|
|
 Previous Article | Table of Contents | Next Article 
An In Vitro Analysis of the Combination of Hemophilia A and Factor VLEIDEN
Cornelis van `t Veer,
Neal J. Golden,
Michael Kalafatis,
Paolo Simioni,
Rogier M. Bertina, and
Kenneth G. Mann
From the Department of Biochemistry, University of Vermont, Burlington, VT; the Institute of Medical Semeiotics, University of Padua, Padua, Italy; and the Hemostasis and Thrombosis Research Center, University Hospital, Leiden, The Netherlands.
The classification of factor VIII deficiency, generally used based on plasma levels of factor VIII, consists of severe (<1% normal factor VIII activity), moderate (1% to 4% factor VIII activity), or mild (5% to 25% factor VIII activity). A recent communication described four individuals bearing identical factor VIII mutations. This resulted in a severe bleeding disorder in two patients who carried a normal factor V gene, whereas the two patients who did not display severe hemophilia were heterozygous for the factor VLEIDEN mutation, which leads to the substitution of Arg506  Gln mutation in the factor V molecule. Based on the factor VIII level measured using factor VIII-deficient plasma, these two patients were classified as mild/moderate hemophiliacs. We studied the condition of moderate to severe hemophilia A combined with the factor VLEIDEN mutation in vitro in a reconstituted model of the tissue factor pathway to thrombin. In the model, thrombin generation was initiated by relipidated tissue factor and factor VIIa in the presence of the coagulation factors X, IX, II, V, and VIII and the inhibitors tissue factor pathway inhibitor, antithrombin-III, and protein C. At 5 pmol/L initiating factor VIIa.tissue factor, a 10-fold higher peak level of thrombin formation (350 nmol/L), was observed in the system in the presence of plasma levels of factor VIII compared with reactions without factor VIII. Significant increase in thrombin formation was observed at factor VIII concentrations less than 42 pmol/L (~6% of the normal factor VIII plasma concentration). In reactions without factor VIII, in which thrombin generation was downregulated by the addition of protein C and thrombomodulin, an increase of thrombin formation was observed with the factor VLEIDEN mutation. The level of increase in thrombin generation in the hemophilia A situation was found to be dependent on the factor VLEIDEN concentration. When the factor VLEIDEN concentration was varied from 50% to 150% of the normal plasma concentration, the increase in thrombin generation ranged from threefold to sevenfold. The data suggested that the analysis of the factor V genotype should be accompanied by a quantitative analysis of the plasma factor VLEIDEN level to understand the effect of factor VLEIDEN in hemophilia A patients. The presented data support the hypothesis that the factor VLEIDEN mutation can increase thrombin formation in severe hemophilia A.
Blood, Vol. 90 No. 8 (July 15), 1997:
pp. 3067-3072
© 1997 by The American Society of Hematology.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. Franchini and P. M. Mannucci
Interactions between genotype and phenotype in bleeding and thrombosis
Haematologica,
May 1, 2008;
93(5):
649 - 652.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Szlam, T. Taketomi, C. A. Sheppard, C. L. Kempton, J. H. Levy, and K. A. Tanaka
Antithrombin Affects Hemostatic Response to Recombinant Activated Factor VII in Factor VIII Deficient Plasma
Anesth. Analg.,
March 1, 2008;
106(3):
719 - 724.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kurnik, W. Kreuz, S. Horneff, C. During, R. Schobess, C. Bidlingmaier, C. E. Ettingshausen, A. Krumpel, N. Bogdanova, and U. Nowak-Gottl
Effects of the factor V G1691A mutation and the factor II G20210A variant on the clinical expression of severe hemophilia A in children results of a multicenter study
Haematologica,
July 1, 2007;
92(7):
982 - 985.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Kubisz, J. Stasko, M. Dobrotova, J. Ivankova, and D. Mesko
Severe Hemophilia and Physiologic Inhibitors of Coagulation
Clinical and Applied Thrombosis/Hemostasis,
July 1, 2005;
11(3):
331 - 334.
[Abstract]
[PDF]
|
|
|
|
|
|
|
E. Castoldi, J. W. P. Govers-Riemslag, M. Pinotti, D. Bindini, G. Tans, M. Berrettini, M. G. Mazzucconi, F. Bernardi, and J. Rosing
Coinheritance of Factor V (FV) Leiden enhances thrombin formation and is associated with a mild bleeding phenotype in patients homozygous for the FVII 9726+5G>A (FVII Lazio) mutation
Blood,
December 1, 2003;
102(12):
4014 - 4020.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. G. Mann, S. Butenas, and K. Brummel
The Dynamics of Thrombin Formation
Arterioscler. Thromb. Vasc. Biol.,
January 1, 2003;
23(1):
17 - 25.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. G. Mann and M. Kalafatis
Factor V: a combination of Dr Jekyll and Mr Hyde
Blood,
January 1, 2003;
101(1):
20 - 30.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Corral, J. A. Iniesta, R. Gonzalez-Conejero, M. Villalon, and V. Vicente
Polymorphisms of clotting factors modify the risk for primary intracranial hemorrhage
Blood,
May 15, 2001;
97(10):
2979 - 2982.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Hedner, D. Ginsburg, J. M. Lusher, and K. A. High
Congenital Hemorrhagic Disorders: New Insights into the Pathophysiology and Treatment of Hemophilia
Hematology,
January 1, 2000;
2000(1):
241 - 265.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. Lenting, J. A. van Mourik, and K. Mertens
The Life Cycle of Coagulation Factor VIII in View of Its Structure and Function
Blood,
December 1, 1998;
92(11):
3983 - 3996.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Laffan and E. Tuddenham
Science, medicine, and the future: Assessing thrombotic risk
BMJ,
August 22, 1998;
317(7157):
520 - 523.
[Full Text]
|
|
|
| |
