PC amidolytic activities of most variant carriers were similar to those of non‐carriers, but the mean anticoagulant activity was only 72.7 U dL−1. Expression studies in vitro showed that the anticoagulant activity of the mutant PC was 43.6% of that of the wild‐type PC. Conclusions: We identified what is, so far, the most common genetic risk factor for VT in the Chinese population, with its prevalence being approximately 2.36%.

Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

“…In China, two recent studies found two predominant mutations of PROC, Lys173del and Arg189Trp, both in VTE patients and in the general population (Table 3). 32,33 In our study, Lys173del and Arg189Trp were observed in three and one patients, respectively, but not in the population group ( Figure 1A). Of note, all three patients with heterozygous Lys173del also had another PROC mutation (Table 2).…”

“…Since Lys173del does not result in a significant decrease of the amidolytic activity of PC, it is plausible that any heterozygous carriers of Lys173del in the patient or population group would have been missed in this study. 33 Studies from Western countries have shown that PC deficiency is the most frequent natural anticoagulant deficiencies in VTE patients, followed by PS and AT deficiency, with limited reports on predominant mutations. 2,9 Ala416Ser (or Ala384Ser) of SERPINC1 (antithrombin Cambridge II) was reported to be frequent both in VTE patients and in the general population in Britain, while it was not detected in China.…”

“…Although the PC activities of these three patients were 41-62%, the phase of the two mutations could not be inferred without testing their parents because of the minimal decrease of the amidolytic activity of PC in Lys193del carriers. 33 The two SERPINC1 mutations in Patient SMC-Pt-AT21 were inferred to be on the same allele (cis) considering the AT activity of 43%. Of note, the mean age of onset of disease in four patients with severe deficiency from Genetic thrombophilia in Korea haematologica | 2014; 99(3) 567 © F e r r a t a S t o r t i F o u n d a t i o n compound heterozygous mutations was lower than that in the other four patients (23 versus 39 years).…”

Fetal hydrocephalus and neonatal stroke as the first presentation of protein C deficiency

“…In 92 term newborns with ischemic strokes [8], 62 patients (68%) had at least one prothrombotic risk factor compared with 44 controls (24%), and PC-type I deficiency was found in 6 neonates. Table 1 shows the summary of heritable PC-deficiency associated with fetal ventriculomegaly [3,5,6]. Four reported patients were considered to carry the biallelic mutation.…”

“…Direct sequencing of the coding and promoter regions of PROC determined a heterozygous mutation in exon 7 of PROC c.574_576delAAG, p.Lys193del in both the infant and his healthy father. The 3-base deletion raises the thromboembolic risk in Japanese [5] and Chinese populations [6]. The infant had no explainable causes of ventriculomegaly and infarction other than the deletion, although PC-activity of his father was 100% (one time study).…”