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New Anticoagulants; Basic Knowledge and Clinical Applications: Part II

Firouz Madadi MD, Mehrnoush Hassas Yeganeh MD*, Firouzeh Madadi MD, Hamid Reza Seyyed Hosseinzadeh MD

Shahid Beheshti University of Medical Sciences, Tehran, Iran

* Corresponding Author

Vol 1, Num 2, October 2014



Inhibitors of propagation of coagulation: factors V and X

New anticoagulant drugs targeting coagulation factor X

Fxa is a good target for new anticoagulants.(Figure 1) It plays a crucial role in the activation of the coagulation since it is able to activate prothrombin upon binding FVa and it has been demonstrated that, when activated, 1 molecule of FXa can generate >1000 thrombin molecules.(1)

Drugs inhibiting FXa have been extensively studied and a large body of both experimental and clinical data have been obtained. Drugs inhibiting FXa may act directly or indirectly via AT.(2-5) The need for AT binding in order to exert anti-FXa activity implies the formation of a drug-AT complex. The complex has a high molecular weight and therefore it is able to inhibit circulating FXa but unable to enter into the clot and to block the functionally active, thrombus-bound, FXa. By contrast, drugs able to inhibit directly FXa are small molecules, capable of entering into the thrombus and therefore inhibiting both circulating and thrombus-bound Fxa.

Indirect factor Xa inhibitors: fondaparinux, idraparinux and idrabiotaparinux

Like UFH and LMWH, this class of antithrombotic drugs needs AT in order to exert its pharmacological action which consists in inhibition of FXa activity and, consequently, of thrombin generation.


Fondaparinux is the first of a new class of synthetic antithrombotic agents inhibiting FXa. It is a fully synthetically produced pentasaccharide, which is identical to the sequence present in the native heparin molecule that binds to AT with high affinity and, by this mechanism, specifically inhibits FXa. The drug has been tested in a number of phase III clinical studies and it is licensed in EU for the prevention of venous thromboembolism (VTE) in patients who are scheduled for orthopaedic or general surgery and in those with medical conditions.(4-70)

Fondaparinux is also licensed for treatment of patients with VTE and in those with non-ST and ST-segment elevation acute coronary syndromes (ACS). More specifically, fondaparinux proved superior to the LMWH enoxaparin in high risk orthopaedic surgery, such as hip fracture, elective hip surgery, total hip replacement and total knee replacement.(8) Prolonging the duration of prophylaxis with fondaparinux, 2.5 mg once a day subcutaneously from 1 to 4 weeks after fracture, has impressively decreased the rate of venographically documented DVT from 35% to 1.4% (P = 0.0001) and that of symptomatic VTE from 2.7% to 0.3% (P = 0.021).(9)

Studies on treatment of patients with VTE demonstrated that fondaparinux was equally effective and safe compared with enoxaparin or UFH in the treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE).(10, 11) A recent randomized trial on more than 3000 patients with superficial vein thrombosis of the legs, compared fondaparinux at a dose of 2.5 mg subcutaneously once a day for 45 days with placebo. The study demonstrated that active treatment significantly reduced the incidence of the primary efficacy outcome of symptomatic DVT, PE, extension to safenofemoral junction, recurrence of superficial vein thrombosis and death (0.9% in the active treatment group vs. 5.9% in the placebo group), with a relative risk reduction with fondaparinux of 85%.(P<0.001) No significant difference was observed in bleeding complications between the two groups.(12)

Interestingly, patients exposed to fondaparinux have been reported to develop anti-heparin/platelet factor 4 antibodies. However, the drug does not bind to platelets or platelet factor 4 owing to absent or weak 'cross-reactivity' with this epitope.(13) Consequently fondaparinux will not cause Heparin-induced Thrombocytopenia (HIT) and the drug has also proved effective in treating this disorder.(14)

Idraparinux and idrabiotaparinux (Fig 2)

