Fibrinogen and Antifibrinolytic Proteins: Interactions and Future Therapeutics
Abstract
:1. Introduction
2. Interactions of Fibrinogen with Antifibrinolytic Proteins
2.1. Alpha-2 Antiplasmin (α2AP)
2.1.1. Role of α2AP Genetic and Post-Translational Variants
2.1.2. Effects of Congenital and Acquired Deficiency of α2AP
2.1.3. Role of α2AP in Thrombotic Disorders
2.2. Thrombin Activatable Fibrinolysis Inhibitor (TAFI)
2.2.1. TAFI Activation and Role of TAFI in Fibrinolysis
2.2.2. Role of TAFI Genetic and Post-Translational Variants
2.2.3. Effects of TAFI Deficiency
2.2.4. Role of TAFI in Thrombotic Disorders
2.3. Complement C3
2.3.1. Interaction of C3 with Fibrin(ogen) and Role in Fibrinolysis
2.3.2. Role of C3 Genetic and Post-Translational Variants
2.3.3. Effects of C3 Deficiency
2.3.4. Role of C3 in Thrombotic Disorders
2.4. PAI-2
2.4.1. Cross-Linking to Fibrin and Inhibition of Plasmin Generation by PAI-2
2.4.2. Role of PAI-2 Genetic and Post-Translational Variants
2.4.3. Effects of PAI-2 Deficiency
2.4.4. Role of PAI-2 in Thrombotic Disorders
3. Targeting the Antifibrinolytic Proteins for Developing Therapeutics
3.1. Therapeutics for Thrombotic Disorders
3.1.1. Targeting α2AP
3.1.2. Targeting TAFI
3.1.3. Targeting Complement C3
3.1.4. Targeting PAI-2
3.2. Therapeutics for Bleeding Disorders
4. Conclusions and the Future
Author Contributions
Funding
Conflicts of Interest
References
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α2AP | TAFI | C3 | PAI-2 | |
---|---|---|---|---|
Mass (kDa) | ~70 | 56 | 187 | 47 |
Human gene | SERPINF2 | CPB2 | C3 | SERPINB2 |
Synthesis/expression | Liver, kidney, and brain | Liver and megakaryocytes | Liver and immune cells | Monocytes, macrophages, keratinocytes, fibroblasts, and placenta |
Circulating plasma concentration | 70 µg/mL | 4–15 µg/mL | 1.2 mg/mL | Below detection limit |
Antifibrinolytic function | Direct binding to, and inhibition of, plasmin and cross-linking into the clot making it more resistant to lysis | Protects the clot from lysis by cleaving off C-terminal lysine residues from fibrin, which reduces plasminogen and tPA binding and subsequent plasmin generation | Incorporation into the fibrin clot causes prolongation of fibrinolysis | Cross-linking into fibrin at a site close to tPA binding site affects fibrin clot lysis |
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Pechlivani, N.; Kearney, K.J.; Ajjan, R.A. Fibrinogen and Antifibrinolytic Proteins: Interactions and Future Therapeutics. Int. J. Mol. Sci. 2021, 22, 12537. https://doi.org/10.3390/ijms222212537
Pechlivani N, Kearney KJ, Ajjan RA. Fibrinogen and Antifibrinolytic Proteins: Interactions and Future Therapeutics. International Journal of Molecular Sciences. 2021; 22(22):12537. https://doi.org/10.3390/ijms222212537
Chicago/Turabian StylePechlivani, Nikoletta, Katherine J. Kearney, and Ramzi A. Ajjan. 2021. "Fibrinogen and Antifibrinolytic Proteins: Interactions and Future Therapeutics" International Journal of Molecular Sciences 22, no. 22: 12537. https://doi.org/10.3390/ijms222212537