Elevated plasma levels of soluble platelet glycoprotein VI (GPVI) in patients with thrombotic microangiopathy

Yamashita, Yoshiki; Naitoh, Katsuki; Wada, Hideo; Itō, Makoto; Mastumoto, Takeshi; Ohishi, Koshi; Hosaka, Yoshitaka; Nishikawa, Masakatsu; Katayama, Naoyuki

doi:10.1016/j.thromres.2013.11.023

Cited by 33 publications

(18 citation statements)

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“…Metalloproteolytic shedding is the predominant mechanism by which the GPIba and GPVI ligand-binding ectodomains are released [31]. Proteolysis of these receptors occurs via activation of platelet membrane-bound ADAM-17 and ADAM-10, and is a mechanism that can downregulate platelet adhesion and signaling, and limit thrombus formation in conditions of pathophysiologic shear [20], coagulopathy [32], and stroke [33,34], and in the setting of thrombocytopenia [35,36]. Loss of these receptors in patients with cardiac comorbidities is an additional novel finding of this study, and might imply an important regulatory role for physiologic shear stress in maintaining stable levels of GPIba and GPVI on circulating platelets.…”

Section: Discussionmentioning

confidence: 99%

Mechanical circulatory support is associated with loss of platelet receptors glycoprotein Ibα and glycoprotein VI

Lukito

Wong

Jia

et al. 2016

Journal of Thrombosis and Haemostasis

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Background Ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) are associated with bleeding that is not fully explained by anticoagulant or antiplatelet use. Exposure of platelets to elevated shear in vitro leads to increased shedding. Objectives To investigate whether loss of platelet receptors occurs in vivo, and the relationship with acquired von Willebrand syndrome (AVWS). Methods Platelet counts, coagulation tests and von Willebrand factor (VWF) analyses were performed on samples from 21 continuous flow VAD (CF-VAD), 20 ECMO, 12 heart failure and seven aortic stenosis patients. Levels of platelet receptors were measured by flow cytometry or ELISA. Results The loss of high molecular weight VWF multimers was observed in 18 of 19 CF-VAD and 14 of 20 ECMO patients, consistent with AVWS. Platelet receptor shedding was demonstrated by elevated soluble glycoprotein (GP) VI levels in plasma and significantly reduced surface GPIbα and GPVI levels in CF-VAD and ECMO patients as compared with healthy donors. Platelet receptor levels were also significantly reduced in heart failure patients. Conclusions These data link AVWS and increased platelet receptor shedding in patients with CF-VADs or ECMO for the first time. Loss of the platelet surface receptors GPIbα and GPVI in heart failure, CF-VAD and ECMO patients may contribute to ablated platelet adhesion/activation, and limit thrombus formation under high/pathologic shear conditions.

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Section: Discussionmentioning

confidence: 99%

Mechanical circulatory support is associated with loss of platelet receptors glycoprotein Ibα and glycoprotein VI

Lukito

Wong

Jia

et al. 2016

Journal of Thrombosis and Haemostasis

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“…The plasma level of sGPVI was quantified using a sandwich enzyme-linked immunosorbent assay, which consisted of 2 mouse anti-GPVI monoclonal antibodies, F1232-7-1 and F1232-10-2 able to recognize the extracellular domain 1 (D1) N-terminal loop and extracellular domain D2 loop of GPVI, respectively. 24,25 The VWF and VWFpp levels were measured with a VWF & Propeptide Assay kit (GTI Diagnostics, Waukesha, Wisconsin). 26 The ADAMTS13 was measured using FRETS-VWF73, which was chemically synthesized by the Peptide Institute, Inc (Osaka, Japan) according to the method of Kokame et al 27 The present study was approved by the ethical committee of Mie University Hospital in accordance with the ethical standards established in the Declaration of Helsinki (No.…”

Section: Methodsmentioning

confidence: 99%

Platelet Activation Assessed by Glycoprotein VI/Platelet Ratio Is Associated With Portal Vein Thrombosis After Hepatectomy and Splenectomy in Patients With Liver Cirrhosis

