P-selectin antibody treatment after blunt thoracic trauma prevents early pulmonary arterial thrombosis without changes in viscoelastic measurements of coagulation

Abstract

INTRODUCTION:Previously, in a murine model of blunt thoracic trauma, we provided evidence of primary pulmonary thrombosis associated with increased expression of the cell adhesion molecule, P-selectin. In this study, mice are treated with P-selectin blocking antibody after injury to investigate the clinical viability of this antibody for the prevention of pulmonary thrombosis. In addition, viscoelastic testing is performed to investigate if P-selectin inhibition has a detrimental impact on normal hemostasis. METHODS:A murine model of thoracic trauma was used. Mice were divided into sham control and experimental injury groups. Thirty minutes after trauma, mice were treated with the following: P-selectin blocking antibody, isotype control antibody, low-dose heparin, high-dose heparin, or normal saline. At 90 minutes, whole blood was collected for characterization of coagulation by viscoelastic coagulation monitor (VCM Vet; Entegrion, Durham, NC). Mean clotting time, clot formation time, clot kinetics (α angle), and maximum clot firmness were compared between each treatment group. RESULTS:Mice that received P-selectin antibody 30 minutes after blunt thoracic trauma had four-to fivefold less (p < 0.001) arterial fibrin accumulation than those that received the isotype control. In both sham and trauma groups, compared with vehicle (normal saline) alone, no statistical difference was noted in any coagulation parameters after injection with P-selectin antibody, isotype control, or low-dose heparin. In addition, blinded histopathological evaluation yielded no difference in hemorrhage scores between injured mice treated with P-selectin blocking antibody and those treated with isotype antibody control. CONCLUSION:This study supports the clinical use of P-selectin blocking antibody for the prevention of pulmonary thrombosis by confirming its efficacy when given after a blunt thoracic trauma. In addition, we demonstrated that the administration of P-selectin antibody does not adversely affect systemic coagulation as measured by viscoelastic testing, suggesting that P-selectin antibody can be safely given during the acute posttraumatic period.

Platelet dysfunction after trauma: From mechanisms to targeted treatment

“…Endothelial dysfunction can be worsened by crystalloid resuscitation 108 . Additionally, platelet‐endothelial interactions distant from localized endothelial injury may aggravate endothelial dysfunction and contribute to thrombosis 109 . VWF multimers are continuously released, and ADAMTS13 is decreased, associated with microthrombi formation and organ dysfunction 76,78 .…”

“…108 Additionally, platelet-endothelial interactions distant from localized endothelial injury may aggravate endothelial dysfunction and contribute to thrombosis. 109 VWF multimers are continuously released, and ADAMTS13 is decreased, associated with microthrombi formation and organ dysfunction. 76,78 Moreover, histones and HMGB1 remain significantly elevated for multiple days following injury.…”

“…194 Similarly, inhibition of P-selectin prevented pulmonary arterial thrombosis in a murine model of traumatic chest injury. 109 Platelet aggregation reduction can be achieved by targeting GPIIbIIIa (e.g., tirofiban). In a model of systemic inflammation, induced by extracorporeal circulation, tirofiban protected platelets and decreased platelet-leukocyte binding.…”

Nanoparticles of a New Small-Molecule P-Selectin Inhibitor Attenuate Thrombosis, Inflammation, and Tumor Growth in Two Animal Models

“…3,4 This binding mediates the adhesion of platelets, leukocytes, T cells, endothelial cells, and tumor cells, resulting in inflammation, thrombosis and tumor growth and metastasis. It is evident that inhibiting the binding between P-selectin and PSGL1 sheds light on drug development for treating inflammation, 5 arterial thrombosis, 6 venous thrombosis, 7 tumor growth, 8 tumor metastasis, 8 and cancer-associated thrombosis. [9][10][11] Currently, drugs designed for this purpose mainly fall into three types: monoclonal antibodies, including inclacumab 12 and crizanlizumab, 13 glycosulfopeptides mimicking truncated N-terminal PSGL1 monomers like GSnP-6, 14 and small-molecule inhibitors, such as GMI-1070, 15 bimosiamose (TBC1269), 16 and PSI-697.…”

“… 3 , 4 This binding mediates the adhesion of platelets, leukocytes, T cells, endothelial cells, and tumor cells, resulting in inflammation, thrombosis and tumor growth and metastasis. It is evident that inhibiting the binding between P-selectin and PSGL1 sheds light on drug development for treating inflammation, 5 arterial thrombosis, 6 venous thrombosis, 7 tumor growth, 8 tumor metastasis, 8 and cancer-associated thrombosis. 9–11 …”