Idraparinux is a synthetic hypermethylated derivative of fondaparinux with high affinity for AT. The drug is eliminated by the kidney with a plasma half-life of 80–130 h, thus allowing once weekly subcutaneous administration.(15) A main problem of the drug is the delayed elimination after prolonged administration, which may explain the high incidence of hemorrhagic complications observed in clinical trials.(16) For this reason idrabiotaparinux was developed in order to obtain a rapid inhibition of anticoagulant activity. Idrabiotaparinux differs from idraparinux in that it contains a biotin moiety that enables reversal of the anticoagulant effect with intravenous avidin. Avidin, a protein derived from egg white, binds the biotin moiety with high affinity to form a complex that is rapidly cleared by the kidney.(17)

Idrabiotaparinux and idraparinux are similarly effective and safe for DVT treatment and both drugs have similar time course of FXa inhibition. Moreover, the anticoagulant effect of idrabiotaparinux can be rapidly reversed after intravenous avidin infusion.(17, 18)

Direct factor Xa inhibitors: otamixaban, rivaroxaban, apixaban and edoxaban


The parenteral direct FXa inhibitor otamixaban has a rapid onset of action, a short half-life and a limited (<25%) renal excretion. It also has a predictable anticoagulant effect which obviates the need for routine coagulation monitoring [19]. Finally, unlike UFH or LMWH the drug does not cause HIT. For all these reasons otamixaban might be a good candidate to replace UFH or LMWH in patients with ACS who are scheduled or not for PCI.(20)

Rivaroxaban, apixaban and edoxaban

These factor Xa inhibitors are small, orally active molecules, which are able to bind reversibly to the active site of FXa. Though numerous agents are currently under development, those more extensively studied in large scale clinical trials are rivaroxaban, apixaban and edoxaban(Fig 2).

Rivaroxaban is a selective and competitive active site-directed, reversible factor Xa inhibitor with selectivity for factor Xa that is >10,000-fold that for other trypsin-like serine proteases.(21) Rivaroxaban acts through electrostatic interaction with Asp189 in the S1 pocket of factor Xa. This interaction involves the chlorine substituent of the chlorothiophene moiety, which interacts with the aromatic ring of Tyr228 at the bottom of the S1 pocket.(22) Because rivaroxaban is a nonbasic, small molecule (the molecular weight is 436 g/mol) it can inhibit not only free factor Xa but also prothrombinase complex and clot-associated factor Xa.(23,24) This range of activities is unique to small, direct inhibitors because the factor Xa incorporated in the prothrombinase complex is protected from inhibition by antithrombin and by antithrombin-dependent anticoagulants.

Inhibition of factor Xa activity by rivaroxaban is highly dependent on the concentration of the drug. Rivaroxaban induces prolongation of the PT, aPTT, and heparin clotting time, among other tests.(23,25) On the other hand, rivaroxaban does not affect the bleeding time or platelet aggregation.(23,26) Animal models demonstrated dose-dependent reduction of thrombus formation by rivaroxaban.(23)

Pharmacokinetics and Pharmacodynamics (Table 1)

In healthy men aged 19 to 45 years, single doses of rivaroxaban administered after a fasting period of 10 h produced a median inhibition of factor Xa activity that ranged from 20% with the 5-mg dose to 61% with the maximum dose of 80 mg.(27) The maximum inhibition of factor Xa activity occurred between 1 and 4 h after drug administration, and the half-life of the biologic effect was 6 to 7 h. Factor Xa activities did not return to normal until after 24 h, when doses >5 mg were administered.(27)

The effect on PT prolongation had a similar profile, as did effects on the aPTT and HEPTEST (a low-molecular-weight heparin activity assay). Conversely, rivaroxaban had no effect on thrombin and antithrombin activity.(27) Peak plasma concentration of the drug occurred at 2 h, and the terminal half-life was between 7 and 17 h. At doses >10 mg, the increases in peak plasma concentration and AUC were less than dose proportional.