Matsui

Usui

Wada

et al. 2017

Clin Appl Thromb Hemost

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Portal vein thrombosis (PVT) is a serious complication after hepatobiliary-pancreatic surgery. Portal vein thrombosis often develops in patients with liver cirrhosis (LC) postoperatively, although they have low platelet counts. Platelet activation is one of the causes of thrombosis formation, and soluble form of glycoprotein VI (sGPVI) has received attention as a platelet activation marker. We had prospectively enrolled the 81 consecutive patients who underwent splenectomy (Sx) and/or hepatectomy: these patients were divided as Sx (n = 38) and hepatectomy (Hx, n = 46) groups. The 3 patients who underwent both procedures were added to both groups. Each group was subdivided into patients with non-LC and LC: non-LC-Sx (n = 22) and LC-Sx (n = 16), non-LC-Hx (n = 40) and LC-Hx (n = 6). The presence of PVT was diagnosed by using enhanced computed tomography (CT) scan. Platelet counts were significantly lower in LC-Sx than in non-LC-Sx, and incidence of PVT was significantly higher in LC-Sx than in non-LC-Sx (68.8% vs 31.8%, P = .024). Soluble form of glycoprotein VI /platelet ratios on preoperative day and postoperative day 1 were significantly higher in LC-Sx than in non-LC-Sx. Incidence of PVT was significantly higher in LC-Hx than in non-LC-Hx (50.0% vs 7.5%, P < .01). Soluble form of glycoprotein VI /platelet ratios were significantly higher in LC-Hx before and after Hx, compared to non-LC-Hx. Patients with LC stay in hypercoagulable state together with platelet activation before and after surgery. Under this circumstance, alteration of portal venous blood flow after Sx or Hx is likely to cause PVT in patients with LC.

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“…28,29 Elevated fluid shear stress and active factor X (FXa) also trigger GPVI shedding, quantified by detection of the soluble ectodomain fragment (sGPVI) in plasma by an enzyme-linked immunosorbent assay. 30,31 Plasma sGPVI reflects platelet activation in thrombotic conditions including microangiopathy, 32 stroke, 33 DIC, 33 and Alzheimer's disease 34 and rheumatoid arthritis. 28,35 However, elevated plasma sGPVI levels in these patient groups is surprising, as only a fraction of platelets would be exposed to collagen, FXa, or elevated shear, and neither FcgRIIA or CLEC-2 plays major roles in hemostasis/thrombosis.…”

Section: Introductionmentioning

confidence: 99%

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Montague

Delierneux

Lecut³

et al. 2018

Blood Advances

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• Soluble GPVI is elevated in patients with thermal injury with sepsis, and sGPVI levels augment severity score prediction of mortality.• The GPVI ligand, fibrin, induces GPVI shedding without requirement for platelet activation or signaling Soluble glycoprotein VI (sGPVI) is shed from the platelet surface and is a marker of platelet activation in thrombotic conditions. We assessed sGPVI levels together with patient and clinical parameters in acute and chronic inflammatory conditions, including patients with thermal injury and inflammatory bowel disease and patients admitted to the intensive care unit (ICU)for elective cardiac surgery, trauma, acute brain injury, or prolonged ventilation. Plasma sGPVI was measured by enzyme-linked immunosorbent assay and was elevated on day 14 after thermal injury, and was higher in patients who developed sepsis. sGPVI levels were associated with sepsis, and the value for predicting sepsis was increased in combination with platelet count and Abbreviated Burn Severity Index. sGPVI levels positively correlated with levels of D-dimer (a fibrin degradation product) in ICU patients and patients with thermal injury. sGPVI levels in ICU patients at admission were significantly associated with 28-and 90-day mortality independent of platelet count. sGPVI levels in patients with thermal injury were associated with 28-day mortality at days 1, 14, and 21 when adjusting for platelet count. In both cohorts, sGPVI associations with mortality were stronger than D-dimer levels. Mechanistically, release of GPVI was triggered by exposure of platelets to polymerized fibrin, but not by engagement of G protein-coupled receptors by thrombin, adenosine 59-diphosphate, or thromboxane mimetics. Enhanced fibrin production in these patients may therefore contribute to the observed elevated sGPVI levels. sGPVI is an important platelet-specific marker for platelet activation that predicts sepsis progression and mortality in injured patients.

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Elevated plasma levels of soluble platelet glycoprotein VI (GPVI) in patients with thrombotic microangiopathy

Cited by 33 publications

References 33 publications

Mechanical circulatory support is associated with loss of platelet receptors glycoprotein Ibα and glycoprotein VI

Mechanical circulatory support is associated with loss of platelet receptors glycoprotein Ibα and glycoprotein VI

Platelet Activation Assessed by Glycoprotein VI/Platelet Ratio Is Associated With Portal Vein Thrombosis After Hepatectomy and Splenectomy in Patients With Liver Cirrhosis

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

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