**2. Nowadays antithrombotic therapy**

Antithrombotic drugs are used for prevention and treatment of thrombosis. Targeting the thrombi components and the pathology, these agents include *antiplatelet* drugs, *anticoagulants*, and *fibrinolytic* agents [20]. The two first agents act to prevent the thrombus formation during the primary and secondary hemostasis process, while the fibrinolytic agents act when the thrombus is already formed (**Figure 3**) [21].

There is a great variety of commercial drugs for the treatment of antithrombotic pathologies with a wide range of disadvantages and side effects as summarized in **Table 1**.

Various clinical trials have verified the value of standard antiplatelet and anticoagulant agents, which include aspirin (antiplatelet), vitamin K antagonists (VKA) (warfarin), FXa indirect inhibitors (fondaparinux sodium), DTI (argatroban), UFH, LMWH, and TII for wide-ranging prevention and treatment of arterial and venous thromboembolic diseases and cardiovascular pathologies [21–30].

It is evident that, given the prevalence and implications of serious thrombosis, there exists a strong necessity for effective prophylaxis and treatment, and the use of oral anticoagulants is widespread.


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

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 mes-

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

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

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

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.

Antithrombotic drugs are used for prevention and treatment of thrombosis. Targeting the thrombi components and the pathology, these agents include *antiplatelet* drugs, *anticoagulants*, and *fibrinolytic* agents [20]. The two first agents act to prevent the thrombus formation during the primary and secondary hemostasis process, while the fibrinolytic agents act when the

There is a great variety of commercial drugs for the treatment of antithrombotic pathologies

Various clinical trials have verified the value of standard antiplatelet and anticoagulant agents, which include aspirin (antiplatelet), vitamin K antagonists (VKA) (warfarin), FXa indirect inhibitors (fondaparinux sodium), DTI (argatroban), UFH, LMWH, and TII for wide-ranging prevention and treatment of arterial and venous thromboembolic diseases and cardiovascular

It is evident that, given the prevalence and implications of serious thrombosis, there exists a strong necessity for effective prophylaxis and treatment, and the use of oral anticoagulants is

with a wide range of disadvantages and side effects as summarized in **Table 1**.

aggregations of activated platelets, red blood cells, and cross-linked fibrin protein.

sage to the Assembly of the World Health Organization (WHO) [13].

cause chronic leg pain, edema, and ulcers [14–16].

14 Anticoagulant Drugs

main cause of death in Chile is cardiovascular disease [9, 10].

**2. Nowadays antithrombotic therapy**

thrombus is already formed (**Figure 3**) [21].

pathologies [21–30].

widespread.

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

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 properties in comparison with UFH.

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

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


**Table 1.** Disadvantages and side effects of commercial antithrombotic agents [31].

ratio (INR) range. Monitoring of warfarin therapy is critical due to the variability and relatively narrow therapeutic index, which frequently leads to a higher risk of thromboembolism or excessive anticoagulation with subsequent increased risk of bleeding [36, 37].

In recent years, investigation has been focused on novel classes of anticoagulants (small molecules) which target a specific enzyme or coagulation step in the coagulation cascade, including complex inhibitor of factor VIIa-tissue factor, factor IXa inhibitors, and factor XIa, direct thrombin inhibitors, and synthetic direct and indirect inhibitors of Factor Xa (activated Factor X). All of the features mentioned have led to the development of new anticoagulants, includ-

FXa Direct Synthetic Inhibitors

17

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

Factor X or Stuart-Prower Factor named after the male patient named Stuart in 1957 and a female patient named Prower with FX deficiency [45, 46]. Moreover, Factor X has long been known to have a key role in hemostasis and plays a central part in the blood-clotting cascade by catalyzing

the production of thrombin, which leads to clot formation and wound closure [33, 47].

ing direct FXa inhibitors [42–44].

**Figure 5.** (a-b) VKA. (c) Indirect FXa inhibitor.

**3. Clotting cascade: factor Xa function**

**Figure 4.** Chronological development of anticoagulants.

Other drugs available for short-term anticoagulation include UFH, LMWHs, fondaparinux (**Figure 5c**) as an indirect FXa inhibitor, and direct thrombin inhibitors (DTIs) such as argatroban, bivalirudin, and hirudin. All these anticoagulants require parenteral administration with their consequent disadvantage. However, LMWH and VKA are the basis for contemporary thromboprophylaxis and treatment in Chile as it is all around the world. The difficulties and inadequacies around the practical and medical aspects of these anticoagulants have encouraged the development of novel drugs that are less expensive for the patient and the health care system [38–41].

