Ann Lab Med.  2013 Jan;33(1):8-13. 10.3343/alm.2013.33.1.8.

Activated Protein C Anticoagulant System Dysfunction and Thrombophilia in Asia

• Hamasaki N
• Kuma H
• Tsuda H

• KMID: 1781292
• DOI: http://doi.org/10.3343/alm.2013.33.1.8

Abstract

Thrombophilia that is common among Caucasians is caused by genetic polymorphisms of coagulation factor V Leiden (R506Q) and prothrombin G20210A. Unlike that in Caucasians, thrombophilia that is common in the Japanese and Chinese involve dysfunction of the activated protein C (APC) anticoagulant system caused by abnormal protein S and protein C molecules. Approximately 50% of Japanese and Chinese individuals who develop venous thrombosis have reduced activities of protein S. The abnormal sites causing the protein S molecule abnormalities are distributed throughout the protein S gene, PROS1. One of the most common abnormalities is protein S Tokushima (K155E), which accounts for about 30% of the protein S molecule abnormalities in the Japanese. Whether APC dysfunction occurs in other Asian countries is an important aspect of mapping thrombophilia among Asians. International surveys using an accurate assay system are needed to determine this.

Keyword

Venous thromboembolism; Activated protein C anticoagulant system; Asian thrombophilia; Deep vein thrombosis; Protein S; Quantitative assay of protein S

MeSH Terms

Asian Continental Ancestry Group
Blood Coagulation
Blood Proteins/genetics/metabolism
Humans
Protein C/genetics/*metabolism
Protein S/chemistry/genetics/metabolism
Thrombophilia/epidemiology/*etiology
Venous Thrombosis/etiology/genetics
Blood Proteins
Protein C
Protein S

Figure

• 

  Fig. 1 Structural model of protein S and its variants (Courtesy of Dr. Yoshito Abe, Laboratory of Protein Structure, Function and Design, Graduate School of Pharmaceutical Sciences, Kyushu University). Variants of the protein S molecule observed in our laboratory are shown by space-filling symbols in individual domains of the Gla domain (A), EGF domain (B), and SHB domain (C). Since only the EGF3-4 domain structure of protein S was determined [58], the other domains were prepared by homology modeling using the Swiss-model web server [59]. The coordinates of the structures of the Gla domain of factor IX [60], EGF domain of blood coagulation factor VIIA [61], and laminin G-like domain of Gas6 [62] were used as templates for homology modeling. The whole structural model of protein S was constructed by connecting each domain corresponding to an amino acid sequence.

• 

  Fig. 2 Coagulation and anticoagulation systems. The anticoagulant systems of TFPI and AT directly inhibit tissue factor-initiated blood coagulation and coagulation factor Xa/thrombin, respectively. In the APC anticoagulant system, when thrombin is produced by the coagulation system, it forms a complex with thrombomodulin (TM) on the surface of the vascular endothelium and loses its activity to convert fibrinogen (Fbg) to fibrin (Fb) and instead converts protein C to APC. With the help of protein S (PS), the APC/PS complex inhibits coagulation factors Va and VIIIa. Thus, the activity of the APC anticoagulation system is regulated in proportion to the activity of the coagulation system.

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