**2.4 Protein S**

Protein S is a vitamin K-dependent glycoprotein synthesized by the liver with an important role in coagulation, where it acts as a cofactor for protein C to inactivate coagulation factors Va and VIIIa and also as a cofactor for tissue factor pathway inhibitory protein, leading to inactivation of factor Xa and tissue factor/factor VII. In the human body, protein S exists in two forms—one free and one bound to the complementary protein C4b [13, 14].

Protein S deficiency is an unusual condition caused by quantitative or qualitative abnormalities following point mutations in the PROS1 gene. Mutations are transmitted in an autosomal dominant manner with incomplete penetrance. Homozygous individuals have a higher risk of thrombosis than heterozygous individuals, of whom only an estimated 50% develop venous thromboembolism, the other half remaining asymptomatic. More than 200 genetic mutations have been identified, causing a range of defects, which can be classified into three types—type I is characterized by low levels of total S protein and free S protein, type II total S protein concentrations are normal but with low activity, while type III has normal levels of total S protein but low levels of free S protein [13].

A quantitative or qualitative deficiency of protein S will have great implications in the regulation of coagulation, as the natural anticoagulant mechanisms will be less effective in inactivating coagulation factors Va, VIIIa, and VIIa, thus favoring a thrombosis-prone state.

#### **2.5 Antiphospholipid syndrome**

Antiphospholipid syndrome is an autoimmune-generated hypercoagulable state caused by the presence of antiphospholipid antibodies and is the most common cause of acquired thrombophilia. It is characterized by the presence of at least one of three antiphospholipid antibodies, which are lupus anticoagulant, anticardiolipin antibodies, or antibeta2 glycoprotein antibodies, in addition to one or more clinical manifestations of thrombosis [15, 16].

The condition can be classified into a primary antiphospholipid syndrome, which occurs without a concurrent autoimmune disease, and a secondary antiphospholipid syndrome, in the presence of another autoimmune condition, the most prominent example being systemic lupus erythematosus [15].

Two profile risks for thrombosis have been identified in terms of the type and titer of antibodies present:

A high-risk profile involves one of the following: Thromboembolism risk profile:


A low-risk profile requires transient isolation of anticardiolipin antibodies or antibeta2 glycoprotein antibodies at low-to-medium titers [16].

The mechanisms involved in the generation of hypercoagulability require further investigation, as the few proposed mechanisms cannot exclusively explain this condition. Antiphospholipid antibodies are thought to interfere with platelet and endothelial cell membranes, proteins in the coagulation cascade or inhibit protein C.

The types, isotypes, and titers of antibodies found to correlate directly with the risk of thrombosis risk increases with higher titers, the presence of IgG antibodies, or the identification of lupus anticoagulant [15].

#### **2.6 Malignancy**

Thromboembolic complications in cancer patients are the second leading cause of mortality, presenting in various forms from venous or arterial thrombosis to disseminated intravascular coagulation. Venous thromboembolism is a significant cause of morbidity and mortality, with pulmonary embolism being three times more common than in a person who has developed venous thrombosis but does not have cancer [17, 18].

Other rarer thrombotic complications are also seen more frequently in patients with cancer, such as disseminated intravascular coagulation and thrombotic microangiopathy. Disseminated intravascular coagulation is a condition in which the coagulation cascade is activated systemically, resulting on the one hand in the formation of fibrin deposits that move to different organs blocking microcirculation, and on the other hand consuming clotting factors and platelets, which can lead to life-threatening bleeding [17, 19].

It has long been observed that patients with cancer and thromboembolic disease are strongly associated, but despite this, the mechanisms leading to the hypercoagulable state are numerous, complex, and not yet fully understood. Tumor-specific factors are also thought to play a role, because of the variable risk of thrombosis for different cancers. Returning to Virchow's triad, all three conditions for thrombosis can occur

#### *Anticoagulation in Thrombophilia DOI: http://dx.doi.org/10.5772/intechopen.103038*

simultaneously in a cancer patient, the best example being venous stasis following venous compression by a tumor [17, 18].

Various cancer therapies can also contribute to a prothrombotic state, with many reports suggesting an association between chemotherapy and arterial thrombosis. The most implicated agents are platinum-based therapeutics (cisplatin) and those that interfere with vascular endothelial growth factor, either to inhibit it directly (bevacizumab) or to inhibit its receptor tyrosine kinase (sorafenib) [20].

#### **2.7 Pregnancy**

The hypercoagulable state observed during pregnancy is the result of physiological, hormonal, and physical changes that affect women during pregnancy and in the peri- and post-natal periods.

As a result of hormonal changes, levels of certain clotting factors are increased, such as those of factors VII, VIII, X, von Willebrand factor, and fibrinogen. Meanwhile, during the second and third trimesters, resistance to activated protein C has been observed, as well as decreased activity of protein S. The number of studies has also reported decreased activity of the fibrinolytic pathway, due to an increase in its inhibitors, such as plasminogen activator inhibitor 1 and 2 and activable fibrinolytic inhibitor. All of these changes contribute to a tilting of the coagulation balance toward a prothrombotic state [21, 22].

Physical changes that promote thrombosis include prolonged bed rest in the peripartum period and mechanical compression of the pelvic veins by the gravid uterus, leading to decreased venous return from the lower extremities, consecutive stasis, and the development of venous thrombosis [21].

#### **2.8 Heparin-induced thrombocytopenia**

Heparin-induced thrombocytopenia (HIT) is a condition mediated by the immune system through the development of heparin-dependent antibodies that have activated platelets, thereby increasing the risk of both venous and arterial thrombosis [15, 23].

IgG antibodies are directed against the antigenic complex formed by the binding of platelet factor 4 to heparin on the surface of platelets. This, in turn, activates surrounding platelets, leading to thrombin generation and the procoagulant state with the characteristic clinical manifestations of thrombocytopenia and thrombosis [23].

The diagnosis is confirmed by a decrease in platelets below 150,000/mL or by 50% from baseline in the presence of IgG HIT antibodies. The condition usually develops between 5 and 14 days after the start of heparin treatment, but may also develop within the first 24 hours in the case of previously administered heparin treatment. The risk is higher in surgical patients, especially following orthopedic and cardiac surgery, and is related to the period of exposure to heparin. Although heparin-induced thrombocytopenia is usually the result of treatment with unfractionated heparin, the occurrence of this condition has also been observed after administration of LMWH due to cross-reactivity between the two classes [15].

#### **2.9 SARS-CoV-2**

COVID-19 infection with severe acute respiratory syndrome coronavirus 2 has been shown to lead to a prothrombotic state, with variably reported incidences ranging from 11 to 70%, conditional on case severity and other predisposing factors.

The pathogen is thought to injure the vascular endothelium by attaching spike protein to the angiotensin-converting enzyme 2 receptors, thereby altering the properties of the endothelium into a thrombogenic surface, favoring platelet adhesion, hypercoagulability, and the development of micro or macrothrombosis at this level [11, 24].
