Diagnostic Accuracy in Acute Venous Thromboembolism: Comparing D-Dimer, Thrombin Generation, Overall Hemostatic Potential, and Fibrin Monomers

Maria Farm; Aleksandra Antovic; David E. Schmidt; Niklas Bark; Nida Soutari; Anwar J. Siddiqui; Margareta Holmström; Iva Pruner; Jovan P. Antovic

doi:10.1055/s-0040-1714210

TH Open, Table of Contents

CC BY 4.0 · TH Open 2020; 04(03): e178-e188
DOI: 10.1055/s-0040-1714210

Original Article

Diagnostic Accuracy in Acute Venous Thromboembolism: Comparing D-Dimer, Thrombin Generation, Overall Hemostatic Potential, and Fibrin Monomers

Maria Farm

¹Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

²Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden

,

Aleksandra Antovic

³Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁴Academic Specialist Center, Center for Rheumatology, Stockholm Health Services, Stockholm, Sweden

,

David E. Schmidt

⁵Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden

⁶Coagulation Unit, Division of Haematology, Karolinska University Hospital, Stockholm, Sweden

,

Niklas Bark

²Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden

,

Nida Soutari

¹Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

²Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden

,

Anwar J. Siddiqui

⁷Emergency Medicine Function, Karolinska University Hospital, Stockholm, Sweden

,

Margareta Holmström

⁸Division of Diagnostics and Specialist Medicine, Unit of Internal Medicine, Medicine and Caring Sciences, Department of Health, Linköping University, Linköping, Sweden

,

Iva Pruner

¹Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

,

Jovan P. Antovic

¹Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

²Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden

› Author Affiliations

Abstract

Introduction For acute venous thromboembolism (VTE), a biomarker with higher specificity than D-dimer would be of great clinical use. Thrombin generation and overall hemostatic potential (OHP) reflect the hemostatic balance by globally assessing multiple coagulation factors and inhibitors. These tests discriminate between healthy controls and patients with a prothrombotic tendency but have yet to be established as clinical biomarkers of VTE.

Objective This study compares endogenous thrombin potential (ETP) and OHP to D-dimer and fibrin monomers (FM) in outpatients with suspected VTE.

Methods A cross-sectional diagnostic study where 954 patients with suspected pulmonary embolism or deep venous thrombosis were recruited consecutively from the medical emergency department at Karolinska University Hospital. D-dimer, FM, OHP, and ETP were analyzed in a subpopulation of 60 patients with VTE and 98 matched controls without VTE. VTE was verified either by ultrasonography or computed tomography and clinical data were collected from medical records.

Results Compared with healthy controls, both VTE and non-VTE patients displayed prothrombotic profiles in OHP and ETP. D-dimer, FM, ETP area under the curve (AUC), and ETP T_lag were significantly different between patients with VTE and non-VTE. The largest receiver-operating characteristic AUCs for discrimination between VTE and non-VTE, were found in D-dimer with 0.94, FM 0.77, and ETP AUC 0.65. No useful cutoff could be identified for the ETP or the OHP assay.

Conclusion Compared with D-dimer, neither ETP nor OHP were clinically viable biomarkers of acute venous thrombosis. The data indicated that a large portion of the emergency patients with suspected VTE were in a prothrombotic state.

Keywords

predictive value of tests - global hemostatic assays - clinical studies - deep vein thromboses - pulmonary embolism

