Heightened Thrombin Generation in Individuals with Resistance to Activated Protein C

Summary

We chose to evaluate whether or not a state of biochemical hypercoagulability was present in 74 individuals (69 heterozygotes and 5 homozygotes) resistant to activated protein C (APC) due to the Arg506 -> Gin mutation in the factor V gene. To this end, plasma levels of two markers of thrombin formation, prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complexes (TAT), were measured. High levels of F1+2 and TAT were found in 32% and 23% of APC-resistant individuals vs 4% in controls. The levels of these markers tended to be particularly elevated in three homozygous subjects. A significant positive correlation between F1+2 and TAT was present in APC-resistant individuals. No relationship between marker values and the previous occurrence of thrombotic episodes was found. Therefore, by measuring F1+2 and TAT a state of biochemical hypercoagulability has been identified in about one-third of APC-resistant individuals. This frequency is similar to that previously observed in comparable individuals with inherited deficiencies of protein C and protein S, which are usually associated with a stronger thrombotic tendency than APC-resistant individuals.

• References

• 1 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: 343-350
• 2 Mannucci PM. Mechanisms, markers and management of coagulation activation. Br Med Bull 1994; 50: 851-870
• 3 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein. Proc Natl Acad Sci USA 1993; 90: 1004-1008
• 4 Bertina RM, Koeleman RPC, 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: 64-67
• 5 Catto A, Carter A, Ireland H, Bayston TA, Philippou H, Barret J, Lane DA, Grant PJ. Factor V Leiden gene mutation and thrombin generation in relation to the development of acute stroke. Arterioscl Thromb Vase Biol 1995; 15: 783-785
• 6 de Ronde H, Bertina RM. Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost 1994; 72: 880-886
• 7 Mannucci PM, Tripodi A. Laboratory screening of inherited thrombophilic syndromes. Thromb Haemost 1987; 57: 247-251
• 8 Greengard JS, Eichinger S, Griffin JH, Bauer KA. Variability of thrombosis among homozygous siblings with resistance to activated protein C due to Arg ⟶ Gln mutation in the gene for factor V. N Engl J Med 1994; 331: 1559-1562
• 9 Kalafatis M, Rand MD, Mann KG. The mechanism of inactivation of human factor V and human factor Va by activated protein C. J Biol Chem 1994; 269: 3869-3880
• 10 Heeb MJ, Kojima Y, Greengard JS, Griffin JH. Activated protein C resistance: molecular mechanisms based on studies using purified Gin 506 factor V. Blood 1995; 85: 3405-3411
• 11 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: 200-202
• 12 Martinelli I, Faioni EM, Monzani ML, Mannucci PM. Inherited resistance to activated protein C (APC): clinical and laboratory features. Blood 1994; 10 (Suppl. 01) 84a
• 13 Finazzi G, Barbui T. Different incidence of venous thrombosis in patients with inherited deficiencies of anti thrombin III, protein C and protein S. Thromb Haemost 1994; 71: 15-16
• 14 Bauer KA, Barzegar S, Rosenberg RD. Influence of anticoagulants used for blood collection on plasma prothrombin fragment 1+2 measurements. Thromb Res 1991; 63: 617-628