Targeted SERPIN (TaSER): A dual‐action antithrombotic agent that targets platelets for SERPIN delivery

Sanrattana, Wariya; Smits, Simone M.; Barendrecht, Arjan D.; Kleef, Nadine D van; Otmani, Hinde El; Zivkovic, Minka; Roest, Mark; Renné, Thomas; Clark, Chantal C.; Maat, Steven de; Maas, Coen

doi:10.1111/jth.15554

Cited by 8 publications

(5 citation statements)

References 37 publications

(74 reference statements)

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“…Perfusion experiments were performed using citrated whole blood as described by Sanrattana et al [ 47 ]. In brief, glass coverslips (24 × 50 mm) were coated with 100 µg/mL Horm collagen in HEPES buffer (pH 7.4, 1.5h, RT) and blocked with 1% human serum albumin in HEPES buffer for 30 min.…”

Section: Methodsmentioning

confidence: 99%

Small-Molecule Cyclophilin Inhibitors Potently Reduce Platelet Procoagulant Activity

Bael

Vandenbulcke

Ahmed–Belkacem

et al. 2023

IJMS

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Procoagulant platelets are associated with an increased risk for thrombosis. Procoagulant platelet formation is mediated via Cyclophilin D (CypD) mediated opening of the mitochondrial permeability transition pore. Inhibiting CypD activity could therefore be an interesting approach to limiting thrombosis. In this study, we investigated the potential of two novel, non-immunosuppressive, non-peptidic small-molecule cyclophilin inhibitors (SMCypIs) to limit thrombosis in vitro, in comparison with the cyclophilin inhibitor and immunosuppressant Cyclosporin A (CsA). Both cyclophilin inhibitors significantly decreased procoagulant platelet formation upon dual-agonist stimulation, shown by a decreased phosphatidylserine (PS) exposure, as well as a reduction in the loss of mitochondrial membrane potential. Furthermore, the SMCypIs potently reduced procoagulant platelet-dependent clotting time, as well as fibrin formation under flow, comparable to CsA. No effect was observed on agonist-induced platelet activation measured by P-selectin expression, as well as CypA-mediated integrin αIIbβ3 activation. Importantly, whereas CsA increased Adenosine 5′-diphosphate (ADP)-induced platelet aggregation, this was unaffected in the presence of the SMCypIs. We here demonstrate specific cyclophilin inhibition does not affect normal platelet function, while a clear reduction in procoagulant platelets is observed. Reducing platelet procoagulant activity by inhibiting cyclophilins with SMCypIs forms a promising strategy to limit thrombosis.

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Section: Methodsmentioning

confidence: 99%

Small-Molecule Cyclophilin Inhibitors Potently Reduce Platelet Procoagulant Activity

Bael

Vandenbulcke

Ahmed–Belkacem

et al. 2023

IJMS

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“…Serine protease inhibitor (SERPIN)-based fusion proteins have also been proposed as antiplatelet therapy ( 66 ). A fusion protein called TaSER (targeted SERPIN), consisting of a variable heavy domain of heavy chain (VHH) with function-blocking activity against GPIb α and a thrombin-specific SERPIN, has been shown to block VWF binding and limit thrombus formation ( 67 ). Various monoclonal antibodies directed against VWF are also being pursued as antiplatelet therapy.…”

Section: The Present and Future Of Antiplatelet Therapeuticsmentioning

confidence: 99%

Novel strategies in antithrombotic therapy: targeting thrombosis while preserving hemostasis

Sim,

Shiferawe,

Wood

2023

Front. Cardiovasc. Med.

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Antithrombotic therapy is a delicate balance between the benefits of preventing a thrombotic event and the risks of inducing a major bleed. Traditional approaches have included antiplatelet and anticoagulant medications, require careful dosing and monitoring, and all carry some risk of bleeding. In recent years, several new targets have been identified, both in the platelet and coagulation systems, which may mitigate this bleeding risk. In this review, we briefly describe the current state of antithrombotic therapy, and then present a detailed discussion of the new generation of drugs that are being developed to target more safely existing or newly identified pathways, alongside the strategies to reverse direct oral anticoagulants, showcasing the breadth of approaches. Combined, these exciting advances in antithrombotic therapy bring us closer than we have ever been to the “holy grail” of the field, a treatment that separates the hemostatic and thrombotic systems, preventing clots without any concurrent bleeding risk.

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“…Frontiers in Biomaterials Science frontiersin.org platelet interactions with thrombin and inhibit thrombus formation. Additional loading of an antithrombotic, an α1-antitrypsin variant, enhanced clot inhibition (Sanrattana et al, 2022). This particular set of studies is notable due to its multi-targeted strategy in both blocking platelet binding with scFv as well as inhibiting thrombin with the α1antitrypsin variant.…”

Section: Materials Compositionmentioning

confidence: 99%

Biomaterials for treating sepsis-induced thromboinflammation

Lutz,

Brown

2023

Front. Biomater. Sci.

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Sepsis is a common and life-threatening disorder with an alarmingly high mortality rate. Unfortunately, this rate has not decreased significantly over the last decade and the number of septic cases is increasing each year. Despite sepsis affecting millions of people annually, there is still not an established standard of care. The development of a therapy that targets the thromboinflammation characteristic of sepsis is imperative. Until recently, research has focused on uncovering individual pathways to target. As more of the pathophysiology of sepsis has become understood and more biomarkers uncovered, the interplay between endothelial cells, platelets, and leukocytes has emerged as a critical event. Therefore, a multi-targeted approach is clearly required for designing an effective treatment for sepsis. The versatility of biomaterials offers a promising solution in that they can be designed to target and affect multiple pathways and systems and safely inhibit excessive inflammation while maintaining hemostasis. Already, studies have demonstrated the ability of biomaterials to target different processes and stages in sepsis-induced inflammation and coagulopathy. Moreover, some biomaterials offer inherent anti-inflammatory and hemostatic qualities. This review aims to discuss the most recent advancements in biomaterial development designed to address inflammation, coagulopathy, and thromboinflammation.

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Targeted SERPIN (TaSER): A dual‐action antithrombotic agent that targets platelets for SERPIN delivery

Cited by 8 publications

References 37 publications

Small-Molecule Cyclophilin Inhibitors Potently Reduce Platelet Procoagulant Activity

Small-Molecule Cyclophilin Inhibitors Potently Reduce Platelet Procoagulant Activity

Novel strategies in antithrombotic therapy: targeting thrombosis while preserving hemostasis

Biomaterials for treating sepsis-induced thromboinflammation

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