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INTRODUCTION A better understanding of the molecular mechanisms underlying blood coagulation, recombinant DNA technology, isolation and characterization of anticoagulant proteins , and improvements in structure-based drug design have accelerated the pace of drug discovery. With these advances, we now have an array of new anticoagulants that target specific clotting enzymes or steps in coagulation. The limitations of existing oral and parenteral anticoagulants have prompted a search for novel agents. As new drug targets are identified and potent inhibitors are developed, the validity of these targets requires testing in well-designed clinical trials.

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Characteristics of an ideal anticoagulant are : Oral administration. Single daily dose. Predictable dose response and kinetics. High clinical efficacy. Low rate of complications. No routine monitoring required. Wide therapeutic window. No dose adjustment required. Minimal or no interaction with food or other drugs. Inhibition of both free and clot-bound activated coagulation factors.

Current Limitations:

Current Limitations Limitations Consequences UFH ► Parenteral ► Unpredictable due to unspecific binding ► Risk of HIT ► Inconvenient for long term use ► Monitoring of aPTT required LMWH ► Parenteral ► Risk of HIT ► Inconvenient and expensive for long term use ► Monitoring of platelets VKAs ► Unpredictable ► Slow onset of action ► Narrow therapeutic window ► Food and drug interactions ► Regular monitoring and dose adjustments ► Risk of adverse events (bleeding) Fondaparinux ► Parenteral ► Inconvenient and expensive for long term use Lassen MR. Vasc Health Risk Manag. 2008;4(6):1373-86.

Site of Action for New Anti-thrombotic Agents:

Site of Action for New Anti-thrombotic Agents Fibrin Clot Intrinsic Extrinsic XII VII VIII IX XI Fibrinogen II V T issue F actor X Direct Xa Inhibitors “- xaban ” AT Indirect Xa Inhibitors “- parinux ” Direct Thrombin Inhibitors “- gatran ” warfarin

New and Emerging Anticoagulants:

New and Emerging Anticoagulants Anti – Xa : direct Rivaroxaban (oral) Apixaban (oral) Betrixiban (oral) Edoxaban (oral) Otamixaban ( parenteral ) LY – 517717 (oral) DU – 176B (oral) DX – 9065a ( parenteral ) PRT054021 (oral) Anti – Xa : indirect Idraparinux biotinylated ( parenteral ) Fondaparinux Anti – IIa Dabigatran (oral) Odiparcil (oral) Flovagatran ( parenteral ) Pegmusirudin ( parenteral ) Peg Hirudin Desiruidin ximelagatran

Inhibitors of initiation of coagulation:

Inhibitors of initiation of coagulation Drugs that target the factor VIIa /tissue factor complex inhibit the initiation of coagulation. A recombinant form of TFPI ( tifacogin ) has been evaluated in patients with sepsis. NAPc2 :An 85-amino acid polypeptide that was originally isolated from the canine hookworm, Ancylostoma caninum . NAPc2 binds to a noncatalytic site on factor X or factor Xa . Once bound to factor Xa , the NAPc2/factor Xa complex inhibits factor VIIa bound to tissue factor. Because it binds to factor X with high affinity, NAPc2 has a half-life of approximately 50 h after subcutaneous injection. Synthetic inhibitors . Several synthetic compounds that inhibit factor VIIa within the factor VIIa /tissue factor complex have been identified.

Tissue Factor Pathway Inhibitor:

Tissue Factor Pathway Inhibitor

Inhibitors of propagation of coagulation:

Inhibitors of propagation of coagulation Drugs that block factor IXa , factor Xa or their respective cofactors, factor VIIIa and factor Va , inhibit the propagation of coagulation. New factor Xa inhibitors include agents that block factor Xa indirectly or directly. Indirect inhibitors act by catalyzing factor Xa inhibition by antithrombin . In contrast, direct factor Xa inhibitors bind directly to the active site of factor Xa , thereby blocking its interaction with its substrates. Unlike the heparin/ antithrombin complex, direct factor Xa inhibitors not only inhibit free factor Xa , but also inactivate factor Xa bound to platelets within the prothrombinase complex.

