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The inhibition of plasmin, plasma kallikrein, plasma permeability factor, and the C'1r subcomponent of the first component of complement by serum C'1 esterase inhibitor

Authors:
Oscar D. Ratnoff
Oscar D. Ratnoff
Oscar D. Ratnoff
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Jack Pensky
Jack Pensky
Jack Pensky
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Derek Ogston
Derek Ogston
Derek Ogston
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George B. Naff
George B. Naff
George B. Naff
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Abstract

The fraction of human serum designated as C'1 esterase inhibitor is known to inhibit the action of C'1 esterase, a plasma kallikrein, and PF/Dil, an enzyme in plasma enhancing cutaneous vascular permeability. In the present study, C'1 esterase inhibitor has been found to block the actions of plasmin and the C'1r subcomponent of the first component of complement, and to retard the generation of PF/Dil. No inhibition of blood clotting or of the generation of plasmin was demonstrable.
The inhibition of plasmin, plasma kallikrein, plasma permeability factor, and the C'1r subcomponent of the first component of complement by serum C'1 esterase inhibit
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The inhibition of plasmin, plasma kallikrein, plasma permeability factor, and the C'1r subcomponent of the first component of complement by serum C'1 esterase inhibit
or.pdf
Available via license: CC BY-NC-SA 4.0
Content may be subject to copyright.
The inhibition of plasmin, plasma kallikrein, plasma permeability factor, and the C'1r subcomponent of the first component of complement by serum C'1 esterase inhibit
or.pdf
Available via license: CC BY-NC-SA 4.0
Content may be subject to copyright.
The inhibition of plasmin, plasma kallikrein, plasma permeability factor, and the C'1r subcomponent of the first component of complement by serum C'1 esterase inhibit
or.pdf
Available via license: CC BY-NC-SA 4.0
Content may be subject to copyright.
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... The main inhibitor of both the classical pathway and the lectin pathway of the complement system is C1 inhibitor 35 , which directly inhibits the enzymatic activity of C1r/C1s in the classical pathway and MASP1/MASP2 in the lectin pathway. C1 inhibitor can also inhibit components of the KKS, such as activated FXII (FXIIa), FXI and plasma kallikrein, as well as plasmin, thereby affecting the fibrinolytic system 35 . ...
... The main inhibitor of both the classical pathway and the lectin pathway of the complement system is C1 inhibitor 35 , which directly inhibits the enzymatic activity of C1r/C1s in the classical pathway and MASP1/MASP2 in the lectin pathway. C1 inhibitor can also inhibit components of the KKS, such as activated FXII (FXIIa), FXI and plasma kallikrein, as well as plasmin, thereby affecting the fibrinolytic system 35 . Active plasma kallikrein is inhibited by both C1 inhibitor and the large glycoprotein α 2 -macroglobulin 36 . ...
Crosstalk between the renin–angiotensin, complement and kallikrein–kinin systems in inflammation
Article
  • Nov 2021
  • NAT REV IMMUNOL
During severe inflammatory and infectious diseases, various mediators modulate the equilibrium of vascular tone, inflammation, coagulation and thrombosis. This Review describes the interactive roles of the renin–angiotensin system, the complement system, and the closely linked kallikrein–kinin and contact systems in cell biological functions such as vascular tone and leakage, inflammation, chemotaxis, thrombosis and cell proliferation. Specific attention is given to the role of these systems in systemic inflammation in the vasculature and tissues during hereditary angioedema, cardiovascular and renal glomerular disease, vasculitides and COVID-19. Moreover, we discuss the therapeutic implications of these complex interactions, given that modulation of one system may affect the other systems, with beneficial or deleterious consequences. The renin–angiotensin, complement and kallikrein–kinin systems comprise a multitude of mediators that modulate physiological responses during inflammatory and infectious diseases. This Review investigates the complex interactions between these systems and how these are dysregulated in various conditions, including cardiovascular diseases and COVID-19, as well as their therapeutic implications.
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... Plasmin is modulated by 2-macroglobin, a nonspecific protease inactivator. C1-esterase inhibitor, a physiological inhibitor of plasma kallikrein and FXIIa, also attenuates the nonspecific plasminogen activation [51,52]. Moreover, thrombinactivated fibrinolysis inhibitor (TAFI), a non-serpin inhibitor, removes C-terminal lysine and arginine residues on fibrin. ...
