In order to explore the role of a disintegrin and metalloproteinase (ADAM) proteolysis and direct mechanical damage in non-physiologic shear stress (NPSS)-caused platelet receptor shedding, the healthy donor blood treated with/without ADAM inhibitor was exposed to NPSS (150 Pa). The expression of the platelet surface receptors glycoprotein (GP) Ibα and GPVI in NPSS-damaged blood was quantified with flow cytometry. The impact of ADAM inhibition on adhesion of NPSS-damaged platelets on von Willibrand factor (VWF) and collagen was explored with fluorescence microscopy. The impact of ADAM inhibition on ristocetin- and collagen-caused aggregation of NPSS-damaged platelets was examined by aggregometry. The results showed that ADAM inhibition could lessen the NPSS-induced loss of platelet surface receptor GPIbα (12%) and GPVI (9%), moderately preserve adhesion of platelets on VWF (7.4%) and collagen (8.4%), and partially restore the aggregation of NPSS-sheared platelets induced by ristocetin (18.6 AU*min) and collagen (48.2 AU*min). These results indicated that ADAM proteolysis played a role in NPSS-induced receptor shedding. However, the ADAM inhibition couldn’t completely suppress the NPSS-caused loss of the platelet surface receptors (GPIbα and GPVI), only partially prevented the NPSS-induced reduction of platelet adhesion to VWF and collagen, and the agonist (ristocetin and collagen)-caused platelet aggregation. These results suggested that the direct mechanical damage is partially responsible for NPSS-induced receptor shedding in addition to the ADAM proteolysis. In conclusion, NPSS relevant to blood contacting medical devices can induce ADAM proteolysis and direct mechanical damage on the platelet receptor GPIbα and GPVI, leading to comprised hemostasis.
*Beijing Advanced Innovation Center for Biomedical Engineering, Beihang University, Beijing, China;
†School of Biological Science and Medical Engineering, Beihang University, Beijing, China;
‡Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and
§Fischell Department of Bioengineering, A. James Clark School of Engineering, University of Maryland, College Park, Maryland.
Submitted for consideration January 2019; accepted for publication in revised form May 2019.
Disclosure: The authors have no conflicts of interest to report.
This work was supported by the National Institutes of Health (Grant number: R01HL124170).
Correspondence: Zhongjun J. Wu, Department of Surgery, University of Maryland School of Medicine, 10 South Pine Street, MSTF 436, Baltimore, MD 21201. Email: firstname.lastname@example.org.