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Stratification of Patients With Unprovoked Venous Thromboembolism According to the Risk of Recurrence
Over the years routine screening for single laboratory and clinical risk factors (thrombophilia screening) was considered integral to the medical care of patients with VTE to assess their risk of recurrence. More recently, this strategy has largely been abandoned; the relevance of many of these risk factors to the risk of recurrence is either only moderate, unknown, or regarded as controversial. Moreover, the determination of some laboratory markers of thrombophilia either lacks standardization or is too elaborate for routine clinical purposes. Most patients carry more than one risk factor, and their combined effect on the recurrence risk is largely unknown.
Residual vein thrombosis has been associated with an increased risk of recurrence and has been used to guide duration of anticoagulation. However, the clinical relevance of residual vein thrombosis to predict recurrence is debated. Moreover, the definition of vein recanalization lacks standardization, and assessment requires a high degree of expertise.
Global Markers of Coagulation
Venous thrombosis is a multicausal disease. It is, therefore, desirable to use a more global approach to assess multifactorial thrombophilia and hence to estimate the overall risk of recurrence in an individual patient. Indeed, patients with unprovoked VTE can be stratified according to their recurrence risk by global markers of coagulation including the activated partial thromboplastin time or by a partial thromboplastin time-based assay that measures the overall function of the protein C pathway (ProC Global, Siemens Dade Behring, Marburg, Germany). The most promising markers, however, are thrombin generation and D-dimer in particular. By use of thrombin generation parameters, including peak thrombin levels or the endogenous thrombin, potential identification of patients at low or high risk of recurrence is feasible and has been demonstrated in different patient cohorts and by different assay systems.
Palareti and colleagues were the first to demonstrate that D-dimer levels measured 1 month after discontinuation of oral anticoagulation have a high negative predictive value for recurrence regardless of the presence or absence of hereditary thrombophilia. By use of lower cutoff levels for D-dimer (<250 ng/mL), patients with a particularly low risk of recurrence can be identified. The relevance of measuring D-dimer for risk stratification has been assessed by systematic reviews. A patient-level meta-analysis showed that, in patients with a first unprovoked VTE the timing of postanticoagulation D-dimer testing (<3 weeks, 3 to 5 weeks, >5 weeks), patient age (≤65 or >65 years), and the assay cut point used (500 ng/mL and 250 ng/mL) did not affect the ability of D-dimer to distinguish patients with a higher or lower risk for recurrent VTE.
Measurement of D-dimer has also been used in a large randomized, controlled trial for deciding on the duration of anticoagulation. The study confirmed that patients with low D-dimer after withdrawal of anticoagulation have a low risk of recurrence (4.4 recurrences/100 patient-years). Patients with high D-dimer in whom anticoagulation was stopped after 6 months had a fivefold higher risk of recurrence than those who received anticoagulation for a longer period of time (10.9 vs 2.0 recurrences/100 patient-years). In a subsequent study the same investigators found that repeated testing of D-dimer after withdrawal of anticoagulation for a first episode of unprovoked venous thrombosis may help tailor the duration of treatment.
Until the results of ongoing large clinical studies further investigating the usefulness of D-dimer to predict recurrence are available, measuring D-dimer to guide the duration of anticoagulation in patients with unprovoked VTE cannot be recommended for routine patient care.
Prediction Models of Recurrent Venous Thromboembolism
A novel approach for assessing risk of recurrent VTE consists of linking clinical patient characteristics with laboratory testing. In women with unprovoked VTE, the combination of four risk factors, namely absence of symptoms of the postthrombotic syndrome, high D-dimer, high body mass index, and advanced age, were predictors of a low recurrence risk. Importantly, in this study D-dimer was measured during rather than after discontinuation of anticoagulation.
Within the frame of the Austrian Study on Recurrent Venous Thromboembolism (AUREC), we set out to develop a simple risk model that improves prediction of the recurrence risk in all patients with unprovoked DVT and/or PE and followed 929 patients after discontinuation of anticoagulation. We preselected age, sex, thrombus location, body mass index, factor V Leiden, the prothrombin mutation, and D-dimer as relevant risk factors based on the following criteria: impact on the recurrence risk has been independently confirmed, simple assessment, and reproducibility. These variables were analyzed in a Cox proportional hazards model, and those associated with recurrence were used to compute risk scores. Only the patient's sex, thrombus location, and D-dimer were relevant predictors of the recurrence risk. Using these variables we developed a nomogram that can be used to calculate risk scores and to estimate the cumulative probability of recurrence in an individual patient.
Other models with the aim to improve prediction of recurrence are currently being developed. Thus far, none of these models has been externally validated; thus generalizability is a concern.
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