Platelet activation biomarkers in Berkeley sickle cell mice and the response to prasugrel

Ohno, Kousaku; Tanaka, Hisako; Samata, Naozumi; Jakubowski, Joseph A.; Tomizawa, Atsuyuki; Mizuno, Makoto; Sugidachi, Atsuhiro

doi:10.1016/j.thromres.2014.07.035

Cited by 9 publications

(12 citation statements)

References 23 publications

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“…However, there was no difference in the ADP-stimulated expression of activated GPIIb-IIIa in SS and SSCKO mice as compared to AA, suggesting that plasma ADP mediated activation might have rendered sickle platelets refractory to further ADP stimulation (Figure 1A – B). Both the mean fluorescent intensity and percentage of platelets positive for P-selectin were similar for AA, SS, and SSCKO mice (supplemental Figure 1A – B), consistent with studies in young Berkeley sickle mice showing no difference in the expression of P-selectin on circulating platelets compared to control mice [13]. …”

Section: Resultssupporting

confidence: 85%

“…Previous studies in the Berkeley sickle mice have demonstrated activated circulating platelets in vivo [13]. Analyses of platelet mean fluorescence intensity revealed that at baseline (unstimulated), the SS and SSCKO mice exhibit increased expression of activated GPIIb-IIIa compared to control AA mice (Figure 1B) ( n = 6 mice per group; P < 0.05).…”

Section: Resultsmentioning

confidence: 75%

“…Basal and PAR4-TRAP-stimulated expression of GPIIb-IIIa was quantified by flow cytometry as previously described with slight modifications [13]. The mean fluorescence intensity (MFI) of all platelets is included in the data reported [30].…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, increased platelet and thrombotic activity in SCD correlates with clinical complications such as pulmonary arterial hypertension (PAH), deep vein thrombosis, and stroke [9–11]. Patients with SCD and mouse models show platelet activation [7, 12, 13], yet mechanisms underlying platelet dysfunction in SCD remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Calpain-1 regulates platelet function in a humanized mouse model of sickle cell disease

Nwankwo

Gremmel

Gerrits

et al. 2017

Thrombosis Research

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One of the major contributors to sickle cell disease (SCD) pathobiology is the hemolysis of sickle red blood cells (RBCs), which release free hemoglobin and platelet agonists including adenosine 5’-diphosphate (ADP) into the plasma. While platelet activation/aggregation may promote tissue ischemia and pulmonary hypertension in SCD, modulation of sickle platelet dysfunction remains poorly understood. Calpain-1, a ubiquitous calcium-activated cysteine protease expressed in the hematopoietic cells, mediates aggregation of platelets in healthy mice. We generated calpain-1 knockout Townes sickle (SSCKO) mice to investigate the role of calpain-1 in the steady state and hypoxia/reoxygenation (H/R)-induced sickle platelet activation and aggregation, clot retraction, and pulmonary arterial hypertension. Using multi-electrode aggregometry, which measures platelet adhesion and aggregation in whole blood, we determined that steady state SSCKO mice exhibit significantly impaired PAR4-TRAP-stimulated platelet aggregation as compared to Townes sickle (SS) and humanized control (AA) mice. Interestingly, the H/R injury induced platelet hyperactivity in SS and SSCKO, but not AA mice, partially rescued the aggregation defect in SSCKO mice. The PAR4-TRAP-stimulated GPIIb-IIIa/αIIbβ3 integrin activation was normal in SSCKO platelets suggesting that an alternate mechanism mediates the impaired platelet aggregation in steady state SSCKO mice. Taken together, we provide the first evidence that calpain-1 regulates platelet hyperactivity in sickle mice, and may offer a viable pharmacological target to reduce platelet hyperactivity in SCD.

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Section: Resultssupporting

confidence: 85%

Section: Resultsmentioning

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Calpain-1 regulates platelet function in a humanized mouse model of sickle cell disease

Nwankwo

Gremmel

Gerrits

et al. 2017

Thrombosis Research

Self Cite

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“…In a small study, eptifibatide failed to reduce time to VOC resolution (NCT00834899), 90 and no further studies of this drug are currently ongoing. Prasugrel has shown promising results in sickle mice, 91 in which it partially attenuated both basal and agonist-stimulated platelet activation. A multicenter phase 2 study of prasugrel in adults with SCD showed that biomarkers of in vivo platelet activation were significantly reduced in individuals with SCD receiving prasugrel compared with placebo; however, only nonsignificant decreases in pain were observed.…”

Section: Antiplatelet Agentsmentioning

confidence: 99%

Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease

Telen

2016

Blood

119

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Despite Food and Drug Administration (FDA) approval of hydroxyurea to reduce the frequency of vaso-occlusive episodes, sickle cell disease (SCD) has continued to be treated primarily with analgesics for pain relief. However, elucidation of the multiple pathophysiologic mechanisms leading to vaso-occlusion and tissue injury in SCD has now resulted in a burgeoning effort to identify new treatment modalities to prevent or ameliorate the consequences of the disease. Development of new drugs as well as investigation of drugs previously used in other settings have targeted cell adhesion, inflammatory pathways, upregulation of hemoglobin F, hemoglobin polymerization and sickling, coagulation, and platelet activation. Although these efforts have not yet yielded drugs ready for FDA approval, several early studies have been extremely encouraging. Moreover, the marked increase in clinical pharmaceutical research addressing SCD and the new and old drugs in the pipeline make it reasonable to expect that we will soon have new treatments for SCD.

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CRISPR technology in human diseases

Feng,

Li,

Zhou

et al. 2024

MedComm

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Gene editing is a growing gene engineering technique that allows accurate editing of a broad spectrum of gene‐regulated diseases to achieve curative treatment and also has the potential to be used as an adjunct to the conventional treatment of diseases. Gene editing technology, mainly based on clustered regularly interspaced palindromic repeats (CRISPR)–CRISPR‐associated protein systems, which is capable of generating genetic modifications in somatic cells, provides a promising new strategy for gene therapy for a wide range of human diseases. Currently, gene editing technology shows great application prospects in a variety of human diseases, not only in therapeutic potential but also in the construction of animal models of human diseases. This paper describes the application of gene editing technology in hematological diseases, solid tumors, immune disorders, ophthalmological diseases, and metabolic diseases; focuses on the therapeutic strategies of gene editing technology in sickle cell disease; provides an overview of the role of gene editing technology in the construction of animal models of human diseases; and discusses the limitations of gene editing technology in the treatment of diseases, which is intended to provide an important reference for the applications of gene editing technology in the human disease.

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Platelet activation biomarkers in Berkeley sickle cell mice and the response to prasugrel

Cited by 9 publications

References 23 publications

Calpain-1 regulates platelet function in a humanized mouse model of sickle cell disease

Calpain-1 regulates platelet function in a humanized mouse model of sickle cell disease

Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease

CRISPR technology in human diseases

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