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Semin Thromb Hemost 2000; 26(6): 631-642
DOI: 10.1055/s-2000-13221
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Use of D-Dimer Assays in the Diagnosis of Venous Thrombosis

Carl-Erik Dempfle
  • From the University of Heidelberg, Mannheim University Hospital, I. Department of Medicine, Mannheim, Germany
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Publikationsdatum:
31. Dezember 2000 (online)

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ABSTRACT

In the course of fibrin formation, the D-domains of adjacent fibrin molecules within the fibrin polymer are covalently linked by factor XIIIa, leading to the formation of a D-domain dimer. Proteolysis of this cross-linked fibrin generates fibrin fragments D-dimer and E as terminal products. Fragment D-dimer therefore is an indicator for the proteolysis of cross-linked fibrin, whereas the monomeric fragment D can stem from fibrinogen and non-cross-linked fibrin. Various monoclonal antibodies have been prepared that distinguish between fragments D-dimer and D and allow the detection of fibrin derivatives in the presence of fibrinogen. These anti-D-dimer-antibodies have been shown to react with fragment D-dimer, but also detect dimeric D-domains within larger fibrin compounds, including cross-linked fibrin complexes generated in an early phase of coagulation activation. Assay systems for D-dimer antigen therefore may uncover intravascular clot formation early, by detection of fibrin complexes, and after completion of clot formation, by the detection of proteolytic fragments released from the particulate clot. Various trials have shown that low concentrations of D-dimer antigen in the blood exclude recent venous thrombosis or pulmonary embolism. Elevated levels may be caused by venous thrombotic disease, but also by a variety of other conditions, leading to intra- or extravascular fibrin formation. Assay systems include manual immunoagglutination assays, immunofiltration assays, microtiter plate enzyme-linked immunosorbent assay (ELISA) systems, automated ELISA systems, and latex-enhanced photometric immunoassays. According to clinical studies, D-dimer assays may be the ``first line'' of technical screening in symptomatic outpatients with suspected venous thrombosis or pulmonary embolism, but further prospective management trials, and improved standardization of assay systems, are needed for the validation of this approach.

KEYWORD

D-dimer - venous thrombosis - pulmonary embolism - assay systems - outpatient diagnosis

REFERENCES

  • 1 Bettelheim F R, Bailey K. The products of the action of thrombin on fibrinogen.  Biochim Biophys Acta . 1952;  9 578-579
    CrossrefPubMedSuche in Google Scholar
  • 2 Olexa S A, Budzynski A Z. Evidence for four different polymerization sites involved in human fibrin formation.  Proc Natl Acad Sci USA . 1980;  77 1374-1378
    PubMedSuche in Google Scholar
  • 3 Greenberg C S, Achyuthan K E, Rajagopalan S, Pizzo S V. Characterization of the fibrin polymer structure that accelerates thrombin cleavage of plasma factor XIII.  Arch Biochem Biophys . 1988;  262 142-148
    CrossrefPubMedSuche in Google Scholar
  • 4 Marder V J, Budzynski A Z, Barlow G H. Comparison of the physicochemical properties of fragment D derivatives of fibrinogen and fragment D-D of cross-linked fibrin.  Biochim Biophys Acta . 1976;  427 1-14
    PubMedSuche in Google Scholar
