SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Disclosure of Conflict of Interests
  4. References

See also Tang L, Lu X, Yu JM, Wang QY, Yang R, Guo T, Mei H, Hu Y. PROC c.574_576del polymorphism: a common genetic risk factor for venous thrombosis in the Chinese population. This issue, pp 2019–26.

Natural anticoagulation in healthy individuals is primarily achieved through the actions of three systems, involving: (i) tissue factor pathway inhibitor; (ii) antithrombin; and (iii) activated protein C (APC). The APC anticoagulation system is unique in the sense that its anticoagulant function is activated only when thrombin is formed by the coagulation system, and thus APC activity is regulated proportionately by procoagulant activity [1,2].

Protein C is a serine protease zymogen. When the protein C molecule is partially cleaved by the thrombin–thrombomodulin complex, a final product of the coagulation system, the resulting APC exhibits serine protease activity. However, the APC molecule by itself does not have sufficient protease activity. It acquires sufficient function only after forming a complex with protein S (the APC anticoagulation system) [3,4]. This complex cleaves coagulation activated factor V, first at Arg506 and then at Arg306, thus inactivating the factor and inhibiting its cofactor function. Protein S is an important cofactor that impacts on APC anticoagulant activity. FV Leiden (R506Q), which shows resistance to the APC anticoagulation system, has arginine at position 506 replaced with glutamine. As a result, this variant FV cannot be cleaved by APC at this position, and inactivation of this factor is slowed [3,4]. The APC system can still, however, cleave at Arg306 in FV Leiden to inactivate this variant, but the control of coagulation is delayed as compared with normal FV. Because of this, FV Leiden carriers have relatively stronger procoagulant activity, and it is believed that this leads to excessive thrombus formation and results in a predisposition to thrombosis. Approximately 30% of Caucasian patients with venous thrombosis are carriers of FV Leiden [4,5].

In 1997, soon after FV Leiden was established as a cause of thrombophilia in Caucasians [6–9], Shen et al. [10] reported that there was no carrier of FV Leiden among 85 Taiwanese patients of Chinese origin with venous thromboembolism, and yet there were strong genetic factors that predisposed to the development of venous thrombosis. They indicated that 47 of 85 (55%) thrombosis patients had reduced APC anticoagulant activity (28 had low protein S function, 16 had low APC activity, and three had both low protein S and APC activities). Liu et al. [11] published a similar report after studying Chinese thrombosis patients.

In the current issue of JTH, Tang et al. [12], from Huazhong University, China, reported that a variant of protein C, PROC c.574_576del (K150del), was found at a high prevalence in patients suffering from venous thrombosis, and that there was a lower prevalence in healthy individuals. The PROC c.574_576del (K150del) variant was identified in 68 (6.78%) of 1003 patients and in 25 (2.42%) of 1031 healthy individuals. The PROC c.574_576del (K150del) variant was associated with both decreased APC anticoagulant activity and an increased risk of venous thrombosis, with an odds ratio of 2.7. The anticoagulant activity of the variant expressed in vitro in COS-7 or HEK-293 cells was ∼ 40%, consistent with the value of plasma from the homozygous patient. In their previous publication [13], they reported that another variant of protein C, PROC c.565C>T (R147W), was a genetic risk factor for venous thrombosis in the Chinese population, with an odds ratio of 7.1. They also found some other variants of protein C and of protein S molecules, and excluded the FV Leiden trait in the Chinese population with modified APC resistance tests. These reports [10–13] suggest that thrombophilia in Chinese is likely to result from an abnormality in the APC anticoagulation system.

From our survey of the Japanese population [14], we observed that 49 of 85 (58%) patients suffering from deep vein thrombosis (DVT) had reduced activity of factors of the APC anticoagulation system (22 had low protein S activity, nine had low APC activity, and 18 had both low protein S and APC activities), and that the reduced activity was attributable to genetic abnormalities of protein S or protein C in 27 (32%) of the patients. The PROC c.574_576del (K150del) and PROC c.565C>T (R147W) variants were also observed in Japanese patients with DVT [14]. The age at first occurrence of DVT was unexpectedly low, peaking at 20–30 years of age, and in ∼ 60% of the patients the first event occurred before they reached the age of 40 years [15]. These findings suggest that an individual’s constitutional factors have a strong influence on the development of venous thromboembolism.

