Coagulation factor XII in thrombosis and inflammation.

Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. The factor XII-driven contact system starts coagulation and inflammatory mechanisms via the intrinsic pathway of coagulation and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood; however, its in vivo functions are just beginning to emerge. Challenging the concept of the coagulation balance, targeting factor XII or its activator polyphosphate, provides protection from thromboembolic diseases without interfering with hemostasis. This suggests that the polyphosphate/factor XII axis contributes to thrombus formation while being dispensable for hemostatic processes. In contrast to deficiency in factor XII providing safe thromboprotection, excessive FXII activity is associated with the life-threatening inflammatory disorder hereditary angioedema. The current review summarizes recent findings of the polyphosphate/factor XII-driven contact system at the intersection of procoagulant and proinflammatory disease states. Elucidating the contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory disorders.

[1]  Evi X. Stavrou,et al.  A Flow Cytometry‐Based Assay for Procoagulant Platelet Polyphosphate , 2018, Cytometry. Part B, Clinical cytometry.

[2]  Evi X. Stavrou,et al.  Factor XII and uPAR upregulate neutrophil functions to influence wound healing , 2018, The Journal of clinical investigation.

[3]  T. Renné,et al.  Factor XII-Driven Inflammatory Reactions with Implications for Anaphylaxis , 2017, Front. Immunol..

[4]  A. Clermont,et al.  Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke. , 2017, Blood.

[5]  T. Renné,et al.  Factor XII Contact Activation , 2017, Seminars in Thrombosis and Hemostasis.

[6]  T. Renné,et al.  Polyphosphate nanoparticles on the platelet surface trigger contact system activation. , 2017, Blood.

[7]  J. Emsley,et al.  Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation. , 2017, Blood.

[8]  G. Rennert,et al.  Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. , 2017, Blood.

[9]  J. Weitz,et al.  Factors XI and XII as Targets for New Anticoagulants , 2017, Front. Med..

[10]  Y. Liu,et al.  Localization of Short-Chain Polyphosphate Enhances its Ability to Clot Flowing Blood Plasma , 2017, Scientific Reports.

[11]  J. Weitz,et al.  Emerging anticoagulant strategies. , 2017, Blood.

[12]  J. Nussberger,et al.  Bradykinin in idiopathic non‐histaminergic angioedema , 2017, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[13]  Stephanie A. Smith,et al.  Polyphosphate and RNA Differentially Modulate the Contact Pathway of Blood Clotting* , 2016, The Journal of Biological Chemistry.

[14]  A. S. Lionikiene,et al.  Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity. , 2016, Blood.

[15]  J. Montaner,et al.  Hyperfibrinolysis increases blood-brain barrier permeability by a plasmin- and bradykinin-dependent mechanism. , 2016, Blood.

[16]  T. Renné,et al.  Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations. , 2016, The Journal of allergy and clinical immunology.

[17]  Hugh Kim,et al.  Polyphosphate is a novel cofactor for regulation of complement by a serpin, C1 inhibitor. , 2016, Blood.

[18]  Evi X. Stavrou,et al.  Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection , 2016, Nature Communications.

[19]  A. Pagnier,et al.  Hereditary angioedema with normal C1 inhibitor and factor XII mutation: a series of 57 patients from the French National Center of Reference for Angioedema , 2016, Clinical and experimental immunology.

[20]  L. K. Ely,et al.  Factor XIa–specific IgG and a reversal agent to probe factor XI function in thrombosis and hemostasis , 2016, Science Translational Medicine.

[21]  S. Zeerleder,et al.  Angioedema attacks in patients with hereditary angioedema: Local manifestations of a systemic activation process. , 2016, The Journal of allergy and clinical immunology.

[22]  Takashi Ito,et al.  DAMP and DIC: The role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. , 2016, Blood reviews.

[23]  C. Ruppert,et al.  Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells , 2016, Nature Communications.

[24]  C. Maas,et al.  Bradykinin: Inflammatory Product of the Coagulation System , 2016, Clinical Reviews in Allergy & Immunology.

[25]  M. Cicardi,et al.  Angioedema Phenotypes: Disease Expression and Classification , 2016, Clinical Reviews in Allergy & Immunology.

[26]  G. Stoll,et al.  FXIIa inhibitor rHA‐Infestin‐4: Safe thromboprotection in experimental venous, arterial and foreign surface‐induced thrombosis , 2016, British journal of haematology.

[27]  T. Renné,et al.  Contact system revisited: an interface between inflammation, coagulation, and innate immunity , 2016, Journal of thrombosis and haemostasis : JTH.

[28]  N. Mutch.  Polyphosphate as a haemostatic modulator. , 2016, Biochemical Society transactions.

[29]  C. Hack,et al.  Hereditary Angioedema Attacks: Local Swelling at Multiple Sites , 2016, Clinical Reviews in Allergy & Immunology.

