Drospirenone enhances GPIb-IX-V-mediated platelet activation.
BACKGROUND
Epidemiologic studies recently revealed that using drospirenone (DRSP)-containing contraceptives is associated with an increased risk of thrombosis in women. However, the underlying causality is unclear.


OBJECTIVE
To study the effects of DRSP on coagulation in vitro and the probable mechanisms involved.


METHODS
First, the effects of DRSP on the activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT) and fibrinogen (FIB) were measured. Then, the effects of DRSP on platelet activation were investigated in response to low levels of collagen, adenosine 5'-diphosphate (ADP), thrombin, U46619, adrenaline and botrocetin/von Willebrand factor (VWF).


RESULTS
DRSP has no direct effect on APTT, PT, TT, FIB and platelet aggregation induced by low levels of collagen, ADP, thrombin, U46619 or adrenaline. However, DRSP enhances botrocetin/VWF-induced platelet aggregation and VWF receptor glycoprotein Ib-IX-V (GPIb-IX-V)-mediated signaling. This enhancement can be blocked by the progesterone receptor membrane component 1 (PGRMC1) inhibitor AG205, or by the ADP scavenger apyrase and the cyclooxygenase inhibitor indomethacin.


CONCLUSIONS
Although DRSP did not directly induce platelet activation, it obviously facilitated VWF receptor GPIb-IX-V-mediated platelet activation. The potential DRSP-binding protein PGRMC1 may play a role in this process. Our study also suggested that the inhibition of thromboxane A2 production and the activation of ADP receptors might prevent the side-effects of DRSP.
Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
X
X
Fan
Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
X
X
Chen
Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
C
C
Wang
Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J
J
Dai
Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Y
Y
Lu
Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
K
K
Wang
Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J
J
Liu
Department of Cardiology, Third People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J
J
Zhang
Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
X
X
Wu
D000244:Adenosine Diphosphate / Q000378:metabolism; D000736:Androstenes / Q000494:pharmacology*; D001081:Apyrase / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D003271:Contraceptive Agents, Female / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000378:metabolism; D013928:Thromboxane A2 / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D000736:Androstenes; D003271:Contraceptive Agents, Female; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; C115296:PGRMC1 protein, human; D019038:Platelet Glycoprotein GPIb-IX Complex; D011980:Receptors, Progesterone; D014841:von Willebrand Factor; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D001081:Apyrase; C035144:drospirenone; D007213:Indomethacin
PGRMC1 protein, human; drospirenone; glycoprotein Ib-IX complex; platelets; thrombosis