Platelets and shear stress

Kroll, MH; Hellums, J. D.; McIntire, L.V.; Schafer, AI; Moake, JL

doi:10.1182/blood.v88.5.1525.bloodjournal8851525

Cited by 84 publications

(90 citation statements)

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“…SP-8008 inhibited the earliest event of platelet adhesion, disturbing the interaction of vWF and platelet GP Ib by favourable binding to vWF under high shear stress. Signals transduced from vWF binding can lead to the secretion of platelet granule and GP IIb/IIIa activation, which is important in platelet activation process (Kroll et al, 1996). Activated GP IIb/IIIa binds to its plasma ligand, predominantly finbrinogen, thus facilitating the signalling that follows ligand binding (Watson et al, 2005), playing a crucial role in forming a stable platelet aggregate (Davi & Patrono, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…This whole process has been called "shear stress-induced platelet aggregation" (SIPA; Kroll et al, 1996;Wootton & Ku, 1999). Raised levels of SIPA are observed in the patients with acute atherothrombosis and are considered as a major pathological contributor to fatal thrombosis (Kawano et al, 2002;Tanigawa et al, 2000;Uchiyama et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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Antithrombotic effect of SP‐8008, a benzoic acid derivative, through the selective inhibition of shear stress‐induced platelet aggregation

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Kim

Bian

et al. 2020

British J Pharmacology

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Background and Purpose Bleeding is one of the most critical adverse effects of antithrombotic drugs, and many efforts have been made to discover novel antiplatelet agents without bleeding complications. Shear stress‐induced platelet aggregation (SIPA), where the interaction of von Willebrand factor (vWF) and platelet glycoprotein (GP) Ib constitutes the initial step, is a promising target to overcome bleeding problems, as SIPA occurs only in pathological conditions. Here, we describe SP‐8008, a novel modulator of vWF–GP Ib interactions and evaluated its antiplatelet/antithrombotic effects. Experimental Approach Newly synthesized compounds were screened for antiplatelet effects in vitro, using human platelets exposed to high shear stress. Aggregation, intracellular calcium level, granule secretion, and integrin activation were assessed. Molecular modelling using virtual docking and flow cytometry were used to evaluate effects on vWF–GP Ib interactions. Antithrombotic effects in vivo were determined in rats, using arterial thrombosis and shear stress‐specific thrombosis. Transection tail bleeding time was used to evaluate adverse effects. Key Results SP‐8008 was a potent inhibitor of SIPA, with IC50 of 1.44 ± 0.09 μM. SP‐8008 effectively and broadly blocked shear stress‐induced platelet activation events, without any significant toxicity. Importantly, SP‐8008 was highly selective against SIPA, effectively interfering with vWF–GP Ib engagement. Most importantly, SP‐8008 exerted significant antithrombotic effects in vivo in both shear stress‐specific and arterial thrombosis, without prolonging bleeding time. Conclusions and Implications Our results demonstrated that SP‐8008 can be a novel selective antiplatelet agent with improved safety profile.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antithrombotic effect of SP‐8008, a benzoic acid derivative, through the selective inhibition of shear stress‐induced platelet aggregation

Ngo

Kim

Bian

et al. 2020

British J Pharmacology

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“…Although circulating levels of VWF are high, platelets are not activated by the soluble protein. Under high shear conditions, soluble VWF has been shown to activate platelets, in vitro (Ikeda et al, 1991;Kroll et al, 1996); whereas exposure of platelets to immobilized VWF over 60 min under static conditions results in platelet adhesion and spreading in the absence of applied force (Savage et al, 1992). Stirring platelets with VWF immobilized on polystyrene beads results in rapid adhesion of platelets to the bead followed by degranulation leading to platelet aggregation around the VWF beads.…”

Section: Discussionmentioning

confidence: 99%

Platelet activation by a novel solid‐phase agonist: effects of VWF immobilized on polystyrene beads

et al. 1997

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Summary.The interaction between platelets stirred in suspension and VWF immobilized on polystyrene beads was studied. Platelets aggregated and released ATP in response to stirring with VWF beads. Closer examination of the interaction using transmission electron microscopy revealed that the platelets did not simply aggregate with one another but initially adhered to the beads and spread. Platelets in suspension then bound to the bead-adherent platelets forming layers of platelets associated with each bead. The VWF bead-induced platelet activation was completely inhibited by addition of monoclonal antibody (mAb) to GPIb or GPIIb/IIIa. In addition, the activation response was inhibited in the presence of aspirin, indomethacin or the thromboxane receptor antagonist BM13.177, demonstrating a dependence on an intact cyclo-oxygenase pathway.Platelet function studies were carried out on 30 patients with a history of mild bleeding using conventional optical aggregation and VWF bead-induced platelet activation. 12 patients were abnormal by conventional optical aggregometry, whereas 27 patients showed depressed ATP release in response to VWF beads. The results suggest that easily-bruised patients may have a platelet function defect rather than a vascular-based abnormality and that VWF bead-induced platelet activation is a more sensitive test for detecting platelet dysfunction.

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“…The trigger threshold of shear‐induced vWF unfolding has been reported between 5000 and 5522 s −1 (Table 1). 16,17 This is approximately two to three times greater than the reported normal physiologic intravascular shear rate (<2000 s −1 ), 18‐21 but lower than those generated by LVAD (ranging from 1429 to 171 428 s −1 ) 8,22‐27 . While recent research established the relationship between shear rate and pathologic vWF degradation, precisely why bleeding complications only occur in some aVWS patients but not all remain unknown.…”

Section: Introductionmentioning

confidence: 88%