Medicines in Development for Venous Thromboembolism
Preprint
Full-text available
  • Jul 2024
Venous thromboembolism (VTE) is a serious health condition and represents an important cause of morbidity and, in some cases, mortality. According to the latest estimates from the Centers for Disease Control and Prevention, 3 out of 10 people with VTE will have recurrence of clotting event within 10 years. The American Heart Association reports that VTE is more common in people over 40 years of age, and that risk doubles with each decade. The World Health Organization advises that the world’s population of people aged 60 years is going to be doubled by 2050. Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the two main conditions that make up VTE. People with VTE are initially treated with anticoagulants to prevent conditions such as stroke and to reduce the recurrence of VTE. However, thrombolytic therapy is used for people with PE experiencing with low blood pressure or in severe cases of DVT. Despite the approval of direct anticoagulants in 2010, there is clear evidence that the search for new drugs that are more effective or safer than the current antithrombotic treatments continues. Thrombin plays a crucial role in regulating hemostasis and maintaining blood coagulation, and therefore serves as a major target for the treatment of hemostatic disorders such as thromboembolic syndromes, disseminated intravascular coagulation, thrombocytopenia, and acquired hemostatic disorders such as platelet dysfunction and excessive anticoagulation, among other pathologies. This review focuses on the progress in research on new anticoagulants and novel delivery systems for antithrombotic targeting to vascular embolisms.
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... C1INH also has the antifibrinolytic activity through its ability to inhibit plasmin and tissue plasminogen activator [41,42]. The effect of exogenous C1INH on fibrinolysis was assessed using a plasma-based calibrated plasmin generation assay. ...
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... C1INH also has the antifibrinolytic activity through its ability to inhibit plasmin and tissue plasminogen activator [41,42]. The effect of exogenous C1INH on fibrinolysis was assessed using a plasma-based calibrated plasmin generation assay. ...
High plasma levels of C1-inhibitor are associated with lower risk of future venous thromboembolism
Article
Full-text available
  • Mar 2023
  • J THROMB HAEMOST
Background: C1-inhibitor (C1INH) is a broad acting serine protease inhibitor with anticoagulant activity. The impact of C1INH plasma levels within the normal physiological range on risk of venous thromboembolism (VTE) is unknown. We assessed the association of plasma C1INH levels and VTE risk, and evaluated the impact of C1INH on thrombin and plasmin generation in ex vivo assays. Methods: A nested case-control study with 405 VTE patients and 829 age- and sex-matched controls was derived from the Tromsø study. Odds ratios (ORs) with 95% confidence intervals (95% CI) for VTE were estimated across plasma C1INH quartiles. Genetic regulation of C1INH was explored using quantitative trait loci analysis of whole exome sequencing data. The effect of plasma C1INH levels on coagulation was evaluated ex vivo by calibrated automated thrombography. Results: Individuals with C1INH levels in the highest quartile had a lower risk of VTE (OR 0.68, 95% CI: 0.49-0.96) compared to those with C1INH in the lowest quartile. In subgroup analysis, the corresponding ORs were 0.60 (95% CI: 0.39-0.89) for deep vein thrombosis and 0.85 (95% CI: 0.52-1.38) for pulmonary embolism, respectively. No significant genetic determinants of plasma C1INH levels were identified. Addition of exogenous C1INH to normal human plasma reduced thrombin generation triggered by an activator of the intrinsic coagulation pathway, but not when triggered by an activator of the extrinsic coagulation pathway. Conclusions: High plasma levels of C1INH were associated with a lower risk of VTE, and C1INH inhibited thrombin generation initiated by the intrinsic coagulation pathway ex vivo.
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... At some point after C1 activation, C1-INH binds covalently to the active sites on C1r and C1s, inactivating their catalytic function and dissociating them from C1q. C1-INH binding to C1r and C1s is irreversible; it prevents cleavage of C4 and thereby controls the initial amplification step of classical-pathway activation [3]. Thus, C1-INH binding to C1r and C1s acts as an efficient inhibitor of the classical pathway of the complement system [4,5]. C1-INH also limits the activity of MASP-2 and several proteases of the coagulation/anticoagulation system, including factor XI, factor XII, plasma kallikrein, plasmin, and tissue plasminogen activator [3,6]. ...
