Semin Thromb Hemost 2001; 27(6): 657-666
DOI: 10.1055/s-2001-18870
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Fibrin Degradation Products, Fibrin Monomer and Soluble Fibrin in Disseminated Intravascular Coagulation

John T. Horan1 , Charles W. Francis2
  • 1Hematology Unit, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York
  • 2Vascular Medicine Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
Further Information

Publication History

Publication Date:
06 December 2001 (online)

ABSTRACT

Disseminated intravascular coagulation (DIC) is characterized by activation of hemostasis and fibrinolysis resulting in the formation of thrombin and plasmin, and the characteristic effects of these enzymes on plasma fibrinogen can be useful in diagnosis. Thrombin cleaves fibrinopeptides from fibrinogen, forming fibrin monomer that rapidly polymerizes to form a clot. Small amounts can circulate in plasma as ``soluble fibrin,'' which may have a complex composition and include fibrinogen and a variable amount of cross-linking. Plasmic degradation of cross-linked fibrin forms a heterogeneous group of degradation products reactive in assays for D-dimer, and their levels provide a measure of the amount of fibrin formation and lysis. Caution should be exercised in comparing quantitative results using different assays because of problems with standardization and variable reactivity with different molecular forms. Marked elevations of fibrin(ogen) degradation products are a constant finding in experimental animal models of DIC. In human models of DIC resulting from endotoxin infusion, D-dimer is elevated early and high levels persist, reflecting lysis of microvascular fibrin deposits. Elevated levels of D-dimer and soluble fibrin are very sensitive for the diagnosis of DIC, and a normal level has a high negative predictive value. Serial monitoring of soluble fibrin or D-dimer assays may be of value in evaluating the response to therapy and possibly in identifying at-risk patients.

