Biochemical markers for the diagnosis of venous thromboembolism: the past, present and future

Deep venous thrombosis and pulmonary embolism represent two expressions of a similar clinical pathological process traditionally referred to as venous thromboembolism. Several population studies evidence venous thromboembolism as a leading healthcare problem worldwide, highlighting the need for early and reliable diagnosis to enable appropriate triage of affected patients and to optimize outcome. There is still debate, however, on which thrombotic markers to use, as well as their most suitable position within diagnostic algorithms. This article aims to review the pathophysiology and clinical usefulness of past, present and future markers of thrombosis, including soluble fibrin monomers, fibrin/fibrinogen degradation products, thrombin-antithrombin complex, plasmin-antiplasmin complex, fibrinopeptide A and B, prothrombin fragments 1 + 2, thrombus precursor protein, D-dimer, activated protein C-protein C inhibitor complex, myeloperoxidase, thrombin generation assays and proteomic analysis. Several lines of evidence now attest that the global diagnostic performances of some D-dimer assays largely outperform those of any other coagulation or fibrinolytic marker proposed thus far, and a "negative" D-dimer measured with rapid enzyme linked fluorescent immunoassay is now considered the biochemical gold standard for ruling out an acute episode of venous thromboembolism in a patient with a low pretest probability for venous thromboembolism, so that additional testing can be safely omitted. However, to further improve clinical outcomes, the diagnostic efficiency of combining D-dimer testing with other markers covering different pathophysiological aspects of thrombosis such as continuous and progressive thrombin generation (e.g., activated protein C-protein C inhibitor complex) or neutrophil activation (i.e., myeloperoxidase) merits further investigation. Proteomic analysis, which would help to characterize the structure and function of each protein and the complexities of protein-protein interactions in physiological and pathological hemostasis, also holds promise for identifying novel markers and developing effective diagnostic protocols in the future.