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

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Abstract

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.

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Abbreviations

DVT:

Deep venous thrombosis

PE:

Pulmonary embolism

VTE:

Venous thromboembolism

ED:

Emergency department

DD:

D-dimer

CT:

Computed tomography

sFM:

Soluble fibrin monomers

sFMC:

sFM complexes

FDPs:

Fibrin/Fibrinogen degradation products

TAT:

Thrombin–antithrombin complex

PAP:

Plasmin–antiplasmin complex

FPA:

Fibrinopeptide A

FPB:

Fibrinopeptide B

PF1 + 2:

Prothrombin fragments 1 + 2

TpP:

Thrombus precursor protein

APC–PCI:

Activated protein C–protein C inhibitor complex

MPO:

Myeloperoxidase

FXIII:

Factor XIII

PAI-1:

Plasminogen activator inhibitor-1

PAI-2:

Plasminogen activator inhibitor-2

TAFI:

Thrombin activatable fibrinolysis inhibitor

NPV:

Negative predictive value

PPV:

Positive predictive value

ELISA:

Enzyme-linked immunosorbent assay

AUC:

Areas under the Roc Curve

VWF:

von Willebrand Factor

CRP:

C-reactive protein

ELFA:

Enzyme linked fluorescent immunoassay

CUS:

Compression ultrasonography

HTA:

Health Technology Assessment

TGA:

Thrombin generation assay

ETP:

Endogenous thrombin potential

CAT:

Calibrated Automated Thrombogram

MALDI-TOF:

Matrix-assisted laser desorption/ionization-time of flight

SELDI-TOF:

Surface-enhanced laser desorption ionization time-of-flight

MS:

Mass spectrometry

SPECT:

Single photon emission computed tomography

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Authors and Affiliations

  1. U.O. di Diagnostica Ematochimica, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14, 43126, Parma, Italy

    Giuseppe Lippi

  2. U.O. di Pronto Soccorso e Medicina d’ Urgenza, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

    Gianfranco Cervellin

  3. Servizio di Immunoematologia e Trasfusione, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

    Massimo Franchini

  4. Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, Australia

    Emmanuel J. Favaloro

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  1. Giuseppe Lippi
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  2. Gianfranco Cervellin
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  4. Emmanuel J. Favaloro
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Lippi, G., Cervellin, G., Franchini, M. et al. Biochemical markers for the diagnosis of venous thromboembolism: the past, present and future. J Thromb Thrombolysis 30, 459–471 (2010). https://doi.org/10.1007/s11239-010-0460-x

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