Approximately 40% of the administered dose was excreted unchanged via the kidneys when the 1.25-mg dose was administered; this proportion decreased to 10% with the highest doses tested (ie, 60-80 mg). Finally, inhibition of factor Xa activity and PT prolongation correlated strongly with plasma concentrations.(27) When multiple doses were administered at mealtime in healthy male subjects aged 20 to 45 years, the maximum inhibition of factor Xa activity was documented after approximately 3 h and it was dose dependent, ranging from 22% after 5 mg to 68% after 30 mg.(28)

Inhibition was maintained for 8 to 12 h after 5-mg doses and for approximately 12 h after doses of 10 mg to 30 mg. Daily rivaroxaban doses did not cause a further increase in the maximum inhibition of factor Xa activity. A very similar pattern was observed with PT, aPTT, and HEPTEST prolongation, which was dose dependent for all tests, reached maximum levels after 1 to 4 h, and was comparable after the first and last administered dose.(28)

When inhibition of factor Xa activity was compared after once, twice, or three times daily administration of the 5-mg dose, there was no detectable difference between the maximum effect on the first and the last day of administration. The plasma concentrations of rivaroxaban were also dose dependent, with maximum concentrations at 3 to 4 h for all doses and regimens and a half-life of approximately 4 to 6 h on the first day and of approximately 6 to 9 h on the last day of treatment. The correlation between plasma concentrations of rivaroxaban and inhibition of factor Xa activity or PT prolongation was linear.(28)



In humans, CYP3A4 plays a pivotal role in the oxidative metabolism of rivaroxaban.(29) Drugs that inhibit or induce CYP3A4 have the potential to interact with rivaroxaban. However, only drugs that act as strong inhibitors of both CYP3A4 and of P-glycoprotein, a transporter protein of which rivaroxaban is a substrate, have been shown to cause important reduction of the clearance of the drug, thus provoking a significant increase in plasma concentrations. These drugs include azole antimycotics and HIV protease inhibitors.

The concomitant administration of rivaroxaban with ketoconazole 400 mg once daily or with ritonavir 600 mg bid resulted in an approximately 2.5-fold increase in the mean AUC and 1.7-fold increase in the mean Cmax of rivaroxaban, together with significantly increased effects on clotting tests.(30) Thus, the use of rivaroxaban in patients receiving ketoconazole, itraconazole, voriconazole, and posaconazole or any HIV protease inhibitor is currently not recommended. [30] Rivaroxaban should be used with caution when given together with other drugs that strongly inhibit only CYP3A4 or only P-glycoprotein. These drugs include clarithromycin, which at the dose of 500 mg bid leads to a 1.5-fold increase in the mean AUC and to a 1.4-fold increase in the Cmax of the drug, and erythromycin, which at the dose of 500 mg three times daily causes a 1.3-fold increase in both the AUC and the Cmax.(30)

On the other hand, reduced plasma concentrations of rivaroxaban can occur when strong CYP3A4 inducers are coadministered. These include rifampicin (which causes a 50% decrease in the AUC), phenytoin, carbamazepine, phenobarbital, or St. John's wort.(30) The concomitant administration of rivaroxaban with substrates of either CYP3A4 or P-glycoprotein, such as atorvastatin, digoxin, or midazolam, did not result in clinically relevant interactions.(31,32)

The concomitant administration of rivaroxaban and aspirin was tested in a randomized, two-way crossover study.(26) Maximum levels of inhibition of factor Xa activity and maximum prolongation of the PT, aPTT, and the HEPTEST were similar in patients treated with rivaroxaban alone and in patients treated with rivaroxaban plus aspirin. Collagen-stimulated platelet aggregation was inhibited in the aspirin-alone group and in the aspirin plus rivaroxaban group but not in the rivaroxaban-alone group. Inhibition of platelet aggregation with aspirin was 89.3% greater than with rivaroxaban alone, and with aspirin plus rivaroxaban it was 97.4% greater than with rivaroxaban alone. Bleeding time was not affected by rivaroxaban alone, but was prolonged to 1.46 times the baseline by aspirin alone and to 1.96 times the baseline by adding aspirin to rivaroxaban. The combination of aspirin with rivaroxaban prolonged bleeding time more than aspirin alone. Pharmacokinetic parameters of rivaroxaban were not altered by the coadministration of aspirin.

