In the study in this issue by Maas et al. (10
), the authors show that FXII autoactivation occurs in vitro in reaction to misfolded or amorphous protein aggregates of transthyretin (a homotetrameric protein in plasma and CSF), Bence-Jones protein (a monoclonal globulin protein found in blood or urine), glycated albumin, glycated hemoglobin, or the angiostatic drug endostatin (10
). In individuals diagnosed with systemic amyloidosis, a condition characterized by the abnormal deposition of misfolded amyloid proteins in organs and/or tissues, the authors observed significantly elevated levels of activated FXII compared with controls, as assessed by one commercially available assay (10
). The authors go on to show that contact activation initiated by FXII in reaction to these misfolded proteins is associated with elevated levels of plasma kallikrein–C1 inhibitor complexes, but not FXIa–C1 inhibitor complexes, both in vitro and in patients with systemic amyloidosis (10
). This latter finding suggests that PK activation (and consequent activation of the inflammatory kallikrein-kinin and complement systems) triggered by FXII autoactivation in reaction to misfolded or amorphous protein aggregates can proceed independently of the intrinsic coagulation pathway (Figure ).
Do the results of the Maas et al. (10
) study reveal a major new pathway for FXII autoactivation and provide insight regarding a physiologic activity for FXII? What is intriguing about the current investigation is that it demonstrates constitutive FXII contact activation in the disease state of systemic amyloidosis. The data also suggest that FXII autoactivation in reaction to misfolded protein initiates an inflammatory response in reaction to these abnormal protein deposits. Activation of the so-called contact system proteins has been recognized in other pathologic states, such as acute attacks of hereditary angioedema, sepsis, diabetic retinopathy, induced arterial thrombosis, and acute myocardial infarction. However, the authors suggest that in systemic amyloidosis, there is PK activation without FXI activation (10
). This contact activation–mediated disease phenotype also has been recognized in acute attacks of hereditary angioedema, where PK activation and bradykinin formation occur without FXI activation.
There are some methodological questions pertaining to the current study that should be raised (10
). Since the second-order rate constants of plasma kallikrein and FXIa inhibition by C1 inhibitor are similar, but the plasma concentration of PK is 18-fold higher than that of FXI, many more subjects would have had to be studied in the FXI group to conclusively show that FXI was not activated significantly in systemic amyloidosis. Further, the higher coefficient of variation of the controls in the FXIa–C1 inhibitor assay also may have contributed to the lack of differences seen in these patient samples. The mechanism(s) by which PK, but not FXI, activation occurs in response to FXII autoactivation in reaction to misfolded proteins has not been elucidated in the current report (10
). In future studies, it would be helpful to determine whether misfolded protein–triggered autoactivation of purified FXII results in reduced or absent activation of purified FXI compared with PK. Do misfolded proteins only bind HK and PK and not FXI? Finally, why do only aggregated proteins and not fibrillar proteins trigger FXII autoactivation?
FXII autoactivation in reaction to misfolded or amorphous protein aggregates in vivo, although a nonphysiologic event, may in fact constitute a type of detection or defense response to these structurally abnormal proteins. This pathway may constitute a means to regulate complement and inflammatory systems that involve coagulation protein S, thrombomodulin, and thrombin itself. Other biologic substances that have been reported to support FXII autoactivation and arise in disease states include RNA and sulfatides released after cell disruption and platelet polysomes present on a developing thrombus (15
). Unlike the present report (10
), the previous two studies suggested that FXII autoactivation in reaction to a developing thrombus leads to FXI activation and thrombin formation (15
). The Maas et al. report suggests that certain biologic surfaces that trigger FXII autoactivation may lead to differential FXI or PK activation (10
). Pathological contact activation in vivo is mostly associated with artificial substances interacting with the intravascular compartment. An extreme instance of this was reported recently: the infusion of unfractionated heparin adulterated with oversulfated chondroitin sulfate caused constitutional symptoms of nausea, dyspnea, and vomiting and 81 deaths from hypotension (17
). Oversulfated chondroitin sulfate, which in some heparin preparations was as high as 30% wt/wt, was associated with FXII autoactivation, plasma kallikrein formation, bradykinin liberation, and C3a and C5a formation, without evidence of FXI activation (18