Familial Clustering of Factor VIII and von Willebrand Factor Levels

Pieter W. Kamphuisen; Jeanine J. Houwing-Duistermaat; Hans C. van Houwelingen; Jeroen C. J. Eikenboom; Rogier M. Bertina; Frits R. Rosendaal

doi:10.1055/s-0037-1614985

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1998; 79(02): 323-327
DOI: 10.1055/s-0037-1614985

Letters to the Editor

Schattauer GmbH

Familial Clustering of Factor VIII and von Willebrand Factor Levels

Pieter W. Kamphuisen

¹From the Hemostasis and Thrombosis Research Center and the Departments of Medical Statistics

,

Jeanine J. Houwing-Duistermaat

²From the Medical Statistics, Leiden University Medical Center, The Netherlands

,

Hans C. van Houwelingen

²From the Medical Statistics, Leiden University Medical Center, The Netherlands

,

Jeroen C. J. Eikenboom

¹From the Hemostasis and Thrombosis Research Center and the Departments of Medical Statistics

,

Rogier M. Bertina

¹From the Hemostasis and Thrombosis Research Center and the Departments of Medical Statistics

,

Frits R. Rosendaal

¹From the Hemostasis and Thrombosis Research Center and the Departments of Medical Statistics

³From the Clinical Epidemiology, Leiden University Medical Center, The Netherlands

› Author Affiliations

Abstract

Summary

Recently, we found that high levels of clotting factor VIII (>150 IU/dl) are common and make an important contribution to thrombotic risk. The determinants of high factor VIII:C are unclear and might be partly genetic. Therefore, we tested the influence of age, blood group and von Willebrand factor (VWF) levels on factor VIII:C levels, and investigated whether factor VIII:C levels are genetically determined. We performed an analysis of 564 female relatives of hemophilia A patients, who had visited our center for genetic counseling. In univariate analysis, AB0 blood group, age and VWF antigen (VWF:Ag) levels all influenced factor VIII:C levels. After adjustment for the effect of VWF:Ag levels, both blood group and age still had an effect on factor VIII:C levels. In sister pairs, the Pearson correlation coefficient between factor VIII:C levels was 0.17 (p = 0.024) and this correlation remained positive (0.15, p = 0.046) after correction for the influence of VWF:Ag. In mother-daughter pairs, no correlation of factor VIII:C levels was found. The correlation of VWF:Ag levels in sisterpairs was 0.41 (p <0.001) and in mother-daughter pairs 0.44 (p <0.001), in line with the assumption that VWF:Ag levels are under control of autosomal genes. Familial influence on plasma factor VIII:C and VWF:Ag levels was investigated with a recently developed familial aggregation test. This test verifies whether familial aggregation of a particular parameter exists in a set of pedigrees. In 435 women from 168 families, factor VIII:C as well as VWF:Ag levels correlated significantly within families, which suggests a familial influence. The familial aggregation was more prominent for VWF:Ag levels than for factor VIII:C levels, possibly because the genetic effect on VWF:Ag levels is larger than on factor VIII:C levels. Our results support the presence of a familial influence on factor VIII:C as well as on VWF:Ag levels.

Our results support the presence of a familial influence on factor VIII:C as well as on VWF:Ag levels.