Combined anti-C1-INH and radiotherapy against glioblastoma
Article
Full-text available
  • Jan 2023
  • BMC CANCER
Background A more effective immune response against glioblastoma is needed in order to achieve better tumor control. Radiotherapy can induce anti-tumor mediated immune reactions, in addition to its dose response effects. The complement system can function as a bridge between innate and adaptive immune responses. Combining radiotherapy and complement activating therapy is theoretically interesting. Methods Radiotherapy at 8 Gy × 2 was combined with treatment against C1-inhibitor (C1-INH), a potent inhibitor of activation of the classical pathway of the complement system. Anti-C1-INH was delivered as intratumoral injections. Fully immunocompetent Fischer 344 rats with NS1 glioblastoma tumors were treated. Survival was monitored as primary outcome. Models with either intracranial or subcutaneous tumors were evaluated separately. Results In the intracranial setting, irradiation could prolong survival, but there was no additional survival gain as a result of anti-C1-INH treatment. In animals with subcutaneous tumors, combined radio-immunotherapy with anti-C1-INH and irradiation at 8 Gy × 2 significantly prolonged survival compared to control animals, whereas irradiation or anti-C1-INH treatment as single therapies did not lead to significantly increased survival compared to control animals. Conclusions Anti-C1-INH treatment could improve the efficacy of irradiation delivered at sub-therapeutic doses and delay tumor growth in the subcutaneous tumor microenvironment. In the intracranial setting, the doses of anti-C1-INH were not enough to achieve any survival effect in the present setting.
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... Whether this pathway substantially contributes to complement activation in health and disease is unknown. More likely, particularly in C1-INH deficiency, heightened release of anaphylatoxins C3a and C5a could more readily be attributed to 1) excess PKa that can cleave C3 and FB, 2) lack of neutralization of C1r, C1s and MASPs, and 3) lack of inhibition of plasmin (116,120). ...
Coagulation and complement: Key innate defense participants in a seamless web
Article
Full-text available
  • Aug 2022
In 1969, Dr. Oscar Ratnoff, a pioneer in delineating the mechanisms by which coagulation is activated and complement is regulated, wrote, “In the study of biological processes, the accumulation of information is often accelerated by a narrow point of view. The fastest way to investigate the body’s defenses against injury is to look individually at such isolated questions as how the blood clots or how complement works. We must constantly remind ourselves that such distinctions are man-made. In life, as in the legal cliché, the devices through which the body protects itself form a seamless web, unwrinkled by our artificialities.” Our aim in this review, is to highlight the critical molecular and cellular interactions between coagulation and complement, and how these two major component proteolytic pathways contribute to the seamless web of innate mechanisms that the body uses to protect itself from injury, invading pathogens and foreign surfaces.
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Multiple mechanisms underlying anti-prostate cancer activity of surfactant protein D
Chapter
Full-text available
  • Feb 2023
The chapter provides a snapshot of one of the important innate immune receptors, surfactant protein-D (SP-D), as a promising molecule for cancer therapy that targets multiple pathways for its action.
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India@75 (Mishra PK & Srivastava RK)
Book
Full-text available
  • Mar 2023
The Indian Society for the Study of Reproduction and Fertility (ISSRF) published a Special Issue of the Newsletter titled "A Kaleidoscopic View of Advances in Reproductive Health Research as India Turns 75" to commemorate the 75th Anniversary of Indian Independence (Azadi ka Amrit Mahotsav).
