In the October issue of Thrombosis and Haemostasis, Talens et al[1] proposed a general physiological role for certain plasma proteins previously shown
to bind strongly but noncovalently to fibrinogen and/or fibrin. After excluding the
proteins with known hemostatic activities, the authors recognized that some of the
remaining fibrin-bound proteins (clusterin, haptoglobin, α2-macroglobulin, apolipoproteins
E and AI, albumin, serum amyloid P, and α1-antitrypsin) belong to a family of “extracellular
chaperones.”[2] Chaperones assist in refolding misfolded proteins in the endoplasmic reticulum,
keeping them soluble by inhibiting aggregation, and facilitating intracellular protein
trafficking. This concept has been extended to extracellular fluids, including blood,
for several proteins that share functional properties with intracellular chaperones.
The authors hypothesized that fibrin formation is analogous to protein deposition
diseases known to result from aggregation of misfolded proteins and that the extracellular
chaperones can prevent fibrin formation and/or eliminate aged fibrinogen and fibrin
once it has done its job. To prove this hypothesis, the authors established a parallelism
between binding of the nonhemostatic plasma proteins to fibrin and the content of
cross-β-structures in fibrinogen and fibrin, a signature of protein misfolding or
unfolding. The cross-β-structures in fibrinogen and fibrin were formed by prolonged
heating of plasma (mimicking unfolding that occurs with aging) as well as upon enzymatic
conversion of fibrinogen to fibrin, in which formation of β-structures can occur.[1]
[3] Also, the authors showed an inhibitory effect of caseins (known as milk chaperones)
on fibrin formation.
It seems plausible that binding of certain plasma proteins targets both old fibrinogen
and fibrin for clearance from the intravascular space and facilitates their proteolytic
degradation, although the evidence so far is indirect. Whether or not the specific
interactions of nonhemostatic plasma proteins can modulate fibrin(ogen) turnover is
an intriguing idea that requires further investigation.