[30]  Joseph Kalkowski,et al.  Colloidal Confinement of Polyphosphate on Gold Nanoparticles Robustly Activates the Contact Pathway of Blood Coagulation. , 2016, Bioconjugate chemistry.

[31]  Evi X. Stavrou,et al.  Factor XII: a novel target for safe prevention of thrombosis and inflammation , 2015, Journal of internal medicine.

[32]  Evi X. Stavrou,et al.  The polyphosphate-factor XII pathway drives coagulation in prostate cancer-associated thrombosis. , 2015, Blood.

[33]  M. Nöthen,et al.  Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III. , 2015, The Journal of clinical investigation.

[34]  J. Morrissey,et al.  Polyphosphate as modulator of hemostasis, thrombosis, and inflammation , 2015, Journal of thrombosis and haemostasis : JTH.

[35]  S. Meuth,et al.  Blocking of plasma kallikrein ameliorates stroke by reducing thromboinflammation , 2015, Annals of neurology.

[36]  P. Dinarvand,et al.  Inorganic polyphosphate elicits pro‐inflammatory responses through activation of the mammalian target of rapamycin complexes 1 and 2 in vascular endothelial cells , 2015, Journal of thrombosis and haemostasis : JTH.

[37]  Evi X. Stavrou,et al.  Plasma contact system activation drives anaphylaxis in severe mast cell-mediated allergic reactions. , 2015, The Journal of allergy and clinical immunology.

[38]  L. Schaefer,et al.  Heparan Sulfate Proteoglycans Mediate Factor XIIa Binding to the Cell Surface* , 2015, The Journal of Biological Chemistry.

[39]  G. Raskob,et al.  Factor XI antisense oligonucleotide for prevention of venous thrombosis. , 2014, The New England journal of medicine.

[40]  G. Raskob,et al.  Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis , 2014 .

[41]  N. Key.  Epidemiologic and clinical data linking factors XI and XII to thrombosis. , 2014, Hematology. American Society of Hematology. Education Program.

[42]  J. Kizhakkedathu,et al.  Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis. , 2014, Blood.

[43]  Y. Liu,et al.  Size-controlled synthesis of granular polyphosphate nanoparticles at physiologic salt concentrations for blood clotting. , 2014, Biomacromolecules.

[44]  T. Renné,et al.  Factor XII: a drug target for safe interference with thrombosis and inflammation. , 2014, Drug discovery today.

[45]  A. S. Lionikiene,et al.  Single‐chain factor XII exhibits activity when complexed to polyphosphate , 2014, Journal of thrombosis and haemostasis : JTH.

[46]  T. Renné,et al.  Factor XII Regulates the Pathological Process of Thrombus Formation on Ruptured Plaques , 2014, Arteriosclerosis, thrombosis, and vascular biology.

[47]  B. Monia,et al.  Factor XI Regulates Pathological Thrombus Formation on Acutely Ruptured Atherosclerotic Plaques , 2014, Arteriosclerosis, thrombosis, and vascular biology.

[48]  M. Triggiani,et al.  Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group , 2014, Allergy.

[49]  B. Monia,et al.  Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits. , 2014, Blood.

[50]  T. Renné,et al.  Factor XII inhibition reduces thrombus formation in a primate thrombosis model. , 2014, Blood.

[51]  F. D. Nascimento,et al.  The Involvement of Proteoglycans in the Human Plasma Prekallikrein Interaction with the Cell Surface , 2014, PloS one.

[52]  P. Dinarvand,et al.  Polyphosphate amplifies proinflammatory responses of nuclear proteins through interaction with receptor for advanced glycation end products and P2Y1 purinergic receptor. , 2014, Blood.

[53]  Michael J. Wilson,et al.  A Factor XIIa Inhibitory Antibody Provides Thromboprotection in Extracorporeal Circulation Without Increasing Bleeding Risk , 2014, Science Translational Medicine.

[54]  D. Seiffert,et al.  Factor XIIa inhibition by Infestin-4: in vitro mode of action and in vivo antithrombotic benefit , 2013, Thrombosis and Haemostasis.

[55]  J. Andersen,et al.  Novel Family of Insect Salivary Inhibitors Blocks Contact Pathway Activation by Binding to Polyphosphate, Heparin, and Dextran Sulfate , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[56]  T. Renné,et al.  Time-dependent degradation and tissue factor addition mask the ability of platelet polyphosphates in activating factor XII-mediated coagulation. , 2013, Blood.

[57]  R. Manorama,et al.  Inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels. , 2013, Blood.

[58]  O. McCarty,et al.  Factor XII promotes blood coagulation independent of factor XI in the presence of long‐chain polyphosphates , 2013, Journal of thrombosis and haemostasis : JTH.

[59]  T. Renné,et al.  Hereditary angioedema: a bradykinin-mediated swelling disorder , 2013, Thrombosis and Haemostasis.

