ABSTRACT
BACKGROUND: Cardiovascular implantable devices, such as vascular stents, are critical for the treatment of cardiovascular diseases. However, their success is dependent on robust and often long-term antithrombotic therapies. Yet, the current standard-of-care therapies often pose significant bleeding risks to patients. Coagulation factor (F)XI and FXII have emerged as potentially safe and efficacious targets to safely reduce pathologic thrombin generation in medical devices. OBJECTIVES: To study the efficacy of monoclonal antibody-targeting FXII and FXI of the contact pathway in preventing vascular device-related thrombosis. METHODS: The effects of inhibition of FXII and FXI using function-blocking monoclonal antibodies were examined in a nonhuman primate model of nitinol stent-related thrombosis under arterial and venous flow conditions. RESULTS: We found that function-blocking antibodies of FXII and FXI reduced markers of stent-induced thrombosis in vitro and ex vivo. However, FXI inhibition resulted in more effective mitigation of thrombosis markers under varied flow conditions. CONCLUSION: This work provides further support for the translation of contact pathway of coagulation inhibitors for their adjunctive clinical use with cardiovascular devices.
Subject(s)
Alloys , Antibodies, Monoclonal , Factor XII , Factor XI , Stents , Thrombosis , Animals , Thrombosis/prevention & control , Thrombosis/blood , Factor XII/metabolism , Factor XII/antagonists & inhibitors , Factor XII/immunology , Factor XI/antagonists & inhibitors , Factor XI/immunology , Factor XI/metabolism , Antibodies, Monoclonal/pharmacology , Humans , Blood Coagulation/drug effects , Disease Models, Animal , Male , Regional Blood Flow , Fibrinolytic Agents/pharmacologyABSTRACT
Contact activation refers to the process of surface-induced activation of factor XII (FXII), which initiates blood coagulation and is captured by the activated partial thromboplastin time (aPTT) assay. Here, we show the mechanism and diagnostic implications of FXII contact activation. Screening of recombinant FXII mutants identified a continuous stretch of residues Gln317-Ser339 that was essential for FXII surface binding and activation, thrombin generation and coagulation. Peptides spanning these 23 residues competed with surface-induced FXII activation. Although FXII mutants lacking residues Gln317-Ser339 were susceptible to activation by plasmin and plasma kallikrein, they were ineffective in supporting arterial and venous thrombus formation in mice. Antibodies raised against the Gln317-Ser339 region induced FXII activation and triggered controllable contact activation in solution leading to thrombin generation by the intrinsic pathway of coagulation. The antibody-activated aPTT allows for standardization of particulate aPTT reagents and for sensitive monitoring of coagulation factors VIII, IX, XI.
Subject(s)
Blood Coagulation , Factor XII/chemistry , Factor XII/metabolism , Amino Acid Sequence , Animals , Antibodies/pharmacology , Blood Coagulation/drug effects , Blood Platelets/metabolism , Factor XII/genetics , Factor XII/immunology , Factor XIIa/metabolism , Mice , Mutation , Partial Thromboplastin Time/standards , Peptides/chemistry , Peptides/genetics , Peptides/immunology , Peptides/metabolism , Thrombosis/diagnosis , Thrombosis/genetics , Thrombosis/metabolismABSTRACT
Activation of coagulation factor (F) XI promotes multiorgan failure in rodent models of sepsis and in a baboon model of lethal systemic inflammation induced by infusion of heat-inactivated Staphylococcus aureus. Here we used the anticoagulant FXII-neutralizing antibody 5C12 to verify the mechanistic role of FXII in this baboon model. Compared with untreated control animals, repeated 5C12 administration before and at 8 and 24 hours after bacterial challenge prevented the dramatic increase in circulating complexes of contact system enzymes FXIIa, FXIa, and kallikrein with antithrombin or C1 inhibitor, and prevented cleavage and consumption of high-molecular-weight kininogen. Activation of several coagulation factors and fibrinolytic enzymes was also prevented. D-dimer levels exhibited a profound increase in the untreated animals but not in the treated animals. The antibody also blocked the increase in plasma biomarkers of inflammation and cell damage, including tumor necrosis factor, interleukin (IL)-1ß, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, nucleosomes, and myeloperoxidase. Based on clinical presentation and circulating biomarkers, inhibition of FXII prevented fever, terminal hypotension, respiratory distress, and multiorgan failure. All animals receiving 5C12 had milder and transient clinical symptoms and were asymptomatic at day 7, whereas untreated control animals suffered irreversible multiorgan failure and had to be euthanized within 2 days after the bacterial challenge. This study confirms and extends our previous finding that at least 2 enzymes of the contact activation complex, FXIa and FXIIa, play critical roles in the development of an acute and terminal inflammatory response in baboons challenged with heat-inactivated S aureus.
