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Seminars in Immunopathology Aug 2021Coagulation is controlled by a delicate balance of prothrombotic and antithrombotic mechanisms, to prevent both excessive blood loss from injured vessels and pathologic... (Review)
Review
Coagulation is controlled by a delicate balance of prothrombotic and antithrombotic mechanisms, to prevent both excessive blood loss from injured vessels and pathologic thrombosis. The liver plays a pivotal role in hemostasis through the synthesis of plasma coagulation factors and their inhibitors that, in addition to thrombosis and hemostasis, orchestrates an array of inflammatory responses. As a result, impaired liver function has been linked with both hypercoagulability and bleeding disorders due to a pathologic balance of pro- and anticoagulant plasma factors. At sites of vascular injury, thrombus propagation that finally may occlude the blood vessel depends on negatively charged biopolymers, such as polyphosphates and extracellular DNA, that provide a physiological surface for contact activation of coagulation factor XII (FXII). FXII initiates the contact system that drives both the intrinsic pathway of coagulation, and formation of the inflammatory mediator bradykinin by the kallikrein-kinin system. Moreover, FXII facilitates receptor-mediated signalling, thereby promoting mitogenic activities, angiogenesis, and neutrophil stimulation with implications for liver diseases. Here, we summarize current knowledge on the FXII-driven contact system in liver diseases and review therapeutic approaches to target its activities during impaired liver function.
Topics: Blood Coagulation; Factor XII; Humans; Kallikrein-Kinin System; Liver; Thrombosis
PubMed: 34125270
DOI: 10.1007/s00281-021-00876-7 -
Drugs of Today (Barcelona, Spain : 1998) Jul 2019Lanadelumab is a human monoclonal antibody against plasma kallikrein indicated for prevention of attacks of hereditary angioedema (HAE). HAE is caused by SERPING1 gene... (Review)
Review
Lanadelumab is a human monoclonal antibody against plasma kallikrein indicated for prevention of attacks of hereditary angioedema (HAE). HAE is caused by SERPING1 gene mutations resulting in decreased or dysfunctional plasma protease C1 inhibitor (C1-INH) leading to a loss of inhibition of plasma kallikrein activity with subsequent cleavage of high-molecular weight kininogen and release of bradykinin. There is a clear need for a non-plasma-derived, safe, effective and convenient prophylaxis of HAE attacks to reduce patients' daily burden of disease and disability. The percentage of patients who were attack-free for the last 16 weeks of a controlled study was 77% in the group receiving 300 mg lanadelumab every 2 weeks, compared with 3% with placebo. The most common side effects were mild injection-site reactions. Lanadelumab has the potential to change the approach from on-demand treatment to prophylaxis in HAE. Future studies will have to confirm long-term safety and efficacy of prophylactic long-term inhibition of plasma kallikrein.
Topics: Angioedemas, Hereditary; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Controlled Clinical Trials as Topic; Humans; Mutation
PubMed: 31347612
DOI: 10.1358/dot.2019.55.7.2985293 -
Seminars in Thrombosis and Hemostasis Jun 2023Factor XII (FXII), the zymogen of the protease FXIIa, contributes to pathologic processes such as bradykinin-dependent angioedema and thrombosis through its capacity to...
Factor XII (FXII), the zymogen of the protease FXIIa, contributes to pathologic processes such as bradykinin-dependent angioedema and thrombosis through its capacity to convert the homologs prekallikrein and factor XI to the proteases plasma kallikrein and factor XIa. FXII activation and FXIIa activity are enhanced when the protein binds to a surface. Here, we review recent work on the structure and enzymology of FXII with an emphasis on how they relate to pathology. FXII is a homolog of pro-hepatocyte growth factor activator (pro-HGFA). We prepared a panel of FXII molecules in which individual domains were replaced with corresponding pro-HGFA domains and tested them in FXII activation and activity assays. When in fluid phase (not surface bound), FXII and prekallikrein undergo reciprocal activation. The FXII heavy chain restricts reciprocal activation, setting limits on the rate of this process. Pro-HGFA replacements for the FXII fibronectin type 2 or kringle domains markedly accelerate reciprocal activation, indicating disruption of the normal regulatory function of the heavy chain. Surface binding also enhances FXII activation and activity. This effect is lost if the FXII first epidermal growth factor (EGF1) domain is replaced with pro-HGFA EGF1. These results suggest that FXII circulates in blood in a "closed" form that is resistant to activation. Intramolecular interactions involving the fibronectin type 2 and kringle domains maintain the closed form. FXII binding to a surface through the EGF1 domain disrupts these interactions, resulting in an open conformation that facilitates FXII activation. These observations have implications for understanding FXII contributions to diseases such as hereditary angioedema and surface-triggered thrombosis, and for developing treatments for thrombo-inflammatory disorders.
