Intravenous thrombolysis for the management of acute ischemic stroke in patients therapeutically anticoagulated with heparin: A review

Neves, Gabriel; Lee, Jeannie; Bueso, Tulio; Montalván, Víctor; Iskandir, Marina; Shurmur, Scott; Kim, Jong-Yeol

doi:10.1016/j.clineuro.2020.106382

Cited by 4 publications

(3 citation statements)

References 34 publications

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“…Administration of heparin has also been shown to be somewhat beneficial in improving functional outcomes ( 24 , 25 ). However, more recent studies of heparin therapy in stroke, both in the presence of EVT and/or IVT, show no promising efficacy beyond rtPA alone, with evidence of increased bleeding at moderate heparin doses (MR CLEAN-MED) ( 26 , 27 ).…”

Section: Improving Stroke Therapy—ongoing Problems With Adjunctive Th...mentioning

confidence: 99%

Improving treatment for acute ischemic stroke—Clot busting innovation in the pipeline

Liu

Ding

Schoenwaelder

et al. 2022

Front. Med. Technol.

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Acute ischemic stroke is a consequence of disrupted blood flow to the brain, caused by thrombosis—the pathological formation of occlusive clots within blood vessels, which can embolize distally to downstream tissues and microvasculature. The highest priority of stroke treatment is the rapid removal of occlusive clots and restoration of tissue perfusion. Intravenous thrombolysis is the pharmacological standard-of-care for the dissolution of blood clots, wherein thrombolytic drugs are administered to restore vessel patency. While the introduction of recombinant tissue-plasminogen activator (rtPA) in 1996 demonstrated the benefit of acute thrombolysis for clot removal, this was countered by severe limitations in terms of patient eligibility, lytic efficacy, rethrombosis and safety implications. Development of safer and efficacious treatment strategies to improve clot lysis has not significantly progressed over many decades, due to the challenge of maintaining the necessary efficacy-safety balance for these therapies. As such, rtPA has remained the sole approved acute therapeutic for ischemic stroke for over 25 years. Attempts to improve thrombolysis with coadministration of adjunct antithrombotics has demonstrated benefit in coronary vessels, but remain contraindicated for stroke, given all currently approved antithrombotics adversely impact hemostasis, causing bleeding. This Perspective provides a brief history of stroke drug development, as well as an overview of several groups of emerging drugs which have the potential to improve thrombolytic strategies in the future. These include inhibitors of the platelet receptor glycoprotein VI and the signaling enzyme PI3-Kinase, novel anticoagulants derived from hematophagous creatures, and proteolysis-targeting chimeras.

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Section: Improving Stroke Therapy—ongoing Problems With Adjunctive Th...mentioning

confidence: 99%

Improving treatment for acute ischemic stroke—Clot busting innovation in the pipeline

Liu

Ding

Schoenwaelder

et al. 2022

Front. Med. Technol.

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“…1 In clinical practice, unfractionated heparin (UFH, ∼15 kDa) and lowmolecular-weight heparins (LMWHs, 3.5−6.5 kDa) are the primary heparin-type anticoagulants used to prevent and treat acute thrombosis because of their rapid onset of action and effectiveness. 2 UFH is used to treat acute thrombotic events or extracorporeal circulation (i.e., hemodialysis or cardiopulmonary bypass), 3,4 whereas LMWHs have a more predictable dose response and are delivered during prophylaxis of deep vein thrombosis and pulmonary embolism. 5,6 For safer usage, management of anticoagulation with reversal agents is always desirable to neutralize excessive anticoagulation, especially in the cases of overdose, life-threatening bleeding, or urgent highrisk surgery.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The heparin family, as the highest density negatively charged biomacromolecules in nature, is widely used as anticoagulants through accelerating the inhibition of antithrombin for serine proteases within the blood coagulation cascade . In clinical practice, unfractionated heparin (UFH, ∼15 kDa) and low-molecular-weight heparins (LMWHs, 3.5–6.5 kDa) are the primary heparin-type anticoagulants used to prevent and treat acute thrombosis because of their rapid onset of action and effectiveness . UFH is used to treat acute thrombotic events or extracorporeal circulation (i.e., hemodialysis or cardiopulmonary bypass), , whereas LMWHs have a more predictable dose response and are delivered during prophylaxis of deep vein thrombosis and pulmonary embolism. , For safer usage, management of anticoagulation with reversal agents is always desirable to neutralize excessive anticoagulation, especially in the cases of overdose, life-threatening bleeding, or urgent high-risk surgery. ,, Protamine, a small arginine-rich protein, is the only antidote that is clinically approved to neutralize UFH. − However, protamine only shows a maximal reversal efficiency of ca.…”

Section: Introductionmentioning

confidence: 99%

Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo

Zong,

Lei,

et al. 2024

J. Med. Chem.

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Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) are widely applied for surgical procedures and extracorporeal therapies, which, however, suffer bleeding risk. Protamine, the only clinically approved antidote, can completely neutralize UFH, but only partially neutralizes LMWHs, and also has a number of safety drawbacks. Here, we show that caltrop-like multicationic small molecules can completely neutralize both UFH and LMWHs. In vitro and ex vivo assays with plasma and whole blood and in vivo assays with mice and rats support that the lead compound is not only superior to protamine by displaying higher neutralization activity and broader therapeutic windows but also biocompatible. The effective neutralization dose and the maximum tolerated dose of the lead compound are determined to be 0.4 and 25 mg/kg in mice, respectively, suggesting good promise for further preclinical studies.

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Heparin purification by expanded bed anion exchange in a countercurrent chromatography column

Cai

Chen²,

Liu³

et al. 2022

Journal of Chromatography A

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Intravenous thrombolysis for the management of acute ischemic stroke in patients therapeutically anticoagulated with heparin: A review

Cited by 4 publications

References 34 publications

Improving treatment for acute ischemic stroke—Clot busting innovation in the pipeline

Improving treatment for acute ischemic stroke—Clot busting innovation in the pipeline

Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo

Heparin purification by expanded bed anion exchange in a countercurrent chromatography column

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