Subject(s)
Factor XII/metabolism , Multiple Organ Failure/metabolism , Multiple Organ Failure/microbiology , Staphylococcus aureus/physiology , Animals , Antibodies/therapeutic use , Blood Coagulation Disorders/complications , Blood Coagulation Disorders/immunology , Blood Coagulation Disorders/microbiology , Blood Platelets/metabolism , Cellular Microenvironment , Complement Activation , Factor XII/immunology , Female , Fibrinogen/metabolism , Hot Temperature , Inflammation/complications , Inflammation/pathology , Male , Multiple Organ Failure/immunology , Papio , Staphylococcal Infections/drug therapy , Staphylococcal Infections/immunology , Staphylococcal Infections/microbiology , Staphylococcal Infections/pathology , Survival AnalysisABSTRACT
Babesia microti is a protozoan that mainly parasitizes rodent and human erythrocytes. B. microti infection can result in changes in the expression levels of various proteins in the host serum. To explore the mechanism underlying the regulation of serum proteins by the host during B. microti infection, this study used a data-independent acquisition (DIA) quantitative proteomic approach to perform comprehensive quantitative proteomic analysis on the serum of B. microti-infected mice. We identified and analysed 333 serum proteins during the infectious stage and recovery stage within 30 days of infection by B. microti in mice. Through quantitative analysis, we found 57 proteins differentially expressed in the infection stage and 69 proteins differentially expressed in the recovery stage. Bioinformatics analysis revealed that these differentially expressed proteins were mainly concentrated in organelles, cell parts, and extracellular regions that are mainly involved in immune system, metabolic, and cellular processes. Additionally, the differentially expressed proteins mainly had catalytic activity. Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis showed that many of the differentially expressed proteins participate in the complement and coagulation cascade reaction, including complement C3, complement FP, and coagulation factor XII. The results of this study can provide more information for the selection of biomarkers for the early clinical monitoring of babesiosis and help in the treatment of babesiosis.
Subject(s)
Babesia microti/immunology , Babesiosis/genetics , Blood Proteins/genetics , Complement System Proteins/genetics , Host-Pathogen Interactions/genetics , Metabolic Networks and Pathways/genetics , Animals , Babesia microti/growth & development , Babesiosis/blood , Babesiosis/immunology , Babesiosis/parasitology , Biomarkers/blood , Blood Proteins/classification , Blood Proteins/immunology , Complement System Proteins/classification , Complement System Proteins/immunology , Factor XII/genetics , Factor XII/immunology , Female , Gene Expression Profiling , Gene Expression Regulation , Gene Ontology , Host-Pathogen Interactions/immunology , Metabolic Networks and Pathways/immunology , Mice , Mice, Inbred BALB C , Molecular Sequence Annotation , Principal Component Analysis , Proteomics/methodsABSTRACT
Evidence accumulated over the last two decades indicates that recurrent angioedema without wheals constitutes a diverse family of disorders with a much higher complexity than was previously regarded. Indicatively, during the last two years, novel variants of three genes other than SERPING1 and F12 have been identified in association with hereditary angioedema. Most interestingly, functional studies of at least one of these variants (the variant c.807Gâ¯>â¯T of ANGPT1 gene) imply the existence of a new disease endotype in which the altered bradykinin metabolism and function does not play a central role. Therefore, using conventional approaches, it seems that the complexity of this disease cannot be sufficiently elucidated and any attempt to interrelate its many diverse aspects seems unrealistic. Similar to other rare and chronic diseases, a Precision Medicine approach, discovering the right target and giving "the right drug, for the right patient, at the right time, every time" seems the optimal future practice. Herein, we review recent data challenging and dictating the need for a switch of angioedema research into high-throughput approaches and we present the expected advantages for better understanding of the disease and patients management.
