**3. Traditional medications**

Although the present anticoagulant drugs available are safe and effective, the morbidity and mortality caused by atherothrombosis are still unacceptably high [33]. Many of these drugs are mostly associated with several side effects [34]. Statin, such as simvastatin, a lipid-lowering agent, known as 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, is associated with several side effects, including fever, headache, gastric irritation, myositis, hyperuricaemia, rhabdomyolysis, myalgia, renal and hepatic dysfunctions [35]. Acetylsalicylic acid, including aspirin, are antiplatelet synthetic drugs widely prescribed to treat inflammation, headache, fever and thrombosis [36]. Aspirin, in particular, has been reported to inhibit cyclooxygenase (COX), a potent enzyme that catalyses prostaglandin formation by blocking the synthesis of thromboxane A2 (TXA2), an essential mediator of blood clotting [37]. However, aspirin and other related antiplatelet drugs were reported to give recurrent thromboembolic vascular events (aspirin intolerance), including dizziness, nausea, abdominal pain or patients may suffer from increased risk of bleeding [37]. Bleeding is the most common complication associated with warfarin therapy and is related to exponentially higher INR values. The goal of the management is to reduce the INR back to a therapeutic safe level [13]. Existing reports have shown that plant extracts have analgesic, antioxidant, anti-inflammatory, anticoagulative, antiplatelet, anti-atherosclerotic, antithrombosis antiproliferative, and cardioprotective, properties [38, 39]. In this regard, the development of natural-based products to augment conventional synthetic drugs is essential. They are more effective with minimal or without side effects [40]. Some natural-based products commonly used in traditional medicines include:

#### *Anticoagulants and Hypercoagulability DOI: http://dx.doi.org/10.5772/intechopen.103774*

*Ginger (Zingiber officinale Roscoe)* is a well-known natural Chinese herbal medicine, widely used to treat ailments, including gastrointestinal tract disorders, arthritis cardiomyopathy, high blood pressure and palpitations [41]. The main chemical compounds present in ginger include gingerol, shogaol, zingerone and paradol [42]. The 6-Gingerol has a lot of therapeutic potentials, including antioxidant, antitumor and anti-inflammatory effects [43, 44]. Previous report has demonstrated that ginger exhibit anti-atherothrombotic activity by suppressing platelet aggregation and TXB2 secretion in vitro. Previous study has shown that ginger crude extracts exhibit hypotensive, endothelium-independent vasodilatory and cardio-suppressive activities through their specific inhibitory action on voltage-dependent calcium channels [45].

*Allium sativum (garlic)*: Plant extracts facilitate the treatment of atherosclerosis through various mechanisms of action at different pathways [46, 47]. The extracts from garlic have been demonstrated to show the most remarkable and clear cardioprotective activity since garlic can attenuate lipids profile through the inhibition of cholesterol biosynthesis, reduction of LDL, ameliorate arterial hypertension, and prevent platelet aggregation [48–50]. Therefore, garlic appears to be a promising plant for atherothrombotic treatment and prevention. The alliinase enzyme presence in garlic is well potentiated and have been used in the treatment of CVDs. The oxidative inhibitory phytochemicals present in garlic contribute significantly to improving the levels of HDL. The phytochemical contents of garlic also, including selenium, flavonoids, allixin, water and lipid-soluble organosulphur have been identified to regulate oxidative activities, while s-allylcysteine and other water-soluble chemicals of garlic are also found to be responsible for the anti-oxidant effects [38].

*Citrus Limon (lemon):* Over time, the prevalence of CVDs is grossly increasing. Flavonoids are very common plant natural-based products that have multiple therapeutic benefits and other biological functions [51]. The flavonoids contained in citrus included flavanones, flavones, and flavanols. Structurally, flavonoids could be categorised into six major classes, including flavanones, flavones, flavanols, isoflavones, flavonols, and anthocyanidins [52]. Flavonoids are polyphenol compounds associated with antioxidant activities, including inhibition of platelet activation and aggregation, anticancer, and anti-inflammatory activities since an increased dietary intake of antioxidants could prevent atherosclerosis, as increased cholesterol and occlusion is correlated. Structurally, flavonoids could be categorised into six major classes, including flavanones, flavones, flavanols, isoflavones, flavonols, and anthocyanidins [52]. Even though the flavones and flavanols are in low concentrations compared to flavanones, but are more potent antioxidants and free radical scavengers [53]. The high contents of phytochemicals, including naringin, hesperidin, limonene, and other flavonoids in citrus limon could significantly reduce the morbidity or mortality in the patients at risk of developing cardiovascular events [53].

