Anticoagulants and Hypercoagulability

Abstract

Anticoagulants are chemical substances that prevent coagulation or prolong the clotting time by suppressing the functions or synthesis of coagulation factors in the blood. Anticoagulation mechanisms are essential in controlling the formation of a blood clot at the site of injury. The abnormalities in the coagulation and fibrinolytic mechanisms could lead to a hypercoagulability state. Inherited hypercoagulable state due, including Factor V Leiden (FVL), prothrombin gene mutation, defective natural proteins that inhibit coagulation, including antithrombin III (ATIII), protein C and S, high levels of FVII, FIX and FXI, are well-documented. Abnormalities of the fibrinolytic system, including tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA), and elevated levels of plasminogen activator inhibitor-1 (PAI-1) have been linked to hypercoagulation. Acquired conditions, including certain cancers and their medications, trauma or surgery, pregnancy, obesity and hyperlipidaemia, have been implicated with hypercoagulable events. The clinical symptoms of hypercoagulability can be devastating and may even have lethal outcomes. This activity reviews the principles of anticoagulation, haemostasis, deficiencies associated with hypercoagulability (both coagulation and fibrinolytic disorders), mechanisms of action of some natural-based products with anticoagulant potentials and highlights new clinical and traditional therapeutic strategies to be taken in improving healthcare for patients demanding anticoagulation.

1. Introduction

Haemostasis is a protective process that regulates and maintains stable physiology in the system. The physiology of haemostasis is extremely complex and reflects a delicate balance between the constant blood flow and immediate localised response to vascular injury. The process of haemostasis is traditionally divided into a cellular phase (involving platelets), known as the primary haemostatic phase and a fluid phase (involving plasma proteins), also called the secondary haemostatic phase [1]. It associates with other body defence mechanisms, including the immune system and the inflammatory responses [2]. During vascular injury, the increased blood pressure exerted in the blood circulation requires powerful and regulated localised pro-coagulant responses to minimise blood loss without compromising blood flow. Systemic anticoagulant and fibrinolytic components in other ways are also developed to inhibit the extension of the pro-coagulant responses to escalate beyond the vascular endothelial control, which may result in thrombotic formation. Thus, the haemostatic system is defined as a complex, highly regulated and integrated process, comprising both activators and inhibitory pathways, including blood vessels, platelets activities, coagulation and fibrinolytic system together [3]. While the coagulation cascade is aimed at fibrin formation through the production of thrombin, which is converted to fibrinogen (FN) and subsequently to fibrin, in the fibrinolytic system, plasmin is the main enzyme that plays a key role in dissolving the already formed clots by degrading fibrin. Physiological anticoagulation mechanisms function to suppress thrombin generation or inhibit its effects. Alterations to these mechanisms could lead to hypercoagulable states. This chapter will focus on the mechanisms associated with anticoagulation and defects of the anticoagulation mechanisms, leading to hypercoagulable states. The review also gave a concise description of the clinical approaches and traditional intervention to minimise the effects of hypercoagulability, which may progress to cardiovascular diseases (CVDs).

2. Haemostasis

2.1 The crosstalk between coagulation cascade and fibrinolytic system

Knowledge of the universal sequence of events in haemostasis can give vital information to the progress and development of thrombosis [4]. Within the blood coagulation cascade, the extrinsic pathway is mostly activated by vascular endothelial injury. In contrast, the intrinsic pathway is triggered solely through Factor XII (FXII) exposure on the thrombogenic surface. Even though separated, these pathways are interconnected at several points [4]. Both extrinsic and intrinsic pathways are linked to initiating the common pathway, which terminates at the formation of fibrin clots that are subsequently degraded by plasmin during fibrinolysis (Figure 1) [5]. Within the damaged endothelium, platelet adhesion and activation are promoted by the extremely exposed thrombogenic subendothelial extracellular matrix (ECM). Through its interactions with proconvertin (FVII), tissue factor (TF) initiates the coagulation cascade by converting prothrombin to thrombin. During secondary haemostasis, the thrombin generated triggers FN generation, which is converted to an insoluble fibrin plug that formed a fibrin mesh network together with aggregated platelets [4]. These assist to stop the blood flow, thus ensuring “haemostasis” and the final step of the coagulation cascade [6]. At the “thrombus”, the circulating blood cells become trapped into the fibrin structure, and fibrin cross-linked is accomplished by Factor XIII activator (FXIIIa), which is promoted by the thrombin, leading to solid structural stability and the initial step of the fibrinolytic system [7].

