D-Dimers

D-dimers:

  • Plasmin-derived soluble degradation product of cross-linked fibrin
  • The smallest product of fibrin degradation (MW 180 kDa)
  • Relatively stable

Generation of D-dimers (see Figure 1):

  • A multistage process that requires the sequential activity of 3 enzymes:
    • Thrombin
    • Activated factor XIII (factor XIIIa)
    • Plasmin
  • First step is thrombin-mediated conversion of soluble fibrinogen to fibrin monomers:
    • The fibrinogen molecules consist of a central E domain linked by coiled-coil regions to 2 peripheral D domains.
    • To form fibrin monomers, thrombin cleaves short peptides from the NH2-termini of the alpha- and beta-chains to expose “knobs” in the E domains.
  • Second step is spontaneous polymerization end to end in a half-staggered, overlapping manner to form double-stranded fibrin protofibrils (the exposed knobs in the E domains insert into pre-existing “holes” in the D domains). Because the monomers and protofibrils are associated noncovalently, the fibrin network is unstable.
  • Third step is factor XIIIa-mediated cross-linking of the D domains of adjacent fibrin monomers.
  • Fourth step is plasmin-mediated degradation of of the fibrin network into soluble fragments:
    • DD
    • DD(E) domain
    • DD associated with higher molecular weight intermediates (not shown in schematic above)
Figure 1. Generation of D-dimers (including those complexed to fragment E). See description below. Blood contains a mix of DD, DDE and higher-molecular-weight cross-linked (X-linked) fragments. D-dimers from different manufacturers detect different-sized cross-linked fibrin-degradation products (FDPs) in the blood along with the D-dimer (DD) itself. Thus, the term ‘D-dimer’, when used in the context of an assay should be widely interpreted as the totality of all cross-linked soluble materials that are derived from fibrin.

D-dimer assay (see Figure 2):

  • Detects D-dimer and a wide variety of cross-linked fibrin degradation products with different molecular weights.
  • The monoclonal antibodies that are utilized in different assays have different specificities to various cross-linked fibrin degradation products that are present in the plasma of patients.
Figure 2. Reference