Hypoxia and Ischemia Promote a Maladaptive Platelet Phenotype

Abstract

Objective Reduced blood flow and/or tissue oxygen tension conditions result from thrombotic and vascular diseases such as myocardial infarction, stroke, and peripheral vascular disease. It is largely assumed that while platelet activation is increased by an acute vascular event, chronic vascular inflammation, and/or ischemia, the platelet activation pathways and responses are not themselves changed by the disease process. We therefore sought to determine whether the platelet phenotype is altered by hypoxic and ischemic conditions. Approach and Results In a cohort of patients with metabolic and peripheral artery disease (PAD), platelet activity was enhanced and/or inhibition with oral anti-platelet agents was impaired compared to platelets from control subjects, suggesting a difference in platelet phenotype caused by disease. Isolated murine and human platelets exposed to reduced oxygen (hypoxia chamber, 5% O2) had increased expression of some proteins that augment platelet activation compared to platelets in normoxic conditions (21% O2). Using a murine model of critical limb ischemia (CLI), platelet activity was increased even two weeks post-surgery compared to sham surgery mice. This effect was partly inhibited in platelet specific Extracellular Regulated Protein Kinase 5 (ERK5) knockout mice. Conclusions These findings suggest that ischemic disease changes the platelet phenotype and alters platelet agonist responses due to changes in the expression of signal transduction pathway proteins. Platelet phenotype and function should therefore be better characterized in ischemic and hypoxic diseases to understand the benefits and limitations of anti-platelet therapy.

A Sex-Specific Switch in Platelet Receptor Signaling Following Myocardial Infarction

“…Determination of a gender-specific difference in these clinical situations as we present here is a logical extension of those previous studies. We previously reported that proteomic profiles, agonist sensitivity, and anti-platelet medication efficacy are altered in humans and in murine models of MI and peripheral artery disease (1,3). We now suggest, based on the present data, that platelets in patients with acute MI are primed toward augmented PAR signaling in men.…”

“…The mature platelet has a surprisingly dynamic protein expression profile which may be responsible for changes in platelet phenotype. Based on changes in agonist sensitivity, the response to anti-platelet agents, and platelet proteomic profiles, we concluded that the mature platelet phenotype can change in vivo and in vitro in humans and in mouse models of hypoxic and ischemic disease (21). Given our present observation that platelet thrombin signaling differs in men and women in health and following MI, we employed an established murine MI model previously found to have ongoing thrombin-mediated platelet activation in the post MI environment (2).…”

“…Anti-platelet therapy for patients following a diagnosis of MI consists of aspirin and a P2Y 12 receptor antagonists irrespective of whether the diagnosis is STEMI or NSTEMI. Recent data conducted in humans and in relevant murine models of MI and peripheral arterial disease (PAD) suggests the platelet phenotype, platelet receptor signaling, and responsiveness to antiplatelet medications are quite different from healthy platelets in which anti-platelet agents are first characterized (1)(2)(3)(4)(5)(6).…”

Platelet MAPKs—a 20+ year history: What do we really know?

“…Interestingly, in a mesenteric FeCl 3 injury model, Erk5 −/− mice had significantly delayed thrombus formation, suggesting that ERK5 regulates platelet function in a ROS dependent manner 74 . This ROS dependent mechanism was further codified when it was observed that ERK5 is activated in human platelets isolated from patients with peripheral artery disease or with ST‐elevation myocardial infarction 47,90 …”

CD154 Induces Interleukin-6 Secretion by Kidney Tubular Epithelial Cells under Hypoxic Conditions: Inhibition by Chloroquine

“…Platelets are the principal reservoir of CD154 in blood, being readily present and activated in inflamed tissues an important mechanism that provides CD154 in the inflammatory milieu [50]. In vivo, higher platelet reactivity and response to agonists observed in low O 2 conditions suggest that hypoxia favors platelet activation [51,52]. Whether in vivo hypoxia per se is an inducer of platelet activation remains debated.…”