Figure 1.

Coagulation cascade and its interrelationship with the fibrinolytic system. Both extrinsic and intrinsic pathways of the coagulation cascade join to initiate the activation of FX of the common pathway. These unite to a fibrin clot, which is eventually degraded by plasmin in the fibrinolytic system.

During the repair process, the generated thrombus is destroyed by plasmin activities, produced by its zymogen plasminogen, tissue-type plasminogen activator (t-PA) or uPA on the fibrin clot [8]. Proteolysis of fibrin generates soluble fibrin degradation products (FDPs). The fibrinolytic system is extremely controlled by a protease enzyme inhibitor known as plasminogen activator inhibitor-1 (PAI-1), synthesised by endothelium, adipose tissue and the liver. The PAI-1 serves as a potent irreversible inhibitor of plasminogen activators, including t-PA and uPA, which convert plasminogen to plasmin, to promote fibrinolysis. The major plasminogen activator is t-PA, which has a high affinity to fibrin. The t-PA is secreted by endothelial cells or synthesised locally following the activation of endothelium by histamine, adrenalin, thrombin, FXa and hypoxia [9]. The u-PA is another plasminogen activator secreted by several cells, such as fibroblasts, epithelial cells and the placenta. The indigenous form of uPA is transformed into a two-chain protein by plasmin or following stimulation by the contact factors, such as FXII, prekallikrein and high molecular weight kininogen (HMWK) (Figure 1) [10]. The uPA and t-PA convert plasminogen into plasmin through urokinase plasminogen activator-receptor (uPA-R) and LDL-receptor related protein-1 (LRP-1) respectively [11].

2.2 Anticoagulants and the mechanisms of action

Generally, anticoagulants exert their effects at different points of the coagulation cascade. Certain anticoagulants function directly as enzyme inhibitors, while some act indirectly by binding to antithrombin (AT) or inhibiting their production in the liver, such as vitamin K-dependent factors (Figure 2) [12].

Figure 2.

Mechanisms of Anticoagulation. The anticoagulation system inhibits coagulation through a delicate balance between the activators and inhibitors of the coagulation cascade. At the fibrinolytic system, the balance between the activators of the fibrinolysis, including t-PA and u-PA and inhibitors, such as PAI-1 and α2-AP ensures the inhibition of fibrin formation or immediate dissolution of fibrin when it is formed. TF; tissue factor, TFPI; tissue factor pathway inhibitor, TAFI; thrombin activatable fibrinolysis inhibitor, EPCR; endothelial protein C receptor, ZPI; protein Z-dependent protease inhibitor, PZ; protein Z, TM; thrombomodulin, PC; protein C, APC; activated protein C, PS; protein S, HCII; heparin cofactor II, TM; thrombomodulin, t-PA; tissue-type plasminogen, u-PA; urokinase-type plasminogen activator, PAI-1; plasminogen activator inhibitor-1, α2-AP; α2-antiplasmin, FDP; fibrin degradation products. The dashed arrows indicate inhibition while thick arrow lines indicate activation.

