Arg506 to Gin Mutation in the Factor V Gene Causes Poor Fibrinolytic Response in Children after Venous Occlusion

Ulrike Nowak-Göttl; Martha Binder; Angelika Dübbers; Beate Kehrel; Hans-Georg Koch; Hildegard Veltmann; Heinrich Vielhaber

doi:10.1055/s-0038-1657696

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1997; 78(03): 1115-1118
DOI: 10.1055/s-0038-1657696

Rapid Communication

Schattauer GmbH Stuttgart

Arg⁵⁰⁶ to Gin Mutation in the Factor V Gene Causes Poor Fibrinolytic Response in Children after Venous Occlusion

Ulrike Nowak-Göttl

¹The Department of Paediatrics, University Hospital Münster, Germany

,

Martha Binder

¹The Department of Paediatrics, University Hospital Münster, Germany

,

Angelika Dübbers

¹The Department of Paediatrics, University Hospital Münster, Germany

,

Beate Kehrel

²The Department of Internal Medicine, University Hospital Münster, Germany

,

Hans-Georg Koch

¹The Department of Paediatrics, University Hospital Münster, Germany

,

Hildegard Veltmann

¹The Department of Paediatrics, University Hospital Münster, Germany

,

Heinrich Vielhaber

¹The Department of Paediatrics, University Hospital Münster, Germany

› Author Affiliations

Abstract

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Summary

To determine to what extent the Arg⁵⁰⁶ to Gin mutation in the factor V gene influences the fibrinolytic response after 20 min venous occlusion (VO) we investigated a population of APC resistant children (n = 60) and a group of age-matched healthy controls (n = 25). After 20 min VO, symptomatic (n = 30) carriers of the common factor V mutation showed significantly reduced t-PA activities compared with asymptomatic (n = 30) carriers (p <0.0001) and healthy controls (p <0.0001). In contrast, PAI1 activity was significantly (p <0.0001) higher before and after VO in children with the factor V mutation compared with healthy children. No difference was found between symptomatic and asymptomatic probands. A significantly lower PAI 1 antigen decrease along with a lower t-PA antigen release was found in the APC resistant children compared with the controls. No significant difference was seen between individuals with and without previous vascular insults. As the lack of t-PA activity after VO in symptomatic carriers is the most conspicuous result, we suggest that the factor V gene mutation itself might induce the fibrinolytic impairment by increasing the thrombin levels and thus increasing the recently described thrombin-activable fibrinolysis inhibitor (TAFI).

