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Contact Pathway of Coagulation and Inflammation Yi Wu Wu Thrombosis Journal (2015) 13:17 DOI 10.1186/s12959-015-0048-y REVIEW Open Access Contact pathway of coagulation and inflammation Yi Wu Abstract The contact system, also named as plasma kallikrein-kinin system, consists of three serine proteinases: coagulation factors XII (FXII) and XI (FXI), and plasma prekallikrein (PK), and the nonenzymatic cofactor high molecular weight kininogen (HK). This system has been investigated actively for more than 50 years. The components of this system and their interactions have been elucidated from in vitro experiments, which indicates that this system is prothrombotic by activating intrinsic pathway, and proinflammatory by producing bioactive peptide bradykinin. Although the activation of the contact system have been implicated in various types of human disease, in only a few instances is its role clearly defined. In the last 10 years, our understanding of the contact system, particularly its biology and (patho)physiology has greatly increased through investigations using gene-modified animal models. In this review we will describe a revitalized view of the contact system as a critical (patho)physiologic mediator of coagulation and inflammation. Keywords: Contact system, Coagulation, Inflammation, Platelet, Infection, Autoimmune disease, Vascular biology The contact system is a group of plasma proteins that re- fever, Rocky Mountain spotted fever, Crohn’s disease, sponds to the presence of (patho)physiological materials transfusion reactions, renal allograft rejection, nephrotic and invasion pathogens. This system consists of three syndrome, hereditary angioedema, and in extracorporeal serine proteinases: coagulation factors XII (FXII) and XI circulation [1]. In animal models of sepsis, arthritis, and (FXI), and plasma prekallikrein (PK), and the nonenzy- enterocolitis, the inhibitors of contact factor enzymes have matic cofactor high molecular weight kininogen (HK) [1]. modulated hypotension, inflammation or prolonged sur- These plasma proteins were grouped together as the con- vival, suggesting the participation of this system in the tact system, because they required contact with artificial, host defense and innate immunity [3]. The contact system negatively charged surfaces for zymogen activation is evolutionarily conserved (deficiencies in contact factors in vitro. Upon the activation of this system, it can trigger are very rare), and the activation of the contact system blood coagulation and is responsible for the generation of have been implicated in various types of human disease, the proinflammatory products such as bradykinin. This however, it currently still remains a mystery what its system is also called as plasma kallikrein-kinin system, physiological function is in human. In the last 10 years, functioning in a few inflammatory conditions such as because of the studies using gene-modified animal models, rheumatoid arthritis (RA) and inflammatory bowel disease our understanding of the contact system, particularly its (IBD) [2]. physiology and pathophysiology, has greatly increased. In Investigations of their biochemical and biologic proper- this review, we will first describe the molecular and cellu- ties have shown that the contact system proteins interact lar mechanisms that drive contact activation on nonphy- with a number of physiologic and pathophysiologic sys- siological materials. Next, we will summarize the clues tems. The biological role of contact system is to initiate linking the contact system with coagulation and inflam- and participate in the pathophysiological responses to in- mation in health and disease, and will discuss recent find- jury, mainly in the processes of coagulation and inflamma- ings from both fundamental and clinical studies on the tion. The activation of this system has been shown to be contributions of contact system to cardiovascular, infec- involved in a wide variety of human disease states, includ- tious, and inflammatory and autoimmune disease, and ing septicemia and endotoxemia, ARDS, DIC, typhoid their potential to be target for treatment of both throm- botic and inflammatory diseases. Correspondence: [email protected] The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, 3420 N. Broad Street, Philadelphia, PA 19140, USA © 2015 Wu; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wu Thrombosis Journal (2015) 13:17 Page 2 of 9 Assembly-based activation of contact system granules [6]. Polyphosphate can be released from activated In plasma, about 75% of PK circulates bound