Protein S Tokushima (K155E), an abnormal protein S molecule, was discovered almost simultaneously in thrombophilia patients by Shigekiyo et al. [16] and Yamazaki et al. [17] in 1993. Individuals heterozygous for this abnormality are present at the high incidence of one in 55 healthy Japanese. Protein S secreted into blood has the lysine at position 155 replaced by glutamic acid, and it has low protein S activity. A patient with DVT who is a homozygous carrier of protein S Tokushima has been identified. This patient’s blood protein S activity was 35% (the amount of protein S was 94%), and the specific activity (activity/amount of protein S) was reduced to 37% [14]. The specific activity of protein S Tokushima expressed in HEK-293 cells was < 60% [18]. There was some difference in the extent of reduction between in vivo activity and activity in the cultured cell expression system. Nevertheless, the activity of protein S Tokushima was unmistakably reduced. The frequency of heterozygous carriers of protein S Tokushima among healthy Japanese is nearly 2%. The frequency is much higher, approximately 6–9%, among DVT patients [14,19,20]. Thus, we can infer that protein S Tokushima is a thrombophilic risk factor among Japanese.

When protein S or APC activity is reduced, the activity of the APC anticoagulation system is reduced, and this makes it difficult to control coagulation. In this condition, the procoagulant activity becomes relatively stronger than the anticoagulant activity of the APC system, creating a thrombotic tendency and increasing the risk of thrombosis. Many variants of protein C and of protein S, including PROC c.574_576del (K150del), PROC c.565C>T (R147W), and protein S Tokushima, were found at high frequencies in Chinese and Japanese [12–14], and a significant number of Chinese and Japanese patients had low activity of the APC anticoagulation system [10–14]. In these individuals, control by the APC anticoagulation system is also not sufficiently effective.

In short, for both APC resistance in Caucasians and APC dysfunction in Chinese and Japanese, ‘the creation of a condition where coagulation activity becomes relatively stronger than the APC anticoagulation activity’ could be the triggering mechanism for the development of thrombosis in thrombophilic carriers [21]. Thus, APC resistance in Caucasians and APC dysfunction in Asians could be the major risk factors for venous thrombosis, respectively.

Determining whether these prevalent variants of protein C and protein S occur in other Asian countries is an important aspect of mapping thrombophilia among Asians, and will have to await further studies. From a global perspective, our knowledge of the mechanism of thrombophilia in other ethnic groups is wanting. For instance, although African Americans have a higher frequency of venous thrombosis than Americans of European origin, the major risk factor in the former is not clear [22]. Likewise, the mechanism of thrombophilia in people of Arabian origin, who have a higher frequency of FV Leiden than Caucasians, remains to be determined [5]. There is clearly more to learn about the population causes of thrombophilia before we have a global view of the origins of this disorder.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Disclosure of Conflict of Interests
  4. References

