Abstract
d-dimer testing is widely used as part of the diagnostic algorithm for the exclusion of deep vein thrombosis (DVT) but is considered of limited in value for ruling DVT in. Since d-dimers are poorly defined, there is no standardization of the assays and this makes reliable comparisons between clinical studies difficult. We report on a performance evaluation of a new marker of activated coagulation (Activated Protein-C in complex with Protein-C inhibitor, APC–PCI complex) compared to two quantitative d-dimer assays (Vidas®d-dimer Exclusion™and Autodimer®). The post-hoc comparison was made on 350 frozen plasma samples from consecutive outpatients suspected of DVT in a multicenter management study including clinical probability score, d-dimer testing, venous ultrasound and contrast venography as part of the diagnostic algorithm. Results: The APC–PCI complex performed inferior to the d-dimer assays in terms of sensitivity: 74 vs. >93%, negative predictive value: 91 vs. >96% and area under the curve: 0.82 vs. 0.9, but showed a significantly higher specificity: 80 vs. 40–60%. Specificity for the APC–PCI complex did not decrease with higher clinical probability score and the positive predictive value was significantly higher than that of the d-dimer assays in the intermediate/high probability cohort (66 vs. <52%). In this probability cohort, high levels of the APC–PCI complex and to a lesser extent, d-dimers, can give positive predictive values of >90% in up to 20% of the patients which indicates important clinical implications. However, for the exclusion of DVT at the pre-specified cut-off level, the APC–PCI complex perform inferior to the d-dimer assays in this study.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11239-009-0426-z/MediaObjects/11239_2009_426_Fig1_HTML.gif)
Similar content being viewed by others
References
Nordstrom M, Lindblad B, Bergqvist D, Kjallstrom T (1992) A prospective study of the incidence of of deep vein thrombosis within a defined urban population. J Intern Med 232:155–160
Silverstein MD, Heit JA, Mohr DN, Petterson TM, O′Fallon WM, Melton LJ (1998) Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population–based study. Arch Intern Med 158:585–593
Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrom J (2007) Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 5:692–699
Hull R, Hirsch J (1981) Advances and controversies in the diagnosis, prevention, and treatment of venous thromboembolism. Prog haematol 12:73–123
Wells PS, Owen C, Doucette S, Fergusson D, Tran H (2006) Does this patient have deep vein thrombosis? Jama 295(2):199–207
Stein PD, Henry JW, Relyea B (1995) Untreated patients with pulmonary embolism: outcome, clinical, and laboratory assessment. Chest 107:931–935
Goldhaber SZ (1998) Pulmonary embolism. NEJM. 339:93–104
Coon WW, Willis PW III, Symons MJ (1969) Assessment of anticoagulant treatment of venous thromboembolism. Ann Surg 170:559–568
Hull R, Delmore T, Genton E (1979) Warfarin sodium versus low-dose heparin in the long term treatment of venous thrombosis. NEJM 301:855–858
van der Meer FJ, Rosendaal FR, Vanderbroucke JP, Briet E (1993) Bleeding complications in oral antocoagulation therapy. An analysis of riskfactors. Arch Intern Med 153:1557–1562
Righini M, Perrier A, de Moerloose P, Bonamaeux H (2008) D-Dimer for venous thromboembolism diagnosis: 20 years later. J Thromb Haemost 6:1059–1071
Goodacre S, Stevenson M, Wailoo A, Sampson F, Sutton AJ, Thomas S (2006) How should we diagnose deep-vein thrombosis? Q J Med 99:377–388
Stokes KR (1994) Complications of diagnostic venography. Sem Interv Radiol 11:102–106
Morcos SK, Thomsen HS, Webb JAW (1999) Contrast media induced nephrotoxity: a consensus report. Eur Radiol 9:1602–1613
