Hypofibrinolysis as a Risk Factor for Venous Thrombosis.
Authors: Meltzer Mirjam E. , Doggen Carine J.M. , de Groot Philip G. , Rosendaal Frits R. , Lisman Ton 
Published: October 2019

Abstract
Several genetic and acquired risk factors are known to increase the risk of venous thrombosis (VT). The occurrence of multiple risk factors in a single patient may be associated with a thrombotic risk which exceeds the sum of the individual risks, as is for example seen with oral contraceptive use and factor V Leiden. Previously we have shown that reduced fibrinolytic potential a measured by a plasma-based assay increases the risk of VT. Here, we investigated the thrombotic risk in individuals with hypofibrinolysis overall and in combination with the factor V Leiden and prothrombin 20210A mutation, in the Multiple Environmental and Genetic Assessment (MEGA) of risk factors for venous thrombosis study, a large population-based case-control study. In the present analyses, 2420 patients with a first episode of deep vein thrombosis of the leg or a pulmonary embolism and 2943 control subjects (partners and randomly selected individuals) between 18 and 70 years were included. Lysis of a tissue factor-induced clot by exogenous tissue-type plasminogen activator was studied by monitoring changes in turbidity during clot formation and subsequent lysis. Using quartiles of clot lysis time (CLT) based on the values found in the control subjects, we found an increase in risk of VT with each increasing quartile of CLT. The odds ratio (OR) (95% confidence interval (CI)) for individuals in the fourth quartile of CLT compared to individuals in the first quartile was 1.8 (1.5–2.1), after adjustment for age and sex. In younger subjects and women these ORs were slightly elevated (table). In individuals with hypofibrinolysis (i.e., the highest quartile of CLT) and without the factor V Leiden mutation an OR of 1.8 (1.5–2.1) was found compared to those without the mutation and with the lowest CLTs (i.e., in the lowest quartile). Individuals with the factor V Leiden mutation with the lowest CLTs had a risk of VT that was 3.6 (2.4–5.4) times increased, compared to those without the mutation and with the lowest CLTs. The risk of VT increased 6.2–fold (4.2–9.2) for individuals in the fourth quartile of CLT with the factor V Leiden mutation compared to people in the first quartile without the mutation. The same analyses for the prothrombin 20210A mutation gave ORs of 1.8 (1.5–2.1) for hypofibrinolysis only, 3.6 (1.4–9.5) for the mutation only, and 3.2 (1.9–5.3) for the combination. Our study confirms the increased risk of VT in individuals with hypofibrinolysis. This risk is especially pronounced in women and younger individuals. The combination of hypofibrinolysis and the factor V Leiden or prothrombin mutation does not appear to enhance the risk of VT. This study was supported by the Netherlands Heart Foundation (NHF) (Grant no. 2005B060 and 98.113) and the Netherlands Organisation for Scientific research (NWO) (Grant no. 912-03-033/2003).
Risk of VT for individuals in the fourth quartile (Q4) of CLT overall <49 years >49 years women men * Q1 is reference # cases(Q1/Q4) 452/784 275/285 177/499 261/385 191/398 #controles (Q1/Q4) 733/733 458/248 274/485 430/357 303/376 OR (95% CI)* 1.8 (1.5–2.1) 2.5 (1.9–3.2) 1.7 (1.4–2.2) 2.7 (2.1–3.4) 1.6 (1.3–2.1)