**4. Acquired risk factors for venous thrombosis**

VTE due to genetic risk factors (familial or hereditary thrombophilia), discussed above, mostly occur at ages less than 40 years, and they often recurrent. However, there are several acquired risk factors that are usually associated with VTE at above 40 years of age (Florell & Rodgers, 1997).

### **4.1 Lupus Anticoagulants (LA)**

LA is a member of a group of autoantibodies (immunoglobulins) against phospholipids, including anticardiolipin and anti-β2-glycoprotein, which are produced in different autoimmune conditions. They often cause clinical manifestations like thrombosis, pregnancy loss and others, and the clinical condition is termed Antiphospholipid Syndrome (Hoffbrand et al., 2001; Laffan & Manning, 2002b; Ehsan & Plumbley, 2002). LA were given this name in 1972 because they were recognized initially in a patient with systemic lupus erythematosus (SLE) who had bleeding problems. However, later studies confirmed the association of LA with VTE, and not bleeding, but the name persisted (Greaves & Preston, 1991; Bengtsson et al, 1996; Ehsan & Plumbley, 2002). Although the mechanism of causing

Other mutations in the factor V gene were later identified, including Factor V Cambridge (Arg306Thr) (Williamson et al., 1998), Factor V Hong Kong (Arg306Gly) (Chan et al., 1998), Factor V Liverpool (Ile359Thr) (Mumford et al, 2003), and Factor V Kuwait (His1254Arg) (Jadaon et al., 2006). The number of cases reported to have these mutations were small and the relationship with VTE could not be well established like FVL, although many of these cases were reported in patients with VTE. Another mutation in the factor V gene called HR2 Haplotype (His1299Arg) was identified in 1996, which is discussed separately in the

In 1996, a new missense mutation in exon 13 of factor V gene (A4070G) was identified (Lunghi et al., 1996). This mutation leads to an amino acid change, replacing histidine with arginine at amino acid residue position 1299 (His1299Arg). The new mutation was first assigned the name R2 polymorphism because of the use of the restriction enzyme Rsa I in the test used to detect it. Later on, R2 polymorphism was found to be in tight association with at least 12 polymorphisms in the factor V gene. Therefore, these SNPs were collectively called HR2 (Haplotype R2) (Bernardi et al., 1997; Castoldi et al., 2000). Several studies in different parts of the world gave the prevalence of HR2 to be 9.5%–15.2% in VTE cases and 5.8%–10.4% in healthy controls, with an increased risk by at least 2.5-fold (Bernardi et al., 1997; Alhenc-Gelas et al., 1999; Castoldi et al., 2000; Pecheniuk et al., 2001; Margaglione et al., 2002; Castaman et al., 2003; Faioni et al., 2004; Jadaon & Dashti, 2005a). The exact mechanism by which HR2 haplotype increases the risk for development of VTE is still not that clear. However, Castoldi et al (2000) have studied the two isoforms of factor V, V1 and V2, in cases with or without HR2. V1 is 7-fold more thrombogenic than V2. They showed that V1 was present in cases with HR2 more than in cases without the haplotype. This may give a possible explanation for the hypercoagulation and increased risk of developing VTE in carriers of HR2. However, more studies may be needed before understanding the real

VTE due to genetic risk factors (familial or hereditary thrombophilia), discussed above, mostly occur at ages less than 40 years, and they often recurrent. However, there are several acquired risk factors that are usually associated with VTE at above 40 years of age (Florell &

LA is a member of a group of autoantibodies (immunoglobulins) against phospholipids, including anticardiolipin and anti-β2-glycoprotein, which are produced in different autoimmune conditions. They often cause clinical manifestations like thrombosis, pregnancy loss and others, and the clinical condition is termed Antiphospholipid Syndrome (Hoffbrand et al., 2001; Laffan & Manning, 2002b; Ehsan & Plumbley, 2002). LA were given this name in 1972 because they were recognized initially in a patient with systemic lupus erythematosus (SLE) who had bleeding problems. However, later studies confirmed the association of LA with VTE, and not bleeding, but the name persisted (Greaves & Preston, 1991; Bengtsson et al, 1996; Ehsan & Plumbley, 2002). Although the mechanism of causing

following section.

**3.11 HR2 haplotype** 

mechanism involved in that.

**4.1 Lupus Anticoagulants (LA)** 

Rodgers, 1997).

**4. Acquired risk factors for venous thrombosis** 

VTE is still not clear, the involvement of phospholipids in the Coagulation process and its regulators may give a possible explanation. In fact, there are *in vitro* evidences that LA lead to inhibition of APC, AT and fibrinolysis, and increase in expression of TF. In addition, LA were shown to directly contribute to hypercoagulability in animal models (Roubey, 1994; Kinev & Roubey, 2008; Farmer-Boatwright & Roubey, 2009). The prevalence of LA was reported to be up to 20% of VTE cases, with up to 10-fold increased risk of developing VTE (Ghosh et al., 2001; Galli et al., 2002; Ehsan & Plumbley, 2002; Jadaon & Dashti, 2005b; Farmer-Boatwright & Roubey, 2009; Anderson & Weitz, 2010).

#### **4.2 Pregnancy, childbirth and hormone therapy**

Pregnancy and delivery (and post-delivery up to 6 weeks after childbirth) account for more than 6-fold increased risk of developing VTE. This may be due to changes in the Coagulation and Fibrinolysis processes happening during these events, which include increased levels of most clotting factors and their activators, with reduced fibrinolysis and PS level. Women taking oral contraceptives or receiving hormone replacement therapy were also found to have higher risk of developing VTE, which may again be attributed to increased clotting factors and decreased AT and tPA (Rosing et al., 1997; Hoffbrand et al., 2001; Ehsan & Plumbley, 2002; Chan, 2010; Anderson & Weitz, 2010).

#### **4.3 Other acquired risk factors**

VTE are common complications of major trauma like in surgery, fractures and blood transfusion, especially in elder and obese patients. VTE was also noticed to be secondary to other diseases like liver and kidney diseases, myeloproliferative disorders, disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS) (Hoffbrand et al., 2001; Ehsan & Plumbley, 2002). Furthermore, patients with cancers of the gastrointestinal and urogenital tracts and the lungs were reported to have higher risk of VTE. This may be due to activation of clotting factors by the cancerous cells themselves or the chemotherapy these patients usually receive which affects the liver and vitamin K metabolism, or predisposes to DIC (Dahlbäck, 1995; Florell & Rodgers, 1997; Hoffbrand et al., 2001; Ehsan & Plumbley, 2002; Anderson & Weitz, 2010; Vossen et al., 2011). Therefore, such diseases affect the Coagulation and Fibrinolysis processes in favour of developing VTE. Also, VTE in such diseases, especially those involving chronic inflammation, maybe due to increased C4bBP which captures more PS and lowers the availability of the active free PS and therefore may cause hypercoagulation. VTE was also present in many cases challenged with prolonged immobilization like being confined to bed due to major illnesses or post-operation, or after long airplane journey. The latter attracted a lot of public attention and was referred to in the media as "traveller's thrombosis" or "economy-class syndrome" (Hoffbrand et al., 2001; O'Keeffe & Baglin, 2003; DeHart, 2003; Bhatia et al., 2009).