Bounamaeux H, de Moerloose P, Perrier A et al (1997) D-dimer testing in suspected venous thromboembolism: an update. QJM 90:437–442
Perrier A, Desmarais S, Goehring C et al (1997) D-dimer testing for suspected pulmonary embolism in outpatients. Am J Respir Crit Care Med 156:492–496
Risch L, Monn A, Luthy R et al (2004) The predictive characteristics of D-dimer testing in outpatients with suspected venous thromboembolism. A Bayesian approach. Clin Chem Acta 345:79–87
Tick LW, Nijkeuter M, Kramer MHH, Hovens MMC, Buller HR, Leebeek FWG, Huisman MV (2008) High D-dimers levels increase the likelihood of pulmonary embolism. J Intern Med 264:195–200
Stein PD, Hull RD (2004) D-dimer for the exclusion of acute deep vein thrombosis and pulmonary embolism: a systematic review. Ann Intern Med 140(8):589–602
Di Nisio M, Squizzato A, Rutjes AW, Buller HR, Zwinderman AH, Bossuyt PM (2007) Diagnostic accuracy of D-dimer tests for exclusion of venous thromboembolism: a systematic review. J Thromb Haemost 5(2):296–304
Espana F, Vicente V, Scharrer I, Tabernero D, Griffin JH (1990) Determination of plasma protein C inhibitor and of two activated protein C inhibitor complexes in normals and in patients with intravascular coagulation and thrombotic disease. Thromb Res 59:593–608
Minamikawa K, Wada H, Wakita Y et al (1994) Increased activated protein C-protein C inhibitor complex levels in patients with pulmonary embolism. Thromb Haemost 71:192–194
Strandberg K, Astermark J, Björgell O, Becker C, Nilsson PE, Stenflo J (2001) Complexes between activated protein C and protein C inhibitor measured with a new method. Thromb Haemost 86:1400–1408
Strandberg K, Kjellberg M, Knebel R, Lilja H, Stenflo J (2001) A sensitive immunochemical assay for measuring the concentration of the activated protein-Cprotein C inhibitor complex in plasma. Thromb Haemost 86:604–610
Roumen-Klappe EM, den Heijer M, van Uum SH, van der Ven-Jongekrijg J, van der Graaf F, Wollersheim H (2002) Inflammatory response in acute phase of deep vein thrombosis. J Vasc Surg 35:701–706
Wells PS, Anderson DR, Bormanis J et al (1997) Value of assessment of pretest probability of deep vein thrombosis in clinical management. Lancet 350:1795–1798
Elf JL, Nilsson C, Strandberg K, Svensson PJ (2009) Clinical probability assessment and D-dimer determination in patients with suspected deep vein thrombosis, a prospective multicenter management study. Thromb Res 123:612–616
Strandberg K, Svensson A, Stenflo J (2003) Stabilyte tubes that contain strongly acidic citrate prevent in vitro complex formation between activated protein C and protein C inhibitor. Thromb Haemost 89:947–949
Altman DG (1999) Practical statistics for medical research, First edn. Chapman and Hall, Florida
Nieuwenhuizen W, Emeis JJ, Vermond A (1982) Catabolism of purified rat fibrin(ogen) plasmin degradation products in rats. Thromb Haemost 48:59–61
Wells PS, Anderson DR, Rodger M et al (2003) Evaluation of D-dimer in the diagnosis of suspected deep vein thrombosis. NEJM 349:1227–1235
Le Gal G, Righini M, Parent F, van Strijen M, Coutraud F (2006) Diagnosis and management of subsegmental pulmonary embolism. J Thromb Haemost 4:724–731
Acknowledgment
We thank bioMerieux for providing the miniVidas device and the reagent. Substantial help in the statistical calculations has been provided by Håkan Lövkvist at the regional competence center for statistics, Skåne, Sweden.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Elf, J.L., Strandberg, K. & Svensson, P.J. The diagnostic performance of APC–PCI complex determination compared to d-dimer in the diagnosis of deep vein thrombosis. J Thromb Thrombolysis 29, 465–470 (2010). https://doi.org/10.1007/s11239-009-0426-z
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11239-009-0426-z