2.2.1 The mode of actions of the common anticoagulants

1. Vitamin K dependent anticoagulant

Coumarin and its derivatives are a class of vitamin K–dependent anticoagulants (VKAs). Warfarin is the most common anticoagulant agent currently in use. It functions to inhibit vitamin K epoxide reductase (VKOR), which is necessarily required for the gamma-carboxylation of vitamin K-dependent factor, including factors II, VII, IX, X and protein C and S. Inhibition of vitamin K carboxylation triggers the decreased hepatic synthesis activity of clotting factors, leading to an anticoagulated state. Bleeding is the most common complication associated with warfarin therapy and is related to exponentially higher international normalised ratio (INR) values. The goal of the management is to reduce the INR back to a therapeutic safe level and hence are monitored by the value of the INR [13]. The dose-effect is narrow, and its actions are altered intensely by some factors, such as vegetables, greenleaf, some certain fruits, some drugs while inherited mutations in the VKOR complex may lead to resistance [12].

1. Unfractionated heparin (UFH)

Heparin forms a complex with antithrombin III (ATIII) and inactivates several coagulation factors, including FVII. It has a rapid onset of action and a short half-life. Heparin is monitored by activated partial thromboplastin time (aPTT) and anti-Factor Xa activity. The ratio of 1.5–2.2 times is the recommended target for aPTT [12].

1. Low molecular weight heparin (LMWH)

Nadroparin, enoxaparin, and tinzaparin have a shorter half-life compared to UFH. However, LMWH is not necessarily monitored unless in some conditions, such as pregnancy and renal failure [12].

1. Fondaparinux sodium

Fondaparinux sodium also called “Arixtra”, is a new class of synthetic pentasaccharide anticoagulants that bind to ATIII and indirectly inhibit the action of factor Xa. It has a similar mode of action to LMWH but has a longer half-life (17–21 h) than heparin. It does not prevent thrombin generation or interact with platelets but could be an essential and effective alternative to LMWH for the treatment of VTE following an orthopaedic surgical procedure. Fondaparinux is administered subcutaneously and excreted by unsaturated renal filtration [1].

1. Idrabiotaparinux sodium

Idrabiotaparinux sodium is another related family also injected subcutaneously once a week. It has a similar chemical structure and mode of action as fondaparinux but with a half-life of about 5–6 times longer than fondaparinux (fondaparinux’s 17 hours to about 80 hours), indicating that the drug needs to be administered only once a week. The biotin attached to its structure allows its neutralisation with avidin, an egg-derived protein with low antigenicity [2].

1. Inhibitors of FXa

Rivaroxaban, apixaban, edoxaban, betrixaban, apixaban and edoxaban are the common types of FXa inhibitors. They act by inhibiting the cleavage of prothrombin to thrombin through binding to FXa. They do not usually require constant monitoring [14].

1. Inhibitors of thrombin

Bivalirudin and dabigatran are common examples of thrombin inhibitors. They act by inhibiting the cleavage of FN to fibrin and are metabolised in the kidney [12].

2.3 Important pathways associated with anticoagulation mechanisms

2.3.1 In the anticoagulant system

Protein C pathway:Protein C is a vitamin K-dependent serine protease produced in the liver and metabolised to its active form, known as activated protein C (APC) by thrombin. It is a strong anticoagulant that degrades FVa and FVIIIa and limits the coagulation process. The effect of APC is hindered by protein C inhibitors, such as α₂- macroglobulin and α₁-antitrypsin [15].

Thrombomodulin (TM)is a trans-membrane receptor available on endothelial cells. TM binds to thrombin to form a TM–thrombin complex that increases the synthesis of APC through which thrombin efficiently functions as an anticoagulant, that inhibits clot generation on the undamaged endothelium area [15].

Protein Sis a vitamin K-dependent glycoprotein produced by hepatocytes and endothelial cells. It acts as cofactor to APC in the deactivation of FVa and FVIIIa. It is available in the plasma in many forms but only the free form shows anticoagulant activity. It also has anticoagulant activities independent of APC, such as direct reversible suppression of the prothrombinase (FVa–FXa) complex [15].

