P‐ and E‐ selectin in venous thrombosis and non‐venous pathologies

Abstract

Venous thromboembolism is a very common and costly health problem worldwide. Anticoagulant treatment for VTE is imperfect: all have the potential for significant bleeding, and none prevent the development of post thrombotic syndrome after deep vein thrombosis or chronic thromboembolic pulmonary hypertension after pulmonary embolism. For these reasons, alternate forms of therapy with improved efficacy and decreased bleeding are needed. Selectins are a family (P‐selectin, E‐selectin, L‐selectin) of glycoproteins that facilitate and augment thrombosis, modulating neutrophil, monocyte, and platelet activity. P‐ and E‐selectin have been investigated as potential biomarkers for thrombosis. Inhibition of P‐selectin and E‐selectin decrease thrombosis and vein wall fibrosis, with no increase in bleeding. Selectin inhibition is a promising avenue of future study as either a stand‐alone treatment for VTE or as an adjunct to standard anticoagulation therapies.

Exogenous human α-Synuclein acts in vitro as a mild platelet antiaggregant inhibiting α-thrombin-induced platelet activation

“…abciximab) displays no disaggregating effect 28 , 72 . For these reasons, P-selectin has become a major target for anti-aggregating drug development 79 . Hence, the remarkable inhibition of P-selectin exposure by αSyn, along with the moderate inhibitory effect on GpIIb/IIIa expression, can reasonably account for the anti-aggregating effect of the protein observed in MEA tests.…”

How to optimize the prevention of post-thrombotic syndrome: recent advances

“…Inhibitors of CAMs such as P-selectin, E-selectin, ICAM-1 or VCAM-1 were found to accelerate resolution and reduce vein wall fibrosis in animal models of DVT [65,66]. Its clinical relevance is supported by circulating marker studies in DVT patients.…”

“…Consequently, inhibition of CAMs has been considered as a therapeutic target, particularly selectins. Exogenous inhibition of P-selectin or E-selectin has shown great promise by reducing leukocyte extravasation, accelerating thrombus resolution and reducing vein wall fibrosis and thickness in a baboon model, which is considered comparable to human DVT [65]. Several P-selectin antagonists have been developed, and registered antibodies inclacumab and crizanlizumab are currently studied in trials for various diseases, although not in VTE [65].…”

“…Exogenous inhibition of P-selectin or E-selectin has shown great promise by reducing leukocyte extravasation, accelerating thrombus resolution and reducing vein wall fibrosis and thickness in a baboon model, which is considered comparable to human DVT [65]. Several P-selectin antagonists have been developed, and registered antibodies inclacumab and crizanlizumab are currently studied in trials for various diseases, although not in VTE [65]. It must be noted that P-selectin is also present on platelets, making E-selectin a more specific target to inhibit leukocyte extravasation.…”

“…Despite its promise, there are currently no ongoing trials with these drugs in the context of PTS prevention. For now, we will have to wait on its effect and off-target effects in trials with other diseases, of which an overview of was recently published by Purdy et al [65].…”