Emerging anticoagulant strategies

James C. Fredenburgh, Peter L. Gross and Jeffrey I. Weitz

Article Figures & Data


  • Figure 1.

    Overview of coagulation system. Coagulation is initiated by the extrinsic pathway when tissue factor (TF) exposed at sites of vascular injury binds and activates FVII. The activated FVII (FVIIa)–TF complex activates FX in the common pathway to generate prothrombinase, which generates thrombin. Additional activation of coagulation occurs when thrombin-activated platelets release polyphosphate (poly-P) and activated neutrophils extrude DNA and RNA to form NETs. NETs and poly-P activate the contact pathway, which yields FXIa and leads to additional thrombin generation via the common pathway. Poly-P amplifies this pathway by promoting thrombin-mediated activation of FXI.

  • Figure 2.

    The contact system. Polyphosphates (P-P-P-P-P-P) bind FXII and promote its autoactivation to FXIIa. HK binds polyphosphates and promotes FXI activation by FXIIa, and the resultant FXIa then propagates coagulation leading to thrombin generation. FXIIa also activates HK-bound prekallikrein (PK) to kallikrein (K), which activates FXII in a reciprocal manner to promote additional FXIIa generation. Release of bradykinin from HK cleaved by K induces an inflammatory response.


  • Table 1.

    New indications for direct oral anticoagulants

    IndicationNCT numberInterventionControlDurationSample sizeEfficacy outcomeSafety outcome
    Arterial thrombosis
     Embolic stroke of unknown sourceRE-SPECT ESUS 02239120Dabigatran 150 or 110 mg BIDAspirin3 y6000Recurrent strokeMajor bleeding
    NAVIGATE ESUS 02313909Rivaroxaban 15 mg ODAspirin3 y7000Recurrent stroke or systemic embolismMajor bleeding
     Coronary or peripheral artery diseaseCOMPASS 01776424Rivaroxaban 5 mg BID or rivaroxaban 2.5 mg BID plus aspirinAspirin5 y27 000Major adverse cardiac eventsMajor bleeding
    VOYAGER 02504216Rivaroxaban 2.5 mg BID on top of aspirinPlacebo on top of aspirin2 y6500Cardiovascular death, myocardial infarction, stroke, acute limb ischemia, or amputationMajor bleeding
    Venous thrombosis
     Primary preventionEPCAT II 01720108Rivaroxaban 10 mg ODAspirin10 or 30 d3426Symptomatic VTEMajor or clinically relevant nonmajor bleeding
     Secondary preventionEINSTEIN Choice 02064439Rivaroxaban 10 mg OD or rivaroxaban 20 mg ODAspirin1 y3399Recurrent VTEMajor bleeding
    • BID, twice daily; COMPASS, Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease; EINSTEIN Choice, Reduced-dosed Rivaroxaban in the Long-term Prevention of Recurrent Symptomatic Venous Thromboembolism; EPCAT II, Extended Venous Thromboembolism Prophylaxis Comparing Rivaroxaban to Aspirin Following Total Hip and Knee Arthroplasty; NAVIGATE ESUS, Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source; NCT, national clinical trial (; OD, once daily; RE-SPECT ESUS, Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source; VOYAGER, Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities.

  • Table 2.

    Strategies to target factor XII or factor XI

    StrategyMechanism of action
    Antisense oligonucleotidesReduce hepatic synthesis of factor XII or factor XI
    AptamersBind factor XII or factor XI and block activity
    AntibodiesBind factor XII or factor XI and block activation or activity
    Small moleculesBind reversibly to active site of factor XIIa or factor XIa and block activity
    Polyanion antagonistsNeutralize polyphosphates or nucleic acids via ionic interactions, thereby attenuating contact pathway activation
  • Table 3.

    Pharmacological features of factor XII– or factor XI–directed strategies

    FeatureAntisense oligonucleotidesAntibodiesAptamersSmall molecules
    DeliveryParenteralParenteralParenteralParenteral or oral
    Onset of actionDelayedImmediateImmediateImmediate
    Offset of actionDelayedDelayedRapidRapid
    Renal clearanceNoNoNoVariable
    Hepatic metabolismNoNoNoVariable
    Potential clinical indicationsChronicAcute or chronicAcute or chronicAcute or chronic
  • Table 4.

    Relative advantages and disadvantages of factor XII or factor XI as targets for new anticoagulants

    Factor XIIFactor XI
    Epidemiological dataWeakStronger
    Risk for bleedingNoneLow
    Level of evidence for role in thrombosisPreclinicalPhase 2
    Potential for bypassing inhibitionThrombin-mediated activation of factor XI could bypass factor XII inhibitionNone
    Potential for off target effectsMay modulate inflammation by inhibiting bradykinin generationUnlikely
  • Table 5.

    Potential Indications for factor XII– or factor XI–directed strategies

    Primary VTE prophylaxisLong-acting strategies such as antisense oligonucleotides or antibodies permit simple and safe single-dose regimens for extended thromboprophylaxis in medically ill patients or after major orthopedic surgery
    Secondary VTE prophylaxisMay be safer than current therapies for secondary prevention in patients with unprovoked or cancer-associated venous thromboembolism
    Prevention of recurrent ischemia after ACSMay provide a safer anticoagulant platform on top of single- or dual-antiplatelet therapy
    End-stage renal diseaseMay be safe and effective for reducing cardiovascular death, myocardial infarction, and stroke in patients receiving hemodialysis
    High-risk atrial fibrillation patientsMay be safer than current therapies for stroke prevention in patients with atrial fibrillation at high risk of bleeding such as those with a history of major bleeding or with end-stage renal disease
    Medical devicesMay be more effective and safer than current therapies to prevent clotting on mechanical heart valves, left ventricular assist devices, small caliber grafts, or central venous catheters
    Extracorporeal circuitsMay be more effective and safer than heparin to prevent clotting on extracorporeal membrane oxygenator or cardiopulmonary bypass circuits