Altered expression of platelet proteins and calpain activity mediate hypoxia-induced prothrombotic phenotype

Abstract

Key Points• Hypoxia induces altered platelet proteome/reactivity, which correlates with a prothrombotic phenotype.• CAPNS1-dependent calpain activity in platelet activation cascade is associated with hypoxia-induced thrombogenesis.Oxygen-compromised environments, such as high altitude, air travel, and sports, and pathological conditions, such as solid tumors, have been suggested to be prothrombotic. Despite the indispensable role of platelets in thrombus formation, the studies linking hypoxia, platelet reactivity, and thrombus formation are limited. In the present study, platelet proteome/reactivity was analyzed to elucidate the acute hypoxia-induced prothrombotic phenotype. Rats exposed to acute simulated hypoxia (282 torr/8% oxygen) demonstrated a decreased bleeding propensity and increased platelet reactivity. Proteomic analysis of hypoxic platelets revealed 27 differentially expressed proteins, including those involved in coagulation. Among these proteins, calpain small subunit 1, a 28-kDa regulatory component for calpain function, was significantly upregulated under hypoxic conditions. Moreover, intraplatelet Ca 21 level and platelet calpain activity were also found to be in accordance with calpain small subunit 1 expression. The inhibition of calpain activity demonstrated reversal of hypoxia-induced platelet hyperreactivity. The prothrombotic role for calpain was further confirmed by an in vivo model of hypoxia-induced thrombosis. Interestingly, patients who developed thrombosis while at extreme altitude had elevated plasma calpain activities and increased soluble P-selectin level. In summary, this study suggests that augmented calpain activity is associated with increased incidence of thrombosis under hypoxic environments. (Blood. 2014;123(8):1250-1260

Alpha-2-Antiplasmin : A Fibrinolytic Peptide, could be a Potential Biomarker for Diagnosis of High Altitude Induced Pulmonary Hypertension

“…Conversely, some studies have demonstrated that high altitude exposure decrease the expression of coagulation factors and increase the fibrinolytic peptides 22 . Supporting the earlier notion, experimental animal studies have also demonstrated an increase in levels of coagulatory factors in animals exposed to hypobaric hypoxic 23,24 . High altitude living has been reported to cause pulmonary hypertension and however the pathophysiological mechanisms not yet understood completely.…”

Inhibit the calpain to climb the mountain

“…1 However, additional mechanisms could also influence the outcome of this study. Recently, much attention was focused on procoagulant microparticles released from many cell types, including platelets, and their contribution to activation of coagulation and thrombosis.…”

“…1 Using proteomic analysis of platelets and in vivo models of thrombosis, the authors elegantly demonstrated that enhanced calpain activity, regulated by CAPNS1, significantly contributes to platelet reactivity and thrombosis under hypoxic conditions. The observations from animal models were further supported by human data showing increased calpain activity and elevation in markers of platelet activation in the plasma of patients who developed deep vein thrombosis at high altitude.…”

“…1 The authors observed the splicing of TF pre-messenger RNA (premRNA) and increased levels of TF protein in platelets isolated from hypoxic rats. The splicing of TF pre-mRNA was previously shown in activated human platelets 8 ; however, the ability of platelets to synthesize TF protein is still debated.…”

“…Both studies found evidence of several features of the anemia of critical illness including an increase in hepcidin expression and serum iron levels 6 hours following the inflammatory injection. Both studies implicated hepcidin as the mediator of the hypoferremia and anemia, as injection of the killed B abortus bacteria in A model of the pathophysiology of the anemia of inflammation based on the findings in Kim et al and Gardenghi et al 1,2 Injection of heat-killed B abortus stimulates an inflammatory response including increased production of hepcidin and IL-6. Hepcidin binds to the iron exporter ferroportin resulting in internalization of the protein, increased macrophage iron storage, and subsequent hypoferremia.…”