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Thromboinflammation Supports Complement Activation in Cancer Patients With COVID-19
Article
Full-text available
  • Aug 2021
Background COVID-19 pathology is associated with exuberant inflammation, vascular damage, and activation of coagulation. In addition, complement activation has been described and is linked to disease pathology. However, few studies have been conducted in cancer patients. Objective This study examined complement activation in response to COVID-19 in the setting of cancer associated thromboinflammation. Methods Markers of complement activation (C3a, C5a, sC5b-9) and complement inhibitors (Factor H, C1-Inhibitor) were evaluated in plasma of cancer patients with (n=43) and without (n=43) COVID-19 and stratified based on elevated plasma D-dimer levels (>1.0 μg/ml FEU). Markers of vascular endothelial cell dysfunction and platelet activation (ICAM-1, thrombomodulin, P-selectin) as well as systemic inflammation (pentraxin-3, serum amyloid A, soluble urokinase plasminogen activator receptor) were analyzed to further evaluate the inflammatory response. Results Increases in circulating markers of endothelial cell dysfunction, platelet activation, and systemic inflammation were noted in cancer patients with COVID-19. In contrast, complement activation increased in cancer patients with COVID-19 and elevated D-dimers. This was accompanied by decreased C1-Inhibitor levels in patients with D-dimers > 5 ug/ml FEU. Conclusion Complement activation in cancer patients with COVID-19 is significantly increased in the setting of thromboinflammation. These findings support a link between coagulation and complement cascades in the setting of inflammation.
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Molecular Basis for Bordetella pertussis Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex
Article
Full-text available
  • Mar 2021
Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glycoprotein, a C1 inhibitor (C1-INH), is a key regulator (inhibitor) of serine proteases of all the above-mentioned pathways. Recently, an autotransporter protein, virulence-associated gene 8 (Vag8), produced by the whooping cough pathogen, Bordetella pertussis , was shown to bind to C1-INH and interfere with its function. Here, we present the structure of the Vag8–C1-INH complex determined using cryo-electron microscopy at a 3.6-Å resolution. The structure shows a unique mechanism of C1-INH inhibition not employed by other pathogens, where Vag8 sequesters the reactive center loop of C1-INH, preventing its interaction with the target proteases. IMPORTANCE The structure of a 10-kDa protein complex is one of the smallest to be determined using cryo-electron microscopy at high resolution. The structure reveals that C1-INH is sequestered in an inactivated state by burial of the reactive center loop in Vag8. By so doing, the bacterium is able to simultaneously perturb the many pathways regulated by C1-INH. Virulence mechanisms such as the one described here assume more importance given the emerging evidence about dysregulation of contact activation, coagulation, and fibrinolysis leading to COVID-19 pneumonia.
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THE ENZYMATIC NATURE OF C'1r
Article
Human C'1, a macromolecular complex composed of three subunits, is the zymogen for at least two distinct enzymes. Preparations of one subunit, C'1r, functioned as a protease which converted another subunit, C'1s, to C'1 esterase. The conversion of C'1s to C'1 esterase by C'1r was blocked by Liquoid, phenyl methylsulfonyl fluoride, and calcium ions, but not by soybean trypsin inhibitor, hirudin, or heparin. Preparations of C'1r also possessed two additional functions, i.e., the ability to hydrolyze certain synthetic amino acid esters and to participate in immune hemolysis. Evidence was presented which indicates that these three functions are properties of a single entity, C'1r, but not of the same portion of its molecular structure. These observations suggest that C'1r has at least two active sites, one for its reaction with C'1q, an additional subunit of C'1, and one for its reaction with C'1s; together, the three subcomponents, C'1q, C'1r, and C'1s, form a single functional unit, the first component of complement.
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Mechanisms of Activation of C′I and Inhibition of C′I Esterase
Chapter
  • May 2008
enzymic processes;genetic controls;proenzyme activation;synthetic subtrates;esterase inhibitor
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Hereditary Angioneurotic Edema. II. Deficiency of Inhibitor for Serum Globulin Permeability Factor and/or Plasma Kallikrein
Article
  • Jul 1962
  • J Allergy
Studies of a 33-year-old Caucasian woman with hereditary angioneurotic edema and her two sons, of whom only one is definitely affected with the disease, have revealed that the inborn biochemical lesion is likely an inherited deficiency of serum inhibitor to plasma kallikrein and/or serum globulin permeability factor. The patient showed a significantly greater bluing response to intradermal injections of diluted autologous serum or to plasma kallikrein than did the normal controls and this response, unlike that of the control subjects, continued to increase for a period of hours. By use of an enzymatic determination utilizing p-toluenesulfonyl-l-arginine methyl ester as the substrate, it is possible to demonstrate a deficiency in both patients to an inhibitor of plasma kallikrein. A variety of other known permeability factors have been excluded as the potential agent involved.
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