Tissue factor pathway inhibitor (TFPI)is a polypeptide synthesised by the endothelial cells and circulates in the plasma. It is the major inhibitor of the TF pathway, named the extrinsic pathway. It inhibits the coagulation cascade through the binding of the circulating FVIIa, that has been exposed to TF. It also binds to FXa to establish a TFPI–FXa complex, which reversibly inhibited FXa. Protein S facilitates the reaction between the TFPI and FXa in the presence of calcium ions and phospholipid, the activity of which is independent of APC [15].

Protein Z-dependent protease inhibitor (ZPI)has been recently identified as the component of the anticoagulant system. It is a plasma enzyme synthesised by the liver. It suppresses FXa activities in an interaction that involves both PZ and calcium. The PZ is a vitamin K-dependent glycoprotein and acts as a cofactor for ZPI [15].

2.3.2 In the fibrinolytic system

Plasmin or plasminogenis the major enzyme of the fibrinolytic system produced in the liver, as plasminogen proenzyme is released into the circulation. Although it could not cleave fibrin but has an affinity to fibrin, which is incorporated in the clot and transformed to plasmin through the t-PA and u-PA. Plasmin acts as a serine protease that cleaves fibrin to form soluble FDP. Plasmin exhibits positive feedback on its production [15].

Plasminogen activators:The t-PA is a serine protease that is released into the blood through the damaged endothelial cells. It binds to fibrin and converts clot-bound plasminogen to plasmin. The t-PA significantly contribute to the dissolution of fibrin and the maintenance of vascular integrity. The u-PA is found in the blood and ECM. It binds to a specific cell surface receptor known as the u-PAR, which stimulate the cell-bound plasminogen [15].

Fibrin as a cofactor:t-PA and plasminogen can bind to fibrin and form a tertiary complex, which is essential for plasmin formation. Thus, fibrin serves a dual purpose as a cofactor for plasminogen activation and a final substrate for plasmin generation. The partly degraded fibrin by plasmin offers much more efficient binding sites for plasminogen, which allows for the deposition of plasminogen on the clot, resulting in facilitated plasmin formation clot lysis [16].

Inhibitors of fibrinolysis (plasminogen activator inhibitors):The PAIs inhibit the progress of plasminogen to plasmin. Many types of PAIs have been identified and documented, but PAI type-1 has been investigated as the major physiological inhibitor. It is a glycoprotein produced by several cell types, such as megakaryocytes, endothelial cells, hepatocytes, and adipocytes. PAI-1 suppresses fibrinolysis by irreversibly inhibiting t-PA and u-PA. PAI-1 is taken up during the process and thus described as a ‘suicide inhibitor’ [16].

The a₂-Antiplasmin (a₂-AP)is the main inhibitor of plasmin. It is a circulating glycoprotein synthesis by the liver, which suppresses plasmin activity in one of the fastest proteins–protein interactions. The α₂-Macroglobulin is also produced by the liver and has been recognised as the secondary inhibitor of plasmin in plasma. It functions to deactivate plasminogen activators, APC, and thrombin [16].

Thrombin activatable fibrinolysis inhibitor (TAFI)is a plasma proenzyme that is produced by the liver and described as procarboxypeptidase U (unstable procarboxypeptidase), plasma procarboxypeptidase B, or procarboxypeptidase R. It is stimulated to carboxypeptidase by thrombin. TAFIa creates a useful link between coagulation and fibrinolytic systems. It removes lysine (and arginine) residues from the C-terminal of fibrin, which is essentially required for the binding of plasminogen to t-PA. This makes fibrin an ineffective co-factor, which lead to a decreased t-PA-mediated plasminogen activation. It also enhances the inhibition of plasmin by a₂-antiplasmin [15].

