Deletion of platelet CLEC-2 decreases GPIbα-mediated integrin αIIbβ3 activation and decreases thrombosis in TTP

Shao, Bojing; Hoover, Christopher; Shi, Huiping; Lee, Robert H.; Chen, Junmei; Shan, Xindi; Song, Jianhua; McDaniel, Michael; Zhou, Mianwei; McGee, Samuel; Vanhoorelbeke, Karen; Bergmeier, Wolfgang; López, José A.; George, James N.; Xia, Lijun

doi:10.1182/blood.2021012896

Cited by 14 publications

(17 citation statements)

References 58 publications

(75 reference statements)

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“…In contrast, the adhesion of platelets on plaque under flow is abrogated when the GPVI-collagen interaction is blocked by an anti-GPVI antibody, suggesting platelet activation by plaque is almost entirely mediated by GPVI (47,48). More recently, it has been shown that deletion of CLEC-2 (using the PF4-Cre) decreases GPIb-mediated integrin IIb3 activation, which may also contribute to the loss of platelet activation perfused at arterial shear in the GPIb-Cre + mice (49).…”

Section: Discussionmentioning

confidence: 99%

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CLEC-2 Supports Platelet Aggregation in Mouse but not Human Blood at Arterial Shear

et al. 2022

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C-type lectin-like receptor 2 (CLEC-2) is highly expressed on platelets and a subpopulation of myeloid cells, and is critical in lymphatic development. CLEC-2 has been shown to support thrombus formation at sites of inflammation, but to have a minor/negligible role in hemostasis. This identifies CLEC-2 as a promising therapeutic target in thromboinflammatory disorders, without hemostatic detriment. We utilized a GPIb-Cre recombinase mouse for more restricted deletion of platelet-CLEC-2 than the previously used PF4-Cre mouse. CLEC1bfl/flGPIb-Cre+ mice are born at Mendelian ratio, with a mild reduction in platelet count, and present with reduced thrombus size post-FeCl3-induced thrombosis, compared to littermates. Antibody-mediated depletion of platelet count in C57BL/6 mice, to match CLEC1bfl/flGPIb-Cre+ mice, revealed that the reduced thrombus size post-FeCl3-injury was due to the loss of CLEC-2, and not mild thrombocytopenia. Similarly, CLEC1bfl/flGPIb-Cre+ mouse blood replenished with CLEC-2-deficient platelets ex vivo to match littermates had reduced aggregate formation when perfused over collagen at arterial flow rates. In contrast, platelet-rich thrombi formed following perfusion of human blood under flow conditions over collagen types I or III, atherosclerotic plaque or inflammatory endothelial cells were unaltered in the presence of CLEC-2-blocking antibody, AYP1, or recombinant CLEC-2-Fc. The reduction in platelet aggregation observed in CLEC1bfl/flGPIb-Cre+ mice during arterial thrombosis is mediated by the loss of CLEC-2 on mouse platelets. In contrast, CLEC-2 does not support thrombus generation on collagen, atherosclerotic plaque or inflamed endothelial cells in human at arterial shear.

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Section: Discussionmentioning

confidence: 99%

“…contribute to the loss of platelet activation perfused at arterial shear in the GPIb-Cre + mice (49).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

CLEC-2 Supports Platelet Aggregation in Mouse but not Human Blood at Arterial Shear

et al. 2022

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“…Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal disorder characterized by systemic microvascular thrombosis (1). Based on its etiology, TTP can be divided into hereditary TTP and acquired TTP, and the latter can be further divided into idiopathic TTP and secondary TTP according to whether the etiology is clear.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the efficacy and safety of caplacizumab versus placebo in thrombotic thrombocytopenic purpura: a meta-analysis and systematic review based on randomized controlled trials

Chen¹,

Li²,

Xiao³

et al. 2022

Ann Transl Med

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Background: We conducted this meta-analysis to investigate the efficacy and safety of caplacizumab in patients with thrombotic thrombocytopenic purpura (TTP). TTP is a potentially fatal disorder characterized by systemic microvascular thrombosis.Methods: Randomized controlled trials (RCTs) were conducted from PubMed, Embase, Cochrane Library and Web of Science, China National Knowledge Infrastructure (CNKI), VIP and Wanfang databases. RCTs of caplacizumab treatment for TPP were mainly included. Data from eligible studies were extracted and analyzed using relative effect sizes versus placebo use. The Cochrane bias assessment tool was used to assess the risk of bias of included studies, and the assessment results were presented graphically in Revman5.3.Results: Four RCTs with a total of 416 patients were included, all of which were of high quality.Caplacizumab was associated with improvements in platelet counts normalization time [weighted mean difference (WMD) −1.18, 95% confidence interval (CI): −2.55 to 0.19, I 2 =69.9%, P=0.036], plasma exchange (PE) time (WMD −2.97, 95% CI: −4.44 to −1.50, I 2 =8.2%, P=0.163) and hospital stay (WMD −2.88, 95% CI: −4.56 to −1.21, I 2 =48.7%, P=0.036). In addition, the occurrence of adverse events was also investigated.The difference in mortality between the two groups was not statistically significant [relative risk (RR) 0.56, 95% CI: 0.18 to 1.72, I 2 =22.7%, P=0.275], relapse (RR 0.68, 95% CI: 0.13 to 3.49, I 2 =78.3%, P=0.01), or major thrombotic events (RR 1.01, 95% CI: 0.65 to 1.57, I 2 =43.4%, P=0.151).Conclusions: Caplacizumab shortens the platelet normalization time, PE time, and hospital stay in patients with TTP, and did not significantly increase the risk of adverse events. These results indicate that caplacizumab treatment provides significant benefits to patients with TTP. Even though this is evidence from RCTs, few original studies were included, so more multicenter RCTs are required.

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“…Our recent observations in a mouse model of TTP documented that adhesion of platelet GPIbα to VWF caused activation of the platelet fibrinogen receptor, αIIbβ3, allowing fibrinogen binding and initiation of platelet aggregation (Figure 1). 5 Thrombus size was decreased by pre-treatment of mice with aspirin, which blocks the activation of αIIbβ3, or eptifibatide, which blocks binding of fibrinogen to αIIbβ3. 5 Based on these experimental observations, we considered that aspirin may diminish the risk for stroke and other thrombotic events in patients with hTTP and in iTTP during remission.…”

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confidence: 99%

“…5 Thrombus size was decreased by pre-treatment of mice with aspirin, which blocks the activation of αIIbβ3, or eptifibatide, which blocks binding of fibrinogen to αIIbβ3. 5 Based on these experimental observations, we considered that aspirin may diminish the risk for stroke and other thrombotic events in patients with hTTP and in iTTP during remission.…”

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confidence: 99%

Aspirin prophylaxis for hereditary and acquired thrombotic thrombocytopenic purpura?

et al. 2022

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Deletion of platelet CLEC-2 decreases GPIbα-mediated integrin αIIbβ3 activation and decreases thrombosis in TTP

Cited by 14 publications

References 58 publications

CLEC-2 Supports Platelet Aggregation in Mouse but not Human Blood at Arterial Shear

CLEC-2 Supports Platelet Aggregation in Mouse but not Human Blood at Arterial Shear

Comparison of the efficacy and safety of caplacizumab versus placebo in thrombotic thrombocytopenic purpura: a meta-analysis and systematic review based on randomized controlled trials

Aspirin prophylaxis for hereditary and acquired thrombotic thrombocytopenic purpura?

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