Subject(s)
Angioedemas, Hereditary , Precision Medicine , Angioedemas, Hereditary/drug therapy , Angioedemas, Hereditary/genetics , Angioedemas, Hereditary/immunology , Angiopoietin-1/genetics , Angiopoietin-1/immunology , Complement C1 Inhibitor Protein/genetics , Complement C1 Inhibitor Protein/immunology , Factor XII/genetics , Factor XII/immunologyABSTRACT
INTRODUCTION: Hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is a rare disease with unpredictable, self-limiting and localized swelling episodes involving the cutaneous and subcutaneous tissues. In the last decade, the spectrum of the possibilities to control the disease has considerably changed with the development of biologic therapies making necessary a careful evaluation of the differences among current and emerging treatments to properly optimize the management of patients. AREAS COVERED: This review serves to summarize the literature regarding the use of biologics for the treatment of C1-INH-HAE. Medications already available on the market and new drugs in different phases of development are addressed. EXPERT OPINION: The advent of biologic therapies dramatically improved the lives of patients with C1-INH-HAE although further improvement is still needed. Whether this is cost/effective will be answered in the next years when we will see if these major advances will benefit the majority of the patients.
Subject(s)
Angioedemas, Hereditary/drug therapy , Biological Products/therapeutic use , Angioedemas, Hereditary/genetics , Antibodies, Monoclonal/therapeutic use , Bradykinin B2 Receptor Antagonists/therapeutic use , Complement C1 Inhibitor Protein/metabolism , Complement C1 Inhibitor Protein/therapeutic use , Factor XII/immunology , Genetic Therapy , Humans , Kallikreins/antagonists & inhibitors , Kallikreins/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/therapeutic useABSTRACT
PURPOSE OF REVIEW: The contact system is a plasma protease cascade, which activates the proinflammatory kallikrein-kinin system and the procoagulant intrinsic coagulation pathway. Recent advances demonstrating the novel functions of this system as a key player of innate immune system will be introduced in the present review. RECENT FINDINGS: The role of the contact system is to initiate and participate in pathophysiological responses to injury, mainly the processes of coagulation and inflammation. The past few years have seen substantial progress, showing a new role of this system in regulation of innate immunity. The relationship between high-molecular-weight kininogen and lipopolysaccharide (LPS) has been investigated and a new function of high-molecular-weight kininogen has been identified as the critical LPS carrier supporting endotoxemia. In contrast, the role of high-molecular-weight kininogen in Klebsiella pneumoniae sepsis is limited. Coagulation factor XII (FXII) plays a detrimental role in murine wound healing and host defense against K. pneumoniae sepsis. In the pathogenesis of arthritis and colitis, the activation of plasma kallikrein and downstream cleavage of high-molecular-weight kininogen and release of bradykinin constitutes a critical pathway in the innate immune mechanism, whereas FXII is not important. SUMMARY: Current findings indicate that the plasma contact system functions as an important constituent of innate immune system, contributing to the pathogenesis of the immunological and infectious diseases.
Subject(s)
Bradykinin/immunology , Immunity, Innate , Kininogens/immunology , Plasma/immunology , Animals , Arthritis/immunology , Arthritis/pathology , Colitis/immunology , Colitis/pathology , Factor XII/immunology , Humans , Klebsiella Infections/immunology , Klebsiella Infections/pathology , Klebsiella pneumoniae/immunology , Lipopolysaccharides/immunology , Lipopolysaccharides/toxicity , Mice , Sepsis/immunology , Sepsis/pathology , Wound Healing/immunologySubject(s)
Antibodies, Blocking/pharmacology , Bradykinin/blood , Factor XII/immunology , Angioedema/drug therapy , Animals , Antibodies, Blocking/therapeutic use , Complement C1 Inhibitor Protein/genetics , Humans , Macaca fascicularis , Male , Mice, Inbred BALB C , Mice, Knockout , Passive Cutaneous Anaphylaxis/drug effectsABSTRACT
Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.