  • 5 Gaffney P J, Joe F. The lysis of crosslinked human fibrin by plasmin yields initially a single molecular complex, D-Dimer-E.  Thromb Res . 1979;  15 673-687
    CrossrefPubMedSuche in Google Scholar
  • 6 Rylatt D B, Blake A S, Cottis L E. An immunoassay for human D dimer using monoclonal antibodies.  Thromb Res . 1983;  31 767-778
    CrossrefPubMedSuche in Google Scholar
  • 7 Elms M J, Bunce I H, Bundesen P G. Measurement of crosslinked fibrin degradation products-an immunoassay using monoclonal antibodies.  Thromb Haemost . 1983;  50 591-594
    PubMedSuche in Google Scholar
  • 8 Whitaker A N, Elms M J, Masci P P. Measurement of cross linked fibrin derivatives in plasma: an immunoassay using monoclonal antibodies.  J Clin Pathol . 1984;  37 882-887
    PubMedSuche in Google Scholar
  • 9 Rowbotham B J, Whitaker A N, Masci P P. Plasma cross-linked fibrin degradation product (XLFbDP) assays in an in vivo model of fibrinolysis.  Blood Coag Fibrinolysis . 1990;  1 653-661
    PubMedSuche in Google Scholar
  • 10 Gaffney P J, Edgell T, Creighton Kempsford J L. Fibrin degradation product (FnDP) assays: analysis of standardization issues and target antigens in plasma.  Br J Haematol . 1995;  90 187-194
    PubMedSuche in Google Scholar
  • 11 Pfitzner S A, Dempfle C E, Heene D L. Fibrin detected in plasma of patients with disseminated intravascular coagulation by fibrin-specific antibodies consists primarily of high molecular weight factor XIIIa-crosslinked and plasmin-modified complexes partially containing fibrinopeptide A.  Thromb Haemost . 1997;  78 1069-1078
    PubMedSuche in Google Scholar
  • 12 Whitaker A N, Rowe E A, Masci P P, Gaffney P J. Identification of D-dimer-E complex in disseminated intravascular coagulation.  Thromb Res . 1980;  18 453-459
    CrossrefPubMedSuche in Google Scholar
  • 13 Brummel K E, Butenas S, Mann K G. An integrated study of fibrinogen during blood coagulation.  J Biol Chem . 1999;  274 22862-22870
    CrossrefPubMedSuche in Google Scholar
  • 14 Boneu B, Bes G, Pelzer H. 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
    PubMedSuche in Google Scholar
  • 15 Perrier A, Desmarais S, Miron M J. Non-invasive diagnosis of venous thromboembolism in outpatients.  Lancet . 1999;  353 190-195
    Suche in Google Scholar
  • 16 Lindahl T L, Lundahl T H, Ranby M, Fransson S G. Clinical evaluation of a diagnostic strategy for deep venous thrombosis with exclusion by low plasma levels of fibrin degradation product D-dimer.  Scand J Clin Lab Invest . 1998;  58 307-316
    PubMedSuche in Google Scholar
  • 17 Perrier A, Desmarais S, Goehring C. D-dimer testing for suspected pulmonary embolism in outpatients.  Am J Resp Crit Care Med . 1997;  156 492-496
    PubMedSuche in Google Scholar
  • 18 Dvorak H F, Quay S C, Orenstein N S. Tumor shedding and coagulation.  Science . 1981;  212 923-924
    CrossrefPubMedSuche in Google Scholar
  • 19 Sorensen J V, Jensen H P, Rahr H B. Fibrinogen and fibrin derivatives in traumatized patients: relation to injury severity and posttraumatic pulmonary dysfunction.  Haemostasis . 1993;  23 91-97
    PubMedSuche in Google Scholar
  • 20 Brenner B, Pery M, Lanir N. Application of a bedside whole blood D-dimer assay in the diagnosis of deep vein thrombosis.  Blood Coag Fibrinolysis . 1995;  6 219-222
    PubMedSuche in Google Scholar
  • 21 Wells P S, Anderson D R, Bormanis J. Application of a diagnostic clinical model for the management of hospitalized patients with suspected deep-vein thrombosis.  Thromb Haemost . 1999;  81 493-497
