Dysfunctional Activated Protein C (PC Cádiz) in a Patient with Thrombotic Disease

Summary The partial characterization of a dysfunctional protein C (PC), provisionally named “PC Cádiz”, in a 45-year-old male patient suffering from recurrent venous thrombosis is described. The only defect found in laboratory assays for haemostasis and hepatic function was a half normal level of both amidolytic and anticoagulant protein C activity, measured by different functional assays that use thrombin-thrombomodulin complex and a snake venom to activate protein C. Protein C antigen was always found to be within normal levels. Two young daughters of the propositus were found to have the same defect. Double-crossed immunoelectrophoresis, performed in the presence and absence of Ca2+ in the first dimension, showed no clear differences between patient and control PC. PC adsorption to barium salts was also found to be normal. Measurement of the PC activation peptide in the barium citrate eluates after PC activation showed no significant differences between patient and 10 normal controls, the concentration of this peptide being very similar to that of PC zymogen in the same eluates before PC activation. These results indicate that this abnormal PC is able to be normally activated by thrombin-thrombomodulin complex but does not exhibit serine protease activity, probably due to a defect in the PC molecule near the active site center.

[1]  C. Esmon,et al.  Acquired deficiencies of protein S. Protein S activity during oral anticoagulation, in liver disease, and in disseminated intravascular coagulation. , 1988, The Journal of clinical investigation.

[2]  F. Taylor,et al.  Protein S is a cofactor for activated protein C neutralization of an inhibitor of plasminogen activation released from platelets. , 1987, Blood.

[3]  P. Comp,et al.  The regulation of hemostasis: the protein C system. , 1986, The New England journal of medicine.

[4]  C. Hickton,et al.  A functional assay of protein C in human plasma. , 1986, Thrombosis research.

[5]  Silvana,et al.  Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states. , 1986, The Journal of clinical investigation.

[6]  R. Marlar.  Protein C in Thromboembolic Disease , 1985, Seminars in thrombosis and hemostasis.

[7]  J. Griffin,et al.  Activated protein C stimulates the fibrinolytic activity of cultured endothelial cells and decreases antiactivator activity. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[8]  D. Beeler,et al.  Detection of protein C activation in humans. , 1984, The Journal of clinical investigation.

[9]  T. Barbui,et al.  HEREDITARY DYSFUNCTIONAL PROTEIN C (PROTEIN C BERGAMO) AND THROMBOSIS , 1984, The Lancet.

[10]  R. Bertina,et al.  The Use of a Functional and Immunologic Assay for Plasma Protein C in the Study of the Heterogeneity of Congenital Protein C Deficiency , 1984, Thrombosis and Haemostasis.

[11]  J. Griffin,et al.  Proteolytic inactivation of human factor VIII procoagulant protein by activated human protein C and its analogy with factor V. , 1984, Blood.

[12]  C. Esmon,et al.  Determination of functional levels of protein C, an antithrombotic protein, using thrombin-thrombomodulin complex. , 1984, Blood.

[13]  R. Bertina,et al.  Protein C Deficiency in a Dutch Family with Thrombotic Disease , 1982, Thrombosis and Haemostasis.

[14]  F. Walker.  Regulation of activated protein C by protein S. The role of phospholipid in factor Va inactivation. , 1981, The Journal of biological chemistry.

[15]  C. Esmon,et al.  Generation of fibrinolytic activity by infusion of activated protein C into dogs. , 1981, The Journal of clinical investigation.

[16]  J. Griffin,et al.  Deficiency of protein C in congenital thrombotic disease. , 1981, The Journal of clinical investigation.

[17]  R. Carroll,et al.  Lysis of clots prepared from whole blood and plasma. , 1981, Federation proceedings.

[18]  C. Esmon,et al.  Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[19]  W. Kisiel.  Human Plasma Protein C: ISOLATION, CHARACTERIZATION, AND MECHANISM OF ACTIVATION BY α-THROMBIN , 1979 .