Abstract
Under ischemic conditions, tissues are exposed to hypoxia. Although human physiology, to a certain extent, can adapt to hypoxic conditions, the impact of low oxygen levels on platelet function is unresolved. Therefore, we explored how reduction of atmospheric oxygen levels to 1% might affect agonist-induced aggregation and static adhesion of isolated human platelets. We uncovered that isolated, washed human platelets exposed to hypoxic conditions show reduced thrombin receptor-activating peptide-6 (TRAP-6) and convulxin-induced aggregation. Of note, this hypoxia-triggered effect was not observed in platelet-rich plasma. Independent of the agonist used (TRAP-6, ADP), activation of the platelet fibrinogen receptor integrin αIIbβ3 (GPIIbIIIa, CD41/CD61) was strongly reduced at 1% and 8% oxygen. The difference in agonist-induced integrin αIIbβ3 activation was apparent within 5 minutes of stimulation. Following hypoxia, re-oxygenation resulted in the recovery of integrin αIIbβ3 activation. Importantly, platelet secretion was not impaired by hypoxia. Static adhesion experiments revealed decreased platelet deposition to fibrinogen coatings, but not to collagen or vitronectin coatings, indicating that specifically the function of the integrin subunit αIIb is impaired by exposure of platelets to reduced oxygen levels. Our results reveal an unexpected effect of oxygen deprivation on platelet aggregation mediated by the fibrinogen receptor integrin αIIbβ3.
Highlights
Under ischemic conditions, tissues are exposed to hypoxia
Because little is known on the role of defined hypoxic conditions on the function of isolated human platelets and since the existing literature on the impact of oxygen on platelets in animal models and human pathophysiology is controversial, we set out to test whether and how 30 minutes of incubation of isolated, washed human platelets in a 1% oxygen atmosphere impacts platelet aggregation
We uncovered that hypoxia-exposed washed platelets showed an aggregation response to 10 μM thrombin receptoractivating peptide-6 (TRAP-6), that was impaired by one third relative to washed platelet preparations from the same donor that were kept under normoxia (Fig. 1a)
Summary
Tissues are exposed to hypoxia. human physiology, to a certain extent, can adapt to hypoxic conditions, the impact of low oxygen levels on platelet function is unresolved. We uncovered that isolated, washed human platelets exposed to hypoxic conditions show reduced thrombin receptoractivating peptide-6 (TRAP-6) and convulxin-induced aggregation Of note, this hypoxia-triggered effect was not observed in platelet-rich plasma. A prothrombotic role of hypoxia is supported by a recent study with rats that were exposed to acute stimulated hypoxia of 8% oxygen[4] Under these conditions, increased platelet reactivity, exposure of activation markers, and an augmented clot reaction were reported. Healthy men exposed for a short time to acute hypoxia (8% oxygen) did not show significant changes in blood coagulation or platelet function[5] It has been demonstrated in mouse models that exposure to hypoxia results in increased von Willebrand Factor (VWF) expression in the lung, brain, and heart endothelium, which is mediated by the transcription factors Nuclear Factor-I and YY16. Inhibition of xanthine oxidase reversed the anti-platelet activities of nitrite under hypoxic and normoxic conditions[9]
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