The concomitant administration of rivaroxaban and a nonsteroidal antiinflammatory drug was also tested in a randomized two-way crossover study.(33) Healthy men aged between 18 and 45 years were randomized to receive 15 mg of rivaroxaban alone or 15 mg rivaroxaban plus naproxen 500 mg. After 14 days all subjects crossed over. Maximum inhibition of factor Xa activity and maximum prolongations of the PT, aPTT, and HEPTEST were similar between the two groups. Bleeding time was significantly increased by the combined use of rivaroxaban and naproxen as compared with rivaroxaban alone.

Plasma concentrations of rivaroxaban were slightly increased, by 10% for both the AUC and the Cmax after the coadministration of naproxen. Finally, the concomitant administration of drugs that alter the gastric pH, such as the histamine H2 antagonist ranitidine or the antacid aluminum-magnesium hydroxide had no effect on the plasma concentrations or pharmacodynamics of rivaroxaban.(34)

Environmental Factors:

The effect of food on the absorption of rivaroxaban was tested in healthy male subjects aged 18 to 45 years.(34) After a single dose of 5 mg, the absorption of rivaroxaban was found to be slower in the fed state than the fasting state, with a delay in the median time to reach the peak plasma concentration from 2.75 h to 4.0 h. The AUC and the Cmax both increased with the concomitant administration of food, by 28% and 41%, whereas the terminal half-life remained unchanged. The fed state increased the time to maximum prolongation of the PT and maximum inhibition of factor Xa activity and also the maximum effect on these clotting tests.

Thus, absorption of rivaroxaban was moderately increased after the administration of food, with a resulting increase in pharmacokinetic and pharmacodynamics parameters. In addition, concomitant food intake reduced interindividual variability, whereas elimination remained unchanged. No pharmacokinetic differences were documented when high-fat, high-calorie meals were compared with high-carbohydrate meals. These food effects have been attributed to a prolonged length of stay in the stomach that is possibly related to the lipophilicity and limited aqueous solubility of the drug.(34)

Monitoring Anticoagulant Intensity

The predictable pharmacologic profile of rivaroxaban allows the administration of the drug at fixed doses without the need for routine laboratory monitoring or dose adjustments. However, there may be rare situations, as in the case of overdose or unexpected bleeding, assessment of compliance, evaluation of drug interactions, or assessment of drug accumulation in renal or hepatic impairment, when the availability of a quantitative clotting assay might be valuable.

Despite the predictable, dose-dependent effects of rivaroxaban on the PT and (to a lesser extent) the aPTT, and on tests measuring thrombin generation, there are currently no validated laboratory assays that can be recommended to monitor rivaroxaban or any recommendations for dose adjustments based on observed test results. For instance, the thromboplastins used for PT clotting assays have differing sensitivities to factor Xa inhibitors, and the INR introduced to correct for differences in PT sensitivity when monitoring the VKAs does not adequately correct for differences in assay sensitivity to direct factor Xa inhibitors.

Smith and Morissey (35) evaluated the effects of five commercial thromboplastin reagents on sensitivity of the PT to rivaroxaban and its correlation with the INR. PT ratios (ie, PT with drug/PT without drug) were measured using normal human plasma to which rivaroxaban 1 m g/mL was added in vitro. PT ratios varied from 2.25 to 7.32 with the different thromboplastins; subsequent conversion to an INR further exacerbated the observed differences in sensitivities to rivaroxaban between the various PT assays.

Recently, Samama et al (25) carried out a study that aimed to identify a clotting test suitable for monitoring rivaroxaban activity by evaluating the effects on a number of different assays of increasing the drug concentration in pooled citrated normal human platelet-poor plasma. There was a concentration-dependent prolongation of the PT and aPTT, but the increases in clotting times varied depending on the thromboplastin reagent used.(25) The effect of rivaroxaban on the aPTT was weaker than that on the PT.