2.4 Diseases of the anticoagulant system (hypercoagulable states)

2.4.1 Virchow’s triad

In 1845, the German physician, anthropologist, pathologist, prehistorian, and biologist, Rudolf Ludwig Carl Virchow hypothesised that three factors are important to the development of thrombosis; vascular endothelial injury, haemodynamic alterations and hypercoagulability, which interact with each other (Figure 3) [17]. The vascular endothelial injury was identified first as the main initiator of arterial thrombosis alongside traumatic or endocardial damaged. Moreover, the dysfunctional endothelial cells can secrete a significant concentration of procoagulant agents, including platelet adhesion molecules, TF, and PAI-1 while generating little anticoagulant effectors, such as TM and PCL [18]. The haemodynamic changes may promote procoagulant activities and leucocytic adhesions by modifying the gene expression of the endothelial cells. Although blood stasis is the main trigger for venous thrombosis, turbulent blood flow could also facilitate cardiac and arterial thrombosis. In hypercoagulability, blood clotting factors themselves facilitate thrombogenesis through heritable hypercoagulable states, such as mutations in Factor V Leiden (FVL) and prothrombin. Additionally, disseminated intravascular coagulopathy (DIC), heparin-mediated thrombocytopenia, and Trousseau’s syndrome have been linked with hypercoagulability [18].

Figure 3.

Mechanisms of Virchow Triad in the Pathophysiology of Thrombus Formation: Rudolf Virchow proposed a triad of conditions that predisposes to thrombotic formation. They include abnormalities in the blood vessel wall, blood stasis and hypercoagulability. Inflammation, endothelial dysfunction, and atherosclerosis constituted abnormalities in the blood vessel wall. Abnormal blood flow arises from haemorheology and turbulence at bifurcations and stenotic sites. The hypercoagulability encompasses the abnormal blood constituents, including dysfunctional platelet, coagulation and endogenous fibrinolytic abnormalities, and metabolic factors.

Hypercoagulability or thrombophilia defines a pathologic condition of exaggerated coagulation or coagulation without bleeding episode. It represents the increased risk for thrombose [19]. Hypercoagulability states are either acquired or inherited but real thrombosis originates as a result of interactions of both genetic and environmental agents. It encompasses a wide range of coagulation abnormalities characterised by a thrombotic event, such as deep vein thrombosis (DVT) and pulmonary embolism (PE). Congenital hypercoagulability included prothrombin G20210A gene mutation, deficiencies in protein C and protein S, AT deficiency and a single-point mutation on the FVL. Acquired conditions usually result from trauma or surgery, certain medications while the APS has been identified as the most common acquired thrombophilia in the general population [20]. The genetic abnormalities of the fibrinolytic system are not common, however, the acquired hyperfibrinolysis has been identified as the major cause of severe haemorrhage [15].

2.4.2 Agents of hypercoagulability

Antithrombin III (ATIII) deficiency: ATIII inhibit coagulation by binding to heparin of the endothelial cells and forms a complex with thrombin [thrombin-antithrombin (TAT) complex]. The deficiency could manifest as an early age thrombosis and have the highest risk of thrombotic events among the hypercoagulable disorders. The incidence rate may be 1:500 in the general population. ATIII is produced in the liver independent of vitamin K. Its deficiency could occur because of decreased synthesis or increased loss, due to nephrotic syndrome, microangiopathy, and cardiopulmonary bypass surgery, enteropathy, DIC, sepsis, burn, and trauma [21]. Qualitative deficiency of ATIII, also known as a type-II deficiency, defines mutations that either involves the heparin-binding site (HBS), the reactive site (RS), leading to pleiotropic effects (PE), characterised by normal ATIII levels but with decreased activity [22].

