Refrigeration-Induced Binding of von Willebrand Factor Facilitates Fast Clearance of Refrigerated Platelets

Chen, Wen–Chun; Druzak, Samuel; Wang, Yingchun; Josephson, Cassandra D.; Hoffmeister, Karin M.; Ware, Jerry; Li, Renhao

doi:10.1161/atvbaha.117.310062

Cited by 44 publications

(39 citation statements)

References 41 publications

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“…S5). This conclusion is also supported by previous studies that VWF binding to platelets was induced during cold storage and that refrigeration-induced binding of VWF to platelets facilitates their rapid clearance by inducing GPIbα-mediated signaling 20,33,34 . GPIb-IX complex is a sensor for shear stress-induced platelet activation 35 .…”

Section: Discussionsupporting

confidence: 85%

Calcium ion chelation preserves platelet function during cold storage

Xiang

Zhang

et al. 2020

Preprint

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Objective: Platelet transfusion is a life-saving therapy to prevent or treat bleeding in patients with thrombocytopenia or platelet dysfunction. However, for more than six decades, safe and effective strategies for platelet storage have been an impediment to widespread use of platelet transfusion. Refrigerated platelets are cleared rapidly from circulation, precluding cold storage of platelets for transfusion. Consequently, platelets are stored at room temperature (RT) with an upper limit of 5 days due to risks of bacterial contamination and loss of platelet function. This practice severely limits platelet availability for transfusion. This study is to identify the mechanism of platelet clearance after cold storage and develop a method for platelet cold storage. Approach and Results:We found that rapid clearance of cold-stored platelets was largely due to integrin activation and apoptosis. Deficiency of integrin β3 or caspase-3 prolonged cold-stored platelets in circulation. Pre-treatment of platelets with EGTA, a cell impermeable calcium ion chelator, reversely inhibited cold storage-induced platelet activation and consequently prolonged circulation of cold-stored platelets. Moreover, transfusion of EGTA-treated, cold-stored platelets, but not RT-stored platelets, into the mice deficient in glycoprotein Ibα significantly shortened tail-bleeding times and diminished blood loss. Conclusion:Integrin activation and apoptosis is the underlying mechanism of rapid clearance of platelets after cold storage. Addition of a cell impermeable calcium ion chelator to platelet products is potentially a simple and effective method to enable cold storage of platelets for transfusion.

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Section: Discussionsupporting

confidence: 85%

Calcium ion chelation preserves platelet function during cold storage

Xiang

Zhang

et al. 2020

Preprint

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“…The authors demonstrated that the inhibition of this binding and the consequent downstream cascade, using a specific peptide that recognizes GPIb-α, significantly increased recovery and life-span of cold-stored PLTs. 28 Another study showed that a specific caspase-3 inhibitor significantly improves PLT functionality and viability during seven days of storage. 29 This, together with our results, suggests that inhibition of apoptosis seems to be a promising approach to reduce cold-stored lesions.…”

Section: Discussionmentioning

confidence: 99%

Cold storage of platelets in additive solution: the impact of residual plasma in apheresis platelet concentrates

et al. 2018

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Platelet transfusion became an indispensable therapy in the modern medicine. Although the clinical advantage of platelet transfusion is well established, adverse reactions upon transfusion, especially transmission of bacterial infection, still represent a major challenge. While bacterial contamination is favored by the storage of platelets at room temperature, cold storage may represent a solution for this clinically relevant issue. In this study, we aimed to elucidate whether plasma has protective or detrimental effects on cold-stored platelets. We investigated the impact of different residual plasma contents in apheresis-derived platelet concentrates, stored at 4°;C or room temperature, on platelet function and survival. We found that platelets stored at 4°C have higher expression of apoptosis marker compared to room temperature-stored platelets leading to an accelerated clearance from the circulation in a humanized animal model. While cold-induced apoptosis was independent of the residual plasma concentration, cold storage was associated with better adhesive properties and higher response to activators. Of note, delta granule-related functions, such as ADP-mediated aggregation and CD63 release, were better preserved at 4°C especially in 100% plasma. An extended study to assess cold-stored platelet concentrates produced under standard care GMP conditions showed that platelet function, metabolism and integrity were better compared to those stored at room temperature. Taken together, our results show that residual plasma concentration does not have a cardinal impact on the cold storage lesions of apheresis-derived platelet concentrates and indicate that the current generation of additive solutions is suitable substitutes for plasma to store platelets at 4°C.

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“…43,97 Because murine GPIba does not have N-glycosylation sequence motifs, it could not be involved in direct binding with the AMR. 50 Instead, because refrigeration induces binding of plasma VWF to GPIba on the platelet, 43,100 treatment of OGE could conceivably preclude the VWF-GPIba interaction and subsequent clustering of GPIba in refrigerated platelets ( Figure 6C). Consistent with the aforementioned trigger model, shear treatment of refrigerated WT platelets, but not VWF 2/2 ones, results in MSD unfolding, platelet desialylation, and PS exposure.…”

Section: Platelet Storage By Refrigerationmentioning

confidence: 99%

“…Consistent with the aforementioned trigger model, shear treatment of refrigerated WT platelets, but not VWF 2/2 ones, results in MSD unfolding, platelet desialylation, and PS exposure. 100 Furthermore, refrigerated VWF 2/2 platelets, or refrigerated WT platelets incubated with a peptide that inhibits GPIba interaction with VWF, exhibit markedly higher posttransfusion recovery than WT. 100 Thus, it appears that VWF binding, GPIba clustering, platelet desialylation, and PS exposure are key steps to the fast clearance of refrigerated platelets.…”

Section: Platelet Storage By Refrigerationmentioning

confidence: 99%

Mechanisms of platelet clearance and translation to improve platelet storage

Quach

Chen

2018

Blood

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Hundreds of billions of platelets are cleared daily from circulation via efficient and highly regulated mechanisms. These mechanisms may be stimulated by exogenous reagents or environmental changes to accelerate platelet clearance, leading to thrombocytopenia. The interplay between antiapoptotic Bcl-x and proapoptotic molecules Bax and Bak sets an internal clock for the platelet lifespan, and BH3-only proteins, mitochondrial permeabilization, and phosphatidylserine (PS) exposure may also contribute to apoptosis-induced platelet clearance. Binding of plasma von Willebrand factor or antibodies to the ligand-binding domain of glycoprotein Ibα (GPIbα) on platelets can activate GPIb-IX in a shear-dependent manner by inducing unfolding of the mechanosensory domain therein, and trigger downstream signaling in the platelet including desialylation and PS exposure. Deglycosylated platelets are recognized by the Ashwell-Morell receptor and potentially other scavenger receptors, and are rapidly cleared by hepatocytes and/or macrophages. Inhibitors of platelet clearance pathways, including inhibitors of GPIbα shedding, neuraminidases, and platelet signaling, are efficacious at preserving the viability of platelets during storage and improving their recovery and survival in vivo. Overall, common mechanisms of platelet clearance have begun to emerge, suggesting potential strategies to extend the shelf-life of platelets stored at room temperature or to enable refrigerated storage.

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Refrigeration-Induced Binding of von Willebrand Factor Facilitates Fast Clearance of Refrigerated Platelets

Cited by 44 publications

References 41 publications

Calcium ion chelation preserves platelet function during cold storage

Calcium ion chelation preserves platelet function during cold storage

Cold storage of platelets in additive solution: the impact of residual plasma in apheresis platelet concentrates

Mechanisms of platelet clearance and translation to improve platelet storage

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