Rivaroxaban also prolonged the thromboelastograph parameters. Standard methods for the HEPTEST and the prothrombinase-induced clotting time resulted in paradoxical responses. Tests used to measure antifactor Xa activity of the low-molecular-weight heparins showed dose-dependent effects but were associated with some degrees of variation. Finally, rivaroxaban also caused a dose-dependent increase of the diluted Russell viper venom ratio. Specific calibration of some of these tests may lead to the availability of an appropriate assay to monitor the pharmacodynamics effects of the drug. Neither the PT (expressed either in seconds or as a ratio) nor the aPTT should be used to monitor the anticoagulant effect of rivaroxaban.


There is currently no specific antidote available to antagonize the effects of rivaroxaban. In case of overdose, the use of activated charcoal to reduce absorption is suggested.(30) Because of the high plasma protein binding, rivaroxaban is unlikely to be dialyzable. In case of active bleeding, possible strategies currently include discontinuation of treatment and administration of blood products or component transfusion if required to treat an identified deficiency. [30] However, there is currently no direct evidence in humans to support the efficacy of blood product transfusion or other interventions in improving hemostasis when patients have received rivaroxaban.

Recently, Perzborn et al (36) reported the results of a study carried out in rats treated with high-dose rivaroxaban, which aimed to assess the efficacy of prothrombin complex concentrate. After determination of baseline mesenteric bleeding time, rats were initially treated with IV rivaroxaban and subsequently received fourfactor prothrombin complex concentrates at 25 U/kg or 50 U/kg. Prolongation of the bleeding time was almost completely abrogated by higher dose of prothrombin complex concentrates, whereas the lower dose was ineffective. The use of recombinant factor VIIa is also suggested in the presence of life-threatening bleeding based on some preclinical data.(30)

A reconstructed recombinant factor Xa has been recently proposed as a potential antidote for factor Xa inhibitors. This is a catalytically inactive factor Xa that has no procoagulant or anticoagulant activity and does not interfere with the prothrombinase complex but maintains high affinity for factor Xa inhibitors. In plasma, the addition of the antidote dose-dependently reversed factor Xa inhibition as measured by anti-factor Xa units, tissue factor-initiated thrombin generation, and clotting assays. In vivo, the antidote completely reversed PT prolongation induced by intravenous infusion of rivaroxaban in rats.

    Table 1: Summary of the pharmacology of apixaban, rivaroxaban and dabigatran.
    Figure 1: New anticoagulants and their targets in coagulation cascade.
    Figure 2: Chemical structures of anticoagulants with activity against Factor X and their comparison to dabigatran.


    Apixaban is a highly selective, reversible, direct Factor Xa inhibitor (37) that inhibits both free Factor Xa (Ki 0.08 nM) and prothrombinase activity (38, 39), as well as clot-bound Factor Xa activity.(40) In healthy subjects, apixaban was absorbed relatively rapidly, with a maximum plasma concentration achieved approximately 3 h postdose. The mean terminal half-life of apixaban ranged between 8 and 15 h.(41)

    Apixaban is eliminated via multiple pathways, including oxidative metabolism, renal, and intestinal routes. After oral administration, the majority (56%) of the recovered dose is in feces, with urinary excretion also representing a significant elimination pathway (approximate 22% of the recovered dose). The parent compound is the major component in plasma, urine, and feces in humans. There are also several metabolites that account for approximately one-third of the total recovered dose, the most prominent being O-demethyl apixaban sulfate.(37)(Table 1)

    Concomitant administration of ketoconazole or other potent cytochrome P450 3A4 inhibitors with apixaban should be avoided because they substantially increase apixaban levels. The effects of apixaban and moderate cytochrome P450 3A4 inhibitors (i.e. cimetidine, diltiazem, selective serotonin receptor inhibitors) should be used with caution. The effect of concomitant administration of apixaban and the statins, which are also metabolized by cytochrome P450 3A4, has not been reported.(42)


    Edoxaban (DU-176b) is an oral, direct, specific Factor Xa inhibitor (Ki 0.56 nM), with an approximate 10,000-fold selectivity for Factor Xa over thrombin (43). Its antithrombotic efficacy was initially examined in a venous stasis thrombosis model. Edoxaban dose-dependently inhibited thrombus formation, prolonged prothrombin time, and inhibited Factor Xa activity.

