Hypofibrinolysis a Risk For Venous Thrombosis

By Sharon Worcester

ORLANDO -- Hypofibrinolysis is a risk factor for venous thrombosis, particularly in women, younger individuals, and those who also have Factor V Leiden, Dr. Mirjam E. Meltzer reported at the annual meeting of the American Society of Hematology.

In a study of 2,420 patients with a first episode of pulmonary embolism or deep vein thrombosis of the leg, and 2,943 controls, increased clot lysis time (CLT) was associated with increased venous thrombosis risk, said Dr. Meltzer of University Medical Center, Utrecht, the Netherlands.

Lysis of a tissue factor-induced clot by exogenous tissue-type plasminogen activator was assessed by monitoring changes in turbidity during clot formation and subsequent lysis. Quartiles of CLT were established based on values in control subjects.

Each increasing quartile of CLT was shown to be associated with an increase in venous thrombosis risk, she explained.

Individuals with hypofibrinolysis (those in the fourth quartile of CLT), compared with those in the first quartile, had an odds ratio for venous thrombosis of 1.8 after adjusting for age and sex. The risk was slightly increased in women and younger patients.

For example, women younger than 49 years had an odds ratio for venous thrombosis of 2.5, and those over age 49 years had an odds ratio of 1.7, compared with the 1.8 overall odds ratio. And women had an overall odds ratio of 2.7, compared with 1.6 for men.

Study participants were between ages 18 and 70, and were from the Multiple Environmental and Genetic Assessment (MEGA) of risk factors for venous thrombosis study, a population-based, case-control study.

Venous thrombosis risk in this analysis was determined for hypofibrinolysis alone, as well as in combination with Factor V Leiden and prothrombin 20210A mutations.

The venous thrombosis risk was increased threefold in those with Factor V Leiden alone, and sevenfold in those with both hypofibrinolysis and Factor V Leiden, compared with subjects in the first quartile of CLT, Dr. Meltzer said.

A similar analysis of those with hypofibrinolysis and the prothrombin 20210A mutation showed the mutation did not enhance the risk over the threefold increased risk in those with prothrombin 20210A alone.

The findings confirm those from smaller studies showing a link between hypofibrinolysis and increased venous thrombosis risk, she noted.

When asked to comment on this article, Dr. Thomas Wakefield stated: "Plasminogen Activator Inhibitor-1 [PAI-1] is the primary inhibitor of plasminogen activators in plasma. It is secreted in an active form from liver and endothelial cells and is stabilized by binding to vitronectin. It inactivates both tissue plasminogen activator [tPA] and urokinase-type plasminogen activator [uPA].

"PAI-1 levels are elevated by hyperlipidemia, and PAI-1 elevation appears to synergize with Factor V Leiden genetic abnormalities." Dr. Wakefield is a professor of surgery at the University of Michigan, Ann Arbor.

"It is plausible that elevated PAI-1 could suppress fibrinolysis and increase VTE. Studies on the role of elevated levels of PAI-1 to venous thrombosis have been contradictory. In the current study, another marker of the fibrinolytic potential, clot lysis time, was found to correlate with VTE risk. Individuals with hypofibrinolysis (those in the fourth quartile of CLT), compared with those in the first quartile, had an odds ratio for venous thrombosis of 1.8 after age and sex adjustment," he added.

"The risk was found to be slightly increased in women and younger patients. Additionally, consistent with the synergy between Factor V Leiden and PAI-1 elevations, the authors found that venous thrombosis risk was increased 3 times in those with Factor V Leiden alone, but 7 times in those with both hypofibrinolysis and Factor V Leiden.

"The importance of the fibrinolytic system to VTE needs to be further studied, and results, such as those reported in the current study, validated. This is a fruitful area for research," Dr. Wakefield concluded.