The ACCP has published reguler guidelines for the prevention of VTE since 1986. The ninth ACCP provides evidence-based guidelines in 2012 for VTE prevention in patients who have undergone THA and TKA. İt has based on the use of prophylaxis to reduce the patient important outcomes of fatal and symptomatic DVT, whis is balanced against the hazard of an increase in symtomatic bleeding [1] [6] . ACCP have recommended in patients who have undergone THA or TKA that use of one of the following for a minimum of 10 to 14 days rather than no anti-thrombotic prophylaxis: low molecular weight heparin (LMWH), fondaparinux, apixaban, dabigatran, rivaroxaban, low dose unfractionated heparin (LDUH), adjusted dose vitamin K antagonist (VKA), aspirin, or an intermittent pneumatic compression device (IPCD). Also ACCP recommend extending thrombo-prophylaxis in out patient period for up to 35 days from the day of surgery and using dual prophylaxis with an antithrom- botic agent and an IPCD during hospital stay [1] [6] .

For patients who have increased bleeding risk, the ACCP recommends an intermittent pneumatic com- pression device or no prophylaxis.

Among recommended drugs by ACCP which needs parenteral application or labratory monitorization, in patients undergoing major orthopaedic surgery and who decline ora re uncooperative with injection or an IPCD, ACCP recommends using Apixaban or Debigatran [1] .

The American Academy of Orthopaedic Surgeons has developed its own guideline recommendations that were updated most recently in September 2011 [7] . This evidance based guideline recommends that all patients be assesed preoperatively for risk of VTE and bleeding so AAOS does not recommend specific agents or duration for prophylaxis as ACCP’s recommends. The AAOS guideline have not accepted the use of venographically detected asymptomatic DVT as a valid outcome when assesing the efficacy of thromboprophylaxis in clinical studies and instead consider fatal PE as only clinically relevant outcome [7] [8] . Patints undergoing THA or TKA who have also had a previous VTE are recommended to receive both pharmacologic prophylaxis and mechanical compressive devices, whereas those who have a known bleeding disorder and active liver disease are recommended to solely use mechanical compressive devices for preventing VTE [8] [9] .

LMWH is generated from unfractionated heparin via physical, chemical, enzymatic depolarization. Its com- monly used forms are enoxaparine, dalteparin and tinzaparin. For prevention of VTE after major orthopaedic surgery only enoxaparin and dalteparin are used [6] [10] .

LMWHs are applied subcutaneously, with enoxaparin prescribed either as a 30 mg dose given twice a day (North American regimen) or as a 40 mg dose given once a day (European standart). According to ACCP guidelines prophylaxis should started 12 hours before surgery and 12 - 24 h after surgery and using of LMWH should continiue minimum 10 - 14 days postoperativelly [1] .

LMWHs have rapid antithrombotic effect and do not necessitate any daily laboratory monitoring. Several prospective comparative randomize control trials have been performed to assess the effectiveness of LMWH after THA and TKA surgeries. In studies compared UFH and warfarin, LMWH have shown superior efficiency to preventing DVT [11] [12] . In a meta-analysis performed by Westrich et al., in terms of rates of DVT, LMWH beter than warfarin and aspirin [13] . The other meta-analysis performed by Brookhental et al., they showed that LMWH protected significantly beter than warfarin from both proximal and distal DVT [14] . Rates of sym- tomatic PE, fatal embolism, major hemorrhage or total mortality were similar between two groups.

Including compared enoxaparin with the novel oral anticoagulants (NOAC) (rivaroxaban, dabigatran, apixaban) a meta-analysis study performed by Outes et al., demonstrated that NOAC are higher in efficacy, but also have higher risk of bleeding [15] . On the other hand, in the same study there was no significant difference between LMWH and NOAC after balancing efficacy and safety (symtomativ DVT or PE with clinically relevant bleed- ing events).

