Research Article: Synergistic Effects of Hypofibrinolysis and Genetic and Acquired Risk Factors on the Risk of a First Venous Thrombosis

Date Published: May 6, 2008

Publisher: Public Library of Science

Author(s): Mirjam E Meltzer, Ton Lisman, Carine J. M Doggen, Philip G de Groot, Frits R Rosendaal, Henri Bounameaux

Abstract: BackgroundPreviously, we demonstrated that hypofibrinolysis, a decreased capacity to dissolve a blood clot as measured with an overall clot lysis assay, increases the risk of venous thrombosis. Here, we investigated the combined effect of hypofibrinolysis with established risk factors associated with hypercoagulability.Methods and FindingsFibrinolytic potential was determined with a plasma-based clot lysis assay in 2,090 patients with venous thrombosis and 2,564 control participants between 18 and 70 y of age enrolled in the Multiple Environmental and Genetic Assessment (MEGA) of risk factors for venous thrombosis study, a population-based case-control study on venous thrombosis. Participants completed a standardized questionnaire on acquired risk factors.Hypofibrinolysis alone, i.e., clot lysis time (CLT) in the fourth quartile (longest CLT) (in absence of the other risk factor of interest) increased thrombosis risk about 2-fold relative to individuals with CLT in the first quartile (shortest CLT). Oral contraceptive use in women with CLT in the first quartile gave an odds ratio (OR) of 2.6 (95% confidence interval [CI] 1.6 to 4.0), while women with hypofibrinolysis who used oral contraceptives had an over 20-fold increased risk of venous thrombosis (OR 21.8, 95% CI 10.2 to 46.7). For immobilization alone the OR was 4.3 (95% CI 3.2 to 5.8) and immobilization with hypofibrinolysis increased the risk 10.3-fold (95% CI 7.7 to 13.8). Factor V Leiden alone increased the risk 3.5-fold (95% CI 2.3 to 5.5), and hypofibrinolysis in factor V Leiden carriers gave an OR of 8.1 (95% CI 5.3 to 12.3). The combination of hypofibrinolysis and the prothrombin 20210A mutation did not synergistically increase the risk. All ORs and 95% CIs presented are relative to individuals with CLT in the first quartile and without the other risk factor of interest.ConclusionsThe combination of hypofibrinolysis with oral contraceptive use, immobilization, or factor V Leiden results in a risk of venous thrombosis that exceeds the sum of the individual risks.

Partial Text: A hypercoagulable state, an increased capacity to form thrombin, is known to be associated with an increased risk of venous thrombosis [1]. However, the role of the fibrinolytic system in the development of venous thrombosis has not yet been extensively investigated.

In this study, 2,090 patients, 1,128 partner controls, and 1,436 random controls were included. Mean age at time of blood draw of patients was 49 y (range 19–71y) and mean age of all control participants was 48 y (range 18–71 y). Of the patient group 926 participants (44%) were men, whereas in the control group 1,226 participants (48%) were men. Of the 2,090 patients, 650 were diagnosed with an isolated PE, 1,245 with an isolated DVT of the leg, and 195 of all the patients were diagnosed with both a PE and a DVT of the leg.

In this large population-based case-control study, including over 4,500 individuals, we have shown that decreased fibrinolytic activity, as measured with a plasma-based assay, was associated with an increased risk of a first venous thrombosis. The combination of hypofibrinolysis with immobilization, factor V Leiden, and especially oral contraceptive use, resulted in high relative risks. CLTs were associated with age, BMI, diabetes, oral contraceptive use, and the prothrombin 20210A mutation.



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