In the October issue of Thrombosis and Haemostasis, Talens et al1 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 remainingfibrin-bound proteins (clusterin, haptoglobin,α2-macroglobulin, apolipoproteins E and AI, albumin, serum amyloid P, and α1-antitrypsin) belong to a familyof “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 parallelismbetween bindingof thenonhemostaticplasmaproteins tofibrinand the content of cross-β-structures in fibrinogen and fibrin, a signature of proteinmisfolding or unfolding. The cross-β-structures in fibrinogen and fibrin were formed by prolonged heating of plasma (mimickingunfolding thatoccurswith aging) aswell 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.
Rustem I Litvinov, John W Weisel
Thrombosis and haemostasis