Subject(s)
Adaptive Immunity , Dendritic Cells/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Factor XII/immunology , Multiple Sclerosis/immunology , Adult , Aged , Animals , Cell Differentiation , Factor XII/metabolism , Female , Humans , Interleukin-17/metabolism , Kallikreins/metabolism , Kinins/metabolism , Male , Mice, Inbred C57BL , Middle Aged , Multiple Sclerosis/blood , Receptors, Urokinase Plasminogen Activator/metabolism , T-Lymphocytes/metabolism , Young AdultABSTRACT
Alzheimer's disease (AD) is often characterized by vascular pathology, a procoagulant state, and chronic inflammation. The mechanisms behind these abnormalities in AD are not clear. Here, we review evidence for the role of the AD-associated peptide Aß in promoting inflammation and thrombosis in AD via its interaction with the circulating proteins factor XII and fibrinogen.
Subject(s)
Alzheimer Disease/blood , Alzheimer Disease/immunology , Amyloid beta-Peptides/immunology , Blood Coagulation , Inflammation/blood , Inflammation/immunology , Alzheimer Disease/complications , Alzheimer Disease/pathology , Animals , Factor XII/immunology , Fibrinogen/immunology , Humans , Inflammation/complications , Inflammation/pathologyABSTRACT
Angioedema is defined as local, noninflammatory, self-limiting edema that is circumscribed owing to increased leakage of plasma from the capillaries located in the deep layers of the skin and the mucosae. Two mediators, histamine and bradykinin, account for most cases of angioedema. Angioedema can occur with wheals as a manifestation of urticaria, and this form is frequently allergic. In the present review, we discuss nonallergic angioedema without wheals, which can be divided into 3 acquired and 4 hereditary forms. Histamine is the mediator in acquired angioedema of unknown etiology (idiopathic histaminergic acquired angioedema), whereas in other forms the main mediator is bradykinin. Angioedema can be caused by C1-inhibitor deficiency (C1-INH-hereditary angioedema and C1-INH-acquired angioedema), mutations in coagulation factor XII (FXII-hereditary angioedema), and treatment with angiotensin-converting enzyme inhibitors (ACEI-acquired angioedema). Etiology remains unclear in acquired angioedema (idiopathic nonhistaminergic acquired angioedema) and in 1 type of hereditary angioedema (hereditary angioedema of unknown origin). Several treatments are licensed for hereditary C1-INH deficiency. Plasma-derived and recombinant C1-INHs, the bradykinin receptor blocker icatibant, and the plasma kallikrein inhibitor ecallantide have been approved for on-demand treatment to reverse angioedema symptoms. Attenuated androgen and plasma-derived C1-INH are approved for prophylaxis (AU)
Angioedema se define como un edema local, autolimitado, no-inflamatorio. Se trata de un edema circunscrito debido a la trasvasación de plasma de los capilares localizados en los sustratos profundos de la piel y de las mucosas. En la mayoría de los casos están implicados dos mediadores, la histamina y la serotonina. Puede manifestarse en forma de habones como en la urticaria de origen alérgico. El angioedema de origen no alérgico es el motivo de esta revisión. Se puede presentar bajo 3 formas adquiridas y 4 formas hereditarias. La histamina es el mediador implicado en el angioedema adquirido de etiología desconocida (angioedema adquirido idiopático histaminérgico). En las otras formas se sospecha que es la serotonina el mediador principal. La etiología del angioedema puede ser identificado en 4 tipos: una deficiencia de C1-inhibidor (C1-INH-angioedema hereditario y C1-INH-angioedema adquirido), mutaciones en el factor XII de coagulación (FXII-angioedema hereditario), tratamiento con inhibidores del enzima convertidor de la angiotensina (ACEi-angioedema adquirido). En uno de los adquiridos (angioedema adquirido idiopático no histaminérgico) y en el hereditario de origen desconocido, no se ha identificado todavía su etiología. Varios tratamientos están aprobados para revertir los síntomas clínicos y se aplican en la deficiencia de angioedema hereditario por déficit de C1-INH: Derivados de plasma y C1-INHs recombinantes, icatibant como bloqueante del receptor de la bradiquinina y ecallantide como inhibidor de la kalicreina. Los andrógenos atenuados y los derivados plasmáticos de C1-INH se utilizan en la profilaxis de los ataques (AU)
Subject(s)
