The role of fibrin monomers in optimizing the diagnostic work-up of deep vein thrombosis

Summary

Despite the use of a clinical score and D-dimers to exclude deep vein thrombosis (DVT), the majority of patients still need repeated ultrasound (US).The aim of the study was to investigate whether fibrin monomers (FMs), as markers of thrombin generation, have additional value in the diagnosis of DVT. This is a posthoc analysis of 464 outpatients, participants in a management study using D-dimers (Tina-Quant® ) and a clinical score in the exclusion of DVT. Two new FM assays (Auto LIA-FM^® and IATRO SF^®, Japan) were performed. Overall sensitivity, negative predictive value (NPV) and specificity of the D-dimer test were 98%, 98% and 42%.The optimal cut-off point for the Auto LIAFM test was ≤ 3 µ g/ml with values of 88%, 88% and 59%, respectively. The IATRO SF test had an optimal cut-off point of ≤ 2 µ g/ ml with values of 92%, 81 and 22%, respectively.The NPV of a non-high clinical score and a normal D-dimer (n=97) was 100%. In patients with a high clinical score (n=160), the NPV of the D-dimer was 88%. In these patients, a single US combined with a normal D-dimer or FM test had an equal NPV as serial US (100 versus 98%, respectively) and lead to a reduction in the need for US by 36–53%, respectively. In patients with abnormal D-dimer concentrations (n=343), a normal US combined with a normal Auto LIA-FM test had a NPV of 97%,which was also true for serial US.This could lead to a reduction in the need for US by 45%. The present studied FMs are inferior to theTina-Quant D-dimer test when used as primary screening tool to exclude DVT.Adding these FMs to patients with a normal Tina-Quant D-dimer has no benefit. In patients with a high pretest clinical probability score, a single US in combination with a normal D-dimer or FM test might be as safe as serial US. In patients with abnormal D-dimer concentrations and a normal US, a normal FM test might be able to replace the second US.

Keywords

D-dimer - fibrin monomer - diagnosis - venous thromboembolism - deep vein thrombosis - ultrasonography

