Download PDF
Thromb Haemost 1997; 77(05): 0825-0828
DOI: 10.1055/s-0038-1656061
Cinical Studies
Schattauer GmbH Stuttgart

High Prevalence of Elevated Factor VIII Levels in Patients Referred for Thrombophilia Screening: Role of Increased Synthesis and Relationship to the Acute Phase Reaction

J O’Donnell
1   The Department of Haematology, Royal Postgraduate Medical School, London, UK
,
E G D Tuddenham
2   The MRC Haemostasis Research Group, London, UK
,
R Manning
1   The Department of Haematology, Royal Postgraduate Medical School, London, UK
,
G Kemball-Cook
2   The MRC Haemostasis Research Group, London, UK
,
D Johnson
2   The MRC Haemostasis Research Group, London, UK
,
M Laffan
1   The Department of Haematology, Royal Postgraduate Medical School, London, UK
› Author Affiliations
Further Information

Publication History

Received 25 July 1996

Accepted after resubmission 15 January 1997

Publication Date:
11 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

A recent report from the Leiden Thrombophilia Survey identified high factor VIII activity levels as an independent risk factor for venous thromboembolism in a population survey. As the study measure for factor VIII was a one-stage coagulation assay, and since markers for the acute phase reaction were not assessed, it remained uncertain whether the increase was due to a constitutional increased rate of synthesis, to circulating activated factor VIII, or to an acute phase response.

We added factor VIII activity assay (FVIII:C), factor VIII antigen (FVIILAg), vWF antigen (vWF:Ag), ABO blood group, fibrinogen and C-reactive protein to our routine thrombophilia screen of patients referred because of unexplained thromboembolism.

Elevated FVIILC (>1.5 iu/ml) emerged as the single commonest abnormality detected in 25.4% of a group of 260 such patients.

FVIILC and FVIILAg were highly correlated (p = 0.003), showing that this represented a true increase in FVIII. In 4 of 46 patients this was clearly attributable to an acute phase reaction. Eleven others showed minor elevation of ESR and one of CRP. Neither FVIILC or FVIII:Ag showed significant correlation with fibrinogen, ESR or C-reactive protein by non parametric analysis.

Although there was an excess of patients with B blood group (known to be associated with FVIILC levels which are -15% higher than those in blood group 0), this could not account for the marked elevation of factor VIII observed in these patients.

We conclude that factor VIII activity assay should be a routine part of thrombophilia screening. We are investigating the cause of the increased synthesis, initially by means of family studies and linkage analysis with polymorphic markers of the FVIII locus. We postulate that it may be constitutive in some cases and in others an abnormal or exaggerated response to inflammatory stimuli.

 

  • References

  • 1 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-155
    CrossrefPubMedSearch in Google Scholar
  • 2 Dahlbäck B, Carlsson M, Svenson 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
    CrossrefPubMedSearch in Google Scholar
  • 3 Koster T, Rosendal FR, de RondeH, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-1506
    CrossrefPubMedSearch in Google Scholar
  • 4 Bertina RM, Koelman RPC, Koster T, Rosendaal FR, Dirven RJ, de RondeH, van derFelden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67
    CrossrefPubMedSearch in Google Scholar
  • 5 Meade TW, Mellows S, Brozovic 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 Heart Study. Lancet 1986; 2: 533-537
    PubMedSearch in Google Scholar
  • 6 Preston AE, Barr A. The plasma concentration of factor VIII in the normal population. Brit J Haemat 1964; 10: 238-245
    CrossrefPubMedSearch in Google Scholar
  • 7 Orstavik K, Magnus P, Reisner H, Berg K, Graham J, Nance W. Factor VIII and Factor IX in a Twin Population. Evidence for a major effect of ABO locus on factor VIII level. Am J Hum Genet 1985; 37: 089-101
    PubMedSearch in Google Scholar
  • 8 McCallum CJ, Peake IR, Newcombe RG, Bloom AL. Factor VIII levels and blood group antigens. (Letter) Thromb Haemost 1983; 50: 757
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Sodetz J, Paulson J, McKee P. Carbohydrate composition and identification of blood group A, B, and H oligosaccharide structures on human factor VUI/von Willebrand factor. J Biol Chem 1979; 254: 10754-10760
    CrossrefPubMedSearch in Google Scholar
  • 10 Mohanty D, Ghosh K, Marwaha N, Kaur S, Chauhan A, Das KC. Major blood group antigens – a determinant factor of factor VIII levels in blood. (Letter) Thromb Haemost 1984; 51: 414
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Gill JC, Endres-Brooks J, Bauer PJ, Marks Jr WJ, Montgomery RR. The effect of ABO blood groups on the diagnosis of von Willebrand disease. Blood 1987; 69: 1691-1695
    CrossrefPubMedSearch in Google Scholar
  • 12 Figueiredo MS, Brownlee GG. CIS acting elements and transcription factors involved in the promoter activity of the human FVIII gene. J Biol Chem 1995; 270: 11828-11838
    CrossrefPubMedSearch in Google Scholar
  • 13 Kemball-Cook G, Tuddenham EGD. The Factor VIII mutation database on the world wide web: the Haemophilia A Mutation, Search Test and Resource Site. Hamsters update (v3.0) Nucleic Acids Res 1997 25. (in press)
    PubMedSearch in Google Scholar