Reversing the deleterious effects of α2-antiplasmin on tissue plasminogen activator therapy improves outcomes in experimental ischemic stroke
Aiilyan K Houng, Dong Wang, Guy L Reed, Aiilyan K Houng, Dong Wang, Guy L Reed
Abstract
High blood levels of α2-antiplasmin have been associated with failed tissue plasminogen activator (TPA) therapy for ischemic stroke. Yet, other data suggests that α2-antiplasmin may be protective in stroke, because it defends against bleeding and excitotoxicity. To address this paradox, we examined the effects of high α2-antiplasmin levels and α2-antiplasmin inactivation in mice treated with TPA 0.5-2.5h after middle cerebral artery (MCA) thromboembolism. Brain infarction, swelling, hemorrhage, blood brain barrier breakdown and neuronal apoptosis were measured by a blinded observer. Thrombus dissolution was determined by gamma counting. During TPA treatment, high α2-antiplasmin blood levels increased brain infarction (2.2-fold) and swelling (3.7-fold), but decreased MCA thrombus dissolution. Conversely, α2-antiplasmin inactivation during TPA treatment reduced brain infarction, hemorrhage and swelling, but increased MCA thrombus dissolution. Inactivation of α2-antiplasmin during TPA treatment reduced neuronal apoptosis and blood brain barrier breakdown. Inactivation of α2-antiplasmin also reduced short-term mortality. Taken together these data show that α2-antiplasmin opposes the effects of TPA therapy and contributes to enhanced brain injury after experimental thromboembolic stroke. Conversely, α2-antiplasmin inactivation during TPA treatment improves thrombus dissolution and reduces brain infarction, swelling and hemorrhage. Consistent with clinical observations, these data suggest that α2-antiplasmin exerts deleterious effects that reduce the efficacy and safety of TPA therapy for ischemic stroke.
Keywords: Apoptosis; Edema; Fibrinolysis; Hemorrhage; Mortality; Stroke; Thrombosis.
Copyright © 2014 Elsevier Inc. All rights reserved.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4066326/bin/nihms-568366-f0001.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4066326/bin/nihms-568366-f0002.jpg)
Figure 3
Low dose TPA with a2AP…
Figure 3
Low dose TPA with a2AP inactivation improves stroke outcomes vs. low dose TPA…
Figure 4
Treatment with low dose TPA…
Figure 4
Treatment with low dose TPA with a2AP inactivation reduces mortality, brain infarction, hemorrhage…
Figure 5
TPA treatment with a2AP inactivation…
Figure 5
TPA treatment with a2AP inactivation decreases breakdown of the blood brain barrier and…
- Releasing the Brakes on the Fibrinolytic System in Pulmonary Emboli: Unique Effects of Plasminogen Activation and α2-Antiplasmin Inactivation.Singh S, Houng A, Reed GL. Singh S, et al. Circulation. 2017 Mar 14;135(11):1011-1020. doi: 10.1161/CIRCULATIONAHA.116.024421. Epub 2016 Dec 27. Circulation. 2017. PMID: 28028005 Free PMC article.
- Matrix Metalloproteinase-9 Mediates the Deleterious Effects of α2-Antiplasmin on Blood-Brain Barrier Breakdown and Ischemic Brain Injury in Experimental Stroke.Singh S, Houng AK, Reed GL. Singh S, et al. Neuroscience. 2018 Apr 15;376:40-47. doi: 10.1016/j.neuroscience.2017.12.021. Epub 2017 Dec 30. Neuroscience. 2018. PMID: 29294343 Free PMC article.
- Microvascular thrombosis, fibrinolysis, ischemic injury, and death after cerebral thromboembolism are affected by levels of circulating α2-antiplasmin.Reed GL, Houng AK, Wang D. Reed GL, et al. Arterioscler Thromb Vasc Biol. 2014 Dec;34(12):2586-93. doi: 10.1161/ATVBAHA.114.304530. Epub 2014 Sep 25. Arterioscler Thromb Vasc Biol. 2014. PMID: 25256235 Free PMC article.
- α2-Antiplasmin: New Insights and Opportunities for Ischemic Stroke.Reed GL, Houng AK, Singh S, Wang D. Reed GL, et al. Semin Thromb Hemost. 2017 Mar;43(2):191-199. doi: 10.1055/s-0036-1585077. Epub 2016 Jul 29. Semin Thromb Hemost. 2017. PMID: 27472428 Free PMC article. Review.
- Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic.Yepes M, Roussel BD, Ali C, Vivien D. Yepes M, et al. Trends Neurosci. 2009 Jan;32(1):48-55. doi: 10.1016/j.tins.2008.09.006. Epub 2008 Oct 27. Trends Neurosci. 2009. PMID: 18963068 Review.
- "Super" SERPINs-A stabilizing force against fibrinolysis in thromboinflammatory conditions.Humphreys SJ, Whyte CS, Mutch NJ. Humphreys SJ, et al. Front Cardiovasc Med. 2023 Apr 19;10:1146833. doi: 10.3389/fcvm.2023.1146833. eCollection 2023. Front Cardiovasc Med. 2023. PMID: 37153474 Free PMC article. Review.
- Plasmin Inhibitor in Health and Diabetes: Role of the Protein as a Therapeutic Target.Alsayejh B, Kietsiriroje N, Almutairi M, Simmons K, Pechlivani N, Ponnambalam S, Ajjan RA. Alsayejh B, et al. TH Open. 2022 Nov 18;6(4):e396-e407. doi: 10.1055/a-1957-6817. eCollection 2022 Oct. TH Open. 2022. PMID: 36452200 Free PMC article. Review.
- Nanogels as Novel Nanocarrier Systems for Efficient Delivery of CNS Therapeutics.Zhang Y, Zou Z, Liu S, Miao S, Liu H. Zhang Y, et al. Front Bioeng Biotechnol. 2022 Jul 19;10:954470. doi: 10.3389/fbioe.2022.954470. eCollection 2022. Front Bioeng Biotechnol. 2022. PMID: 35928954 Free PMC article. Review.
- Uncovering the Neuroprotective Effect of Hedysarum multijugum Maxim-Chuanxiong Rhizoma Compound on Cerebral Infarction through Quantitative Proteomics.Wang G, Zeng X, Yang K, Gong S, Ge A, Liu W, He Q, Zhang W, Ge J. Wang G, et al. Evid Based Complement Alternat Med. 2022 Mar 26;2022:5241902. doi: 10.1155/2022/5241902. eCollection 2022. Evid Based Complement Alternat Med. 2022. PMID: 35378910 Free PMC article.
- Fibrinogen and Antifibrinolytic Proteins: Interactions and Future Therapeutics.Pechlivani N, Kearney KJ, Ajjan RA. Pechlivani N, et al. Int J Mol Sci. 2021 Nov 21;22(22):12537. doi: 10.3390/ijms222212537. Int J Mol Sci. 2021. PMID: 34830419 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- Apoptosis / drug effects
- Blood-Brain Barrier / drug effects
- Blood-Brain Barrier / metabolism
- Brain Edema / drug therapy
- Brain Edema / metabolism
- Brain Ischemia / blood
- Brain Ischemia / drug therapy*
- Disease Models, Animal
- Fibrinolytic Agents / pharmacology
- Fibrinolytic Agents / therapeutic use*
- Male
- Mice
- Mice, Inbred C57BL
- Neurons / drug effects
- Neurons / metabolism
- Stroke / blood
- Stroke / drug therapy*
- Tissue Plasminogen Activator / pharmacology
- Tissue Plasminogen Activator / therapeutic use*
- alpha-2-Antiplasmin / metabolism*
- Fibrinolytic Agents
- alpha-2-Antiplasmin
- Tissue Plasminogen Activator
- Full Text Sources
- Other Literature Sources
- Medical
NCBI Literature Resources
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![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4066326/bin/nihms-568366-f0003.jpg)
Figure 4
Treatment with low dose TPA…
Figure 4
Treatment with low dose TPA with a2AP inactivation reduces mortality, brain infarction, hemorrhage…
Figure 5
TPA treatment with a2AP inactivation…
Figure 5
TPA treatment with a2AP inactivation decreases breakdown of the blood brain barrier and…
- Releasing the Brakes on the Fibrinolytic System in Pulmonary Emboli: Unique Effects of Plasminogen Activation and α2-Antiplasmin Inactivation.Singh S, Houng A, Reed GL. Singh S, et al. Circulation. 2017 Mar 14;135(11):1011-1020. doi: 10.1161/CIRCULATIONAHA.116.024421. Epub 2016 Dec 27. Circulation. 2017. PMID: 28028005 Free PMC article.
- Matrix Metalloproteinase-9 Mediates the Deleterious Effects of α2-Antiplasmin on Blood-Brain Barrier Breakdown and Ischemic Brain Injury in Experimental Stroke.Singh S, Houng AK, Reed GL. Singh S, et al. Neuroscience. 2018 Apr 15;376:40-47. doi: 10.1016/j.neuroscience.2017.12.021. Epub 2017 Dec 30. Neuroscience. 2018. PMID: 29294343 Free PMC article.