REFERENCES

  • 1 Sasaki T, Page I H, Shainoff J R. Soluble complex of fibrinogen and fibrin.  Science . 1966;  152 1069-1071
  • 2 Jakobsen E, Ly B, Kierulf P. Incorporation of fibrinogen into soluble fibrin complexes.  Thromb Res . 1974;  4 499-507
  • 3 Greenberg C S, Miraglia C C, Rickles F R, Shuman M A. Cleavage of blood coagulation factor XIII and fibrinogen by thrombin during in vitro clotting.  J Clin Invest . 1985;  75 1463-1470
  • 4 Ly B, Jakobsen E. Some aspects of the bonds interlinking soluble fibrin complexes in human plasma.  Thromb Res . 1975;  6 65-73
  • 5 Seneri G GN, Gensini G F, Abbate R, Favilla S. Occurrence of soluble very-high-molecular-weight fibrinogen complexes in hypercoagulable states. An in vitro and in vivo study on their features.  Thromb Haemost . 1979;  42 1561-1573
  • 6 Francis C W, Connaghan D G, Scott W L, Marder V J. Increased plasma concentration of crosslinked fibrin polymers in acute myocardial infarction.  Circulation . 1987;  75 1170-1177
  • 7 Grøn Bennick A, Nieuwenhuizen W, Brosstad F. Normal and fibrinaemic patient plasma contain high-molecular-weight crosslinked fibrin(ogen) derivatives with intact fibrinopeptide A.  Thromb Res . 1990;  57 259-270
  • 8 Marder V J, Budzynski A Z. Data for defining fibrinogen and its plasmic degradation products.  Thrombosis et Diathesis Haemorrhagica . 1975;  33 199-207
  • 9 Francis C W, Marder V J, Barlow G H. Plasmic degradation of crosslinked fibrin: Characterization of new macromolecular soluble complexes and a model of their structure.  J Clin Invest . 1980;  66 1033-1043
  • 10 Francis C W, Marder V J. A molecular model of plasmic degradation of crosslinked fibrin.  Semin Thromb Haemost . 1982;  8 25-35
  • 11 Pizzo S V, Taylor Jr M L, Schwartz M L. Subunit structure of fragment D from fibrinogen and cross-linked fibrin.  J Biol Chem . 1973;  248 4584-4590
  • 12 Gaffney P J, Brasher M. Subunit structure of the plasmin- induced degradation products of crosslinked fibrin.  Biochim Biophys Acta . 1973;  295 308-313
  • 13 Gaffney P J, Lane D A, Kakkar V V. Characterization of a soluble D-dimer-E complex in crosslinked fibrin digests.  Thromb Res . 1975;  7 89-99
  • 14 Alkjaersig N, Davies A, Fletcher A. Fibrin and fibrinogen proteolysis products: comparison between gel filtration and SDS polyacrylamide electrophoresis analysis.  Thromb Haemost . 1977;  38 524-525
  • 15 Francis C W, Marder V J, Martin S E. Plasmic degradation of crosslinked fibrin. I. Structural analysis of the particulate clot and identification of new macromolecular soluble complexes.  Blood . 1980;  56 456-464
  • 16 Lane D A, Preston F E, VanRoss M E, Kakkar V V. Characterization of serum fibrinogen and fibrin fragments produced during disseminated intravascular coagulation.  Br J Haematol . 1978;  40 609-615
  • 17 Graeff H, Hafter R, Bachmann L. Subunit and macromolecular structure of circulating fibrin from obstetric patients with intravascular coagulation.  Thromb Res . 1979;  16 313-328
  • 18 Connaghan D G, Francis C W, Lane D A, Marder V J. Specific identification of fibrin polymers, fibrinogen degradation products, and crosslinked fibrin degradation products in plasma and serum with a new sensitive technique.  Blood . 1985;  65 589-597
  • 19 Proietti A B, McGuire M, Bell W. Specific identification of fibrin(ogen) degradation products in plasma and serum using blotting and peroxidase labeled antiserum.  Am J Hematol . 1990;  34 270-274
  • 20 Shainoff J R, Valenzuela R, Urbanic D A. Fibrinogen Aα and γ-chain dimers as potential differential indicators of atherosclerotic and thrombotic vascular disease.  Blood Coagul Fibrinolysis . 1990;  1 499-503
  • 21 Pfitzner S A, Dempfle C E, Matsuda M. 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
  • 22 Grøn Bennick A, Nieuwenhuizen W, Brosstad F. Normal and fibrinaemic patient plasma contain high-molecular weight crosslinked fibrin(ogen) derivatives with intact fibrinopeptide A.  Thromb Res . 1990;  57 259-270
  • 23 Kierulf P. Studies on soluble fibrin in plasma. II. N-terminal analysis of a modified fraction 1 (Cohn) from patient plasmas.  Scand J Clin Lab Invest . 1973;  31 37-42
  • 24 Niewiarowski S, Gurewich V. Laboratory identification of intravascular coagulation: The serial dilution protamine sulfate test for the detection of fibrin monomer and fibrin degradation products.  J Lab Clin Med . 1971;  77 665-676
  • 25 Godal H C, Abildgaard U. Gelation of soluble fibrin in plasma by ethanol.  Scand J Haematol . 1966;  3 342-350
  • 26 Matthias F R, Reinicke R, Heene D L. Affinity chromatography and quantitation of soluble fibrin from plasma.  Thromb Res . 1977;  10 365-384
  • 27 Hurlet-Jensen A, Cummins H Z, Nossel H L. Fibrin polymerization and release of fibrinopeptide B by thrombin.  Thromb Res . 1982;  27 419-427
  • 28 Higgins D L, Lewis S D, Shafer J A. Steady state kinetic parameters for the thrombin-catalyzed conversion of human fibrinogen to fibrin.  J Biol Chem . 1983;  258 9276-9282
  • 29 Schielen W JG, Adams H H M P, van Leuven K. The sequence γ-(312-324) is a fibrin-specific epitope.  Blood . 1991;  77 2169-2173
