The Frequency of Type I Heterozygous Protein S and Protein C Deficiency in 141 Unrelated Young Patients with Venous Thrombosis

Summary

The frequency of heterozygous protein C and protein S deficiency, detected by measuring total plasma antigen, in a group (n = 141) of young unrelated patients (<45 years old) with venous thrombotic disease was studied and compared to that of antithrombin III, fibrinogen, and plasminogen deficiencies. Among 91 patients not receiving oral anticoagulants, six had low protein S antigen levels and one had a low protein C antigen level. Among 50 patients receiving oral anticoagulant therapy, abnormally low ratios of protein S or C to other vitamin K-dependent factors were presented by one patient for protein S and five for protein C. Thus, heterozygous Type I protein S deficiency appeared in seven of 141 patients (5%) and heterozygous Type I protein C deficiency in six of 141 patients (4%). Eleven of thirteen deficient patients had recurrent venous thrombosis. In this group of 141 patients, 1% had an identifiable fibrinogen abnormality, 2% a plasminogen abnormality, and 3% an antithrombin III deficiency. Thus, among the known plasma protein deficiencies associated with venous thrombosis, protein S and protein C. deficiencies (9%) emerge as the leading identifiable associated abnormalities.

Key words

Protein S - Protein C - Thrombosis - Venous thrombosis

• References

• 1 Walker FJ. Protein S and the regulation of activated protein C. Semin Thrombos Haemostas 1984; 10: 131-138
• 2 Walker FJ. The regulation of activated protein C by a new protein. A possible function for bovine protein S. J Biol Chem 1980; 255: 5521-5524
• 3 Marlar RA, Kleiss AJ, Griffin JH. Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood 1982; 59: 1067-1072
• 4 Suzuki K, Stenflo J, Dahlback B, Teodorsson B. Inactivation of human coagulation Factor V by activated protein C. J Biol Chem 1983; 258: 1914-1920
• 5 Comp PC, Esmon CT. Generation of fibrinolytic activity by infusion of activated protein C into dogs. J Clin Invest 1981; 68: 1221-8
• 6 Sakata Y, Curriden S, Lawrence D, Griffin JH, Loskutoff DJ. Activated protein C stimulates the fibrinolytic activity of cultured endothelial cells and decreases antiactivator activity. Proc Natl Acad Sci USA 1985; 82: 1121-1125
• 7 Gardiner JE, Mc Gann MA, Berridge CW, Fulcher C, Zimmerman TS, Griffin JH. Protein S as a cofactor for activated protein C in plasma and in the inactivation of purified Factor VIII:C. Circulation 1984; 70: 205 (Abstr)
• 8 Suzuki K, Nishioka J, Matsuda M, Maruayama H, Hashimoto S. Protein S is essential for the activated protein C-catalyzed inactivation of platelet associated Factor Va. J Biochem 1984; 96: 455-460
• 9 Stern DM, Nawroth PP, Harris K, Esmon CT. Cultured bovine aortic endothelial cells promote activated protein C-protein S mediated inactivation of Factor Va. J Biol Chem 1986; 261: 713-718
• 10 Harris KW, Esmon CT. Protein S is required for bovine platelets to support activated protein C binding and activity. J Biol Chem 1985; 260: 2007-2010
• 11 Dahlback B. Purification of human C4b-binding protein and formation of its complex with vitamin K-dependent protein S. Biochem J 1983; 209: 847-856
• 12 Dahlback B, Stenflo J. High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein. Proc Natl Acad Sci USA 1981; 78: 2512-2516
• 13 Comp PC, Vigani S, Di Angelo A, Thurneau G, Kaufman C, Esmon CT. Acquired protein S deficiency occurs in pregnancy, the nephrotic syndrome and acute systemic lupus erythematosus. Blood 1985; 65: 348a (Abstr)
• 14 Comp PC, Thurnau GR, Welsh J, Esmon CT. Functional and immunologic protein S levels are decreased during pregnancy. Blood 1986; 68: 881-885
• 15 Comp PC, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-2088
• 16 Walker FJ. Identification of a new protein involved in the regulation of the anticoagulant activity of activated protein C. J Biol Chem 1986; 261 (23) 10941-10944
• 17 Schwarz HP, Heeb MJ, Wencel-Drake J, Griffin JH. Identification and quantitation of protein S in human platelets. Blood 1985; 66: 1452-1455