PubMed: 37276883
DOI: 10.1055/s-0043-1769509 -
Drugs Oct 2018Shire is developing lanadelumab (Takhzyro™) for the prevention of hereditary angioedema (HAE) attacks. Lanadelumab is a fully human monoclonal antibody that inhibits... (Review)
Review
Shire is developing lanadelumab (Takhzyro™) for the prevention of hereditary angioedema (HAE) attacks. Lanadelumab is a fully human monoclonal antibody that inhibits plasma kallikrein. Mutations in the SERPING1 gene lead to C1 inhibitor deficiency or dysfunction, resulting in uncontrolled plasma kallikrein activity, which in turn produces excessive bradykinin, a vasodilator thought to cause angioedema symptoms. Subcutaneous administration of lanadelumab significantly reduced HAE attacks versus placebo in patients aged ≥ 12 years with type I or II HAE in a phase III trial. Based on these results, lanadelumab is recently approved in the USA for the prevention of HAE attacks in patients aged ≥ 12 years. It is also preregistered in the EU, Canada, Australia and Switzerland. This article summarizes the milestones in the development of lanadelumab leading to this first approval.
Topics: Angioedemas, Hereditary; Antibodies, Monoclonal, Humanized; Child; Clinical Trials, Phase II as Topic; Complement C1 Inhibitor Protein; Drug Approval; Humans; Kallikreins; Mutation
PubMed: 30267321
DOI: 10.1007/s40265-018-0987-2 -
Allergy and Asthma Proceedings Nov 2020Hereditary Angioedema (HAE) is a potentially life-threatening condition. With episodic, unpredictable swelling, HAE negatively affect the quality of life for those... (Review)
Review
Hereditary Angioedema (HAE) is a potentially life-threatening condition. With episodic, unpredictable swelling, HAE negatively affect the quality of life for those affected individuals. To reduce the morbidity and mortality of HAE are the primary goal for the disease management. In addition to have access to therapeutic drugs for their acute HAE attacks, many patients require long term prophylaxis (LTP) to reduce their attack frequency and severity. Preventing HAE attack by regular administration of medicine has become an important part of HAE disease management. Over the past few years, growing number of therapeutic options for the HAE LTP have made it possible for physicians to choose the most appropriate and effective treatment for individual patients. C1 INH concentrate and plasma kallikrein inhibitors (IV or SC) have largely replaced the oder modality of treatment consisting different androgen derivatives or antifibrinolytics. Additional options, such as oral kallikrein inhibitor, antisense RNA/plasma kallikrein, anti-Factor 12a, bradykinin receptor blocker or future gene therapy are under clinical investigation. The significant cost and the uncertainty of its long term safety may be the primary limiting factors for its clinical application. The limited data for young children and pregnant women pose additional challenge for physicians to assess the risk and benefit when considering LTP treatment.
Topics: Angioedemas, Hereditary; Complement C1 Inhibitor Protein; Humans; Patient Preference; Precision Medicine; Psychiatric Rehabilitation; Quality of Life
PubMed: 33109324
DOI: 10.2500/aap.2020.41.200092 -
Frontiers in Allergy 2022Hereditary angioedema (HAE) is a rare disease caused by mutations in the gene. This results in deficient or dysfunctional C1 esterase inhibitor (C1-INH) and affects... (Review)
Review
Hereditary angioedema (HAE) is a rare disease caused by mutations in the gene. This results in deficient or dysfunctional C1 esterase inhibitor (C1-INH) and affects multiple proteases involved in the complement, contact-system, coagulation, and fibrinolytic pathways. Current options for the treatment and prevention of HAE attacks include treating all affected pathways direct C1-INH replacement therapy; or specifically targeting components of the contact activation system, in particular by blocking the bradykinin B receptor (B2R) or inhibiting plasma kallikrein, to prevent bradykinin generation. Intravenously administered plasma-derived C1-INH (pdC1-INH) and recombinant human C1-INH have demonstrated efficacy and safety for treatment of HAE attacks, although time to onset of symptom relief varied among trials, specific agents, and dosing regimens. Data from retrospective and observational analyses support that short-term prophylaxis with intravenous C1-INH products can help prevent HAE attacks in patients undergoing medical or dental procedures. Long-term prophylaxis with intravenous or subcutaneous pdC1-INH significantly decreased the HAE attack rate vs. placebo, although breakthrough attacks were observed. Pathway-specific therapies for the management of HAE include the B2R antagonist icatibant and plasma kallikrein inhibitors ecallantide, lanadelumab, and berotralstat. Icatibant, administered for treatment of angioedema attacks, reduced B2R-mediated vascular permeability and, compared with placebo, reduced the time to initial symptom improvement. Plasma kallikrein inhibitors, such as ecallantide, block the binding site of kallikrein to prevent cleavage of high molecular weight kininogen and subsequent bradykinin generation. Ecallantide was shown to be efficacious for HAE attacks and is licensed for this indication in the United States, but the labeling recommends that only health care providers administer treatment because of the risk of anaphylaxis. In addition to C1-INH replacement therapy, the plasma kallikrein inhibitors lanadelumab and berotralstat are recommended as first-line options for long-term prophylaxis and have demonstrated marked reductions in HAE attack rates. Investigational therapies, including the activated factor XII inhibitor garadacimab and an antisense oligonucleotide targeting plasma prekallikrein messenger RNA (donidalorsen), have shown promise as long-term prophylaxis. Given the requirement of lifelong management for HAE, further research is needed to determine how best to individualize optimal treatments for each patient.