noncova- platelets and can drive contact system activation [6]. Besides lently to HK in 1:1 ratio, while the rest PK circulates platelets, bacteria such as Escherichia coli, Vibrio cholerae, freely. Besides PK, HK forms a heterodimer with factor Corynebacterium diphtheriae, Haemophilus influenzae con- XI, both of PK and FXI are surface bound via HK and tain large amounts of polyphosphate, which is longer than share a conserved HK-binding site. The nonenzymatic that from platelet and contains > 300 phosphate units [7]. cofactor HK is responsible for binding to negatively Bacterial polyphosphate activates FXII and initiates bradyki- charged surfaces and assembly of these proteins forming nin production that could contribute to leukocyte chemo- a complex [1]. Once FXII is bound to surfaces, it under- taxis, pain sensation, and vascular leakage [8]. goes conformational changes to become autoactivated (auto-activation), the activated FXIIa catalyzes the acti- Misfolded protein aggregates vation of PK. Meanwhile, FXII is increasingly susceptible Misfolded protein aggregates are a protein activator of to cleavage by plasma kallikrein (PK) and activated FXII the contact system [9]. The in vitro study has shown (FXIIa) itself. Activated plasma kallikrein converts FXII that a variety of misfolded protein aggregates such as ag- into FXIIa (trans-activation), thereby forming an activa- gregates of amyloid β peptide directly activates FXII, tion feedback loop, which overcomes inactivation of kal- leading to kallikrein activation [9]. Consistently, bradyki- likrein and FXII by their counterpart inhibitors, such as nin is produced in the cerebrospinal fluid of patients C1-esterase inhibitor. In the absence of factor XII, pre- with Alzheimer’s disease. In patients suffering from sys- kallikrein does not become activated on an artificial sur- temic amyloidosis, a disease in which aggregates of im- face. It is because of this finding that this system is munoglobulin light chains circulate and deposit, FXII- called the contact system. In the early phase of contact driven activation of the kallikrein-kinin system is also activation, the independent binding ability of HK to the observed. Binding of FXII to misfolded protein aggre- surface is limited. However, once PK and FXII are acti- gates differs in that to negatively charged surfaces, its vated, single chain HK can be cleaved into two-chain binding to surfaces is mediated by the fibronectin type 1 HKa and release bradykinin. Compared with HK, HKa domain, and its binding to aggregates is via the fibronec- has greater capacity of binding to the surfaces and pro- tin type 2, second EGF, and kringle domains. inflammatory effect [4]. Moreover, Factor XI is activated in complex with HK and FXII, whereby the intrinsic Phosphatidylserine (PS) pathway of coagulation is initiated. All these above infor- We recently have reported that in purified systems HK mation is accumulated from in vitro observations, how is specifically associated with PS liposome, and is cleaved the contact system is activated in vivo has not been in the presence of PK and XII [4]. By recognizing PS, well-characterized. HK preferentially binds to apoptotic cells, but not viable cells, which mediates phagocytosis of apoptotic cells Molecules-mediated assembly and activation of contact (efferocytosis). HK binding to apoptotic cells induces its system rapid cleavage to the two-chain form of HK (HKa) and The contact system is mostly known for its activation by bradykinin. Both the H chain and L chain of HKa are negatively charged molecular surfaces, such as kaolin, associated with PS liposome and apoptotic cells [4]. glass, silica, ellagic acid, dextran sulfate, oversulfated chondroitin sulfate and nanoparticles [1]. Although Collagen these are multiple non-physiological contact activators, Factor XII binds to collagen fibrils of various origins, this reaction forms the basis for the activated partial which are of negative charges [10]. When exposed to thromboplastin time clotting assay (aPTT). This assay is plasma, collagen type I induces thrombin formation and routinely used to evaluate defects in the intrinsic path- plasma clotting, which is dependent on FXII activity [10]. way of coagulation, such as hemophilia A and B. Recent In addition, PK also binds to collagen, thereby inhibiting studies have identified endogenous activators of contact collagen-induced platelet aggregation [11]. system, such as polyphospahte, collagen, misfolded pro- tein aggregates, lipopolysaccharides (LPS), glycosamino- Cell membrane-mediated
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