Protein C and S deficiencies: Protein C and S deficiencies might be inherited but are sometimes inducible by some other conditions, including vitamin K antagonists, liver dysfunction, renal failure, DIC, and active thrombosis. Protein S promotes the activity of the enhanced protein C. The aetiology of acquired protein S defects are similar to acquired protein C deficiency, including warfarin therapy, liver cirrhosis, pregnancy, chronic disease and vitamin K deficiency. Protein C binds to TM and becomes APC. APC has been reported to exhibit anti-inflammatory, anticoagulant, and cytoprotective activities. It inactivates coagulation FV and VIII while FVL mutation is a major cause for APC resistance and the most prevalent genetic thrombophilia [22].

The FV Leiden mutation: Is the most frequent inherited risk factor for thrombophilia. The FV Leiden mutation is believed to increase the risk of arterial thrombosis. It increases the chance of thrombosis by facilitating the synthesis of thrombin [21].

The prothrombin G20210A mutation: Prothrombin also known as FII, is the precursor of thrombin, known to be associated with a single point mutation. The prothrombin G20210A mutation is the second inherited risk factor for thrombosis. It leads to increased levels of prothrombin that shows an increased risk for arterial and venous thrombotic events caused by a single point mutation [15].

Hyperhomocysteinemiais characterised by premature thrombosis initiated by defective methionine metabolic pathway. Deficiencies of vitamin B₆, B₁₂, folate or defective enzymes activities, including cystathionine beta-synthase (CBS) or methylenetetrahydrofolate reductase (MTHFR), inhibit the effects of homocysteine metabolism. Other factors, such as hypothyroidism, renal failure, certain medications, including methotrexate, phenytoin, and carbamazepine improve homocysteine levels [23].

Elevated factor VIII (FVIII)is associated with an increased chance of thrombosis. An ABO blood group O individuals present with the lower levels of FVIII. An increased concentration of FVIII is linked with APC resistance irrespective of FV mutation while its low levels correlate with haemophilia A patients bleeding [22].

The sticky platelet syndromeis an autosomal dominant disorder through which platelets interacts with epinephrine or adenosine diphosphate (ADP) to stimulate hypercoagulability [15].

Antiphospholipid syndrome (APS)is the common acquired thrombophilia in which the antibodies are directed against phospholipids of cell membranes. The conditions occur in 3%–5% of the general population and are associated with arterial and venous thrombosis, sometimes leading to foetal loss. The diagnosis of antiphospholipid antibodies (APLAs) included lupus anticoagulant (LA), anti-beta-2-glycoprotein and anticardiolipin that lead to the prolongation of coagulation (aPTT) [19].

The interrelationship between inflammation and the coagulation system: Inflammation promotes a hypercoagulable state. The activation of the complement system by endotoxin lead to thrombocytopenia and hypercoagulability. The association between inflammation and coagulation was demonstrated in subjects with vasculitis, septic thromboembolism and purpura [24]. While coagulation inhibits the accumulation of infection, certain bacteria utilise fibrinolytic activities to counteract the effects. For instance, autoimmune conditions, such as immune thrombocytopenic purpura, polyarteritis nodosa, polymyositis, dermatomyositis, systemic lupus erythematosus, dermatomyositis, inflammatory bowel disease, and Behcet’s syndrome, all facilitate the progress to thrombotic events [25].

Disorders of the fibrinolytic system, including plasminogen, dysfibrinogenemia, t-PA and FXII deficiencies, which are involved in plasmin generation, as well as an increase in PAI levels. Plasminogen defects clinically have similar thrombin manifestation to protein C deficiency at an early age. Inherited conditions of the fibrinolytic system are uncommon, and when the deficiency resulted in a hyperfibrinolytic state, then it could lead to a bleeding episode. Mutations that suppress the fibrinolytic system could predispose to thromboembolic events [15].

Plasminogen deficiency: Type-1 plasminogen deficiency, termed hypoplasminogenaemia, is a quantitative abnormality associated with decreased amounts and activities of plasminogen, characterised by hydrocephalus and uncommon inherited conjunctivitis. Type II plasminogen deficiency, known as dysplasminogenaemia, attributed to decreased activities of plasminogen due to a malfunctioning plasminogen molecule [26].

