Anticoagulant SERPINs: Endogenous Regulators of Hemostasis and Thrombosis

Grover, Steven P.; Mackman, Nigel

doi:10.3389/fcvm.2022.878199

Cited by 31 publications

(27 citation statements)

References 268 publications

(307 reference statements)

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“…The balance, i.e., homeostasis of the coagulation-fibrinolysis system, is based on a delicate balance between proteases. In addition, the negative control of coagulation and fibrinolysis is exercised through protease inhibitors, such as serin protease inhibitors (SERPINs) [ 113 ]. Anticoagulant SERPINs include antithrombin, heparin cofactor II, protein Z-dependent protease inhibitors (ZPI), protease nexin 1, and the C1-inhibitor.…”

Section: Homeostasis Of Hemostasismentioning

confidence: 99%

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

Pablo-Moreno

Serrano

Revuelta

et al. 2022

IJMS

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The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation factors or by a disturbed balance between the mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement and nonreplacement treatments or in the administration of antifibrinolytic agents. Rebalancing products reestablish hemostasis by inhibiting natural anticoagulant pathways. These agents include monoclonal antibodies, such as concizumab and marstacimab, which target the tissue factor pathway inhibitor; interfering RNA therapies, such as fitusiran, which targets antithrombin III; and protease inhibitors, such as serpinPC, which targets active protein C. In cases of thrombophilia (deficiency of protein C, protein S, or factor V Leiden), treatment may consist in direct oral anticoagulants, replacement therapy (plasma or recombinant ADAMTS13) in cases of a congenital deficiency of ADAMTS13, or immunomodulators (prednisone) if the thrombophilia is autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) is used in the context of severe thrombophilia, regardless of the cause of the disorder. In cases of disseminated intravascular coagulation, the treatment of choice consists in administration of antifibrinolytics, all-trans-retinoic acid, and recombinant soluble human thrombomodulin.

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Section: Homeostasis Of Hemostasismentioning

confidence: 99%

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

Pablo-Moreno

Serrano

Revuelta

et al. 2022

IJMS

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“…4 C1INH is a potent inhibitor of plasma kallikrein, which spans the kallikrein kinin pathway and intrinsic coagulation pathway, and the intrinsic coagulation pathway components activated FXII and activated factor XI. 4,5 Consistent with the function of C1INH as a critical negative regulator of the intrinsic coagulation pathway, patients with HAE in remission have significantly increased plasma levels of the coagulation biomarkers prothrombin fragment 1 + 2, thrombin-antithrombin (TAT) complexes, and Ddimer compared to healthy controls. [6][7][8] The plasma level of these coagulation biomarkers are further increased in HAE patients during acute attacks compared to HAE patients in remission.…”

Section: Hereditary Angioedema Is Associated With An Increased Risk O...mentioning

confidence: 87%

Hereditary angioedema is associated with an increased risk of venous thromboembolism

Grover

Björkman

Egesten

et al. 2022

Journal of Thrombosis and Haemostasis

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“…Modeling analysis of the AT protein revealed that the mutated AT protein lost its domain when interacting with FIXa. Heparin-binding AT action involves two distinct mechanisms: allosteric activation and bridging [64,65]. Among these, FIXa and FXa are the main target proteases that are rapidly inhibited by heparin through the allosteric activation of AT [66,67].…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of two SERPINC1 mutations causing congenital antithrombin deficiency

Wang

Ruan

et al. 2023

Thrombosis J

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Background Antithrombin (AT) is the main physiological anticoagulant involved in hemostasis. Hereditary AT deficiency is a rare autosomal dominant thrombotic disease mainly caused by mutations in SERPINC1, which was usually manifested as venous thrombosis and pulmonary embolism. In this study, we analyzed the clinical characteristics and screened for mutant genes in two pedigrees with hereditary AT deficiency, and the functional effects of the pathogenic mutations were evaluated. Methods Candidate gene variants were analyzed by next-generation sequencing to screen pathogenic mutations in probands, followed by segregation analysis in families by Sanger sequencing. Mutant and wild-type plasmids were constructed and transfected into HEK293T cells to observe protein expression and cellular localization of SERPINC1. The structure and function of the mutations were analyzed by bioinformatic analyses. Results The proband of pedigree A with AT deficiency carried a heterozygous frameshift mutation c.1377delC (p.Asn460Thrfs*20) in SERPINC1 (NM000488.3), a 1377C base deletion in exon 7 resulting in a backward shift of the open reading frame, with termination after translation of 20 residues, and a different residue sequence translated after the frameshift. Bioinformatics analysis suggests that the missing amino acid sequence caused by the frameshift mutation might disrupt the disulfide bond between Cys279 and Cys462 and affect the structural function of the protein. This newly discovered variant is not currently included in the ClinVar and HGMD databases. p.Arg229* resulted in a premature stop codon in exon 4, and bioinformatics analysis suggests that the truncated protein structure lost its domain of interaction with factor IX (Ala414 site) after the deletion of nonsense mutations. However, considering the AT truncation protein resulting from the p.Arg229* variant loss a great proportion of the molecule, we speculate the variant may affect two functional domains HBS and RCL and lack of the corresponding function. The thrombophilia and decreased-AT-activity phenotypes of the two pedigrees were separated from their genetic variants. After lentiviral plasmid transfection into HEK293T cells, the expression level of AT protein decreased in the constructed c.1377delC mutant cells compared to that in the wild-type, which was not only reduced in c.685C > T mutant cells but also showed a significant band at 35 kDa, suggesting a truncated protein. Immunofluorescence localization showed no significant differences in protein localization before and after the mutation. Conclusions The p.Asn460Thrfs*20 and p.Arg229* variants of SERPINC1 were responsible for the two hereditary AT deficiency pedigrees, which led to AT deficiency by different mechanisms. The p.Asn460Thrfs*20 variant is reported for the first time.

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Anticoagulant SERPINs: Endogenous Regulators of Hemostasis and Thrombosis

Cited by 31 publications

References 268 publications

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

Hereditary angioedema is associated with an increased risk of venous thromboembolism

Identification and characterization of two SERPINC1 mutations causing congenital antithrombin deficiency

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