What is the role of activation in the pathophysiology of factor XIII (FXIII) deficiency?

Updated: Aug 01, 2019
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Perumal Thiagarajan, MD  more...
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Answer

Thrombin, generated by reactions initiated by activated tissue factor VII/factor IX pathways (as illustrated in the first diagram below), leads to clot formation. Thrombin releases fibrinopeptide A from the a chain of fibrinogen, then fibrinopeptide B from the b chain of fibrinogen. Fibrin monomers (formed following the release of fibrinopeptides) polymerize spontaneously; this is followed by development of a complex branching clot as a result of the actions of activated FXIII (FXIIIa). [31] The sequence of these final steps is found in the second chart below.

Coagulation reactions leading to thrombin generati Coagulation reactions leading to thrombin generation and activation of factor XIII.
Final steps in clot formation (from article: Facto Final steps in clot formation (from article: Factor XIII).

Thrombin starts the process of FXIII activation by cleaving an activation peptide from subunit A. The subsequent Ca2+ -dependent dissociation of subunit B allows FXIII activation to proceed. Calcium is important for activation of the zymogen (both FXIII and tissue transglutaminase require Ca2+), conformational changes, and opening of the catalytic site of FXIII to its substrate. Calcium also provides physical stability as determined by x-ray crystallography, computer modeling, and other studies; all of the changes allow the active subunit A to perform its functions optimally. [22, 32, 33]

When activated by thrombin, tissue FXIII functions in the same manner as plasma FXIIIa. Platelet FXIII undergoes nonproteolytic activation following the platelet activation-induced rise in cytosolic Ca2+. Activation of the red cell enzyme occurs upon exposure to Ca2+, and red cells that are present in the fibrin clot lyse and release their FXIII as the clot ages. Several controls in the complex activation process focus the actions of FXIIIa on fibrin rather than on fibrinogen. Cross-linking of polymerized soluble fibrin by FXIIIa is the final step in hemostasis, as illustrated in the image below. For extensive details of this activation process, the reader is referred to two recent reviews by Lorand. [22, 29]

Activation of factor XIII and generation of insolu Activation of factor XIII and generation of insoluble cross-linked fibrin. Adapted from Lorand L. Ann N Y Acad Sci. 2001;936:291-311.

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