Despite the accumulated understanding of the clotting system, its complexity has provided a considerable number of obstacles to the discovery and development of potent anticoagulants that are simultaneously effective and safe.

**Figure 4.** Chronological development of anticoagulants.

**Figure 5.** (a-b) VKA. (c) Indirect FXa inhibitor.

ratio (INR) range. Monitoring of warfarin therapy is critical due to the variability and relatively narrow therapeutic index, which frequently leads to a higher risk of thromboembolism

• *Betrixaban:* expensive, anemia, skin rash, drug–drug interactions

Fibrinolytics • *Streptokinase:* expensive, hypotension, rash, fever, chills and rigors, blurred vision, confu-

Other drugs available for short-term anticoagulation include UFH, LMWHs, fondaparinux (**Figure 5c**) as an indirect FXa inhibitor, and direct thrombin inhibitors (DTIs) such as argatroban, bivalirudin, and hirudin. All these anticoagulants require parenteral administration with their consequent disadvantage. However, LMWH and VKA are the basis for contemporary thromboprophylaxis and treatment in Chile as it is all around the world. The difficulties and inadequacies around the practical and medical aspects of these anticoagulants have encouraged the development of novel drugs that are less expensive for the patient and the health care system [38–41].

Despite the accumulated understanding of the clotting system, its complexity has provided a considerable number of obstacles to the discovery and development of potent anticoagulants

or excessive anticoagulation with subsequent increased risk of bleeding [36, 37].

**Table 1.** Disadvantages and side effects of commercial antithrombotic agents [31].

**Antithrombotic agent Commercial agents disadvantages and side effects**

resistance

16 Anticoagulant Drugs

insufficiency

Antiplatelet drugs • *Aspirin:* gastrointestinal complaints, allergy, hepatic and renal pathologies, aspirin

sion, caution in patients with coronary artery diseases • *GPIIb/IIIA receptor antagonists*: bleeding, thrombocytopenia.

Anticoagulants • *Heparin, UFH, and LMWH:* parenteral administration, bleeding, thrombocytopenia,

increasing level of bilirubin, osteoporosis. • *Fondaparinux:* bleeding, there is no antidote

• *Dabigatran etexilate:* bleeding, renal excretion

• *Rivaroxaban:* expensive, renal excretion

• *Thienopyridines:* gastrointestinal complaints, hematologic side effects

• *Dipyridamole:* gastrointestinal complaints, headache, facial flushing, dizziness, hypoten-

• *Lepirudin, bivalirudin, argatroban:* parenteral administration, serious bleeding, hepatic

• *Warfarin or acenocoumarol:* only 3% of administered warfarin is biologically active due to its binding to albumin, narrow therapeutic window, frequent monitoring, drug-food and drug–drug interactions, interference with the synthesis of vitamin K-dependent clotting proteins (FII, FVII, FIX and FX), bleeding, skin necrosis, and fetal abnormalities.

• *Apixaban:* expensive, only for major orthopedic surgery, anemia, hemorrhage, nausea

sion, dizziness, faintness, unusual tiredness or weakness, drug–drug interactions. • *Urokinase:* bleeding gums, difficulty with breathing or swallowing, headache, increased menstrual flow or vaginal bleeding, nosebleeds, paralysis, prolonged bleeding from cuts • *Anistreplase, alteplase, tenecteplase, reteplase:* hemorrhage or hematoma formation at the site of venipuncture, gastrointestinal and genitourinary tract hemorrhage, blood in urine

that are simultaneously effective and safe.

In recent years, investigation has been focused on novel classes of anticoagulants (small molecules) which target a specific enzyme or coagulation step in the coagulation cascade, including complex inhibitor of factor VIIa-tissue factor, factor IXa inhibitors, and factor XIa, direct thrombin inhibitors, and synthetic direct and indirect inhibitors of Factor Xa (activated Factor X). All of the features mentioned have led to the development of new anticoagulants, including direct FXa inhibitors [42–44].
