Erratum: Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib (Blood Advances (2017) 1: 26 (2610-2623) DOI: 10.1182/bloodadvances.2017011999)

In "Acknowledgments" on page 2621 of the 12 December 2017 issue, funding from British Heart Foundation grant RG/15/2/31224 was not mentioned. The error has been corrected in the published article

Platelet-Derived Inhibitors of Platelet Activation

When blood vessels are damaged, circulating platelets come into contact with activating stimuli that trigger aggregation and enable them to form a haemostatic plug. This process is subject to both positive and negative feedback to ensure that platelets respond appropriately to damage and do not form thrombi that totally occlude the vessel. Dysregulation of negative feedback mechanisms is believed to contribute to the increased risk of thrombosis associated with some diseases. Despite the association with thrombosis, platelet derived negative regulators of platelet activation are relatively poorly understood in comparison to mediators of platelet activation. However, it is increasingly apparent that the mechanisms by which platelets restrain activation are diverse and of equal complexity to those that mediate positive signalling. Some regulators, such as RASA3 and JAM-A, act as gatekeepers that must be deactivated for platelet activation to occur. In contrast, regulators that contain ITIMs, such as PECAM-1, are activated following stimulation and mediate negative regulation via phosphatases that restrain activation. Wnt3a and ESAM are thought to directly limit plateletplatelet adhesion by blocking activation of the fibrinogen receptor, integrin αIIbβ3. The various isoforms of PKC expressed by platelets provide a diverse and complex array of inhibitory effects including receptor desensitisation. Many platelet derived inhibitors have been identified but not fully characterised and so questions remain regarding the mechanisms that underlie their effects on platelet activity following their activation, inhibition or genetic disruption. In this chapter the current understanding and recent developments in the field of platelet-derived inhibitors of platelet activation will be discussed

Wnt5a Regulates Midbrain Dopaminergic Axon Growth and Guidance

During development, precise temporal and spatial gradients are responsible for guiding axons to their appropriate targets. Within the developing ventral midbrain (VM) the cues that guide dopaminergic (DA) axons to their forebrain targets remain to be fully elucidated. Wnts are morphogens that have been identified as axon guidance molecules. Several Wnts are expressed in the VM where they regulate the birth of DA neurons. Here, we describe that a precise temporo-spatial expression of Wnt5a accompanies the development of nigrostriatal projections by VM DA neurons. In mice at E11.5, Wnt5a is expressed in the VM where it was found to promote DA neurite and axonal growth in VM primary cultures. By E14.5, when DA axons are approaching their striatal target, Wnt5a causes DA neurite retraction in primary cultures. Co-culture of VM explants with Wnt5a-overexpressing cell aggregates revealed that Wnt5a is capable of repelling DA neurites. Antagonism experiments revealed that the effects of Wnt5a are mediated by the Frizzled receptors and by the small GTPase, Rac1 (a component of the non-canonical Wnt planar cell polarity pathway). Moreover, the effects were specific as they could be blocked by Wnt5a antibody, sFRPs and RYK-Fc. The importance of Wnt5a in DA axon morphogenesis was further verified in Wnt5a−/− mice, where fasciculation of the medial forebrain bundle (MFB) as well as the density of DA neurites in the MFB and striatal terminals were disrupted. Thus, our results identify a novel role of Wnt5a in DA axon growth and guidance

Non-genomic effects of the Pregnane X Receptor negatively regulate platelet functions, thrombosis and haemostasis

The pregnane X receptor (PXR) is a nuclear receptor (NR), involved in the detoxification of xenobiotic compounds. Recently, its presence was reported in the human vasculature and its ligands were proposed to exhibit anti-atherosclerotic effects. Since platelets contribute towards the development of atherosclerosis and possess numerous NRs, we investigated the expression of PXR in platelets along with the ability of its ligands to modulate platelet activation. The expression of PXR in human platelets was confirmed using immunoprecipitation analysis. Treatment with PXR ligands was found to inhibit platelet functions stimulated by a range of agonists, with platelet aggregation, granule secretion, adhesion and spreading on fibrinogen all attenuated along with a reduction in thrombus formation (both in vitro and in vivo). The effects of PXR ligands were observed in a species-specific manner, and the human-specific ligand, SR12813, was observed to attenuate thrombus formation in vivo in humanised PXR transgenic mice. PXR ligand-mediated inhibition of platelet function was found to be associated with the inhibition of Src-family kinases (SFKs). This study identifies acute, non-genomic regulatory effects of PXR ligands on platelet function and thrombus formation. In combination with the emerging anti-atherosclerotic properties of PXR ligands, these anti-thrombotic effects may provide additional cardio-protective benefits