The stepwise process of Fibrin polymerization. The 3 major steps of D-dimer antigen formation are shown. (i) The fibrinogen molecule is cleaved by thrombin to produce fibrin monomers. These monomers associate with fibrinogen or fibrin to form protofibrils. They are held together by noncovalent forces shown as dotted lines between the intermolecular D-domain and D-E domains. (ii) Factor XIIIa formed by thrombin on fibrin polymers then covalently attaches D domains and inserts a covalent intermolecular linkage designated by the diamond-shaped figure. (iii) Plasmin must degrade fibrin at multiple sites to release fibrin degradation products, which then expose the D-dimer antigen epitope. The initial fragments are high-molecular-weight complexes followed by further degradation to produce the terminal D-dimer–E complex, which contains the dimer antigen. The 3 phases of this process are labeled on the right side of the diagram, and the different molecular forms of fibrinogen and its subsequent transformation by thrombin, factor XIIIa, and plasmin are shown on the left side of the diagram. This is a schematic representation of just one protofibril. Multiple protofibrils are aligned side by side and undergo branching to make a fibrin gel.