PubMed: 36172291
DOI: 10.3389/falgy.2022.952233 -
Thrombosis and Haemostasis Jun 2020Cardiovascular disease, including stroke, myocardial infarction, and venous thromboembolism, is one of the leading causes of morbidity and mortality worldwide. Excessive... (Review)
Review
Cardiovascular disease, including stroke, myocardial infarction, and venous thromboembolism, is one of the leading causes of morbidity and mortality worldwide. Excessive coagulation may cause vascular occlusion in arteries and veins eventually leading to thrombotic diseases. Studies in recent years suggest that coagulation factors are involved in these pathological mechanisms. Factors XIa (FXIa), XIIa (FXIIa), and plasma kallikrein (PKa) of the contact system of coagulation appear to contribute to thrombosis while playing a limited role in hemostasis. Contact activation is initiated upon autoactivation of FXII on negatively charged surfaces. FXIIa activates plasma prekallikrein (PK) to PKa, which in turn activates FXII and initiates the kallikrein-kinin pathway. FXI is also activated by FXIIa, leading to activation of FIX and finally to thrombin formation, which in turn activates FXI in an amplification loop. Animal studies have shown that arterial and venous thrombosis can be reduced by the inhibition of FXI(a) or PKa. Furthermore, data from human studies suggest that these enzymes may be valuable targets to reduce thrombosis risk. In this review, we discuss the structure and function of FXI(a) and PK(a), their involvement in the development of venous and arterial thrombosis in animal models and human studies, and current therapeutic strategies.
Topics: Animals; Arterial Occlusive Diseases; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Disease Models, Animal; Enzyme Activation; Factor XI Deficiency; Factor XIa; Factor Xa Inhibitors; Humans; Mice; Mice, Knockout; Plasma Kallikrein; Prekallikrein; Protein Processing, Post-Translational; Species Specificity; Thrombophilia; Thrombosis; Venous Thrombosis
PubMed: 32375196
DOI: 10.1055/s-0040-1710013 -
Drugs Feb 2021Berotralstat (ORLADEYO™) is an orally administered kallikrein inhibitor, which has been developed by BioCryst Pharmaceuticals for hereditary angioedema (HAE). The... (Review)
Review
Berotralstat (ORLADEYO™) is an orally administered kallikrein inhibitor, which has been developed by BioCryst Pharmaceuticals for hereditary angioedema (HAE). The inhibition of kallikrein by berotralstat decreases the production of bradykinin, which prevents the localised tissue oedema that occurs during attacks of HAE. Berotralstat has been approved in the USA, and subsequently in Japan, for prophylaxis to prevent attacks of HAE in adults and paediatric patients aged 12 years or older. This article summarises the milestones in the development of berotralstat leading to this first approval for prophylaxis to prevent attacks of HAE.
Topics: Administration, Oral; Angioedemas, Hereditary; Bradykinin; Enzyme Inhibitors; Humans; Molecular Structure; Plasma Kallikrein; Pyrazoles
PubMed: 33646555
DOI: 10.1007/s40265-021-01475-4 -
ACS Medicinal Chemistry Letters Nov 2023Provided herein are novel plasma kallikrein inhibitors, pharmaceutical compositions, use of such compounds in treating hereditary angioedema, diabetic macular edema, and...
Provided herein are novel plasma kallikrein inhibitors, pharmaceutical compositions, use of such compounds in treating hereditary angioedema, diabetic macular edema, and diabetic retinopathy, and processes for preparing such compounds.
PubMed: 37974944
DOI: 10.1021/acsmedchemlett.3c00441