Activation of the Protein C Pathway in Hereditary Thrombophilia

Summary

Levels of free activated protein C are a measure of the activation of the protein C pathway in vivo. The aim of this study was to establish if the protein C pathway is triggered in familial thrombophilia and if activated protein C levels correlate with type of defect or symptoms. We measured activated protein C in 133 patients with a deficiency of antithrombin (n = 31), protein C (n = 24) or protein S (n = 27) or with resistance to activated protein C (n = 51). Levels of activated protein C were evaluated also in 97 healthy individuals. Results indicate that the levels of activated protein C are higher in patients who have experienced a thrombotic event than in patients who have not and that 71% of patients with levels of activated protein C above the normal reference range had had a venous thromboembolic event. We conclude that the protein C pathway is triggered in patients with thrombophilia and that in symptomatic patients, activated protein C levels are increased and may reflect heightened coagulation activation and scavenging through the protein C pathway.

• References

• 1 De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management.. Blood 1996; 87: 3531-44.
• 2 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosen daal FR, Seligsohn U. Inherited thrombophilia: Part 1.. Thromb Haemost 1996; 76: 651-62.
• 3 Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, Krawczak M, Lind B, Long GL, Poort SR, Saito H, Sala N, Witt I, Cooper D. Protein C deficiency: A database of mutations, 1995 update.. Thromb Haemost 1995; 73: 876-89.
• 4 Koster T, Rosendaal FR, Briët E, van der Meer FJM, Colly LP, Trienekens PH, Poort SR, Reitsma PH, Vandenbroucke JP. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia study).. Blood 1995; 85: 2756-61.
• 5 Martinelli I, Mannucci PM, De Stefano V, Taioli E, Rossi V, Crosti F, Paciaroni K, Leone G, Faioni EM. Differential risks of thrombosis for four coagulation defects associated with inherited thrombophilia.. Blood,. 1998 in press.
• 6 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia: Part 2.. Thromb Haemost 1996; 76: 824-34.
• 7 España F, Vicente V, Tabernero D, Scharrer I, Griffin JH. Determination of plasma protein C inhibitor and of two activated protein C-inhibitor complexes in normals and in patients with intravascular coagulation and thrombotic disease.. Thromb Res 1990; 59: 593-608.
• 8 España F, Zuazu I, Vicente V, Estellés A, Marco P, Aznar J. Quantification of circulating activated protein C in human plasma by immunoassays-Enzyme levels are proportional to total protein C levels.. Thromb Haemost 1996; 75: 56-61.
• 9 Bauer KA, Kass BL, Beeler DL, Rosenberg RD. Detection of protein C activation in humans.. J Clin Invest 1984; 74: 2033-41.
• 10 Bauer KA, Broekmans AW, Bertina RM, Conard J, Horellou M-H, Samama MM, Rosenberg RD. Hemostatic enzyme generation in the blood of patients with hereditary protein C deficiency.. Blood 1988; 71: 1418-26.
• 11 Orthner CL, Kolen B, Drohan WN. A sensitive and facile assay for the measurement of activated protein C activity levels in vivo.. Thromb Haemost 1993; 69: 441-7.
• 12 Gruber A, Griffin JH. Direct detection of activated protein C in blood from human subjects.. Blood 1992; 79: 2340-8.
• 13 Heeb MJ, Mosher D, Griffin JH. Activation and complexation of protein C and cleavage and decrease of protein S in plasma of patients with intravascular coagulation.. Blood 1989; 73: 455-61.
• 14 Vicente V, España F, Tabernero D, Estellés A, Aznar J, Hendl S, Griffin JH. Evidence of activation of the protein C pathway during acute vascular damage induced by Mediterranean Spotted fever.. Blood 1991; 78: 416-22.
• 15 Gruber A, Pal A, Kiss RG, Sas G, Griffin JH. Generation of activated protein C during thrombolysis.. Lancet 1993; 342: 1275-6.
• 16 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: 64-7.
• 17 Hirsch RP, Riegelman RK. (eds): Statistical First Aid.. Blackwell Scientific Publications, Cambridge, MA,; 1992
• 18 Mannucci PM, Tripodi A, Bottasso B, Baudo F, Finazzi G, De Stefano V, Palareti G, Manotti C, Mazzucconi MG, Castaman G. Markers of procoagulant imbalance in patients with inherited thrombophilic syndromes.. Thromb Haemost 1992; 67: 200-2.
• 19 Scarpati EM, Sadler JE. Regulation of endothelial cell coagulant properties.. J Biol Chem 1989; 264: 20705-13.
• 20 Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of the hemostatic system activation.. Blood 1987; 70: 343-50.
• 21 Martinelli I, Bottasso B, Duca F, Faioni E, Mannucci PM. Heightened thrombin generation in individuals with resistance to activated protein C.. Thromb Haemost 1996; 75: 703-5.