    In a single-dose (60 mg) study in healthy subjects, the maximum plasma concentration of edoxaban was observed at 1.5 h after administration, corresponding to the maximum Inhibition of Factor Xa activity, which returned to baseline levels by 12 h. The inhibition of Factor Xa led to a corresponding reduction in thrombin generation and prolongation of clotting times.(44)

    In a multipledose study, edoxaban prolonged the activated partial thromboplastin time and the prothrombin time in a dose-dependent manner.(45) The half-life ranged from 5.8 to 10.7 h, and the rate of plasma protein binding was 40–59%. Urinary excretion of unchanged edoxaban was 36% and 45% of the dose administered (90 and 120 mg daily doses, respectively). There are currently no data available on drug–drug interactions for edoxaban. Food had no clinically significant effects on the pharmacokinetics and pharmacodynamics of edoxaban.(45)


    Semuloparin (AVE5026) is a new ultra low molecular weight heparin (ULMWH), with a molecular weight of 2400 Da. It has an indirect anti-FXa activity, with a ratio anti-FXa : anti-FIIa higher than 30 and a half-life of 11–22 h thus allowing once daily subcutaneous administration.(46, 47) A high anti-FXa to anti-FIIa activity is associated with a high antithrombotic effect and a low prohaemorrhagic tendency. After a single subcutaneous dose AVE5026 is completely absorbed with a bioavailability of 98% compared with intravenous administration. The drug has a linear pharmacokinetic profile and after repeated dosing in elderly subjects a slight increase in accumulation of this agent was seen reflecting renal impairment.(48)


    The indirect FXa inhibitor M118 is a new LMWH with a molecular weight of 6500 Da and a predominant anti-FXa activity (ratio anti-FXa:anti-FIIa = 1.4). M118 has been specifically designed for use in ACS. The drug shows broad anticoagulant activity, including potent activity against both FXa (~240 IU ml-1) and thrombin (FIIa~ 170 IU ml-1). M118 has a high bioavailability (78%) after subcutaneous administration, and predictable pharmacokinetics after subcutaneous and intravenous administration.(49)

    Other advantages of the drug are a half-life of approximately 1 h after intravenous bolus injection and 2–3 h after subcutaneous administration. Additionally, M118 seems not to activate platelets, its activity is monitorable by standard coagulation assays (anti-FXa, anti-FIIa, APTT, and ACT) and is reversible with protamine sulfate (1 mg per 100 IU dose). For all these reasons the drug demonstrates potentially superior properties to conventional LMWHs.(49, 50)


    Betrixaban (PRT-054021), is an oral, direct, competitive, active site-directed, inhibitor of FXa that is able to block both free and prothrombinase bound FXa.(51) The drug has a number of favourable pharmacokinetic and pharmacodynamic characteristics. It has a much higher specificity for FXa than for other coagulation proteins such as thrombin, which reduces its prohaemorrhagic potential. Betrixaban has an almost exclusive biliary excretion with a low renal clearance, corresponding to a urine excretion of about 5% of the administered dose. It can therefore be used in patients with renal impairment.

    Moreover the drug does not interact with the major cytochrome CYP450, and for this reason is has little or no interaction which other drugs. Finally, betrixaban has a half-life of about 15–20 h therefore allowing patients to be maintained within the therapeutic range over the 24 h dosing period.(52) Its negligible renal excretion makes the drug particularly suitable in patients who already have or will develop renal failure.