Full Text

References

References
1 Cohen AT, Gitt AK, Bauersachs R. , et al. The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry. Thromb Haemost 2017; 117 (07) 1326-1337
2 Smith-Bindman R, Lipson J, Marcus R. , et al. Radiation dose associated with common computed tomography examinations and the associated lifetime attributable risk of cancer. Arch Intern Med 2009; 169 (22) 2078-2086
3 Parfrey P. The clinical epidemiology of contrast-induced nephropathy. Cardiovasc Intervent Radiol 2005; 28 (Suppl. 02) S3-S11
4 Refaai MA, Riley P, Mardovina T, Bell PD. The clinical significance of fibrin monomers. Thromb Haemost 2018; 118 (11) 1856-1866
5 Farm M, Siddiqui AJ, Onelöv L. , et al. Age-adjusted D-dimer cut-off leads to more efficient diagnosis of venous thromboembolism in the emergency department: a comparison of four assays. J Thromb Haemost 2018; 16 (05) 866-875
6 Lippi G, Cervellin G, Casagranda I, Morelli B, Testa S, Tripodi A. D-dimer testing for suspected venous thromboembolism in the emergency department. Consensus document of AcEMC, CISMEL, SIBioC, and SIMeL. Clin Chem Lab Med 2014; 52 (05) 621-628
7 Bratseth V, Pettersen AÅ, Opstad TB, Arnesen H, Seljeflot I. Markers of hypercoagulability in CAD patients. Effects of single aspirin and clopidogrel treatment. Thromb J 2012; 10 (01) 12
8 Wexels F, Dahl OE, Pripp AH, Seljeflot I. Thrombin generation in patients with suspected venous thromboembolism. Clin Appl Thromb Hemost 2017; 23 (05) 416-421
9 Haas FJ, Schutgens RE, Kluft C, Biesma DH. A thrombin generation assay may reduce the need for compression ultrasonography for the exclusion of deep venous thrombosis in the elderly. Scand J Clin Lab Invest 2011; 71 (01) 12-18
10 Riva N, Vella K, Hickey K. , et al. Biomarkers for the diagnosis of venous thromboembolism: D-dimer, thrombin generation, procoagulant phospholipid and soluble P-selectin. J Clin Pathol 2018; 71 (11) 1015-1022
11 Chaireti R, Jennersjö C, Lindahl TL. Thrombin generation and D-dimer concentrations in a patient cohort investigated for venous thromboembolism. Relations to venous thrombosis, factor V Leiden and prothrombin G20210A. The LIST study. Thromb Res 2009; 124 (02) 178-184
12 Hunt BJ, Parmar K, Horspool K, Shephard N, Nelson-Piercy C, Goodacre S. ; DiPEP research group. The DiPEP (Diagnosis of PE in Pregnancy) biomarker study: an observational cohort study augmented with additional cases to determine the diagnostic utility of biomarkers for suspected venous thromboembolism during pregnancy and puerperium. Br J Haematol 2018; 180 (05) 694-704
13 Segers O, van Oerle Rv, ten Cate Ht, Rosing J, Castoldi E. Thrombin generation as an intermediate phenotype for venous thrombosis. Thromb Haemost 2010; 103 (01) 114-122
14 Lutsey PL, Folsom AR, Heckbert SR, Cushman M. Peak thrombin generation and subsequent venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE) study. J Thromb Haemost 2009; 7 (10) 1639-1648
15 Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation 2010; 121 (14) 1630-1636
16 van Hylckama Vlieg A, Baglin CA, Luddington R, MacDonald S, Rosendaal FR, Baglin TP. The risk of a first and a recurrent venous thrombosis associated with an elevated D-dimer level and an elevated thrombin potential: results of the THE-VTE study. J Thromb Haemost 2015; 13 (09) 1642-1652
17 Pepperell D, Morel-Kopp M-C, Ward C. Clinical application of fibrinolytic assays. In: Kolev K. , ed. Fibrinolysis and Thrombolysis. Rijeka, Croatia: Intech; 2014: 139-148
18 Antovic JP, Mikovic D, Elezovic I. , et al. Two global haemostatic assays as additional tools to monitor treatment in cases of haemophilia A. Thromb Haemost 2012; 108 (01) 21-31
19 Antovic A. Screening haemostasis--looking for global assays: the Overall Haemostasis Potential (OHP) method--a possible tool for laboratory investigation of global haemostasis in both hypo- and hypercoagulable conditions. Curr Vasc Pharmacol 2008; 6 (03) 173-185