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Fondaparinux and idraparinux are two new parenteral indirect factor Xa inhibitors. Fondaparinux :A synthetic analog of the antithrombin -binding pentasaccharide sequence found in heparin and low-molecular-weight heparin, fondaparinux binds antithrombin and enhances its reactivity with factor Xa . A single daily SC injection is needed because its half-life is approximately 17 hours. The drug is excreted unchanged in the urine. Fondaparinux donot interact with protamine sulfate , the antidote for heparin. If uncontrolled bleeding occurs with fondaparinux , a procoagulant such as recombinant factor VIIa might be effective. Heparin-induced thrombocytopenia is unlikely to occur with fondaparinux . Two pivotal clinical trials MATISSE DVT and MATISSE PE have established the clinical efficacy and safety of the 7.5 mg daily therapeutic dose among patients whose body weight ranges between 50 and 100 kg. Idraparinux : A more highly sulfated derivative of fondaparinux . Idraparinux binds antithrombin with such high affinity that its plasma half-life of 130 h is similar to that of antithrombin . Because of its long half-life, idraparinux can be given subcutaneously on a once-weekly basis.

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Direct Factor Xa Inhibitors Apixaban - Oral tablet Bioavailability: 50% Peak Plasma Levels = 3 hrs Half-life ~ 12 hours Metabolized in liver via CYP3A4 and CYP independent mechanisms No laboratory monitoring required. Rivaroxaban is a competitive reversible antagonist of activated factor X ( Xa ). Rivaroxaban 10 mg tablets are well absorbed (80% bioavailability) with no effect of food on absorption or pharmacokinetic parameters. Plasma concentrations peak at 2.5–4 hours. The plasma elimination half-life is 5–9 hours in young adults and 11–13 hours in older people due to the age-related decline in renal function. This permits once- or twice-daily dosing. Rivaroxaban is metabolised by liver enzymes, principally cytochrome P450 3A4, and also by cytochrome -independent mechanisms. A number of small-molecule, orally administered direct Factor Xa inhibitors are currently in development. These include betrixaban and a group of as yet unnamed clinical entities (LY517717, YM150 and DU-176b).

Inhibitors of fibrin formation:

Inhibitors of fibrin formation Direct thrombin inhibitors include Hirudin ( refludan and lepirudine ) and its derivatives bivalirudine , agatroban , ximelagatran and dabigatran . Hirudin is extracted from the salivary gland of the medicinal leech ( Hirudo medicinalis ) whereas lepirudin is recombinant hirudin . Hirudin inhibits thrombin in a bivalent fashion. The plasma half-life of hirudin is 60 min after IV injection, and 120 min after subcutaneous injection. Hirudin is cleared via the kidneys and should not be used in patients with renal insufficiency. The anticoagulant effect of hirudin can be monitored using the activated partial thromboplastin time (APTT).

Direct Thrombin Inhibitors:

Direct Thrombin Inhibitors IIa Argatroban Melagatran Heparin binding site Catalytic site Substrate Recognition Site IIa IIa Hirudin

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Hirudin has been primarily evaluated for the treatment of acute coronary syndromes such as unstable angina and myocardial infarction (Direct Thrombin Inhibitor Trialists ’ Collaborative Group study) that suggested that hirudin had quite narrow therapeutic window with little added benefit compared to standard heparin. Bivalirudin : A 20-amino acid synthetic polypeptide, bivalirudin is an analog of hirudin . Bivalirudin has a plasma half-life of 25 min after IV injection,and only a fraction is excreted via the kidneys. It undergoes predominant non-organ elimination(proteolysis) . Bivalirubin has been approved by the United states Food and Drug Administration for use in patients with unstable angina in patients undergoing percutaneous cornary intervention.( 0.75mg/kg iv bolus, followed by 1.75mg/kg/hr for duration of procedure).