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References

References
1 Wiman B, Ljungberg B, Chmielewska J, Urden G, Blombäck M, Johnsson H. The role of the fibrinolytic system in deep vein thrombosis. J Lab Clin Med 1985; 105: 265-270
2 Nilsson IM, Ljungner H, Tengbom L. Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: low concentration of plasminogen activator or increased concentration of plasminogen activator inhibitor. Br Med J 1985; 290: 1453-1456
3 Conard J, Veuillet-Duval A, Horellou MH, Samama M. Etude de la coagulation et de la fibrinolyse dans 131 cas de thrombose veineuses recidivantes. Nouv Rev Fr Hematol 1982; 24: 205-209
4 Kominger C, Lechner K, Niessner H, Gössinger H, Kundi M. Impaired fibrinolytic capacity predisposes for recurrence of venous thrombosis. Thromb Haemost 1984; 52: 127-130
5 Isacson S, Nilsson IM. Defective fibrinolysis in blood and vein walls in recurrent idiopathic venous thrombosis. Acta Chir Scand 1972; 138: 313-319
6 Juhan-Vague I, Valadier J, Alessi MC, Aillaud MF, Ansaldi J, Philip-Joet C, Holovet P, Serradimigni A, Collen D. Deficient t-PA release and elevated PA inhibitor levels in patients with spontaneous or recurrent deep venous thrombosis. Thromb Haemost 1987; 57: 67-72
7 Petäjä J. Fibrinolytic response to venous occlusion for 10 and 20 min in healthy subjects and in patients with deep vein thrombosis. Thromb Res 1989; 56: 251-263
8 Stegnar M, Petemel P, Keber D, Vene N. Poor fibrinolytic response to venous occlusion by different criteria in patients with deep vein thrombosis. Thromb Res 1991; 64: 445-453
9 Grimaudo V, Bachmann F, Hauert J, Christe MA, Kruithof EKO. Hypo fibrinolysis in patients with a history of idiopathic deep vein thrombosis and/or pulmonary embolism. Thromb Haemost 1992; 67: 397-401
10 Brommer EJP, Verheijen JH, Chang GTG, Rijken DC. Masking of fibrino lytic response to stimulation by an inhibitor of tissue-type plasminogen activator in plasma. Thromb Haemost 1984; 52: 154-156
11 Jorgensen M, Bonnevie-Nielsen V. Increased concentration of fast-acting plasminogen activator inhibitor in plasma associated with familial venous thrombosis. Br J Haematol 1987; 52: 154-156
12 Legnani C, Maccaferri M, Tonini P, Cassio A, Cacciari E, Coccheri S. Reduced fibrinolytic response in obese children: association with high baseline activity of the fast acting plasminogen activator inhibitor (PAI-1). Fibrinolysis 1988; 02: 211-224
13 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 C. Proc Natl Acad Sci USA 1993; 90: 1004-1008
14 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de RondeH, van derVelden, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67
15 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-522
16 Koster T, Rosendaal FR, de RondeH, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-1506
17 Nowak-Göttl U, Koch HG, Aschka I, Kohlhase B, Vielhaber H, Kurlemann G, Oleszuk-Raschke K, Kehl HG, Jurgens H, Schneppenheim R. Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism. Brit J Haematol 1996; 92: 992-998
18 Sifontes MT, Nuss R, Jacobson LJ, Griffin JH, Manco-Johnson MJ. Thrombosis in otherwise well children with the factor V Leiden mutation. J Pediatrl 1996; 128: 324-328
19 Nowak-Göttl U, Sträter R, Dübbers A, Oleszuk-Raschke K, Vielhaber H. Ischaemic stroke in infancy and childhood: role of the Arg⁵⁰⁶ to Gin muta tion in the factor V gene. Blood Coagulation & Fibrinolysis 1996; 07: 684-688
20 Kohlhase B, Vielhaber H, Kehl HG, Kececioglu D, Koch HG, Nowak-Göttl U. Thromboembolism and resistance to activated protein C in children with underlying cardiac disease. J Pediatr 1996; 129: 677-679
21 Debus O, Koch HG, Kurlemann G, Vielhaber H, Weber P, Nowak-Göttl U. Factor V Leiden and further inherited defects of familial thrombophilia in childhood porencephaly. J Pediatr. 1997 in press.
22 Nowak-Göttl U, Dübbers A, Kececioglu D, Koch HG, Kotthoff S, Runde J, Vielhaber H. Factor V Leiden, protein Cand lipoprotein (a) in catheter related thrombosis in childhood – a prospective study. J Pediatr. 1997 in press.
23 Vielhaber H, Kohlhase B, Kehl HG, Fliedner M, Kececioglu D, Dockhom DwomiczakB, Kehrel B, Veltmann H, Vogt J, Nowak-Göttl U. Flush heparin during cardiac catherisation prevents long-term coagulation activation in children without APC resistance –preliminary results. Thromb Res 1996; 81: 651-656
24 Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan D. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994; 343: 940-943
25 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133
26 Ashka I, Aumann V, Bergmann F, Budde U, Eberl W, Eckhof-Donovan S, Krey S, Nowak-Gottl U, SchobeB R, Sutor AH, Wendisch J. Schneppen heim R: Prevalence of factor V Leiden in children with thrombembolism. EurJ Pediatr 1996; 155: 1009-1014
27 Stefano deV, Finazzi G, Mannucci PM. Inherited thrombophilia: Pathogen esis, clinical syndromes and management. Blood 1996; 87: 3531-3544
28 Nowak-Göttl U, Debus O, Findeisen M, Kassenböhmer R, Koch HG, Pollmann H, Postler C, Weber P, Vielhaber H. Lipoprotein (a): its role in childhood thromboembolism. Pediatrics (electronic pages) 1997; 99 6/e ll
29 Robertson BR, Pandolfi M, Nilsson IM. Fibrinolytic capacity in healthy volunteers as estimated from effect of venous occlusions of arms. Acta Chir Scand 1972; 138: 429-436
30 Nowak-Göttl U, Kohlhase B, Vielhaber H, Aschka I, Schneppenheim R, Jurgens H. APC resistance in neonates and infants: adjustment of the aPTT based method. Thromb Res 1996; 81: 665-670
31 Keber D. On the use of different correction factors for hemoconcentration. Thromb Haemost 1983; 49: 238
32 Wieczorek I, Ludlam CA, MacGregor I. Venous occlusion does not release von Willebrand factor, factor VIII or PAI 1 from endothelial cells – the importance of consensus of the use of correction factors for haemoconcen tration. Thromb Haemost 1993; 69: 91
33 Nowak-Göttl U, Vielhaber H, Schneppenheim R, Koch HG. Coagulation and fibrinolysis in children with APC-resistance: a population study. Fibrinolysis 1996; 10 (02) 25-27
34 Nowak-Göttl U, Vielhaber H, Grohmann J, Schneppenheim R, Koch HG. Arg⁵⁰⁶ to Gin mutation in the factor V gene in infancy and childhood: evidence of fibrinolytic impairment. Eur J Pediatr 1997; 156: 195-198
35 Nguyen G, Horellou MH, Kruithof EKO, Conard J, Samama M. Residual plasminogen activator inhibitor activity after venous stasis as a criterion for hypofibrinolysis: a study in 83 patients with confirmed deep vein thrombosis. Blood 1988; 72: 601-605
36 Bajzar L, Kalafatis M, Simioni P, Tracy PB. An antifibrinolytic mechanism describing the prothrombotic effect associated with factor V Leiden. J Biol Chem 1996; 271: 22949-22952
37 Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chem 1995; 270: 14477-14484
38 Bos R, Revet M, Nieuwenhuizen W. A Bio-immuno assay to determine free tissue-type plasminogen activator (t-PA) in Stabilyte R Plasma. Fibrinoly sis 1994; 08 (02) 163-165
39 Fujii S, Sawa H, Saffitz JE, Lucore CL, Sobel BE. Induction of endothelial cell expression of the plasminogen activator inhibitor type 1 gene by throm bosis in vivo. Circulation 1992; 86: 2000-2010
40 Kluft C, Verheijen JH, Jie AFH, Rijken DC, Preston FE, Ling HS, Jesper senJ, Aasen AO. The postoperative fibrinolytic shut-down: a rapidly reverting acute phase pattern for the fast acting inhibitor of tissue-type plasminogen activator after trauma. Scand J Clin Lab Invest 1985; 45: 605-610
41 Colucci M, Paramo JA, Collen D. Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation. J Clin Invest 1985; 75: 818-824
42 Slagboom PE, Kluft C. Genetic studies of complex diseases: giant steps from promise to proof. Fibrinolysis 1996; 10 (02) 1-2