The D-dimer antigen is a unique marker of fibrin degradation that is formed by the sequential action of 3 enzymes: thrombin, factor XIIIa, and plasmin. First, thrombin cleaves fibrinogen producing fibrin monomers, which polymerize and serve as a template for factor XIIIa and plasmin formation. Second, thrombin activates plasma factor XIII bound to fibrin polymers to produce the active transglutaminase, factor XIIIa. Factor XIIIa catalyzes the formation of covalent bonds between D-domains in the polymerized fibrin. Finally, plasmin degrades the crosslinked fibrin to release fibrin degradation products and expose the D-dimer antigen. D-dimer antigen can exist on fibrin degradation products derived from soluble fibrin before its incorporation into a fibrin gel, or after the fibrin clot has
IntroductionFibrinogen is a soluble plasma glycoprotein that is transformed into highly self-adhesive fibrin monomers after thrombin cleavage. 1 A detailed overview of the process of fibrin formation was recently published. 2 In brief, in the first step of D-dimer formation, thrombin cleavage exposes a previously cryptic polymerization site on fibrinogen that promotes the binding of either another fibrinogen or a monomeric fibrin molecule. 3 Fibrin monomers then bind to one another in an overlapping manner to form 2 molecule thick protofibrils ( Figure 1). 4,5 Plasma remains fluid until 25% to 30% of plasma fibrinogen is cleaved by thrombin, 6 allowing time for fibrin to polymerize while simultaneously promoting thrombin activation of plasma factor XIII. 7 Thrombin remains associated with fibrin, 8 and as additional fibrin molecules polymerize, it activates plasma factor XIII bound to fibrinogen. 9 The complex between soluble fibrin polymers, thrombin, and plasma factor XIII promotes the formation of factor XIIIa before a fibrin gel is detected. 6 In the second step of D-dimer formation, factor XIIIa covalently cross links fibrin monomers via intermolecular isopeptide bonds formed between lysine and glutamine residues within the soluble protofibrils and the insoluble fibrin gel. 10 D-dimer antigen remains undetectable until it is released from crosslinked fibrin by the action of plasmin. In the final step of D-dimer formation, plasmin formed on the fibrin surface by plasminogen activation cleaves substrate fibrin at specific sites ( Figure 1). 11 Fibrin degradation products are produced in a wide variety of molecular weights, including the terminal degradation products of crosslinked fibrin containing D-dimer and fragment E complex (Figure 1). 12,13 It is uncommon to detect circulating terminal fibrin degradation products (D-dimer-E complex) in human plasma, whereas soluble high-molecular-weight fragments that contain the "D-dimer antigen" are present in patients with DIC and other thrombotic disorders. 14 These fragments may be derived from soluble fibrin before it has been incorporated into a fibrin gel, or alternatively may be derived from high-molecular-weight complexes released from an insoluble clot (Figure 2). 15,16 "D-...