Desmopressin induces endothelial P-selectin expression and leukocyte rolling in postcapillary venules

Abstract

Desmopressin, (DDAVP; 1-desamino-8-D-arginine vasopressin) increases the release and activity of von Willebrand factor (vWF); however, its effects on the other major constituent of endothelial Weibel-Palade bodies, P-selectin, has not been investigated. DDAVP-induced P-selectin expression may explain DDAVP's efficacy in bleeding disorders in which vWF levels are normal. Therefore, the objective of this study is to assess the effect of DDAVP on P-selectin expression on endothelial cells of postcapillary venules in vivo and on human umbilical vein endothelium in vitro, and to determine whether DDAVP has direct effects on leukocyte behavior in postcapillary venules. DDAVP (0.1 and 1.0 microgram/mL) induced a significant but transient increase in P-selectin expression on human umbilical vein endothelial cells as well as on rat and human platelets. Immunohistochemical analysis of rat postcapillary venules showed that in contrast to saline, DDAVP injection (1 microgram/kg, intravenous) induced significant endothelial P-selectin expression. DDAVP administration also induced a rapid and significant increase in leukocyte rolling in rat mesenteric venules in vivo. This response was entirely dependent on P-selectin, as an anti-P-selectin antibody rapidly reversed the DDAVP-induced increase in leukocyte rolling. DDAVP induced leukocyte rolling in medium (20 to 40 microns) and large (> 40 microns), but not small (< 20 microns), postcapillary venules. In animals that were treated with DDAVP, there was a steady and significant increase in leukocyte adhesion. This study shows that DDAVP can directly induce P-selectin expression on endothelium in vitro and in vivo and that the latter response is capable of supporting prolonged leukocyte rolling in rat postcapillary venules.

Effects of desmopressin on circulating P‐selectin

“…However, this study does not contradict those results, but strengthens the rationale for our investigation. In conjunction with the results by Kanwar et al (1995), the lack of increase in cP-selectin after DDAVP infusion in our study provides evidence against intracellular storage of a soluble P-selectin in the Weibel-Palade bodies. Also, we can exclude that rapid proteolytic cleavage of membrane P-selectin expressed on the surface of endothelial cells and subsequent shedding of P-selectin occurs under physiological conditions in humans.…”

“…The main finding of our study is the lack of increase in cPselectin after DDAVP infusion, despite very recent evidence that DDAVP increases P-selectin expression on endothelial cells and increases P-selectin-dependent rolling of neutrophils on rat mesenteric venules (Kanwar et al, 1995).…”

“…Given the identical intracellular storage compartment and transport to the cell surface shared by VWF and P-selectin, we hypothesized that DDAVP, a stimulator of VWF release, will also increase P-selectin release, if a soluble P-selectin was present in the Weibel-Palade bodies or in case of rapid proteolytic cleavage of P-selectin expressed on EC. As a Effects of Desmopressin on Circulating P-selectin # 1996 Blackwell Science Ltd, British Journal of Haematology 93: [432][433][434][435][436] concomitant increase in expression of P-selectin with VWF upon DDAVP infusion might contribute to the desired haemostatic effect of DDAVP (Kanwar et al, 1995), we have compared the effect of DDAVP or placebo infusions on circulating P-selectin, circulating platelets and neutrophils.…”

Desmopressin in non‐severe haemophilia A: Test‐response and clinical outcomes in a single Canadian centre review

“…23 In vitro studies have shown improved interaction between platelets and the vascular subendothelium. 24,25 Furthermore, DDAVP has been shown to enhance Na + /Ca 2+ mobilization in platelets enhancing their ability to form procoagulant platelets and increase platelet-dependent thrombin generation. 21,23 We had one instance in which DDAVP at weight-based dose (0.3 mcg/kg) was ineffective in achieving haemostasis in a single patient with a partial test response.…”

The use of haemostatic drugs in haemophilia: desmopressin and antifibrinolytic agents

“…Desmopressin infusion in rats causes an increase in P-selectin expression in endothelial cells [16]. It is known that P-selectin is important in promoting leucocyte adhesion to the subendothelium, which could be relevant in primary haemostasis.…”