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Argatroban: A competitive inhibitor of thrombin, argatroban binds noncovalently to the active site of thrombin to form a reversible complex. The plasma half-life of argatroban is 45 min. It is metabolized in the liver and must be used with caution in patients with hepatic dysfunction. Argatroban is licensed for the treatment of heparin-induced thrombocytopenia.


Dabigatran Oral capsule. Rapid onset of action. Half-life 12-17 hours. Plasma concentrations of dabigatran peak 0.5–2 hours after an oral dose. Renal elimination No routine monitoring required P- gp substrate—use with caution when administered concomitantly with P- gp inhibitors. Interactions have been found with P-glycoprotein inhibitors ( quinidine , amiodarone ) with increased total dabigatran exposure . P-glycoprotein inducers may reduce systemic exposure of dabigatran . No dietary/food interactions. Absorption: very low bioavailability (3.5-5%) Has very low probability with drug-drug interactions. The administration of PPI tends to decrease the absorption. (Needs an acidic environment for absorbtion ) . Approved by both Europe and Canada: shortterm thromboprophylaxis in pts undergoing orthopedic procedures


Ximelagatran First oral direct thrombin inhibitor Prodrug of melagatran . Well absorbed from GI tract Peak absorption in 15-30 minutes. Peak levels in 2-3 hours. Not protein bound. Half-life 3-4 hours. Eliminated via kidneys. Ximelagatran is being evaluated for thromboprophylaxis in high-risk orthopedic patients, for the treatment of venous thromboembolism , for the prevention of cardioembolic events in patients with nonvalvular atrial fibrillation.

Modulation of endogenous fibrinolytic activity:

Modulation of endogenous fibrinolytic activity These include inhibitors of PAI-1, activated TAFI ( TAFIa ), or factor XIIIa . PAI-1 inhibitors : inhibition of PAI-1 results in increased endogenous fibrinolytic activity. Peptides have been identified that block PAI-1 activity. However, the effectiveness of these agents has yet to be tested in vivo . TAFIa inhibitors: A procarboxypeptidase B that serves as a link between coagulation and fibrinolysis has been identified in plasma Activated by the thrombin/ thrombomodulin complex, this enzyme, known as thrombin activatable fibrinolysis inhibitor (TAFI), attenuates fibrinolysis by cleaving carboxyl-terminal lysine residues from fibrin. The removal of these lysine residues decreases plasminogen and plasmin binding to fibrin, thereby retarding the lytic process.

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Factor XIIIa inhibitors: Tridegin , a peptide isolated from the giant Amazon leech, Haementeria ghilianti , is a specific inhibitor of factor XIIIa and enhances fibrinolysis in vitro when added before clotting of fibrinogen. Destabilase , a leech enzyme that hydrolyzes crosslinks , also provides a promising approach to reversing the consequences of factor XIIIa -mediated fibrin crosslinking . Neither of these agents has been tested in humans.

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Property Rivaroxaban Apixaban Idraparinux Dabigatran Target Factor Xa Factor Xa Factor Xa (indirect) Thrombin ROA Oral Oral Subcutaneous Oral Prodrug No No Yes Yes Bioavailability > 80% > 50% 100% 6% Time to peak 3 3 ___ 2 Half-life 9 hrs 9 – 14 hrs 80 hrs 14 – 17 hrs Frequency of Administration Qday BID Q Week Qday or BID Drug Interactions Potent CYP3A4 & P-glycoprotein inhibitors Potent CYP3A4 & P-glycoprotein inhibitors ___ P-glycoprotein inhibitors Renal excretion 66% 25% Yes 80% Safe in pregnancy No No Unknown No Antidote No No No No Adapted from: Gross, PL. Arterioscler Thromb Vasc Biol. 2008; 28:380-386.

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