[60]  Stephanie A. Smith,et al.  Inhibition of polyphosphate as a novel strategy for preventing thrombosis and inflammation. , 2012, Blood.

[61]  B. Sullenger,et al.  Nucleic acid scavengers inhibit thrombosis without increasing bleeding , 2012, Proceedings of the National Academy of Sciences.

[62]  T. Renné,et al.  Platelet‐ and erythrocyte‐derived microparticles trigger thrombin generation via factor XIIa , 2012, Journal of thrombosis and haemostasis : JTH.

[63]  D. Seiffert,et al.  Effects of plasma kallikrein deficiency on haemostasis and thrombosis in mice: Murine Ortholog of the Fletcher Trait , 2012, Thrombosis and Haemostasis.

[64]  B. Monia,et al.  Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. , 2011, Blood.

[65]  T. Renné.  The procoagulant and proinflammatory plasma contact system , 2011, Seminars in Immunopathology.

[66]  C. Esmon,et al.  Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. , 2011, Blood.

[67]  T. Renné,et al.  The Plasma Contact System 2.0 , 2011, Seminars in thrombosis and hemostasis.

[68]  A. Clermont,et al.  Plasma Kallikrein Mediates Retinal Vascular Dysfunction and Induces Retinal Thickening in Diabetic Rats , 2011, Diabetes.

[69]  S. Cichon,et al.  Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. , 2011, Immunity.

[70]  C. Rienstra,et al.  Polyphosphate exerts differential effects on blood clotting, depending on polymer size. , 2010, Blood.

[71]  T. Renné,et al.  Platelet Polyphosphates Are Proinflammatory and Procoagulant Mediators In Vivo , 2009, Cell.

[72]  A. Schmaier,et al.  Deletion of murine kininogen gene 1 (mKng1) causes loss of plasma kininogen and delays thrombosis. , 2007, Blood.

[73]  K. Preissner,et al.  Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation , 2007, Proceedings of the National Academy of Sciences.

[74]  S. Cichon,et al.  Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. , 2006, American journal of human genetics.

[75]  T. Renné,et al.  Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis , 2006, The Journal of experimental medicine.

[76]  T. Renné,et al.  Platelets promote coagulation factor XII-mediated proteolytic cascade systems in plasma , 2006, Biological chemistry.

[77]  James H Morrissey,et al.  Polyphosphate modulates blood coagulation and fibrinolysis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[78]  T. Renné,et al.  Local Bradykinin Formation Is Controlled by Glycosaminoglycans1 , 2005, The Journal of Immunology.

[79]  T. Renné,et al.  Defective thrombus formation in mice lacking coagulation factor XII , 2005, The Journal of experimental medicine.

[80]  E. Oldfield,et al.  Human Platelet Dense Granules Contain Polyphosphate and Are Similar to Acidocalcisomes of Bacteria and Unicellular Eukaryotes* , 2004, Journal of Biological Chemistry.

[81]  A. Kornberg,et al.  Inorganic polyphosphate stimulates mammalian TOR, a kinase involved in the proliferation of mammary cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[82]  A. Davis,et al.  Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. , 2002, The Journal of clinical investigation.

[83]  E. Rosen,et al.  FXI Is Essential for Thrombus Formation Following FeCl3-Induced Injury of the Carotid Artery in the Mouse , 2002, Thrombosis and Haemostasis.

[84]  T. Renné,et al.  Cell surface‐associated chondroitin sulfate proteoglycans bind contact phase factor H‐kininogen , 2001, FEBS letters.

[85]  T. Renné,et al.  High Molecular Weight Kininogen Utilizes Heparan Sulfate Proteoglycans for Accumulation on Endothelial Cells* , 2000, The Journal of Biological Chemistry.

[86]  G. Broze,et al.  Factor XI activation in a revised model of blood coagulation , 1991, Science.

[87]  K Fujikawa,et al.  Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces. , 1991, The Journal of biological chemistry.

[88]  K. Austen,et al.  A PREALBUMIN ACTIVATOR OF PREKALLIKREIN , 1971, The Journal of experimental medicine.

[89]  J. Caen,et al.  Availability of Platelet Factor 3 and Activation of Factor XII in Thrombasthenia , 1965, Nature.

[90]  T. Renné,et al.  Factor XII as a Therapeutic Target in Thromboembolic and Inflammatory Diseases , 2017, Arteriosclerosis, thrombosis, and vascular biology.

[91]  DavidGailani,et al.  Factor XI as a Therapeutic Target , 2016 .

[92]  Jennie Bäck,et al.  Activated human platelets induce factor XIIa-mediated contact activation. , 2010, Biochemical and biophysical research communications.

[93]  J. Griffin,et al.  Contributions of human platelets to the proteolytic activation of blood coagulation factors XII and XI. , 1981, Blood.