*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].

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

*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].

*Hyperhomocysteinemia* is 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 syndrome* is 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].

*α*2*-Antiplasmin deficiency* also termed as Miyasato disease, is an uncommon autosomal condition associated with bleeding episodes due to hyperfibrinolysis [12].

*Dysfibrinogenaemia* is 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].

*Trauma* is 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].

*Heparin* has 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 "heparininduced 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*:

