High Plasma Concentration of Factor VIIIc Is a Major Risk Factor for Venous Thromboembolism

Summary

Background

Established risk factors, including deficiencies of protein C, protein S or antithrombin and the factor V Leiden and prothrombin mutation, are present in about one third of unselected patients with venous thromboembolism. In addition to these inherited thrombophilic defects, elevated plasma levels of factor VIIIc have been suggested to be important in the pathogenesis of (recurrent) venous thromboembolism. The objective of this study was to assess the relevance of factor VIIIc plasma concentration in consecutive patients with venous thromboembolism.

Method

We studied the prevalence of elevated plasma levels of factor VIIIc in 65 patients with a proven single episode and in 60 matched patients with documented recurrent venous thromboembolism. The reference group consisted of 60 ageand sex-matched patients who were referred for suspected venous thromboembolism, which was refuted by objective testing and longterm clinical follow-up. To minimalize the influence of the acute phase, blood was obtained at least 6 months after the thromboembolic event and results were adjusted for fibrinogen and C-reactive protein. Factor VIIIc was re-determined several years after the first measurement in a subset of patients to evaluate the variability over time. To study a possible genetic cause, a family study was done.

Findings

In the control, single and recurrent episode group, the prevalences of plasma levels of factor VIIIc above 175 IU/dl (90th percentile of controls) were 10% (95% CI: 4 to 21%), 19% (95% CI: 10 to 30%) and 33% (95% CI: 22 to 47%), respectively. For each 10 IU/dl increment of factor VIIIc, the risk for a single and recurrent episode of venous thrombosis increased by 10% (95% CI: 0.9 to 21%) and 24% (95% CI: 11 to 38%), respectively. Both low and high plasma levels of factor VIIIc were consistent over time (R = 0.80, p = 0.01). A family study indicated a high concordance for elevated factor VIIIc plasma concentrations among first degree family members. Adjustment for fibrinogen, C-reactive protein and known thrombophilic risk factors did not change the observed association of elevated factor VIIIc with thrombosis.

Interpretation

Elevated plasma levels of factor VIIIc are a significant, prevalent, independent and dose-dependent risk factor for venous thromboembolism. It also predisposes to recurrent venous thromboembolism.

Key words

Thromboembolism - factor VIII - venous thrombosis - risk factor

• References

• 1 Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med 1992; 232: 155-60.
• 2 Heijboer H, Brandjes DP, Buller HR, Sturk A, ten Cate JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deepvein thrombosis. NEJM 1990; 323: 1512-6.
• 3 Pabinger I, Brucker S, Kyrle PA. et al. Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening. Blood Coagul Fibrinolysis 1992; 03: 547-53.
• 4 Koster T, Rosendaal FR, Briet E. et al. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood 1995; 85: 2756-61.
• 5 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
• 6 Dahlback 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: 1004-8.
• 7 Bertin RM, Reitsm PH, Rosendaal FR, Vandenbroucke JP. Resistance to activated protein C and factor V Leiden as risk factors for venous thrombosis. Thromb Haemost 1995; 74: 449-53.
• 8 Koster T, Blann AD, Briet 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: 152-5.
• 9 O’Donnell J, Tuddenham EG, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997; 77: 825-8.
• 10 Kamphuizen PW, Eikelboom JC, Roosendaal FR. et al. High prevalence of factor VIII antigen increase the risk of deep-vein thrombosis but are not related to common factor VIII gene variations. Submitted..
• 11 Lensing AW, Prandoni P, Brandjes D. et al. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. NEJM 1989; 320: 342-5.
• 12 Anonymous. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators. JAMA 1990; 263: 2753-9.
• 13 von Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des fibrinogens. Acta Haematol (Basel) 1957; 17: 237.
• 14 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
• 15 den Heijer M, Koster T, Blom HJ. et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. NEJM 1996; 334: 759-62.
• 16 Balleisen L, Bailey J, Epping PH, Schulte H, van de Loo J. Epidemiological study on factor VII, factor VIII 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.
• 17 Kamphuisen PW, Houwing-Duistermaat JJ, van Houwelingen HC. et al. Familial clustering of factor VIII and von Willebrand factor levels. Thromb Haemost 1998; 79: 323-7.
• 18 Mansvelt EP, Laffan M, McVey JH, Tuddenham EG. Analysis of the F8 gene in individuals with high plasma factor VIII:C levels and associated venous thrombosis. Thromb Haemost 1998; 80: 561-5.