    PubMedSuche in Google Scholar
  • 22 Gogstad G O, Dale S, Brosstad F. Assay of D-dimer based on immunofiltration and staining with gold colloids.  Clin Chem . 1993;  39 2070-2076
    PubMedSuche in Google Scholar
  • 23 Reber G, Vissac A M, de Moerloose P. A new, semi-quantitative and individual ELISA for rapid measurement of plasma D-dimer in patients suspected of pulmonary embolism.  Blood Coag Fibrinolysis . 1995;  6 460-463
    PubMedSuche in Google Scholar
  • 24 Vissac A M, Grimaux M, Chartier S. A new sensitive membrane based ELISA technique for instantaneous D-dimer evaluation in emergency.  Thromb Res . 1995;  78 341-352
    CrossrefPubMedSuche in Google Scholar
  • 25 Hart R, Bate I, Dinh D. The detection of D-dimer in plasma by enzyme immunoassay: improved discrimination is obtained with a more specific signal antibody.  Blood Coag Fibrinolysis . 1994;  5 227-232
    PubMedSuche in Google Scholar
  • 26 Amiral J, Minard F, Plassart V. Reactivity of D-dimer assays with the fibrinogen-fibrin split products generated by thrombolytic agents.  Blood Coag Fibrinolysis . 1990;  1 525-530
    PubMedSuche in Google Scholar
  • 27 Koopman J, Haverkate F, Koppert P. New enzyme immunoassay of fibrin-fibrinogen degradation products in plasma using a monoclonal antibody.  J Lab Clin Med . 1987;  109 75-84
    PubMedSuche in Google Scholar
  • 28 Pittet J L, de Moerloose P, Reber G. VIDAS D-dimer: fast quantitative ELISA for measuring D-dimer in plasma.  Clin Chem . 1996;  42 410-415
    PubMedSuche in Google Scholar
  • 29 Kario K, Matsuo T, Kabayashi H. Rapid quantitative evaluation of plasma D-dimer levels in thrombotic states using an automated latex photometric immunoassay.  Thromb Res . 1992;  66 179-189
    CrossrefPubMedSuche in Google Scholar
  • 30 Dempfle C E, Hafner G, Lestin H G. Multizentrische Evaluierung von Tina-quant a D-dimer.  J Lab Med . 1996;  20 31-37
    PubMedSuche in Google Scholar
  • 31 Kraus M, Aillaud E. Nephelometric determination of plasma D-dimer (abstract).  Ann Hematol . 1994;  A110 (A110)
    PubMedSuche in Google Scholar
  • 32 Korte W, Lutz S, Bossart S. Comparison of new automated latex assays for D-dimer with ELISAs for the exclusion of deep venous thrombosis (abstract).  Ann Hematol . 1998;  A88 (A88)
    PubMedSuche in Google Scholar
  • 33 van der Graaf F, Van den Borne H, Van der Kolk M. Exclusion of deep venous thrombosis with D-dimer testing. Comparison of 13 D-dimer methods in 99 outpatients suspected of venous thrombosis using venography as reference standard.  Thromb Haemost . 2000;  83 191-198
    PubMedSuche in Google Scholar
  • 34 Crippa L, Ravasi F, D'Angelo S V. Diagnostic value of compression ultrasonography and fibrinogen-related parameters for the detection of postoperative deep vein thrombosis following elective hip replacement: a pilot study.  Thromb Haemost . 1995;  74 1235-1239
    PubMedSuche in Google Scholar
  • 35 Harvey R L, Roth E J, Yarnold P R. Deep vein thrombosis in stroke. The use of plasma D-dimer level as a screening test in the rehabilitation setting [see comments].  Stroke . 1996;  27 1516-1520
    PubMedSuche in Google Scholar
  • 36 Dale S, Gogstad G O, Brosstad F. Comparison of three D-dimer assays for the diagnosis of DVT:ELISA, latex and an immunofiltration assay (NycoCard D-Dimer).  Thromb Haemost . 1994;  71 270-274
    PubMedSuche in Google Scholar
  • 37 Ott P, Astrup L, Jensen R H. Assessment of D-dimer in plasma: diagnostic value in suspected deep venous thrombosis of the leg.  Acta Med Scand . 1988;  224 263-267