• References

• 1 Fancher TL, White RH, Kravitz RL. Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review. Br Med J 2004; 329: 821 Erratum in: Br Med J 2004; 329: 1236.
• 2 LaCapra S, Arkel YS, Ku DH. et al. The use of thrombus precursor protein, D-dimer, prothrombin fragment 1.2, and thrombin antithrombin in the exclusion of proximal deep vein thrombosis and pulmonary embolism. Blood Coagul Fibrinolysis 2000; 11: 371-377.
• 3 Kawasaki T, Shinoki N, Iwamoto S. et al. Diagnostic value of plasma thrombin-antithrombin III complex and D-dimer concentration in patients with va cose veins for exclusion of deep-vein thrombosis. Thromb Res 1998; 91: 101-104.
• 4 Cofrancesco E, Cortellaro M, Corradi A. et al. Clinical utility of prothrombin fragment 1+2, thrombin antithrombin III complexes and D-dimer measurements in the diagnosis of deep vein thrombosis following total hip replacement. Thromb Haemost 1998; 79: 509-510.
• 5 Tengborn L, Palmblad S, Wojciechowski J. et al. D-dimer and thrombin/antithrombin III complex-- diagnostic tools in deep venous thrombosis?. Haemostasis 1994; 24: 344-350.
• 6 Boneu B, Bes G, Pelzer H. et al. D-Dimers, thrombin antithrombin III complexes and prothrombin fragments 1+2: diagnostic value in clinically suspected deep vein thrombosis. Thromb Haemost 1991; 65: 28-31.
• 7 Speiser W, Mallek R, Koppensteiner R. et al. D-dimer and TAT measurement in patients with deep venous thrombosis: utility in diagnosis and judgement of anticoagulant treatment effectiveness. Thromb Haemost 1990; 64: 196-201.
• 8 Bozic M, Blinc A, Stegnar M. D-dimer, other markers of haemostasis activation and soluble adhesion molecules in patients with different clinical probabilities of deep vein thrombosis. Thromb Res 2002; 108: 107-114.
• 9 Vogel G, Dempfle CE, Spannagl M. et al. The value of quantitative fibrin monomer determination in the early diagnosis of postoperative deep vein thrombosis. Thromb Res 1996; 81: 241-251.
• 10 Hansson PO, Eriksson H, Eriksson E. et al. Can laboratory testing improve screening strategies for deep vein thrombosis at an emergency unit?. J Intern Med 1994; 235: 143-151.
• 11 Elias A, Cazanave G, Nguyen F. et al. Comparison of the diagnostic performance of three soluble fibrin monomer tests and a D-dimer assay in patients with clinically suspected deep vein thrombosis of the lower limbs. Haematologica 2004; 89: 499-501.
• 12 Caliezi C, Funfsinn N, Mauron T. et al. Performance of a new fibrin monomer assay to exclude deep vein thrombosis in symptomatic outpatients. Thromb Haemost 1999; 81: 50-53.
• 13 Dempfle CE. The use of soluble fibrin in evaluating the acute and chronic hypercoagulable state. Thromb Haemost 1999; 82: 673-683.
• 14 Schutgens RE, Ackermark P, Haas FJLM. et al. Combination of a normal D-dimer concentration and a non-high pretest clinical probability score is a safe strategy to exclude deep venous thrombosis. Circulation 2003; 107: 593-597.
• 15 Wells PS, Anderson DR, Bormanis J. et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350: 1795-1798.
• 16 Goodacre S, Sampson F, Thomas S. et al. Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis. BMC Med Imaging 2005; 05: 6
• 17 Kearon C, Julian JA, Newman TE. et al. Noninvasive diagnosis of deep venous thrombosis. McMaster Diagnostic Imaging Practice Guidelines Initiative. Ann Intern Med 1998;128: 663–677. Erratum in: Ann Intern Med 1998; 129: 425
• 18 McRae SJ, Ginsberg JS. Update in the diagnosis of deep-vein thrombosis and pulmonary embolism. Curr Opin Anaesthesiol 2006; 19: 44-51.
• 19 Linkins LA, Bates SM, Ginsberg JS. et al. Use of different D-dimer levels to exclude venous thromboembolism depending on clinical pretest probability. J Thromb Haemost 2004; 02: 1256-1260.
• 20 Stevens SM, Elliott CG, Chan KJ. et al. Withholding anticoagulation after a negative result on duplex ultrasonography for suspected symptomatic deep venous thrombosis. Ann Intern Med 2004; 140: 985-91.
• 21 Schellong SM, Schwarz T, Halbritter K. et al. Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis. Thromb Haemost 2003; 89: 228-234.
• 22 Elias A, Mallard L, Elias M. et al. A single complete ultrasound investigation of the venous network for the diagnostic management of patients with a clinically suspected first episode of deep venous thrombosis of the lower limbs. Thromb Haemost 2003; 89: 221-227.
• 23 El Kheir D, Büller H. One-time comprehensive ultrasonography to diagnose deep venous thrombosis: is that the solution?. Ann Intern Med 2004; 140: 1052-1053.
• 24 Bates SM, Kearon C, Crowther M. et al. A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis. Ann Intern Med 2003; 138: 787-794.
• 25 Kearon C, Ginsberg JS, Douketis J. et al. Management of suspected deep venous thrombosis in outpatients by using clinical assessment and D-dimer testing. Ann Intern Med 2001; 135: 108-111.
• 26 Perrier A, Desmarais S, Miron MJ. et al. Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet 1999; 353: 190-195.
• 27 Aguilar C, Martinez A, Martinez A. et al. Diagnostic value of d-dimer in patients with a moderate pretest probability of deep venous thrombosis. Br J Haematol 2002; 118: 275-277.