PAI-1 deficiency: Inherited PAI-1 defect is uncommon and is characterised by mild-to-moderate bleeding aggravated by trauma or surgery. It is associated with certain conditions of menorrhagia [26]. High PAI-1 levels have been investigated in certain conditions, including coronary artery disease, obesity, hyperlipidaemia, diabetes mellitus, and might be associated with the increased chance of arterial thrombosis in these disorders [15].

α₂-Antiplasmin deficiencyalso termed as Miyasato disease, is an uncommon autosomal condition associated with bleeding episodes due to hyperfibrinolysis [12].

Dysfibrinogenaemiais a condition associated with the presence of abnormal FN. The symptoms might present either a bleeding tendency, a tendency to thrombosis or a predisposition to both bleeding and thrombosis. While inherited dysfibrinogenaemia is rarely seen, the acquired dysfibrinogenaemia might be present in certain conditions, including multiple myeloma, trauma patients, liver cirrhosis, amniotic fluid embolism, and conditions with an elevated synthesis of t-PA. This disorder could lead to DIC and severe haemorrhage [26].

Common acquired hypercoagulable states:

Smoking: Tobacco has been shown to contain several toxic compounds, including nicotine, which cause significant damage to endothelial cells. Tobacco smoke could inhibit the release of t-PA and TFPI while carbon monoxide promotes the permeability of lipid to the endothelium, which could further progress the formation of atheroma [19].

Traumais the common type of is acquired hypercoagulable state. The imbalance between the procoagulant and anticoagulant agents is more pronounced within the first 24 hours of injury. The multiorgan failure due to respiratory distress syndrome following trauma has been linked with the increased TF levels [19].

Pregnancy: During pregnancy, the imbalance between the elevated procoagulants and the decrease in the anticoagulants, including t-PA, in addition to stasis are triggered by compression of the gravid uterus. Pregnancy increases the time of hypercoagulability during the postpartum period [27].

Heparinhas been prescribed as an anticoagulant but under certain conditions, prolonged heparin administration has been reported to paradoxically cause arterial and venous thrombosis concomitantly with thrombocytopenia, known as “heparin-induced thrombocytopenia (HIT)” [19].

Endogenous and exogenous hormones influence coagulation: Existing reports have shown that oral contraception and hormone therapy could facilitate thrombosis, leading to cardiovascular events. Testosterone therapy has been implicated with thrombotic risk by increasing blood pressure, hyperviscosity, platelet aggregation, and haemoglobin cholesterol [28, 29].

Other acquired hypercoagulability states include:

• Certain medications, such as those prescribed to treat certain cancers, including thalidomide, tamoxifen, bevacizumab, and lenalidomide

• Central venous catheter placement, hyperlipidaemia, obesity

• Prolonged immobility, inactivity or bed rest

• Heart attacks, including cardiac heart failure, stroke pelvic artery diseases, etc.

• Long-distance aeroplane travel, known as “economy class syndrome”

• Previous history of DVT or PE

• Myeloproliferative, including polycythaemia vera or essential thrombocytosis

• Paroxysmal nocturnal haemoglobinuria

• Inflammatory bowel syndrome

• HIV/AIDS

• Nephrotic syndrome (too much protein in the urine).

2.5 Investigations of hypercoagulability

Hypercoagulability has been recognised as an abnormal complex condition of the haemostasis and as such, the diagnosis of hypercoagulability syndromes involves a combination of associated risk factors, screening tests and confirmation tests [21]. Assessment guidelines vary between medical associations. Some associations suggested that young patients with unprovoked or recurrent VTE, patients with a strong family history of abnormal blood clotting, patients with a recurrent blood clot, women with a history of recurrent miscarriage, stroke at a young age, thromboses in unusual sites, such as hepatic, renal, cerebral, mesenteric, neonatal purpura fulminans, warfarin-induced skin necrosis, and foetal loss should be screened for haemophilia. Also, patients with a history of suspected APS, unexplained prothrombin time (PT), thrombin time (TT), may require APS investigation, screening for APLAs and the diluted Russell venom viper test (dRVVT) [21].