- Microvascular thrombosis, fibrinolysis, ischemic injury, and death after cerebral thromboembolism are affected by levels of circulating α2-antiplasmin.Reed GL, Houng AK, Wang D. Reed GL, et al. Arterioscler Thromb Vasc Biol. 2014 Dec;34(12):2586-93. doi: 10.1161/ATVBAHA.114.304530. Epub 2014 Sep 25. Arterioscler Thromb Vasc Biol. 2014. PMID: 25256235 Free PMC article.
- α2-Antiplasmin: New Insights and Opportunities for Ischemic Stroke.Reed GL, Houng AK, Singh S, Wang D. Reed GL, et al. Semin Thromb Hemost. 2017 Mar;43(2):191-199. doi: 10.1055/s-0036-1585077. Epub 2016 Jul 29. Semin Thromb Hemost. 2017. PMID: 27472428 Free PMC article. Review.
- Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic.Yepes M, Roussel BD, Ali C, Vivien D. Yepes M, et al. Trends Neurosci. 2009 Jan;32(1):48-55. doi: 10.1016/j.tins.2008.09.006. Epub 2008 Oct 27. Trends Neurosci. 2009. PMID: 18963068 Review.
- "Super" SERPINs-A stabilizing force against fibrinolysis in thromboinflammatory conditions.Humphreys SJ, Whyte CS, Mutch NJ. Humphreys SJ, et al. Front Cardiovasc Med. 2023 Apr 19;10:1146833. doi: 10.3389/fcvm.2023.1146833. eCollection 2023. Front Cardiovasc Med. 2023. PMID: 37153474 Free PMC article. Review.
- Plasmin Inhibitor in Health and Diabetes: Role of the Protein as a Therapeutic Target.Alsayejh B, Kietsiriroje N, Almutairi M, Simmons K, Pechlivani N, Ponnambalam S, Ajjan RA. Alsayejh B, et al. TH Open. 2022 Nov 18;6(4):e396-e407. doi: 10.1055/a-1957-6817. eCollection 2022 Oct. TH Open. 2022. PMID: 36452200 Free PMC article. Review.
- Nanogels as Novel Nanocarrier Systems for Efficient Delivery of CNS Therapeutics.Zhang Y, Zou Z, Liu S, Miao S, Liu H. Zhang Y, et al. Front Bioeng Biotechnol. 2022 Jul 19;10:954470. doi: 10.3389/fbioe.2022.954470. eCollection 2022. Front Bioeng Biotechnol. 2022. PMID: 35928954 Free PMC article. Review.
- Uncovering the Neuroprotective Effect of Hedysarum multijugum Maxim-Chuanxiong Rhizoma Compound on Cerebral Infarction through Quantitative Proteomics.Wang G, Zeng X, Yang K, Gong S, Ge A, Liu W, He Q, Zhang W, Ge J. Wang G, et al. Evid Based Complement Alternat Med. 2022 Mar 26;2022:5241902. doi: 10.1155/2022/5241902. eCollection 2022. Evid Based Complement Alternat Med. 2022. PMID: 35378910 Free PMC article.
- Fibrinogen and Antifibrinolytic Proteins: Interactions and Future Therapeutics.Pechlivani N, Kearney KJ, Ajjan RA. Pechlivani N, et al. Int J Mol Sci. 2021 Nov 21;22(22):12537. doi: 10.3390/ijms222212537. Int J Mol Sci. 2021. PMID: 34830419 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- Apoptosis / drug effects
- Blood-Brain Barrier / drug effects
- Blood-Brain Barrier / metabolism
- Brain Edema / drug therapy
- Brain Edema / metabolism
- Brain Ischemia / blood
- Brain Ischemia / drug therapy*
- Disease Models, Animal
- Fibrinolytic Agents / pharmacology
- Fibrinolytic Agents / therapeutic use*
- Male
- Mice
- Mice, Inbred C57BL
- Neurons / drug effects
- Neurons / metabolism
- Stroke / blood
- Stroke / drug therapy*
- Tissue Plasminogen Activator / pharmacology
- Tissue Plasminogen Activator / therapeutic use*
- alpha-2-Antiplasmin / metabolism*
- Fibrinolytic Agents
- alpha-2-Antiplasmin
- Tissue Plasminogen Activator
- Full Text Sources
- Other Literature Sources
- Medical
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4066326/bin/nihms-568366-f0004.jpg)
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4066326/bin/nihms-568366-f0005.jpg)
Source: PubMed