High factor VIII (FVIII) levels in venous thromboembolism: role of unbound FVIII

Christian M. Schambeck; Ralf Grossmann; Sarah Zonnur; Mario Berger; Kathleen Teuchert; Alois Spahn; Ulrich Walter

doi:10.1160/TH04-02-0063

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2004; 92(01): 42-46
DOI: 10.1160/TH04-02-0063

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

High factor VIII (FVIII) levels in venous thromboembolism: role of unbound FVIII

Autoren

Christian M. Schambeck

¹Central Laboratory and Blood Coagulation Unit, Department of Clinical Biochemistry and Pathobiochemistry
Ralf Grossmann

¹Central Laboratory and Blood Coagulation Unit, Department of Clinical Biochemistry and Pathobiochemistry
Sarah Zonnur

¹Central Laboratory and Blood Coagulation Unit, Department of Clinical Biochemistry and Pathobiochemistry
Mario Berger

²Medical Department, University of Würzburg, Germany
Kathleen Teuchert

¹Central Laboratory and Blood Coagulation Unit, Department of Clinical Biochemistry and Pathobiochemistry
Alois Spahn

³Computer Centre, University of Würzburg, Germany
Ulrich Walter

¹Central Laboratory and Blood Coagulation Unit, Department of Clinical Biochemistry and Pathobiochemistry

Abstract

Summary

Theoretically, von Willebrand factor (VWF) should be capable of binding all factor VIII (FVIII), but an unbound FVIII (uFVIII) plasma fraction remains. In patients’ status post deep-vein thrombosis (DVT), an altered uFVIII fraction and high FVIII levels might be indicative of dysfunctional FVIII regulation. Out of 928 consecutive DVT patients, 321 were found to have high FVIII levels. After excluding 183 patients with known causes for high FVIII levels, plasma samples with unexplainably high FVIII levels were available from 84 patients. To capture the FVIIIVWF-complex, superparamagnetic polystyrene beads with covalently attached streptavidin were coated with biotinylated anti-rabbit Ig and incubated with rabbit anti-human VWF-Ig. Slowly thawed plasma samples were added to cooled beads, which were then separated by a magnetic particle concentrator. The uFVIII fraction was calculated by dividing the FVIII activity in the supernatant of the FVIII-VWF-complex-free sample by the FVIII activity in the supernatant of the control sample. Additionally, the VWF residuum in the supernatant was determined. Compared to age- and sex-matched blood donors, thrombosis patients showed a significantly higher plasma FVIII/VWF ratio (median: 1.3 vs. 1.0, p<0.001). uFVIII fraction data were adjusted for VWF residuum. After forward stepwise logistic regression, uFVIII had an odds ratio of 0.48 (95% CI 0.34 – 0.65), i. e. the uFVIII fraction was reduced in thrombosis patients. Analysis of covariance confirmed these results: In thrombosis patients, the estimated mean of the uFVIII fraction was significantly lower (6.34% vs. 7.58%, p<0.001). In conclusion, thrombosis patients with high FVIII levels showed a higher FVIII/VWF ratio, similar to mice with defective FVIII clearance.The clearly reduced uFVIII fraction lends further support to the hypothesis of a modified FVIII clearance.

Keywords

Factor VIII - thrombophilia - von Willebrand factor

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Referenzen

References
1 Koster T, Blann AD, Briet E. et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-5.
2 Kyrle PA, Minar E, Hirschl M. et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457-62.
3 Van der Meer FJM, Koster T, Vandenbroucke JP. et al. The Leiden thrombophilia study (LETS). Thromb Haemost 1997; 78: 631-5.
4 Schambeck CM, Hinney K, Haubitz I. et al. Familial clustering of high factor VIII levels in patients with venous thromboembolism. Arterioscler Thromb Vasc Biol 2001; 21: 289-92.
5 Kamphuisen PW, Lensen R, Houwing-Duistermaat JJ. et al. Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia. Br J Haematol 2000; 109: 519-22.
6 Mansvelt EPG, Laffan M, McVey JH. et al. Analysis of the F8 gene in individuals with high plasma factor VIII:C levels and associated venous thrombosis. Thromb Haemost 1998; 80: 561-5.
7 Kamphuisen PW, Eikenboom JCJ, Rosendaal FR. et al. High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene. Br J Haematol 2001; 115: 156-8.
8 Saenko EL, Yakhyaev AV, Mikhailenko I. et al. Role of the low density lipoprotein-related protein receptor in mediation of factor VIII catabolism. J Biol Chem 1999; 274: 37685-92.
9 Weiss HJ, Sussman II, Hoyer LW. Stabilization of factor VIII in plasma by the von Willebrand factor. Studies on posttransfusion and dissociated factor VIII and in patients with von Willebrand’s disease. J Clin Invest 1977; 60: 390-404.
10 Jacquemin M, Lavend’homme R, Benhida A. et al. A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor. Blood 2000; 96: 958-65.
11 Schambeck CM, Hinney K, Gleixner J. et al. Venous thromboembolism and associated high plasma factor VIII levels: linked to cytomegalovirus infection?. Thromb Haemost 2000; 83: 510-11.
12 Eikenboom JCJ, Castaman G, Kamphuisen PW. et al. The factor VIII/von Willebrand factor ratio discriminates between reduced synthesis and increased clearance of von Willebrand factor. Thromb Haemost 2002; 87: 252-7.
13 Bovenschen N, Herz J, Grimbergen JM. et al. Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency. Blood 2003; 101: 3933-9.
14 Lethagen S, Berntorp E, Nilsson IM. Pharmacokinetics and haemostatic effect of different factor VIII/von Willebrand factor concentrates in von Willebrand’s disease type III. Ann Hematol 1992; 65: 253-59.
15 Lenting P, Neels JG, van den Berg BM. et al. The light chain of factor VIII comprises a binding site for low-density lipoprotein receptor-related protein. J Biol Chem 1999; 274: 23734-9.
16 Bovenschen N, Boertjes RC, van Stempvoort G. et al. Low density lipoprotein receptorrelated protein and factor IXa share structural requirements for binding to the A3 domain of coagulation factor VIII. J Biol Chem 2003; 278: 9370-7.