In this prospective cohort study of more than 700 patients with a first unprovoked VTE the risk of recurrent VTE was as high as 21% 5 years after withdrawal of anticoagulants. The principal finding was that hypofibrinolysis was associated with a moderate although statistically not significant increase in the risk of recurrent VTE. We used CLT as a global marker of fibrinolytic capacity and found that patients with CLT values in the 4th quartile of the patient population had a more than 1.6-fold greater recurrence risk compared to the reference group, i.e. patients with CLT values in the 1st quartile. The increased risk of recurrence was, however, seen only in women: women with CLT values in the 4th quartile had a 3-fold greater risk of recurrence compared to women with short CLT values.
Data on the association between hypofibrinolysis and recurrent VTE are scarce and conflicting. Inconsistent study outcomes may well be explained by differences between patient populations, study designs and laboratory test systems. Our findings are in line with our previous analysis performed in the same patient cohort 
. We found a 2-fold greater recurrence risk in patients with TAFI (which is an important determinant of the CLT assay 
) levels exceeding the 75th
percentile compared with lower values. The risk was highest among patients with both high TAFI and high plasma levels of factors VIII, IX or XI. Our findings are also in agreement with data reported by Korninger et al. already several years ago. In this retrospective study of only 121 patients, the recurrence rate was 4.8%/year in patients with a post-occlusion ELT shorter than 60 minutes and was 10.3%/year in those with a longer ELT 
. In the DURAC Study, the proportion of patients, who had t-PA antigen levels above the normal range, was higher among those who experienced recurrence after a first or second VTE compared to those who did not (59% vs. 34%, p<0.001). When the t-PA antigen levels were adjusted for age, no difference between patients with or without recurrence was seen 
. Of note, a large proportion of patients in this study had VTE secondary to a temporary risk factor or more than 2 episodes of VTE. 2 studies, one from Canada and one from the Netherlands 
, found no association between various fibrinolytic variables and risk of recurrent VTE. In the former study, however, fibrinolytic testing was performed in only a small number of patients after anticoagulant therapy had been discontinued, and both patients with provoked and unprovoked VTE were studied. In the latter study, patients older than 70 years of age and patients with PE were excluded. Many patients in this study experienced the index VTE event in the presence of a temporary risk factor and thus have to be regarded as low risk patients unlikely to benefit from indefinite anticoagulation. With the exception of our own study 
, none of the aforementioned reports took a possible difference in fibrinolytic variable levels between men and women into consideration.
Our study has strengths and limitations. With more than 700 consecutive VTE patients (of whom 135 experienced objectively documented recurrence) and a follow-up of almost 4 years in average, our study is one of the largest today. Our study population is homogenous as we only included patients with a first unprovoked VTE. In contrast to patients with secondary VTE, this is the patient population with a high risk of recurrence that might benefit from extended anticoagulation. The patients are seen in our department at regular intervals and the number lost to follow-up is low. Our findings, however, cannot be extrapolated to patients with a provoked VTE or to those with a strong thrombophilic defect, because these patients were excluded and treated on a routine basis for a longer period of time. The CLT assay used in this study employs exogenous tPA to effect lysis. Consequently, the test provides no indication of endogenous tPA activity. Our study is a hypothesis-generating cohort study, which precludes predefinition of certain cutoff values.
What is the clinical relevance of our findings? The optimal duration of secondary thromboprophylaxis entails balancing the risk of recurrent VTE against the risk of bleeding related to anticoagulation. Identification of distinct patients with a recurrence risk that is high enough to justify institution of long-term anticoagulation would allow individualized patient management. Determination of single components of the coagulation system, i.e. laboratory thrombophilia screening, has failed in this respect 
. A more promising approach consists in measuring global coagulation markers, the level of which might reflect multicausal thrombophilia. Indeed, patients can be stratified into high and low risk categories with respect to their recurrence risk by measuring D-Dimer or thrombin generation shortly after cessation of anticoagulation 
. D-Dimer levels have been incorporated in 2 prediction models of recurrent VTE 
, both of which, however, require validation before routine use. In this respect, our findings regarding the potential usefulness of a global indicator of fibrinolytic capacity (such as the CLT) to stratify thrombosis patients according to their recurrence risk are inconclusive. Although we found an association between CLT and risk of recurrent VTE, this relationship is not strong enough to serve as a solid basis on which clinical decisions regarding duration of anticoagulation can be made. It remains, however, to be seen if by combining CLT with other global coagulation markers, for instance D-Dimer or in vitro thrombin generation, or by incorporating CLT in prediction models, discrimination between high and low risk patients in terms of their recurrence risk could be improved.