Antithrombin deficiency and decreased protein C activity in a young man with venous thromboembolism: a case report

Abstract

Antithrombin and protein C are two crucial members in the anticoagulant system and play important roles in hemostasis. Mutations in SERPINC1 and PROC lead to deficiency or dysfunction of the two proteins, which could result in venous thromboembolism (VTE). Here, we report a Chinese 22-year-old young man who developed recurrent and serious VTE in cerebral veins, visceral veins, and deep veins of the lower extremity. Laboratory tests and direct sequencing of PROC and SERPINC1 were conducted for the patient and his family members. Coagulation tests revealed that the patient presented type I antithrombin deficiency combined with decreased protein C activity resulting from a small insertion mutation c.848_849insGATGT in SERPINC1 and a short deletion variant c.572_574delAGA in PROC. This combination of the two mutations was absent in 400 healthy subjects each from southern and northern China. Then, we summarized all the mutations of the SERPINC1 and PROC gene reported in the Chinese Han population. This study demonstrates that the combination of antithrombin deficiency and decreased protein C activity can result in severe VTE and that the coexistence of different genetic factors may increase the risk of VTE.

Keywords

antithrombin deficiency / protein C activity / mutation / variant / venous thromboembolism / anticoagulants

References

[1] Martinelli I, De Stefano V, Mannucci PM. Inherited risk factors for venous thromboembolism. Nat Rev Cardiol 2014; 11(3): 140–156

[2] Reitsma PH, Versteeg HH, Middeldorp S. Mechanistic view of risk factors for venous thromboembolism. Arterioscler Thromb Vasc Biol 2012; 32(3): 563–568

[3] Morange PE, Suchon P, Trégouët DA. Genetics of venous thrombosis: update in 2015. Thromb Haemost 2015; 114(5): 910–919

[4] Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353(9159): 1167–1173

[5] Roemisch J, Gray E, Hoffmann JN, Wiedermann CJ. Antithrombin: a new look at the actions of a serine protease inhibitor. Blood Coagul Fibrinolysis 2002; 13(8): 657–670

[6] van Boven HH, Vandenbroucke JP, Briët E, Rosendaal FR. Gene-gene and gene-environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency. Blood 1999; 94(8): 2590–2594

[7] Jobin F, Vu L, Lessard M. Two cases of inherited triple deficiency in a large kindred with thrombotic diathesis and deficiencies of antithrombin III, heparin cofactor II, protein C and protein S. Thromb Haemost 1991; 66(3): 295–299

[8] Sansores-García L, Majluf-Cruz A. Arterial and venous thrombosis associated to combined deficiency of protein C and antithrombin III. Am J Hematol 1998; 57(2): 182–183

[9] Bowen D, Dasani H, Yung B, Bloom A. Deep venous thrombosis and pulmonary embolism in a patient with type III von Willebrand’s disease, protein C and antithrombin III deficiency. Br J Haematol 1992; 81(3): 446–447

[10] Gouault-Heilmann M, Quetin P, Dreyfus M, Gandrille S, Emmerich J, Leroy-Matheron C, Guesnu M. Massive thrombosis of venous cerebral sinuses in a 2-year-old boy with a combined inherited deficiency of antithrombin III and protein C. Thromb Haemost 1994; 72(5): 782–783

[11] Zeng W, Tang L, Jian XR, Li YQ, Guo T, Wang QY, Liu H, Wu YY, Cheng ZP, Hu B, Lu X, Yu JM, Deng J, Wang HF, Sun CY, Yang Y, Hu Y. Genetic analysis should be included in clinical practice when screening for antithrombin deficiency. Thromb Haemost 2015; 113(2): 262–271

[12] 1000 Genomes Project Consortium, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA. A map of human genome variation from population-scale sequencing. Nature 2010; 467( 7319): 1061–1073

[13] Miyata T, Sakata T, Yasumuro Y, Okamura T, Katsumi A, Saito H, Abe T, Shirahata A, Sakai M, Kato H. Genetic analysis of protein C deficiency in nineteen Japanese families: five recurrent defects can explain half of the deficiencies. Thromb Res 1998; 92(4): 181–187

[14] Tang L, Wang HF, Lu X, Jian XR, Jin B, Zheng H, Li YQ, Wang QY, Wu TC, Guo H, Liu H, Guo T, Yu JM, Yang R, Yang Y, Hu Y. Common genetic risk factors for venous thrombosis in the Chinese population. Am J Hum Genet 2013; 92(2): 177–187

[15] 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. J Thromb Haemost 2012; 10(10): 2019–2026

[16] Safdar H, Cheung KL, Salvatori D, Versteeg HH, Laghmani H, Wagenaar GT, Reitsma PH, van Vlijmen BJ. Acute and severe coagulopathy in adult mice following silencing of hepatic antithrombin and protein C production. Blood 2013; 121(21): 4413–4416

[17] Luxembourg B, Delev D, Geisen C, Spannagl M, Krause M, Miesbach W, Heller C, Bergmann F, Schmeink U, Grossmann R, Lindhoff-Last E, Seifried E, Oldenburg J, Pavlova A. Molecular basis of antithrombin deficiency. Thromb Haemost 2011; 105(4): 635–646

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