Humans , Male , Female , Angioedema/diagnosis , Angioedema/immunology , Angioedema/therapy , Bradykinin/immunology , Bradykinin/therapeutic use , Histamine/immunology , Histamine/therapeutic use , Complement C1 Inhibitor Protein/analysis , Complement C1 Inhibitor Protein/immunology , /analysis , Angioedema/physiopathology , /immunology , Urticaria/complications , Urticaria/immunology , Factor XII/analysis , Factor XII/immunologyABSTRACT
No disponible
Subject(s)
Humans , Female , Adult , Angioedemas, Hereditary/genetics , Angioedemas, Hereditary/immunology , Angioedemas, Hereditary , Complement C1 , Complement C1/immunology , Bradykinin , Bradykinin/immunology , Blood Coagulation Factors , Blood Coagulation Factors/immunology , Factor XII , Factor XII/immunology , Histamine Antagonists/therapeutic use , Adrenal Cortex Hormones/therapeutic useABSTRACT
BACKGROUND: It has been reported that the average activity of coagulation factor XII depends on the ethnicity of the population under study but little information is available on Chinese. We here provide an analysis of the range of activities and antigenic levels of factor XII in healthy Han Chinese and correlate the measurements with polymorphisms and mutations in the corresponding gene. METHODS: Plasma samples were obtained from 549 healthy Chinese adults (264 men, 285 women; age 16-79years) undergoing routine check-ups. The samples were subjected to an activated partial thromboplastin time-based factor XII activity assay as well as an enzyme-linked immunosorbent assay. Partial gene sequence analyses were performed in subjects with low factor XII activity and in normal controls. RESULTS: Ninety-five percent of the subjects had factor XII activities between 47% and 160.25%, with no evidence for an influence of sex or age. Among 15 subjects with activity levels ≤47%, we found one novel nonsense and two missense mutations that may lead to dysfunctional proteins. No mutations were found in a selection of subjects with activities above 47%. Interestingly, however, the particular sequence at a known C/T polymorphism at position 46 just upstream of the translational start codon was correlated with factor XII activity. Subjects homozygous for the T allele, which has an allelic frequency of 0.69, showed significantly lower factor XII activities compared to subjects homozygous for the C allele or those heterozygous for C/T. CONCLUSIONS: The survey determined the normal range of factor XII activities in healthy Chinese and identified mutations as well as a biased representation of a polymorphic nucleotide in subjects with abnormally low activities. The results provide an essential basis for the diagnosis of FXII deficiencies in Chinese.
Subject(s)
Factor XII/genetics , Factor XII/immunology , Genetic Testing/methods , Polymorphism, Single Nucleotide/genetics , Adolescent , Adult , Aged , Base Sequence , China/epidemiology , Female , Humans , Male , Middle Aged , Molecular Sequence Data , Mutation/genetics , Reference Values , Young AdultABSTRACT
PROBLEM: Numerous studies have suggested that factor XII (FXII) deficiency, autoantibodies to FXII (anti-FXII), and antiphosphatidylethanolamine antibodies (aPE) are associated with recurrent pregnancy loss (RPL). aPE in RPL patients recognize the LDC27 peptide of kininogen domain 3. Anti-FXII in RPL patients recognizes the heavy chain of FXII, especially the amino-terminal sequences IPP30 peptide. Previous studies suggested that LDC27 and IPP30 are the responsible sites competing for the same binding site on platelets and inhibiting augmentation of thrombin-induced platelet aggregation. Our aim was to study the influence of antibodies to LDC27 and IPP30 on platelet aggregation. METHODS OF STUDY: In fifteen healthy volunteers, platelet aggregation induced by γ-thrombin in the presence or absence of antibodies to LDC27 and IPP30 was measured. Sixteen RPL patients who were positive for anti-FXII were measured for spontaneous small platelet aggregate (SSPA) formation. RESULTS AND CONCLUSIONS: Antibodies to LDC27 and IPP30 markedly increased aggregation of normal platelets stimulated by γ-thrombin. Augmentation of SSPA formation was more frequent in the patients with RPL who were positive for anti-FXII than in the control group (P = 0.003). This study strongly supports the hypothesis that aPE and anti-FXII may cause RPL due to disruption of the normal antithrombotic effects of kininogens and FXII.
