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Pathophysiological Responses to Endotoxin in Humans
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Anthony F. Suffredini, Naomi P. O’Grady
Humoral defense mechanisms are rapidly activated after endotoxin administration. The contact system composed of Factors XII, XI, prekallikrein, and high molecular weight kininogen amplifies several host inflammatory responses including the initiation of coagulation via the intrinsic pathway, activation of plasminogen and neutrophils, as well as the generation of bradykinin, a potent vasodilator. Within 2 hours of endotoxin administration, functional prekallikrein and Factor XI levels fall accompanied by a rise in α2-macroglobulin-kallikrein complexes (32).
Haemostasis
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
The intrinsic system (Figure 53.2) is activated by contact with negatively charged surfaces, such as collagen and subendothelial connective tissue. This contact phase is unique in that the reactions do not depend on Ca++. Plasma factor XII interacts with the negatively charged surfaces of collagen or subendothelial microfibrils in vivo, or glass in vitro, and activated factor XII (XIIa) is generated. XIIa activates prekallikrein, which further generates additional XIIa, amplifying the initial response. High-molecular-weight kininogen (HMWK) binds to the negatively charged surface in association with factor XII and enhances the activation of factor XI by XIIa. HMWK also promotes the conversion of prekallikrein to kallikrein, which generates more XIIa, releasing kinins at the same time.
Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
There is a complex relationship among the activation of Factor XII, activation of Factor XI, formation of plasmin, formation of kallikrein, and the effect of high-molecular weight kininogen (Figure 23). Subjects with prekallikrein deficiency elicit no special symptoms, but their blood exerts a prolonged clotting time in vitro. They show a defective surface-mediated activation of fibrinolysis and defective permeability enhancement.397,499 In this disease condition kallikrein accelerates the activation of Factor XII and Factor VII, and enhances the conversion of kininogen to bradykinin.245 A defect in kininogen production is due to the deficiency of high-molecular weight kininogen, and it prolongs clotting time in vitro, with an impaired generation of the vascular permeability factor. Various steps involved in blood coagulation and vascular alterations are presented in a scheme (Figure 24).
Emerging drugs for the treatment of hereditary angioedema due to C1-inhibitor deficiency
Published in Expert Opinion on Emerging Drugs, 2022
Andrea Zanichelli, Vincenzo Montinaro, Massimo Triggiani, Francesco Arcoleo, Debora Visigalli, Mauro Cancian
KVD-900 is being tested as on-demand treatment. It targets plasma kallikrein (Figure 1, Table 3). In-vitro studies showed that KVD-900 protected high-molecular-weight kininogen from plasma kallikrein-mediated cleavage. In phase I study, several dosages were tested (from 5 to 600 mg) and 600 mg resulted well-suited for use as on-demand therapy for acute attacks, with a combination of rapid uptake into the plasma and high plasma concentrations. Concentrations increased rapidly, in a dose-proportional manner, with effective concentrations, that were typically reached within 30 minutes. KVD-900 was generally well tolerated, with a total of 12 adverse events, among which the most common were back pain, common cold/flu symptoms, and pyrexia. All doses of KVD-900 over 80 mg provided complete inhibition of plasma kallikrein. Inhibitory effect on plasma kallikrein activity was detected within 10 minutes, whilst within 20 minutes the effect was greater than 95% and lasted at least 10 hours. No gastrointestinal side effects were detected. The phase II study showed that KVD-900 significantly reduced the use of rescue therapy, with 15% of KVD-900 treated attacks rescued compared to 30% on placebo at 12 hours. Time to onset of symptom relief was 1.6 vs. 9 hours in treatment and placebo arm, respectively. There were no serious adverse events reported in the trial and no patients withdrew due to adverse events [26]. The KONFIDENT phase III trial is recruiting. It will evaluate the efficacy and safety of KVD-900 in a large population of adult and adolescent patients with HAE [27].
A focus on the use of subcutaneous C1-inhibitor for treatment of hereditary angioedema
Published in Expert Review of Clinical Immunology, 2020
Maria Fernanda Villavicencio, Timothy Craig
The initial work on SC-C1-INH was [6] an early phase trial to compare pharmacokinetics (PK), pharmacodynamics (PD), and safety of SC human pasteurized C1-INH concentrate compared with IV administration. A single dose of 1000 U in 24 patients with mild to moderate HAE age ≥17 was used and blood samples after treatment were taken at different hours up to 7 days after treatment. The results demonstrated a mean maximum C1-INH functional increase of 33.8% after IV administration and of 9.8% after SC administration. The bioavailability of SC administration was 39.7%. The SC C1-INH had a slower increase of C1-INH activity, lower Cmax (maximum plasma concentration) and markedly delayed Tmax (time to maximum activity) for C1-INH antigen and C4 antigen levels [6]. A decrease in cleaved high-molecular-weight kininogen (cHK) from 44.8% to 42% was also demonstrated. The SC-C1-INH therapy was tolerated well with few adverse events other than injection site reactions. In summary, this study demonstrated the feasibility of using SC C1-INH concentrate for treatment of HAE [6]. See Table 2.
Current and emerging pharmacotherapy for ischemic stroke prevention in patients with atrial fibrillation
Published in Expert Opinion on Pharmacotherapy, 2018
Orsolya Székely, Kazuo Miyazawa, Gregory Yoke Hong Lip
The role of the intrinsic pathway consisting of factor XI, factor XII, prekallikrein (PK), and high molecular weight kininogen (HK) in thrombosis was not clearly defined. Until recently the only activators of the contact system was thought to be the artificial sites and extracorporeal conditions.. Recent evidence suggests that natural polyphosphates (RNA, DNA, inorganic phosphates) derived from activated platelets or injured neutrophils are potent activators of the contact system, acting as a distinct trigger mechanism for coagulation at the site of vascular injury in thromboinflammatory disorders [49–52]. Furthermore emerging research on different experimental thrombosis models (factor XI, XII-deficient mice) has proved that the contact system is essential for thrombus stabilization and growth, whereas hemostasis is not affected [53,54].