Introduction
For the last 25 years, most investigators in the field of plasma kallikrein/kinin have accepted the contact activation hypothesis by factor XII initiates plasma kallikrein/kinin system activation by binding to a physiologic, negatively-charged surface. This hypothesis forms the basis of the common surface-based coagulation assays, such as the activated partial thromboplastin time (aPTT). Also, it may be the mechanism by which the plasma kallikrein/kinin system becomes activated in vivo when exposed to artificial surfaces, such as those used in medical interventions, and following infection.
A physiologic, negatively-charged surface, however, capable of initiating the activation of this system has never been convincingly described. This fact questions the role of this system in vivo. Sulfatides, phospholipids, cholesterol sulfate, chondroitin sulfate, heparins, and other glycosaminoglycans have been proposed as physiologic negatively charged surfaces. The autoactivation of factor XII, which can take several hours depending on the surface, leads to prekallikrein (PK) activation. Kallikrein formation reciprocally activates more factor XII in a reaction that is at least 1,000-fold faster than autoactivation. In addition to the surface, the rate of initiation and amplification of this system is accelerated by high molecular weight kininogen (HK). Activation of the zymogens factor XII and PK result in enzymes that have been proposed to contribute to factor XI activation (coagulation), complement activation, bradykinin (BK) liberation, fibrinolysis, and granulocyte activation in vitro.
It is well known, however, that clinical deficiencies in factor XII, PK, and HK are not associated with bleeding, even though these deficiencies markedly prolong surfaced-activated coagulation assays for hemostasis. This information indicates that this system contributes little, if anything, to hemostasis. Recently, this field has been thoroughly reviewed.1,2 The purpose of this report is to present a new hypothesis for assembly and activation of this system on viable cell membranes and to begin to clarify these proteins’ roles in vivo.
Over 10 years ago, our laboratory developed a working hypothesis to serve as an alternative to the factor XII autoactivation mechanism for the initiation of activation of the proteins of the plasma kallikrein/kinin system. We reasoned that, in vivo, it is the assembly of a multiprotein complex of these proteins on cell receptors that allows for localization and activation of this system. To prove that hypothesis, we sought to accomplish the following three things. First, we attempted to determine whether there is a receptor(s) for the proteins of this system on cell membranes. Second, we sought to show whether the assembly of the proteins of the plasma kallikrein/kinin system on cell membranes results in activation of PK and factor XII. Finally, we attempted to demonstrate biological activities associated with the activation of these proteins on cell membranes. The following report details this work and characterizes a new hypothesis for the assembly and activation of the proteins of the plasma kallikrein/kinin system.