    PubMedSuche in Google Scholar
  • 38 Bounameaux H, Schneider P A, Reber G. Measurement of plasma D-dimer for diagnosis of deep venous thrombosis.  Am J Clin Pathol . 1989;  91 82-85
    CrossrefPubMedSuche in Google Scholar
  • 39 Wahlander K, Tengborn L, Hellström M. Comparison of various D-dimer tests for the diagnosis of deep venous thrombosis.  Blood Coag Fibrinolysis . 1999;  10 121-126
    PubMedSuche in Google Scholar
  • 40 Chang Liem S G, Lustermans F A, van Wersch W J. Comparison of the appropriateness of the latex and ELISA plasma D-dimer determination for the diagnosis of deep venous thrombosis.  Haemostasis . 1991;  21 106-110
    PubMedSuche in Google Scholar
  • 41 Elias A, Aptel I, Huc B. D-dimer test and diagnosis of deep vein thrombosis: a comparative study of 7 assays.  Thromb Haemost . 1996;  76 518-522
    PubMedSuche in Google Scholar
  • 42 Freyburger G, Trillaud H, Labrouche S. D-dimer strategy in thrombosis exclusion. A gold standard study in 100 patients suspected of venous thrombosis or pulmonary embolism: 8 DD methods compared.  Thromb Haemost . 1998;  79 32-37
    PubMedSuche in Google Scholar
  • 43 Janssen M C, Verbruggen H, Wollersheim H. D-dimer determination to assess regression of deep venous thrombosis.  Thromb Haemost . 1997;  78 799-802
    PubMedSuche in Google Scholar
  • 44 Carter C J, Doyle D L, Dawson N. Investigations into the clinical utility of latex D-dimer in the diagnosis of deep venous thrombosis.  Thromb Haemost. 1993;  69 8-11 24
    PubMedSuche in Google Scholar
  • 45 Legnani C, Pancani C, Palareti G. Comparison of new rapid methods for D-dimer measurement to exclude deep vein thrombosis in symptomatic outpatients.  Blood Coag Fibrinolysis . 1997;  8 296-302
    CrossrefPubMedSuche in Google Scholar
  • 46 Turkstra F, van Beek J E, ten Cate W J, Büller H R. Reliable rapid blood test for the exclusion of venous thromboembolism in symptomatic outpatients [see comments].  Thromb Haemost . 1996;  76 9-11
    PubMedSuche in Google Scholar
  • 47 Mayer W, Hirschwehr R, Hippmann G. Whole-blood immunoassay (SimpliRED) versus plasma immunoassay (NycoCard) for the diagnosis of clinically suspected deep vein thrombosis.  Vasa . 1997;  26 97-101
    PubMedSuche in Google Scholar
  • 48 Wells P S, Brill Edwards P, Stevens P. A novel and rapid whole-blood assay for D-dimer in patients with clinically suspected deep vein thrombosis.  Circulation . 1995;  91 2184-2187
    PubMedSuche in Google Scholar
  • 49 Scarano L, Bernardi E, Prandoni P. Accuracy of two newly described D-dimer tests in patients with suspected deep venous thrombosis.  Thromb Res . 1997;  86 93-99
    CrossrefPubMedSuche in Google Scholar
  • 50 Killick S B, Pentek P G, Mercieca J E. Comparison of immunofiltration assay of plasma D-dimer with diagnostic imaging in deep vein thrombosis.  Br J Haematol . 1997;  96 846-849
    CrossrefPubMedSuche in Google Scholar
  • 51 Pannocchia A, Chiappino I, Valpreda S. DVT exclusion in symptomatic outpatients: use of a rapid D-dimer immunofiltration assay and comparison with three enzyme immuno assays.  Fibrinolysis . 1996;  117-119 (117-119)
    PubMedSuche in Google Scholar
  • 52 Leroyer C, Escoffre M, Le Moigne E. Diagnostic value of a new sensitive membrane based technique for instantaneous D-dimer evaluation in patients with clinically suspected deep venous thrombosis.  Thromb Haemost . 1997;  77 637-640
    PubMedSuche in Google Scholar