  • 30 Soe G, Kohno I, Inuzuka K, Itoh Y, Matsuda M. A monoclonal antibody that recognizes a neo-antigen exposed in the E domain of fibrin monomer complexes with fibrinogen or its derivatives: Its application to the measurement of soluble fibrin in plasma.  Blood . 1996;  88 2109-2117
  • 31 Carville D G, Dimitrijevic N, Walsh M. Thrombus precursor protein (TpP): marker of thrombosis early in the pathogenesis of myocardial infarction.  Clin Chem . 1996;  42 1537-1541
  • 32 Wiman B, Ranby M. Determination of soluble fibrin in plasma by a rapid and quantitative spectrophotometric assay.  Thromb Haemost . 1986;  55 189-193
  • 33 Halvorsen S, Skjonsberg R R, Godal H C. Comparison of methods for detecting soluble fibrin in plasma, an in vitro study.  Thromb Res . 1990;  57 489-497
  • 34 McCarron B I, Marder V J, Francis C W. Reactivity of soluble fibrin assays with plasmic degradation products of fibrin and in patients receiving fibrinolytic therapy.  Thromb Haemost . 1999;  82 1722-1729
  • 35 Brenner B, Francis C W, Marder V J. The role of soluble crosslinked fibrin in D-dimer immunoreactivity of plasmic digests.  J Lab Clin Med . 1989;  113 682-688
  • 36 McCarron B I, Marder V J, Kanouse J J, Francis C W. A soluble fibrin standard: Comparable dose-response with immunologic and functional assays.  Thromb Haemost . 1999;  82 145-148
  • 37 Connaghan D G, Francis C W, Ryan D H, Marder V J. Prevalence and clinical implications of heparin-associated false-positive tests for serum fibrin(ogen) degradation products.  Am J Clin Pathol . 1986;  86 304-310
  • 38 Ginsberg J S, Wells P S, Brill-Edwards P. Application of a novel and rapid whole blood assay for D-dimer in patients with clinically suspected pulmonary embolism.  Thromb Haemost . 1995;  73 35-38
  • 39 Uchiba M, Okajima K, Murakami K. Effect of various doses of antithrombin III on endotoxin-induced endothelial cell injury and coagulation abnormalities in rats.  Thromb Res . 1998;  89 233-241
  • 40 Drake T A, Cheng J, Chang A. Expression of tissue factor, thrombomodulin, and E-selectin in baboons with lethal Escherichia coli sepsis [published erratum appears in Am J Pathol 1993;92:143-149].  Am J Pathol . 1993;  91 2850-2856
  • 41 Kruithof E K, Mestries J C, Gascon M P. The coagulation and fibrinolytic responses of baboons after in vivo thrombin generation-effect of interleukin-6.  Thromb Haemost . 1997;  77 905-910
  • 42 Creasey A A, Chang A C, Feigen L. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock.  J Clin Invest . 1993;  91 2850-2856
  • 43 Pajkrt D, van der Poll T, Levi M. Interleukin-10 inhibits activation of coagulation and fibrinolysis during human endotoxemia.  Blood . 1997;  89 2701-2705
  • 44 Pernerstorfer T, Hollenstein U, Hansen J B. Lepirudin blunts endotoxin-induced coagulation activation.  Blood . 2000;  95 1729-1734
  • 45 Yu M, Nardella A, Lechet L. Screening tests of disseminated intravascular coagulation: Guidelines for rapid and specific laboratory diagnosis.  Crit Care Med . 2000;  28 1777-1780
  • 46 Okajima K, Uchiba M, Murakami K. Determination of plasma soluble fibrin using a new ELISA method in patients with disseminated intravascular coagulation.  Am J Hematol . 1996;  51 186-191
  • 47 Carr J M, McKinney M, McDonagh J. Diagnosis of disseminated intravascular coagulation. Role of D-dimer.  Am J Clin Pathol . 1989;  91 280-287
  • 48 Bick R L, Baker W F. Diagnostic efficacy of the D-dimer assay in disseminated intravascular coagulation (DIC).  Thromb Res . 1992;  65 785-790
  • 49 Wada H, Wakita Y, Nakase T. Increased plasma-soluble fibrin monomer levels in patients with disseminated intravascular coagulation.  Am J Hematol . 1996;  51 255-260
  • 50 Lane D A, Ireland H, Knight I. The significance of fibrinogen derivatives in plasma in human renal failure.  Br J Haematol . 1984;  56 251-260
  • 51 van de Water L, Carr J M, Aronson D. Analysis of elevated fibrin(ogen) degradation product levels in patients with liver disease.  Blood . 1986;  67 1468-1473
  • 52 Bounameaux H, de Moerloose P, Perrier A. Plasma measurement of D-dimer as diagnostic aid in suspected venous thromboembolism: An overview [see comments].  Thromb Haemost . 1994;  71 1-6
  • 53 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
  • 54 van Beek J E, van den Ende B, Berckmans R J. A comparative analysis of D-dimer assays in patients with clinically suspected pulmonary embolism.  Thromb Haemost . 1993;  70 408-413
  • 55 Gaffney P J, Edgell T, Creighton-Kempsford L J. Fibrin degradation product (FnDP) assays: Analysis of standardization issues and target antigens in plasma.  Br J Haematol . 1995;  90 187-194
  • 56 Fourrier F, Chopin C, Goudemand J. Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies [see comments].  Chest . 1992;  101 816-823
  • 57 Gando S, Kameue T, Nanzaki S. Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome.  Thromb Haemost . 1996;  75 224-228
  • 58 Wada H, Sakuragawa N, Mori Y. Hemostatic molecular markers before the onset of disseminated intravascular coagulation.  Am J Hematol . 1999;  60 273-278
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