**1.2. Thrombosis**

*Primary hemostasis* causes local vasoconstriction which diminishes blood flow at the injury site and platelet plug formation. *Secondary hemostasis* implicates a series of enzymatic reactions between coagulation factors and cellular activity. These enzymatic reactions convert fibrino-

Lastly, *fibrinolysis* is the biological mechanism which disperses the clot after the blood vessel

The cell-based model includes the interactions between cells, platelets, and coagulation fac-

• *Initiation*: occurs after vascular injury and leads to the production of a small amount of thrombin. Tissue factor (TF) localized to the cell membrane is activated by non-coagulation and coagulation proteases (blood clotting proteins or factors). The produced FVIIa/TF

gen to fibrin, an insoluble strand, which together with platelets forms a thrombus.

tors. This model postulates a three-phase process:

**Figure 1.** Cell-based coagulation model. Figure adapted from Vojacek [8].

has healed.

12 Anticoagulant Drugs

Over the past few decades, the fact that cardiovascular syndromes are a leading cause of heart problems and rising death rates in the US and Europe has been gradually accepted. With more than 24,000 deaths annually, cerebrovascular accidents (CVA) represent almost a third of all deaths [8–12].

**Figure 2.** Thrombus production on blood vessels.

In 2012, the World Health Assembly (WHA) set a global target to reduce premature deaths from non-infectious disease, including cardiovascular disease, by 25% by 2025. Later, in May 2015, the International Society on Thrombosis and Hemostasis (ISTH) and the World Thrombosis Day (WTD) committee appealed for increased attention to thrombosis in a message to the Assembly of the World Health Organization (WHO) [13].

A thrombus formation, which obstructs arterial circulation, can end in acute myocardial infarction (AMI) or ischemic stroke. In venous circulation, deep vein thrombosis (DVT) can cause chronic leg pain, edema, and ulcers [14–16].

A thrombus can partly or completely block blood vessels, which may deprive tissues of a supply of oxygen and nutrients. An embolus (stroke) is a dislodged thrombus that moves through the bloodstream and obstructs another vessel (**Figure 2**). The thrombus is formed by aggregations of activated platelets, red blood cells, and cross-linked fibrin protein.

Thrombosis is a common causal pathology for three prevalent cardiovascular disorders: stroke, acute coronary syndrome (ACS), and venous thromboembolism (VTE) [17, 18]. Additionally, the latest statistical study from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) shows that 25% of the people around the world die from thrombosis-related events. As an example of this statistic, a recent study carried out in Chile found the incidence risk rate for thromboembolic diseases among patients under general surgery is 55%, and the main cause of death in Chile is cardiovascular disease [9, 10].

Several clinical trials have confirmed the efficacy of classic anticoagulants, including vitamin K antagonists (VKA), unfractionated heparin (UFH), and low molecular weight heparins (LMWH weight heparin with reduced activity towards thrombin versus UFH) in prevention and treatment of a wide range of arterial and venous thromboembolic disease prevention [21]. Many approaches have been explored in the development of antithrombotic agents which

FXa Direct Synthetic Inhibitors

15

http://dx.doi.org/10.5772/intechopen.76518

Unfractionated heparin (UFH) was discovered in 1916 and it targets multiple factors in the coagulation cascade, but it has a number of disadvantages, including a parenteral route of administration, frequent laboratory monitoring of coagulation activity, and the risk for patients to develop mortal heparin-induced thrombocytopenia. Low-molecular-weight heparins (LMWHs), developed in the 1980s, promote the inactivation of both thrombin (factor IIa) and factor Xa. LMWHs have largely replaced UFH due to its lower risk of causing bleeding, lower levels of plasma protein binding, good bioavailability and superior pharmacokinetic

However, its use remains limited owing to the need for parenteral administration to patients who will eventually need either to be trained to self-inject or to find assistance from a trained nurse. These anticoagulants all have the limitations mentioned above that restrict their use in

Warfarin, which was discovered in 1941, is the prototype vitamin K antagonist (VKA, **Figure 5a** and **b**). Its use and other VKAs' uses are especially problematic, albeit these anticoagulants offer the convenience of oral administration. Until recently, the VKAs were the only available oral anticoagulants and the most commonly prescribed. However, VKAs have a number of well-documented drawbacks, including a slow onset and offset of action, unpredictable pharmacokinetics and pharmacodynamics, variability in response to the dosage, and multiple food-drug and drug–drug interactions. Furthermore, regular monitoring of coagulation and dose adjustments are required to maintain patients in the target international normalized

the clinic and have created the need for new treatments (**Figure 4**) [33–35].

inhibit enzymes in the coagulation pathways [29, 30, 32].

**Figure 3.** Antithrombotic agents' classification, target points, and commercial drugs [20–27].

properties in comparison with UFH.

Besides, it is important to point out that these diseases have a harsh effect on these people's quality of life and health care costs [19]. Clearly, the high prevalence of thrombosis and its serious implications create an urgent need for safe and reliable prophylaxis and treatment.
