Thromb Haemost 2019; 19(10): 1655-1664
DOI: 10.1055/s-0039-1693737
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

All-Trans Retinoic Acid Impairs Platelet Function and Thrombus Formation and Inhibits Protein Kinase CßI/δ Phosphorylation

Qi Luo*
1  Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
2  Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
3  Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou Medical University, Xuzhou, China
,
Guangyu Wei*
1  Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
2  Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
3  Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou Medical University, Xuzhou, China
,
Xiamin Wang*
1  Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
2  Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
3  Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou Medical University, Xuzhou, China
,
Xiaoqi Xu
1  Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
2  Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
3  Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou Medical University, Xuzhou, China
,
Wen Ju
1  Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
2  Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
3  Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou Medical University, Xuzhou, China
,
Zhenyu Li
1  Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
2  Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
3  Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou Medical University, Xuzhou, China
,
4  ACRF Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
,
Robert K. Andrews
5  Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
,
Lingyu Zeng
1  Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
2  Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
3  Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou Medical University, Xuzhou, China
,
Kailin Xu
1  Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
2  Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
3  Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou Medical University, Xuzhou, China
,
Jianlin Qiao
1  Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
2  Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
3  Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou Medical University, Xuzhou, China
› Author Affiliations
Funding This research was supported by National Natural Science Foundation of China (grant no. 81400082, 81641151, and 81700178), the Natural Science Foundation of Jiangsu Province (grant no. BK20140219 and BK20170259), the funding for the Distinguished Professorship Program of Jiangsu Province, the Shuangchuang Project of Jiangsu Province, the Six Talent Peaks Project of Jiangsu Province (WSN-133), the 333 projects of Jiangsu Province (BRA2017542), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (18KJA320010 and 17KJA320008), Jiangsu Province's Key Provincial Talents Program (ZDRCA2016054), Jiangsu Province’s Graduate Scientific Research Innovation Program (KYCX18-2186, KYCX19-2231, KYCX19-2234) and the National Health and Medical Research Council of Australia.
Further Information

Publication History

14 March 2019

12 June 2019

Publication Date:
01 August 2019 (eFirst)

Abstract

All-trans retinoic acid (ATRA) is widely used for induction of complete remission in patients with acute promyelocytic leukemia (APL). ATRA also regulates protein kinase C (PKC) activity. Therapeutic use of ATRA reportedly interferes with hemostatic function in APL patients, including effects on coagulation or other vascular cells, although effects of ATRA on platelets remain unclear. This study aims to investigate the effect of therapeutic-relevant doses of ATRA on platelet function. Human platelets were preincubated with ATRA (0–20 μM) for 1 hour at 37°C, followed by analysis of aggregation, granule secretion, receptor expression by flow cytometry, platelet spreading, or clot retraction. Additionally, ATRA (10 mg/kg) was injected intraperitoneally into mice and tail bleeding time and arterial thrombus formation were evaluated. ATRA inhibited platelet aggregation and adenosine triphosphate release induced by collagen (5 μg/mL) or thrombin (0.05 U/mL) in a dose-dependent manner without affecting P-selectin expression or surface levels of glycoprotein (GP) Ibα, GPVI, or αIIbβ3. ATRA-treated platelets demonstrated reduced spreading on immobilized fibrinogen or collagen and reduced thrombin-induced clot retraction together with reduced phosphorylation of Syk and PLCγ2. In addition, ATRA-treated mice displayed significantly impaired hemostasis and arterial thrombus formation in vivo. Further, in platelets stimulated with either collagen-related peptide or thrombin, ATRA selectively inhibited phosphorylation of PKCßI (Ser661) and PKCδ (Thr505), but not PKCα or PKCßII phosphorylation (Thr638/641). In conclusion, ATRA inhibits platelet function and thrombus formation, possibly involving direct or indirect inhibition of PKCßI/δ, indicating that ATRA might be beneficial for the treatment of thrombotic or cardiovascular diseases.

* These authors contributed equally to this study.


Supplementary Material