• 18 Fair DS, Marlar RA. Biosynthesis and secretion of Factor VII, protein C, proteinS, and the protein C inhibitor from a human hepatoma cell line. Blood 1986; 67: 64-70
• 19 Stern D, Brett J, Mc Carthy D, Godman G, Harris K, Esmon C, Nawroth P. Synthesis and release of protein S by cultured endothelial cells. Blood 1985; 66 (05) 359a (Abstr)
• 20 Fair DA, Marlar RA, Levin EG. Human endothelial cells synthesize protein S. Blood 1986; 67: 1168-1171
• 21 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-1373
• 22 Broekmans AW, Veltkamp JJ, Bertina R. Congenital protein C deficiency and venous thromboembolism. A study in three Dutch families. N Engl J Med 1983; 309: 340-344
• 23 Seligsohn U, Berger A, Ahead M, Rubin L, Attias D, Zivilin A, Rapaport SJ. Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Engl J Med 1984; 310: 559-562
• 24 Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64: 1297-300
• 25 Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med 1984; 311: 1525-1528
• 26 Broekmans AW, Bertina RM, Reinalda-Poot J, Engesser L, Muller HP, Leeuw JA, Michiels JJ, Brommer EJ P, Brief E. Hereditary protein S deficiency and venous thrombo-embolism. Thromb Haemostas 1985; 53: 273-277
• 27 Griffin JH, Mosher DF, Zimmerman TS, Kleiss AJ. Protein C an antithrombotic protein, is reduced in hospitalized patients with intravascular coagulation. Blood 1982; 60: 261-264
• 28 Marciniak E, Wilson HD, Marlar RA. Neonatal purpura fulminans: A genetic disorder related to the absence of protein C in blood. Blood 1985; 65 (01) 15-20
• 29 Pabinger J, Bertina RM, Lechner K, Niesser H, Korninger C, Duetsch E. Protein S deficiency in 7 Austrian families. Thromb Res 1986; VI: 136 (Abstr)
• 30 Gladson CL, Griffin JH, Hach V, Beck KH, Scharrer J. The incidence of protein C and protein S deficiency in 139 young thrombotic patients. Blood 1985; 66 (05) 350a (Abstr)
• 31 Broekmans AW, van der Linden JK, Jansen-Koeter Y, Bertina RM. Prevalence of protein C (PC) and protein S (PS) deficiency in patients with thrombotic disease. Thromb Res 1986; VI: 135 (Abstr)
• 32 Horellou MH, Conrad J, Bertina RM, Samama M. Congenital protein C deficiency and thrombotic disease in nine French families. Br Med J 1984; 289: 1285-1287
• 33 Broekmans AW, van der Linden IK, Veltkamp JJ, Bertina RM. Prevalence of isolated protein C deficiency in patients with venous thrombotic disease and in the population. Thromb Haemostas 1983; 50: 350 (Abstr)
• 34 Pabinger-Fasching J, Bertina RM, Lechner K, Niessner H, Korninger C. Protein C deficiency in two Austrian families. Thromb Haemostas 1983; 50: 810-813
• 35 Comp PC, Doray D, Patton D, Esmon CT. An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 1986; 67: 504-508
• 36 Briet E, Engesser T, Brommer FT P, Broekmans AW, Bertina RM. Thrombophilia: Its causes and a rough estimate of its prevalence. Thromb Haemostas 1987; 58: 39 (Abstr)
• 37 Miletich JP, Broze GJ. Plasma protein C antigen in the normal population: What is deficiency. Circulation 1986; 74: 92 (Abstr)
• 38 Marciniak E, Farley CH, De Simone PA. Familial thrombosis due to antithrombin III deficiency. Bluud 1974; 43: 219-31
• 39 Aoki N, Moroi M, Sakata Y, Yoshida N, Matsuda M. Abnormal plasminogen. A hereditary molecular abnormality found in a patient with recurrent thrombosis. J Clin Invest 1978; 61: 1186-1195
• 40 Beck EA, Charache P, Jackson DP. A new inherited coagulation disorder caused by an abnormal fibrinogen (“fibrinogen Baltimore”). Nature 1965; 208: 143-145
• 41 Sie P, Dupouy D, Pichon J, Boneu B. Constitutional heparin cofactor II deficiency associated with recurrent thrombosis. Lancet 1985; 24: 414-416
• 42 Tran TH, Zbinden B, Lämmle B, Duckert F. Methodology and clinical significance of heparin cofactor II deficiency in a patient with cerebrovascular thrombosis. Semin Thrombos Haemostas 1985; 11: 342-346
• 43 Beck KH, Walter-Fincke R, Hach V. Scharrer 1. Incidence of protein C deficiency in 132 juvenile thrombosis patients in comparison with other inherited fibrinolysis disorders. Thromb Haemostas 1985; 54: 142 (Abstr)