Subject(s)
Abortion, Habitual/immunology , Autoantibodies/pharmacology , Factor XII/immunology , Kininogens/immunology , Phosphatidylethanolamines/immunology , Platelet Aggregation/drug effects , Abortion, Habitual/blood , Adult , Female , Humans , Platelet Aggregation/immunology , PregnancyABSTRACT
BACKGROUND: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare disorder. Mutations of the gene encoding coagulation factor XII have been identified in a subset of patients with this condition. Our aim was to investigate mutations in the F12 gene in patients with HAE with normal C1-INH from Brazil. METHODS: We studied 5 Brazilian families with index female patients who presented with recurrent angioedema with normal C1-INH and C4 levels. Genomic DNA was isolated from whole blood and PCR was performed. Mutations were detected by the sequencing of exon 9 of the F12 gene and allelic discrimination. RESULTS: The c.983C>A (p.Thr328Lys) mutation was identified in 16 subjects, from 4 of the 5 families studied, including 8 patients with symptoms of HAE with normal C1-INH (87.5% women) and 8 subjects asymptomatic for HAE (25% women). Mean age at onset of symptoms among the FXII-HAE patients was 13.8 years (range 6-25 years). Recurrent abdominal pain (100%) and subcutaneous angioedema (87.5%) were the most frequent clinical presentations. Two patients presented with associated laryngeal edema. In keeping with previous observations in patients with both C1-INH-HAE and HAE with normal C1-INH, all 7 women with FXII-HAE reported triggering or worsening of symptoms upon intake of estrogen-containing oral contraceptives and/or pregnancy. CONCLUSIONS: We report for the first time in Brazil a mutation in the F12 gene as a likely cause of HAE with normal C1-INH in patients with recurrent attacks of angioedema and/or abdominal pain. A higher frequency of abdominal pain attacks and onset of symptoms at a younger age were observed among Brazilian patients when compared to those from other parts of the world.
Subject(s)
Angioedemas, Hereditary/genetics , Complement C1 Inactivator Proteins/immunology , Factor XII/genetics , Point Mutation , Adolescent , Adult , Age of Onset , Aged , Alleles , Angioedemas, Hereditary/blood , Angioedemas, Hereditary/immunology , Brazil , Complement C1 Inhibitor Protein , DNA/chemistry , DNA/genetics , Factor XII/immunology , Female , Humans , Middle Aged , Pedigree , Polymerase Chain Reaction , Sequence Analysis, DNA , Young AdultABSTRACT
Blood coagulation is essential for hemostasis, however excessive coagulation can lead to thrombosis. Factor XII starts the intrinsic coagulation pathway and contact-induced factor XII activation provides the mechanistic basis for the diagnostic aPTT clotting assay. Despite its function for fibrin formation in test tubes, patients and animals lacking factor XII have a completely normal hemostasis. The lack of a bleeding tendency observed in factor XII deficiency states is in sharp contrast to deficiencies of other components of the coagulation cascade and factor XII has been considered to have no function for coagulation in vivo. Recently, experimental animal models showed that factor XII is activated by an inorganic polymer, polyphosphate, which is released from procoagulant platelets and that polyphosphate-driven factor XII activation has an essential role in pathologic thrombus formation. Cumulatively, the data suggest to target polyphosphate, factor XII, or its activated form factor XIIa for anticoagulation. As the factor XII pathway specifically contributes to thrombosis but not to hemostasis, interference with this pathway provides a unique opportunity for safe anticoagulation that is not associated with excess bleeding. The review summarizes current knowledge on factor XII functions, activators and inhibitors.