The author states that he has no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Disclosure of Conflict of Interests
  4. References
  • 1
    Narayanan S, Hamasaki N. Current concepts of coagulation and fibrinolysis. Adv Clin Chem 1999; 33: 13368.
  • 2
    Aiach M, Borgel D, Gaussem P, Emmerich J, Alhenc-Gelas M, Gandrille S. Protein C and protein S deficiencies. Semin Hematol 1997; 34: 20516.
  • 3
    Castoldi E, Rosing J. APC resistance: biological basis and acquired influences. J Thromb Haemost 2010; 8: 44553.
  • 4
    Dahlback B. Resistance to activated protein C as risk factor for thrombosis: molecular mechanisms, laboratory investigation, and clinical management. Semin Hematol 1997; 34: 21734.
  • 5
    Roberts LN, Patel K, Arya R. Venous thromboembolism and ethnicity. Br J Haematol 2009; 46: 36983.
  • 6
    Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 10048.
  • 7
    Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 15036.
  • 8
    Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 646.
  • 9
    Rosendaal FR. Risk factors for venous thrombosis: prevalence, risk, and interaction. Semin Hematol 1997; 34: 17187.
  • 10
    Shen MC, Lin JS, Tsay W. High prevalence of antithrombin III, protein C and protein S deficiency, but no factor V Leiden mutation in venous thrombophilic Chinese patients in Taiwan. Thromb Res 1997; 87: 37785.
  • 11
    Liu HW, Kwong YL, Bourke C, Lam CK, Lie AK, Wei D, Chan LC. High incidence of thrombophilia detected in Chinese patients with venous thrombosis. Thromb Haemost 1994; 71: 41619.
  • 12
    Tang L, Lu X, Yu JM, Wang QY, Yang R, Guo T, Mei H, Hu Y. PROC c.574_576del polymorphism: a common genetic risk factor for venous thrombosis in Chinese population. J Thromb Haemost 2012; 10: 201926.
  • 13
    Tang L, Guo T, Yang R, Mei H, Wang H, Lu X, Yu J, Wang Q, Hu Y. Genetic background analysis of protein C deficiency demonstrates a recurrent mutation associated with venous thrombosis in Chinese population. PLoS ONE 2012; 7: e35773.
  • 14
    Kinoshita S, Iida H, Inoue S, Watanabe K, Kurihara M, Wada Y, Tsuda H, Kang D, Hamasaki N. Protein S and protein C gene mutations in Japanese deep vein thrombosis patients. Clin Biochem 2005; 38: 90815.
  • 15
    Hamasaki N. Japanese thrombophilia: protein S/protein C anomaly as the major risk factor for Japanese thrombophilia. Jpn J Thromb Haemost 2006; 17: 13643 (in Japanese).
  • 16
    Shigekiyo T, Uno Y, Kawauchi S, Saito S, Hondo H, Nishioka J, Hayashi T, Suzuki K. Protein S Tokushima: an abnormal protein S found in a Japanese family with thrombosis. Thromb Haemost 1993; 70: 2446.
  • 17
    Yamazaki Y, Sugiura I, Matsushita T, Kojima T, Kagami K, Takamatsu J, Saito H. A phenotypically neutral dimorphism of protein S: the substitution of Lys155 by Glu in the second EGF domain predicted by an A to G base exchange in the gene. Thromb Res 1993; 70: 395403.
  • 18
    Tsuda H, Urata M, Tsuda T, Wakiyama M, Iida H, Nakahara M, Kinoshita S, Hamasaki N. Four missense mutations identified in the protein S gene of thrombosis patients with protein S deficiency: effects on secretion and anticoagulant activity of protein S. Thromb Res 2002; 105: 2339.
  • 19
    Kimura R, Honda S, Kawasaki T, Tsuji H, Madoiwa S, Sakata Y, Kojima T, Murata M, Nishigami K, Chiku M, Hayashi T, Kokubo Y, Okayama A, Tomoike H, Ikeda Y, Miyata T. Protein S-K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patients. Blood 2006; 107: 17378.
  • 20
    Ikejiri M, Wada H, Sakamoto Y, Ito N, Nishioka J, Nakatani K, Tsuji A, Yamada N, Nakamura M, Ito M, Nobori T. The association of protein S Tokushima-K196E with a risk of deep vein thrombosis. Int J Hematol 2010; 92: 3025.
  • 21
    Hamasaki N, Kanaji T. Clinical role of protein S deficiency in Asian population. In: Tanaka K, Davie EW, eds. Recent Advances in Thrombosis and Hemostasis. Springer, 2008: 597613.
  • 22
    Heit J, Beckman MG, Bockenstedt PL, Grant AM, Key NS, Kulkarni R, Manco-Johnson MJ, Moll S, Ortel TL, Philipp CS. Comparison of characteristics from White- and Black-Americans with venous thromboemoblism: a cross-sectional study. Am J Hematol 2010; 85: 46771.