*Malus Domestica (apple) apple cider vinegar (ACV)*: The chemical constituents available in apple include catechin, caffeic acid, gallic acid, chlorogenic acids and p-coumaric acid have been demonstrated to show high antioxidant potential. Apples have high nutritional value and are important source of several phytochemicals, including phenolic compounds, flavonoids, organic acids, minerals and vitamins, minerals, calcium, potassium, phosphorus and low acetic acid, which have been useful for many years in the treatment of various metabolic conditions [54]. Previous study has indicated that ACV exerts its therapeutic effects by improving atherogenesis, attenuating inflammatory responses and reducing triacylglycerol as observed in mice serum [55]. Dietary flavonoids extracted from apples decreased the levels of inflammation associated biomarkers, such as IL-11 and IL-2 in the intestine of

mice [56]. The phytochemicals present in apples, such as polyphenols, polysaccharides, sterols, and triterpenes, jointly contributed to its antioxidants, anti-cancer, and anti-inflammatory activities, such as anti-inflammatory, anticancer and inhibition of platelet activation [57].

*Honey*: A multi-nutrient food comprising different quantities of minerals, such as aluminium, barium, boron, chlorine, fluoride, iodine, sulphur and potassium, which account for one-third of the total elements [58, 59]. Honey has been demonstrated to contain polyphenols compounds, mostly flavonoids, phenolic acids, and phenolic acid products, which have been reported to contribute greatly to its antioxidant activities [60]. It is naturally produced by bees and is mainly obtained from flowering plants. Honey is divided into two categories; nectar honey, originating from plant nectars, and honeydew honey, mainly secreted by plant-sucking insects (Hemiptera) [61]. Previous results indicated that honey-mediated, inhibition of platelet aggregation, prolongation of aPTT, PT, and TT and reduction in FN levels. The mechanism by which honey inhibits platelet aggregation can be explained by the amount of hydrogen peroxide present in honey. Reports have shown that exogenous exposure to hydrogen peroxide led to platelet inhibition and therefore, it could be hypothesised that the presence of hydrogen peroxide might be the primary basis of honey induced inhibition of platelet aggregation [62]. Moreover, natural honey is known to have suppressive potentials on reactive oxygen species, pinpointing that activated platelets could release various cytokines which in turn might activate phagocytes. Therefore, platelet activated phagocytes lead to an increase in the synthesis of free oxygen radicals. Because honey inhibits platelet aggregation, it is suggested that honey could indirectly suppress the generation of free oxygen radicals. Remarkably, free oxygen radicals have been reported to act on platelet activity through oxidative modification of lipids and their derivatives and hence, it could be proposed that honey might promote platelet function by suppressing LDL oxidation, which could indirectly affect platelet function [63].

Existing reports demonstrate that honey inhibited the coagulation proteins of the three coagulation pathways: intrinsic, extrinsic, and final common pathway. The main reason for the anticoagulant properties of nature might be attributed to the variety of flavonoids contained in honey that may affect the activity of coagulation factors like FN and factor VII. Additionally, honey contains maltose that has been reported to interfere with blood coagulation. The therapeutic potentials of honey comprise various mechanisms that might play a significant role in the prevention of atherosclerotic CVDs. Honey has been reported to inhibit thrombin (main enzyme of blood coagulation) and induce the formation of reactive oxygen species from phagocytes; as free oxygen radicals particularly superoxide and hypochlorous acid provides room for the development of atherosclerotic plaque, thus honey might interrupt the formation of atherosclerotic plaque [62].