Since 1954 in United states, widely using warfarin is a vitamin K antagonist and inhibits vitamin K dependent cloting factors. Althoug it is used orally, it has some restriction such as bleeding risk, potantial drug interaction and requirement for constant monitoring (INR) [16] . Due to orally administration, it provides more compliance compared with parenteral antithrombotic agents. AAOS recommends warfarin using such that INR ≤ 2 during 2 - 6 weeks after TKA and THA surgeries. Several studies have compared the efficacy of warfarin to LMWH for thromboprophylaxis after THA and TKA. All these trials demonstrated that warfarin is an effective and safe anticoagulant. However, warfarin is inferior to LMWH at preventing VTE [12] [17] .

Although warfarin orally administrated, there are some limitation in clinical practice such as narrow the- rapeutic window, exhibit a variable and unpredictable dose response and assosiated with several food and drug interaction.

For last decades, aspirin has been widely using as antitrombotic agent after major orthopaedic surgery. Its phar- macological effects on platelet aggregation via inhibiting thromboxan A2 and thus decreasing thrombus for- mation [18] . The ACCP guideline recommends aspirin as a chemoprophylactic agent, rather than no prophylaxis at all [1] . Although aspirin has referred in to ACCP guideline, it’s usage do not consider to sole agent of throm- boprophylaxis [1] [19] .

As a synthetic pentasaccaride, fondaparinux indirectly inhibits factor Xa through binds to anti-thrombin and prevents thrombus formation [20] . This drug approved by Food and Drug Administration (FDA) and it has taken place in the market since 2002. Inspite of using LMWH after TKA highly DVT rates, fondaparinux was using as 2.5 mg once daily subcutaneous injection. A recent study conducted by Ralay et al., fondaparinux can use orally administration via nanoparticles coated gastroresistant capsules [21] . However, there are no study in the litera- ture about orally administreted fondaparinux.

In literature, a study performed by Bauer et al., in which they performed a double-blind, randomized control trial comparing fondaparinux 2.5 mg once daily to enoxaparin 30 mg given twice a day in patients who under- went major elective orthopaedic surgery. They found that despite of fondaparinux decrease DVT compared to LMWH, it had significantly higer rates of bleeding [22] . A meta-analysis completed by Turpie et al. above mentioned findings was corraborated [23] .

This group includes rivaroxaban, apixaban, endoxaban and betrixaban as orally administreted anti thrombotic agents. After THA and TKA, rivaroxaban and apixaban are roccomended by ACCP guideline [1] . Therefore, we will briefly refer to rivaroxaban and apixaban.

As competitive and reversible direct thrombin inhibitor dabigatran etexilate is a prodrug form. Following its orally taken, it is rapidly converted to dabigatran by esterases in the blood and liver [33] . Approximately 80% of this drug is excreted unchanged via the kidneys and remained amount of the drug via the biliary system after conjugation. In case of renal and hepatic failure the drug is not recommended. In patients with CrCL less than 30 ml/min and elevated liver enzymes raised to more than twice the upper limit of normal, it is conraindicated. Although dabigatran is not metabolised by CYP enzymes, it should be used caution in patients who are treated with strong P-gp inhibitor drugs [34] [35] .

Dabigatran was studied in four phase III trials to prevention of VTE. In RE-NOVATE and RE-NOVATE 2 are after THA and RE-MODEL, RE-MOBILIZE are after TKA. While in RE-NOVATE and RE-MODEL da- bigatran was compared with enoxaparin 40 mg once daily, in RE-MOBILIZE dabigatran was compared with enoxaparin 30 mg twice daily. Dosage of dabigatran was 220 mg and 150 mg once daily in RE-NOVATE, RE- MODEL and RE-MOBILIZE. In RE-NOVATE 2 dosage of dabigatran was 220 mg once daily. All these trials demonstrated that dabigatran had no inferiority and in terms of bleeding outcomes were similar between enoxaparin and dabigatran group [36] -[39] . The results of these trials have been based for approval of dabigatran by european and Canadian regulators in 2008. They recommend the dosage of dabigatran as 220 mg once daily taken in two 110 mg capsules. Patient with moderate renal impairment (CrCL 30 - 50 ml/min) and over 75 years of age recommended dosage of the drug 150 mg once daily in two 75 mg capsules [33] .