Clopidogrel prescription has increased up to 77% over the past 10 years because of the high incidence of cardiovascular disease, especially ischemia because of atherothrombosis [17, 18]. One side effect of clopidogrel is bleeding during and after surgery. Handscel et al (2011) and Doganay et al (2018) reported massive bleeding after tooth extraction (4.5%) and odontectomy (25.7%) in the antiplatelet therapy [19, 20].
Bismuth subgallate (BSG) is one of the natural local haemostatic agents and has been proven to stop bleeding after tonsillectomy [14, 16]. Rat tail bleeding model is the most ideal method for observing bleeding after administration of antiplatelet drugs [21, 22], although it does not fully represent bleeding in the oral cavity. Saliva contains a plasminogen activator and oral movement, such as chewing and talking, can make bleeding last longer [23, 24]. Clinical observations relating to bleeding in the oral cavity still need to be developed further.
It showed clopidogrel extend bleeding time compared to other groups. Bismuth subgallate, both in normal and clopidogrel groups, decreases bleeding time when compared to the group not given bismuth subgallate. Kim et al (2010) also showed shorter bleeding time after bismuth subgallate applied on post-palate excision wounds [10].
Bleeding volume in the clopidogrel group without bismuth subgallate was higher than the normal group of rats without bismuth subgallate. We found similar results in the studies of Saito et al (2016) who measured the volume of bleeding with haemoglobin levels [22]. Bismuth subgallate can decrease bleeding volume, both in the clopidogrel and normal groups, when compared to rats that were not given bismuth subgallate. Research by Callanan et al (1995), Hatton et al (2000) and Sharma et al (2007) also showed a significant reduction in bleeding volume in tonsillectomy patients without systemic abnormalities given topical bismuth subgallate [11, 12, 13].
All samples of clopidogrel groups without bismuth subgallate in this study experienced secondary bleeding (100%), but we did not find it in the groups which were given bismuth subgallate, both in normal and clopidogrel rats (0%). Excessive tail movement might cause secondary bleeding in a normal group sample (14%) when the rat was conscious of the effects of anaesthesia. Research Liu et al (2012) found secondary bleeding in rats given clopidogrel as much as 100%, while 25% of them were excluded because bleeding did not stop after 20 minutes [21].
Clopidogrel in this study could increase bleeding time, bleeding volume, and secondary bleeding because this drug can decrease platelet aggregation and inhibit thrombus formation. This drug active metabolites (clopi-H4) binds to the P2Y12 receptor and inhibits ADP to activate the receptor. Platelets could not bind each other and failed to aggregate [25].
Bismuth subgallate can reduce bleeding time and bleeding volume both in normal and clopidogrel rats, because bismuth ions bind to metallothionein receptors on the surfaces of TF-bearing cells and erythrocytes [26, 27, 28]. These binding increased eryptosis and Reactive Oxygen Species (ROS) formation. Eryptosis formed artificial clots and sped up initial haemostatic plug formation [7, 9]. ROS formation increased TF expression and activation, which was required in thrombin and fibrin formation [29]. Bismuth subgallate also prevents secondary bleeding because it has built a stable blood clot from initial haemostatic plug and fibrin, even though clopidogrel inhibits platelet aggregation. This study concludes that bismuth subgallate sped up formation and stabilized haemostatic plug both on normal and clopidogrel-inhibited platelet aggregation.