Congenital Deficiency of Vitamin K-Dependent Coagulation Factors and Protein C

Summary

A 15-month-old girl from Coimbra (Portugal) had a history of numerous hemorrhagic episodes with multiple bruises, hematomas but not hemarthroses. On serial testing she showed deficiency of factors II, VII, IX, X and protein C. Malabsorption- induced vitamin K deficiency, liver disease or ingestion of a coumarin compound were excluded. An absence of detectable abnormalities was found among her relatives. Consanguinity was not present. The immunologic assay, immunoelectrophoresis or antibody neutralization, revealed much higher levels of these factors than the clotting assay. The non-physiological activator (Echis carinatus venom) produced higher levels of prothrombin activation than those detected by physiological activation. Twodimensional immunoelectrophoresis of the patient’s plasma in calcium showed that prothrombin had the same mobility as acarboxyprothrombin. No significant response to large doses of intravenous vitamin K₃ (6 mg) was observed. Transfusion of 120 ml of frozen fresh plasma led to an immediate increase in the procoagulant activities of vitamin K dependent protein, similar to that found after perfusion of plasma plus vitamin K₃. The results obtained from this patient suggest a defect in the gammacarboxylation mechanism inside the hepatocyte.

Keywords

Vitamin K-dependent proteins - Protein C - Congenital deficiency

• References

• 1 Sperling R, Furie BC, Blumenstein M, Keyt B, Furie B. Metal binding properties of gamma-carboxyglutamic acid. Implications for the vitamin k-dependent blood coagulation proteins J Biol Chem 1978; 253: 3898-3906
• 2 Esmon CT, Suttie JW, Jackson CM. The functional significance of vitamin k action: difference in phospholipid binding between unusual and abnormal prothrombin. J Biol Chem 1975; 250: 4095-4099
• 3 Gallop PM, Lian JB, Hauschka PV. Carboxylated calcium-binding proteins and vitamin k. N Engl J Med 1980; 302: 1460-1466
• 4 Seegers WH, Marlar RA, Walz DA. Anticoagulant effects of autothrombin II-A and prothrombin fragment 1. Thromb Res 1978; 13: 233-243
• 5 Marlar RA, Kleiss AJ, Griffin JH. Human protein C: Inactivation of factors V and VIII in plasma by the activated molecule. Ann N Y Acad Sci 1981; 370: 303-310
• 6 Zolton RP, Seegers WH. Autoprothrombin II-A: Thrombin removal and mechaninsmy of induction of fibrinolysis. Thromb Res 1973; 3: 23-33
• 7 Broekmans AW, Veltkamp JJ, Bertina RM. Congenital protein C deficiency and venous thromboembolism: a study of three dutch families. N Engl J Med 1983; 309: 340-344
• 8 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Widerman G. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1980; 68: 1370-1373
• 9 Suttie JW. Mechanism of action of vitamin k: Demonstration of a liver precursor of prothrombin. Science 1973; 179: 192-194
• 10 Chung KS, Bezeaud A, Goldsmith JC, Me Millan CW, Menache D, Roberts HR. Congenital deficiency of blood clotting factors II, VII, IX and X. Blood 1979; 53: 776-787
• 11 Johnson CA, Chung KS, MC Grath KM, Bean PE, Roberts HR. Characterization of a variant prothrombin in a patient congenitally deficient in factors II, VII, IX and X. Br J Haematol 1980; 44: 461-469
• 12 Goldsmith GH, Pence RE, Ratnoff OD, Adelstein DJ, Furie B. Studies on a family with combined functional deficiencies of vitamin k- dependent coagulation factors. J Clin Invest 1982; 69: 1253-1260
• 13 Samama M, Bertina RM, Conard J, Horellou MH. Combined congenital deficiency in protein C and in factors II, VII, IX and X. Thromb Haemostas 1983; 50: 359 (Abstr)
• 14 O’Reilly RA, Aggeler PM, Hoag MS, Leong L. Studies on the coumarin anticoagulant drugs: the assay of warfarin and its biologic application. Thrombos Diathes Haemorrh 1962; 8: 82-95
• 15 Vicente V, Coppola R, Mannucci PM. The role of the spleen in regulating the plasma levels of factor VIII-von Willebrand’s factor after DDAVP. Blood 1982; 60: 1402-1406
• 16 Biggs R. Human blood coagulation, haemostasis and thrombosis. Blackwell Scientific Publications; Oxford: 1976
• 17 Denson KW E, Borret R, Biggs R. The specific assay of prothrombin using the Taipan snake venom. Br J Haematol 1971; 21: 219-216
• 18 Denson KW E. The specific assay of Prowe-Stuart and factor VII. Acta Haematol 1961; 25: 105-120
• 19 Laurell CB. Quantitative estimation of proteins by electrophoresis in agarose containing antibodies. Anal Biochem 1966; 15: 45-52
• 20 Roberts HR, Grizzle JE, Mc Lester WD, Penick GD. Genetic variants of hemophilia B. J Clin Invest 1968; 47: 360-365
• 21 Weeke B. Crossed immunoelectrophoresis. Scan J Immunol 1973; 2 Suppl (Suppl. 01) 47-56
• 22 Lavergne JM, Josso F. Metabolism of PIVKA II in man. In “Prothrombin and related coagulation factors”. Hemker HC, Veltkamp JJ. (Eds) Leiden University Press; Leiden: 1975. pp 183-190
• 23 Thompsom AR. Factor IX antigen by radioimmunoassay. Abnormal factor IX protein in patients on warfarin therapy and with hemophilia B J Clin Invest 1977; 59: 900-910
• 24 Vermeer C, Soute BA M, Hemker HC. Vitamin k-dependent enzymes in hepatic and non-hepatic tissues. Thromb Haemostas 1983; 50: 352 (Abstr)