20 Vikerfors A, Svenungsson E, Ågren A. , et al. Studies of fibrin formation and fibrinolytic function in patients with the antiphospholipid syndrome. Thromb Res 2014; 133 (05) 936-944
21 Chow V, Reddel C, Pennings G. , et al. Persistent global hypercoagulability in long-term survivors of acute pulmonary embolism. Blood Coagul Fibrinolysis 2015; 26 (05) 537-544
22 Curnow JL, Morel-Kopp MC, Roddie C, Aboud M, Ward CM. Reduced fibrinolysis and increased fibrin generation can be detected in hypercoagulable patients using the overall hemostatic potential assay. J Thromb Haemost 2007; 5 (03) 528-534
23 Edelman JJ, Reddel CJ, Kritharides L. , et al. Natural history of hypercoagulability in patients undergoing coronary revascularization and effect of preoperative myocardial infarction. J Thorac Cardiovasc Surg 2014; 148 (02) 536-543
24 Rooth E, Wallén H, Antovic A. , et al. Thrombin activatable fibrinolysis inhibitor and its relationship to fibrinolysis and inflammation during the acute and convalescent phase of ischemic stroke. Blood Coagul Fibrinolysis 2007; 18 (04) 365-370
25 Lim HY, O'Malley C, Donnan G, Nandurkar H, Ho P. A review of global coagulation assays - is there a role in thrombosis risk prediction?. Thromb Res 2019; 179: 45-55
26 Bombardier C, Villalobos-Menuey E, Ruegg K, Hathaway WE, Manco-Johnson MJ, Goldenberg NA. Monitoring hypercoagulability and hypofibrinolysis following acute venous thromboembolism in children: application of the CloFAL assay in a prospective inception cohort study. Thromb Res 2012; 130 (03) 343-349
27 Siemens Healtcare Diagnostics, Innovance ETP. Kit Insert, 2018 . OPGAG03C0104(1113)
28 He S, Bremme K, Blombäck M. A laboratory method for determination of overall haemostatic potential in plasma. I. Method design and preliminary results. Thromb Res 1999; 96 (02) 145-156
29 Dargaud Y, Wolberg AS, Gray E, Negrier C, Hemker HC. ; Subcommittee on Factor VIII, Factor IX, and Rare Coagulation Disorders. Proposal for standardized preanalytical and analytical conditions for measuring thrombin generation in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2017; 15 (08) 1704-1707
30 Devreese K, Wijns W, Combes I, Van kerckhoven S, Hoylaerts MF. Thrombin generation in plasma of healthy adults and children: chromogenic versus fluorogenic thrombogram analysis. Thromb Haemost 2007; 98 (03) 600-613
31 He S, Antovic A, Blombäck M. A simple and rapid laboratory method for determination of haemostasis potential in plasma. II. Modifications for use in routine laboratories and research work. Thromb Res 2001; 103 (05) 355-361
32 Roche Diagnostics, Tina-quant D-Dimer Gen.2. 2015–10. 0004912551190 COINV50
33 Westerlund E, Woodhams BJ, Eintrei J, Söderblom L, Antovic JP. The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory. Int J Lab Hematol 2013; 35 (06) 666-671
34 Medirox. MRX Owren's PT. Revision: 2018–08–20
35 Clauss A. Gerinnungsphysiologische schnellmetode zur bestimmung des fibrinogens. Acta Haematol 1957; 17: 237-246
36 Siemens Healthcare Diagnostics, Berichrom® Antitrombin III (A). 2013–07 OWWRG17E33 Rev. 03
37 Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 1993; 39 (04) 561-577
38 Clinical and Laboratory Standards Institute (CLSI), Quantitative D-dimer for exclusion of venous thromboembolic disease; approved guideline. CLSI document H59-A. Clinical and Laboratory Standards Institute 950 West Valley Road, Suite 2500 Wayne, PA 19087 USA; 2011;31(6)
39 Kintigh J, Monagle P, Ignjatovic V. A review of commercially available thrombin generation assays. Res Pract Thromb Haemost 2017; 2 (01) 42-48
40 Fleck D, Albadawi H, Wallace A, Knuttinen G, Naidu S, Oklu R. Below-knee deep vein thrombosis (DVT): diagnostic and treatment patterns. Cardiovasc Diagn Ther 2017; 7 (Suppl. 03) S134-S139
41 Holmström M, Lindmarker P, Granqvist S, Johnsson H, Lockner D. A 6-month venographic follow-up in 164 patients with acute deep vein thrombosis. Thromb Haemost 1997; 78 (02) 803-807

Supplementary Material

Supplementary Material