Full Text

References

References
1 Meade TW, Mellows S, Brozowic M, Miller GJ, Chakrabarti RR, North WRS, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park study. Lancet 1986; ii: 533-7.
2 O’Brien JR. Blood group, von Willebrand’s factor and heart disease. Thromb Res 1990; 59: 221.
3 Meade TW, Cooper JA, Stirling Y, Howarth DJ, Ruddock V, Miller GJ. Factor VIII:C, AB0 blood group and the incidence of ischaemic heart disease. Br J Haematol 1994; 88: 601-7.
4 Jansson J-H, Nilsson TK, Johnson O. Von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J 1991; 66: 351-5.
5 Rosendaal FR, Varekamp I, Smit C, Bröcker-Vriends HJT, van Dijck H, Vandenbroucke JP, Hermans J, Suurmeijer TPBM, Briët E. Mortality and causes of death in Dutch haemophiliacs, 1973-86. Br J Haematol 1989; 71: 71-6.
6 Triemstra AHM, Rosendaal FR, Smit C, Van der Ploeg HM, Briët E. Mortality in patients with hemophilia. Changes in a Dutch population from 1986 to 1992 and 1973 to 1986. Ann Intern Med 1995; 123: 823-7.
7 Medalie JH, Levene C, Papier C, Goldbourt U, Dreyfuss F, Oron D, Neufeld H, Riss E. Blood groups, myocardial infarction and angina pectoris among 10,000 adult males. N Eng J Med 1973; 285: 1348-53.
8 Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ, Montgomery RR. The effect of AB0 blood group on the diagnosis of von Willebrand disease. Blood 1987; 69: 1691-5.
9 Jeremic M, Weisert O, Gedde-Dahl TW. Factor VIII:C (AHG) levels in 1016 regular blood donors. Scand J Clin Lab Invest 1976; 36: 461-6.
10 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII:C in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 1525.
11 Balleisen L, Bailey J, Epping PH, Schulte H, van de Loo J. Epidemio-logical study on factor VII, factor VIII:C and fibrinogen in an industrial population: I. Baseline data on the relation to age, gender, body weight, smoking, alcohol, pill-using and menopause. Thromb Haemost 1985; 54: 475-9.
12 Balleisen L, Bailey J, Epping PH, Schulte H, van de Loo J. Epidemio-logical study on factor VII, factor VIII:C and fibrinogen in an industrial population: II. Baseline data on the relation to blood pressure, blood glucose, uric acid and lipid fractions. Thromb Haemost 1985; 54: 721-3.
13 Conlan MG, Folsom AR, Finch A, Davis CE, Sorlie P, Marcucci G, Wu KK. Associations of Factor VIII:C and von Willebrand Factor with age, race, sex, and risk factors for atherosclerosis. Thromb Haemost 1993; 70: 380-5.
14 Tuddenham EGD, Lane RS, Rotblat F, Johnson AJ, Snape TJ, Middleton S, Kernoff PBA. Response to infusions of polyelectrolyte fractionated human factor VIII concentrate in human haemophilia A and von Willebrand’s disease. Br J Haematol 1982; 52: 259-67.
15 Brinkhous KM, Sandberg H, Garris JB, Mattson C, Palm M, Griggs T, Read MS. Purified human factor VIII procoagulant protein: Comparative hemostatic response after infusion into hemophilic and von Willebrand disease dogs. Proc Natl Acad Sci USA 1985; 82: 8752-6.
16 Kerr CB, Preston AE, Barr A, Biggs R. Further studies on the inheritance of factor VIII:C. Br J Haematol 1966; 12: 212-33.
17 Veltkamp JJ, Mayo O, Motulsky AG, Fraser GR. Blood coagulation factors I, II, V, VII, VIII, IX, X, XI and XII in twins. Hum Hered 1972; 22: 102-17.
18 Ørstavik KH, Magnus P, Reisner H, Berg K, Graham JB, Nance W. Factor VIII:C and Factor IX in a twin population. Evidence for a major effect of AB0 locus on factor VIII:C level. Am J Hum Genet 1985; 37: 89-101.
19 Houwing-Duistermaat JJ, Derkx BHF, Rosendaal FR, Van Houwelingen HC. Testing familial aggregation. Biometrics 1995; 51: 1292-301.
20 Bröcker-Vriends AHJT, Briët E, Quadt R, Dreesen JCFM, Bakker E, Claassen-Tegelaar R, Kanhai HHH, van de Kamp JJP, Pearson PL. Genotype assignment of haemophilia A by use of intragenic and extragenic restriction fragment length polymorphisms. Thromb Haemost 1987; 57: 131-6.
21 Filippi G, Mannucci PM, Coppola R, Farris A, Rinaldi A, Siniscalco M. Studies on Hemophilia A in Sardinia bearing on the problems of multiple allelism, carrier detection, and differential mutation rate in the two sexes. Am J Hum Genet 1984; 36: 44-71.
22 Barrow ES, Graham JB. Blood coagulation Factor VIII (antihemophilic factor): with comments on von Willebrand’s disease and Christmas disease. Physiol Rev 1974; 54: 23-74.
23 Sodetz JM, Paulson JC, McKee PA. Carbohydrate composition and identification of blood group A, B, H oligosaccharide structures on human factor VIII/von Willebrand factor. J Biol Chem 1979; 254: 10754-60.
24 Matsui T, Titani K, Mizuochi T. Structures of the asparagine-linked oligosaccharide chains of human von Willebrand factor. J Biol Chem 1992; 267: 8723-31.