    Eribaxaban (PD0348292) is an oral, novel, highly selective inhibitor of FXa. The drug has a 41% bioavailability with a time to peak concentration of 2 h and a half-life of 5.3 h.(53)


    Ym150 is a potent and specific, orally active, direct inhibitor of FXa, that is able to inhibit experimentally clot formation, to prolong prothombin time and FXa clotting time, and to promote clot lysis in vitro without a significant effect on bleeding time. The drug was also demonstrated to act as a potent anticoagulant in both venous and arterial thrombosis in various animal models, with minimal effect on bleeding.(54,55)

    Ym150 is rapidly absorbed and metabolized into the active metabolite YM-222714, which mainly determines the pharmacological effect. Peak plasma YM-222714 concentration is reached within 2 h after intake and the elimination half-life ranged from 18–20 h. Finally, its absorption is not interfered with by food or bile.(53, 56) YM150 is being developed for DVT prophylaxis after major orthopaedic surgery and thromboembolic complications associated with AF.


    TAK-442 is a strong, oral, newly synthesized, selective FXa inhibitor, which through inhibition of FXa, reduces thrombin generation in vitro and is also able to prolong prothrombin time in a dose-dependent manner. The drug is also able to reduce thrombus formation in animal models of venous thrombosis without prolonging bleeding time.(57) It was also demonstrated that TAK-442 does not have any pharmacodynamic or pharmacokinetic interaction when it is co-administered with aspirin or clopidogrel, in an animal model of arterial thrombosis (58), and that the association of the three agents, in the same model, results in a synergistic antithrombotic effect, therefore suggesting that TAK-442 may be theoretically used in patients with ACS, providing incremental antithrombotic benefit without significant safety drawbacks.(59)

    In humans TAK-442 exhibits good oral bioavailability, has a predictable dose-proportional level of anticoagulation after fixed dose administration, and exhibits a renal excretion of about 30% [60]. In healthy subjects, the drug has a rapid onset of action, with a time to peak plasma concentration of 1–2 h, and an elimination half-life of 9–13 h.(52,60)

    New anticoagulant drugs targeting coagulation factor V

    Factor Va plays a crucial role in the activation of the coagulation network and thrombin generation. More specifically, is acts as cofactor of FXa and both, together with platelet membrane phospholipids, form the so called 'prothrombinase complex', which, in turn, converts prothrombin to thrombin on the cell membrane. FVa inhibitors include drotrecogin alpha activated (DrotAA) and ART-123. These drugs have been initially developed for the treatment of severe sepsis with or without disseminated intravascular coagulation (DIC); however ART-123 has also been tested for thromboprophylaxis after total hip replacement.

    Drotrecogin alpha activated

    Drotrecogin alpha activated (DrotAA) is a recombinant form of activated protein C, which is licensed for management of patients with severe sepsis with multiple organ failure in addition to standard therapy. The half-life of DrotAA is about 13 min and its plasma clearance is approximately 41.8 l h-1 in sepsis patients and 28.1 l h-1 in healthy subjects.(61) Infusion of DrotAA was tested in a number of clinical trials in patients with sepsis. In some of these studies an improvement in the coagulation abnormalities associated with severe sepsis was observed thus suggesting that DrotAA may have antithrombotic and anti-inflammatory properties.(62)


    ART-123 is a recombinant human, soluble thrombomodulin alpha. The drug binds to thrombin and the thrombin-ART-123 complex activates protein C, which in turn inhibits FVa (and FVIIIa).(61) The drug showed a favourable antithrombotic profile with less bleeding than other anticoagulants. At doses of 0.03, 0.1, and 0.3 mg plasma ART-123 concentrations declined biexponentially with half-lives of approximately 4 and 20 h, respectively.(63)

    Firouz Madadi MD
    Orthopaedic Surgeon, Associate Professor, Shahid Beheshti University of Medical Sciences, Tehran, Iran


    Mehrnoush hassas Yeganeh MD
    Paediatric Rheumatologist, Assistant Professor, Shahid Beheshti Medical University, Tehran, Iran
    Corresponding Author


    Firouzeh Madadi MD
    Medical student and researcher, Tehran, Iran


    Hamid Reza Seyyed Hosseinzadeh MD
    Orthopaedic surgeon, Associate professor, Shahid Beheshti Medical Univerity, Tehran, Iran


    None declared.


    Financial disclosure:
    None declared.



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