The baseline investigations for hypercoagulability states, including routine coagulation studies, such as aPPT, which measures the blood clot time, usually to monitor heparin treatment, prothrombin time (PT) test is used to calculate INR, to monitor warfarin (Coumadin) treatment, FN levels, d-dimer and complete blood counts (CBC) should be carried out. The most advanced and essential screenings for thrombophilia include functional assays for ATIII, protein C and S deficiencies, PCR for prothrombin G2021A mutation and FVL mutation, testing for APLAs and homocysteine levels [19].

Screening for undetected cancer and unexplained VTE in older patients, including patients history and physical examination, ESR, hepatic and renal function tests, urinalysis, and chest X-ray (XR), tumour markers, CT of the chest, abdomen and pelvis mammography in women above 40 years [20], prostate ultrasound in men of more than 50 years, lower endoscopy, Papanicolaou smear and faecal occult blood test are recommended. In patients with hypercoagulability syndromes, there is an increased risk of venous thrombosis than ischemic stroke. Existing evidence has indicated that venous thrombosis could progress to arterial strokes by paradoxical embolism, therefore young adults with stroke should be screened for venous thrombosis, as the incidence of stroke is gradually increasing in young adults. The report has indicated an association between the homocystinuria and APLA syndrome with arterial strokes, and stroke has been investigated as the common arterial condition progressing to APLA syndrome. Hence, screening for APLA syndrome should be performed on stroke patients younger than 45 years [19].

2.5.1 Other tests to investigate acquired hypercoagulable states

Anticardiolipin antibodies (ACA) or beta-2 glycoproteins, LA, which are part of the APLA syndrome, to evaluate patients with recurrent miscarriage and venous or arterial thrombosis. Heparin antibodies (in patients who have decreased platelet counts after exposure to heparin) [19].

2.6 Management of hypercoagulability

Anticoagulant medications includesynthetic drugs, including warfarin (Coumadin), which is taken orally, heparin, which is given either intravenously (IV), or subcutaneously. LMWH is injected also subcutaneously, fondaparinux (Arixtra) is also injected subcutaneously and are the most commonly prescribed drug available worldwide [19, 26].

The ATIII can be substituted for inherited or acquired defects, such as enhanced consumption in DIC and sepsis. Fresh frozen plasma (FFP) for the maintenance of natural balance between procoagulant and anticoagulant factors [30]. Also, various types of anticoagulants and antiplatelets are established to treat recurrent VTE [31], such as vitamin K antagonist (VKA), aspirin (as evaluated in the WARFASA and ASPIRE trials), rivaroxaban (EINSTEIN trial), dabigatran (RE-MEDY and RE-SONATE trials), and apixaban (AMPLIFY trial. The CLOT trial also evaluated LMWH against warfarin in cancer patients and was approved by food and drugs administration [32], rosuvastatin was approved for the prevention of occurrence of VTE [19].

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:

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 cardio-protective activity since garlic can attenuate lipids profile through the inhibition of cholesterol biosynthesis, reduction of LDL, ameliorate arterial hypertension, and prevent platelet aggregation [48, 49, 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].

4. Conclusion

The anticoagulant mechanisms maintain the constant blood flow while inhibiting the progress to hypercoagulable states. The process of maintaining the delicate balance between the coagulation system, the integrity of the haemostasis and the significant contributions of the various system involved is continuous. Supplementation with traditional medications could be beneficial in the treatment and prevention of hypercoagulable states. Further studies are required to evaluate the new classes of anticoagulants and traditional medications with anticoagulant potentials towards improving healthcare to the patients demanding hypercoagulable therapy.