  • 53 Heaton D C, Billings J D, Hickton C M. Assessment of D-dimer assays for the diagnosis of deep vein thrombosis.  J Lab Clin Med . 1987;  110 588-591
    PubMedSuche in Google Scholar
  • 54 Rowbotham B J, Carroll P, Whitaker A N. Measurement of crosslinked fibrin derivatives-use in the diagnosis of venous thrombosis.  Thromb Haemost . 1987;  57 59-61
    PubMedSuche in Google Scholar
  • 55 Chapman C S, Akhtar N, Campbell S. The use of D-dimer assay by enzyme immunoassay and latex agglutination techniques in the diagnosis of deep vein thrombosis.  Clin Lab Haematol . 1990;  12 37-42
    PubMedSuche in Google Scholar
  • 56 Legnani C, Pancani C, Palareti G. Contribution of a new, rapid, quantitative and automated method for D-dimer measurement to exclude deep vein thrombosis in symptomatic outpatients.  Blood Coag Fibrinolysis . 1999;  10 69-74
    PubMedSuche in Google Scholar
  • 57 Heijboer H, Ginsberg J S, Büller H R. The use of the D-dimer test in combination with non-invasive testing versus serial non-invasive testing alone for the diagnosis of deep-vein thrombosis.  Thromb Haemost . 1992;  67 510-513
    PubMedSuche in Google Scholar
  • 58 Borg J Y, Levesque H, Cailleux N. Rapid quantitative D-dimer assay and clinical evaluation for the diagnosis of clinically suspected deep vein thrombosis [letter].  Thromb Haemost . 1997;  77 602-603
    PubMedSuche in Google Scholar
  • 59 Mossaz A, Gandrille S, Vitoux J F. The value of D-dimer assays in the emergency diagnosis of venous thrombosis (letter).  Presse Med . 1990;  19 1055
    PubMedSuche in Google Scholar
  • 60 van Bergen F P, Knot E A, Jonker J J. Is quantitative determination of fibrin(ogen) degradation products and thrombin-antithrombin III complexes useful to diagnose deep venous thrombosis in outpatients?.  Thromb Haemost . 1989;  62 1043-1045
    PubMedSuche in Google Scholar
  • 61 D'Angelo A, D'Alessandro G, Tomassini L. Evaluation of a new rapid quantitative D-dimer assay in patients with clinically suspected deep vein thrombosis.  Thromb Haemost . 1996;  75 412-416
    PubMedSuche in Google Scholar
  • 62 de Moerloose P, Desmarais S, Bounameaux H. Contribution of a new, rapid, individual and quantitative automated D-dimer ELISA to exclude pulmonary embolism.  Thromb Haemost . 1996;  75 11-13
    PubMedSuche in Google Scholar
  • 63 Bounameaux H, Khabiri E, Huber O. Value of liquid crystal contact thermography and plasma level of D-dimer for screening of deep venous thrombosis following general abdominal surgery.  Thromb Haemost . 1992;  67 603-606
    PubMedSuche in Google Scholar
  • 64 Bounameaux H, Miron M-J, Blanchard J. Measurement of plasma D-dimer is not useful in the prediction or diagnosis of postoperative deep vein thrombosis in patients undergoing total knee arthroplasty.  Blood Coag Fibrinolysis . 1998;  9 749-452
    CrossrefPubMedSuche in Google Scholar
  • 65 Cofrancesco E, Cortellaro M, Corradi A. Clinical utility of prothrombin fragment F1+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
    PubMedSuche in Google Scholar
  • 66 Dunn I D, Hui A C, Triffitt P D. Plasma D-dimer as a marker for postoperative deep venous thrombosis. A study after total hip or knee arthroplasty.  Thromb Haemost . 1994;  72 663-665
    PubMedSuche in Google Scholar
  • 67 Douketis J D, McGinnis J, Ginsberg J S. The clinical utility of a rapid bedside D-dimer assay for screening of deep venous thrombosis following orthopedic surgery.  Thromb Haemost . 1997;  78 1300-1301
    PubMedSuche in Google Scholar