Hypoxia modulates platelet purinergic signalling pathways.

BACKGROUND:  Hypoxia resulting from ascent to high-altitude or pathological states at sea level is known to increase platelet reactivity. Previous work from our group has suggested that this may be adenosine diphosphate (ADP)-specific. Given the clinical importance of drugs targeting ADP pathways, research into the impact of hypoxia on platelet ADP pathways is highly important. METHODS:  Optimul aggregometry was performed on plasma from 29 lowland residents ascending to 4,700 m, allowing systematic assessment of platelet reactivity in response to several platelet agonists. Aggregometry was also performed in response to ADP in the presence of inhibitors of the two main ADP receptors, P2Y1 and P2Y12 (MRS2500 and cangrelor, respectively). Phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a key determinant of platelet aggregation, was analysed using the VASPFix assay. RESULTS:  Hypobaric hypoxia significantly reduced the ability of a fixed concentration of cangrelor to inhibit ADP-induced aggregation and increased basal VASP phosphorylation. However, in the absence of P2Y receptor inhibitors, we did not find evidence of increased platelet sensitivity to any of the agonists tested and found reduced sensitivity to thrombin receptor-activating peptide-6 amide. CONCLUSION:  Our results provide evidence of increased P2Y1 receptor activity at high altitude and suggest down-regulation of the P2Y12 pathway through increased VASP phosphorylation. These changes in ADP pathway activity are of potential therapeutic significance to high-altitude sojourners and hypoxic sea level patients prescribed platelet inhibitors and warrant further investigation

Thromboelastometry and Platelet Function during Acclimatization to High Altitude

Interaction between hypoxia and coagulation is important given the increased risk of thrombotic diseases in chronically hypoxic patients who reside at sea level and in residents at high altitude. Hypoxia alters the proteome of platelets favouring a prothrombotic phenotype, but studies of activation and consumption of specific coagulation factors in hypoxic humans have yielded conflicting results. We tested blood from 63 healthy lowland volunteers acclimatizing to high altitude (5,200 m) using thromboelastometry and assays of platelet function to examine the effects of hypoxia on haemostasis. Using data from two separate cohorts of patients following identical ascent profiles, we detected a significant delay in clot formation, but increased clot strength by day 7 at 5,200 m. The latter finding may be accounted for by the significant rise in platelet count and fibrinogen concentration that occurred during acclimatization. Platelet function assays revealed evidence of platelet hyper-reactivity, with shortened PFA-100 closure times and increased platelet aggregation in response to adenosine diphosphate. Post-expedition results were consistent with the normalization of coagulation following descent to sea level. These robust findings indicate that hypoxia increases platelet reactivity and, with the exception of the paradoxical delay in thromboelastometry clotting time, suggest a prothrombotic phenotype at altitude. Further work to elucidate the mechanism of platelet activation in hypoxia will be important and could impact upon the management of patients with acute or chronic hypoxic respiratory diseases who are at risk of thrombotic events. Erratum to: Thromboelastometry and platelet function during acclimatisation to high altitude (doi: 10.1160/TH17-02-0138) http://eprints.whiterose.ac.uk/129510/ In the Original Article by Rocke et al. “Thromboelastometry and platelet function during acclimatization to high altitude” (Thromb Haemost 2018; 118: 063-071) after publication of the article it has come to the corresponding author's attention that an author was inadvertently omitted from the manuscript. The author, Martin MacInnis, made a significant contribution to: 1. initiating the coagulation research that led to the manuscript, 2. designing the research protocol and performing the initial data analysis, 3. recruiting volunteers, writing applications for ethical approval and making other logistical arrangements that were necessary to complete the study. Martin MacInnis has read and approved the published version of the manuscript. Furthermore, a middle initial was added to the updated list (Shona E. Main) and misspelling of Elizabeth Horn's surname was corrected. The amended author list is as above. https://doi.org

Soluble P-selectin and von Willebrand factor rise in healthy volunteers following non-exertional ascent to high altitude

Reduced oxygen tensions experienced at high altitudes are thought to predispose to thrombosis, yet there are few studies linking hypoxia, platelet activation, and thrombosis. Reports of platelet phenotypes in hypoxia are inconsistent, perhaps due to differing degrees of hypoxia experienced and the duration of exposure. This study aimed to investigate the relationship between soluble P-selectin, a marker of platelet activation, and von Willebrand factor (vWF) on exposure to hypoxia. We measured plasma concentrations of P-selectin and vWF in sixteen healthy volunteers before, during and after the APEX 2 expedition. APEX 2 consisted of a non-exertional ascent to 5,200 m, followed by 7 consecutive days at high altitude. We showed that high altitude significantly increased mean plasma P-selectin and vWF compared to pre-expedition levels. Both plasma marker levels returned to baseline post-expedition. We found a strong positive correlation between vWF and P-selectin, but no association between P-selectin and platelet count. Our results are consistent with previous work showing evidence of platelet activation at high altitude and demonstrate that the rise in P-selectin is not simply due to an increase in platelet count. As vWF and P-selectin could be derived from either platelets or endothelial cells, further work assessing more specific markers of endothelial activation is proposed to provide insight into the source of these potential pro-thrombotic biomarkers at altitude

Erratum to: Thromboelastometry and platelet function during acclimatisation to high altitude

Correction to: Thromboelastometry and Platelet Function during Acclimatization to High Altitude Thromb Haemost 2018; 118(01): 063-071 DOI: 10.1160/TH17-02-0138 In the Original Article by Rocke et al. “Thromboelastometry and platelet function during acclimatization to high altitude” (Thromb Haemost 2018; 118: 063-071) after publication of the article it has come to the corresponding author's attention that an author was inadvertently omitted from the manuscript. The author, Martin MacInnis, made a significant contribution to: 1. initiating the coagulation research that led to the manuscript, 2. designing the research protocol and performing the initial data analysis, 3. recruiting volunteers, writing applications for ethical approval and making other logistical arrangements that were necessary to complete the study. Martin MacInnis has read and approved the published version of the manuscript. Furthermore, a middle initial was added to the updated list (Shona E. Main) and misspelling of Elizabeth Horn's surname was corrected. The amended author list is as above

The susceptibility of salmonid fish to an atypical strain of Aeromonas salmonicida that infects goldfish, Carassius auratus (L.), in Australia

An enzootic, Australian, atypical strain oi Aeromonas salmonicida isolated from diseased goldfish, Carassius auratus (L.), was inoculated into Atlantic salmon, Salmo salar L.. brown trout, 5. trutta L.. rainbow trout, S. gairdneri Richardson, and brook trout. Salvelinus fontinalis (Mitchill), fingerlings by intraperitoneal injection (i.p.) and by bath challenge, the latter with and without prior abrasion of skin. The 10-day LDs(j (i-p.) was estimated to be 7-4 x 10^-^ colony forming units (cfu) for Atlantic salmon, 3-Ox 10 -cfu for brown trout, 3-7x10-cfu for brook trout and 6-4x10^ cfu for rainbow trout. Brown, rainbow and brook trout succumbed to bath challenges with between 10-\u27\u27-10^cfu/mI, developing ulcers of the skin and septicaemia. The organism was trasmitted from inoculated fish to five of 195 within-tank control fish via water and established a carrier state in one of 14 Atlantic salmon. It was concluded that the organism poses a significant threat to the salmonid farming industry and wild saimonid fisheries in Australia