Subject(s)
Anticoagulants/administration & dosage , Blood Coagulation/immunology , Factor XII/immunology , Factor XIIa/immunology , Thrombosis/immunology , Thrombosis/prevention & control , Animals , Blood Coagulation/drug effects , Factor XII/drug effects , Factor XIIa/drug effects , Humans , Models, Cardiovascular , Models, Immunological , Thrombolytic Therapy/methods , Thrombolytic Therapy/trendsABSTRACT
BACKGROUND: High levels of activated proteininhibitor complexes of the intrinsic coagulation proteins are associated with ischemic stroke (IS) but not with myocardial infarction (MI). This study was aimed at determining whether the antigen levels of coagulation factors(factor XII, FXII, and FXI and prekallikrein (PK)are associated with MI and IS, and whether this association is independent of levels of activated proteininhibitor complexes. PATIENTS AND METHODS: The RATIO study included young women (< 50 years) with MI (N = 205)and IS (N = 175), and 638 healthy controls. Antigen levels of FXII, FXI and PK were measured and expressed as percentages of of those in pooled normal plasmas. Odds ratios (ORs) and corresponding 99% confidence intervals (CIs) were calculated for high levels (i.e. ≥ 90th percentile of controls) as measures of rate ratios. RESULTS: After adjustment for potential confounders, high levels of FXII antigen were not associated with MI risk or IS risk(OR(MI) 1.18, 99% CI 0.512.74; ORIS 1.03, 9% CI 0.412.55). High levels of FXI antigen were slightly associated with an increase in MI risk (OR(MI) 1.55, 9% CI 0.743.21), whereas there was a substantial association with IS risk (ORIS 2.65, 9% CI 1.275.56). PK antigen was slightly associated with MI risk but not with IS risk(ORMI 1.54, 9% CI 0.673.52; ORIS 0.90, 9% CI 0.352.33). All associations remained similar after adjustment for levels of proteininhibitor complexes. CONCLUSION: Increased levels of FXI antigen were associated with an increase in IS risk, whereas they showed only a marginal association with MI risk. FXII antigen and PK antigen levels were not substantially associated with MI risk and IS risk.
Subject(s)
Antigens/immunology , Factor XII/immunology , Factor XI/immunology , Ischemia/blood , Myocardial Infarction/blood , Prekallikrein/immunology , Stroke/blood , Adolescent , Adult , Antigens/blood , Antigens/physiology , Case-Control Studies , Factor XI/physiology , Factor XII/physiology , Female , Fibrinolytic Agents/therapeutic use , Humans , Middle Aged , Odds Ratio , Prekallikrein/physiology , Risk Factors , Young AdultSubject(s)
Angioedemas, Hereditary/drug therapy , Complement C1 Inhibitor Protein/therapeutic use , Complement Inactivator Proteins/deficiency , Angioedemas, Hereditary/classification , Angioedemas, Hereditary/immunology , Child, Preschool , Complement Inactivator Proteins/immunology , Factor XII/immunology , Female , HumansABSTRACT
The contact system is a plasma protease cascade that is initiated by coagulation factor XII activation on cardiovascular cells. The system starts procoagulant and proinflammatory reactions, via the intrinsic pathway of coagulation or the 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. Data obtained in genetically engineered mice have revealed an essential function of the contact system for thrombus formation. Severe deficiency in contact system proteases impairs thrombus formation but does not reduce the hemostatic capacity of affected individuals. The system is activated by an inorganic polymer, polyphosphate that is released from activated platelets. Excessive inherited activation of the contact system causes a life-threatening swelling disorder, hereditary angioedema. Activation of the contact system by pathogens contributes to leakage in bacterial infections. Mast-cell-derived heparin triggers contact-system-mediated edema formation with implications for allergic disease states. Here we present an overview about the plasma contact system in occlusive and inflammatory disease and its contribution to health and pathology.