Contribution of clinical chemistry in the diagnostic procedure of deep venous thrombosis

Abstract

One of the most common cardiovascular disorders in industrialized countries is venous thrombo-embolism (VTE). This disorder has a clinical presentation as deep venous thrombosis (DVT) and/or pulmonary embolism. The common diagnostic workup of patients suspected for VTE according to the guidelines is a combination of the score of a clinical decision rule (CDR), information about the probability, and the level of the D-dimer (DD) fragment, information about the degree of coagulation and the breakdown of the formed clot. In practice, if the CDR and the DD level are normal, it is safe to rule out VTE. In all other cases additional imaging is required.

In this thesis we focused on the contribution of clinical chemistry in the diagnostic procedures of outpatients, suspected for DVT, in the exclusion of DVT and a reduction of false-positive results.

The performance of several commercial DD assays in terms of sensitivity and specificity was compared. The sensitivity should be as high as possible (100%) to safely exclude and to avoid false-negative results and the wish is have specificity as high as possible to reduce the number of patients with unnecessary additional imaging tests, the false-positive results. None of the DD assays could be used as standalone test.

The value of the standard procedure in the diagnostic workup, the combination of CDR score and the DD level was evaluated. The number of patients with a normal CDR decreases with age, just as a normal DD level. The standard algorithm is safe for all ages, but less effective in the elderly.

To overcome the age dependence of DD, an early marker of coagulation, the fibrin monomer (FM) was evaluated, for use instead of or combined with the D-dimer assay. It was not possible to use the FM assay as standalone test, but in specific patient groups the number of ultrasonographic examinations can be reduced.

The performance of age dependence cut-off values of the DD level was tested; a higher cut-off level results in a higher specificity. With a dichotomous distribution, < 60 y and ≥ 60 y, it is feasible to change the cut-off value by a sensitivity of 100%, with a reduction of false-positive results.

The new technique of thrombin generation (TG), which informs us about the coagulation potential, was tested. This technique cannot replace the DD, but has added value in specific patient groups. The performance of the TG assay in patients with inherited or acquired thrombophilic risk factors for VTE is evaluated, the time dependent TG parameters are prolonged in patients with factor V Leiden.

Finally we evaluated an assay specific for inflammation dependent fibrinogen degradation product and a second assay, comparable with DD, but with a specific reaction with the D-E fragment. Also these assays could not replace the DD, but offered additional diagnostic value, the first especially in the elderly and the second provided insight in the difference in composition of the fibrin degradation products in DVT positive and negative patients.