THE CONTACT FACTOR INHIBITORS: Battling thromboembolism.

David L. McGlasson, MS, MLS(ASCP)


Thromboembolism is a leading cause of mortality and morbidity.  Treatment with anticoagulants is prescribed, but balancing bleeding and clotting has been a challenge. In the 1940s, unfractionated heparin (UFH) became available for use by intravenous or subcutaneous injections. In the 1950s Vitamin K antagonists (VKA), a converted form of a rodenticide, was developed as an oral anticoagulant called warfarin.  One of the first people of note treated with this new medication was in September 1955. When President Dwight Eisenhower suffered a heart attack, he was successfully treated with warfarin, and the publicity added substantially to the drug’s luster. For 70 years, unfractionated heparins, low molecular weight heparins (LMWH), and VKA were the standard of care.

The limitations of these medications led scientists to search for new anticoagulants for the last several years.  It also has led to a finding of new oral anticoagulants, first called NOACs, that are coagulation factor target-specific oral medications, such as thrombin inhibitors like dabigatran in 2008, FXa inhibitors like rivaroxaban in 2011, apixaban in 2012, and edoxaban in 2015.  These medications are all now commercially available and are now known as direct oral anticoagulants or DOACs.  However, all the aforementioned anticoagulants have one thing in common: risk of hemorrhage. While trying to control the issue of thrombosis, the medical team must be very aware of bleeding risk.

In the last few years there has been a significant amount of research dedicated to developing antithrombotic medications that have a lesser effect on bleeding.  The contact factor proteins of the intrinsic pathway have shown promise in these situations. These factors rarely cause significant bleeding unless trauma is experienced but may contribute to thrombosis.

Studies have been performed to test compounds targeting FXI and FXII in preclinical, Phase II and a few planned Phase III protocols. These compounds have shown promise for anti-thrombotic properties when compared to standard of care medications used to treat venous thrombosis in patients undergoing total knee replacement (TKR).

FXIIa inhibitors have been researched less than FXI.  FXII deficient subjects do not have abnormal bleeding issues. In fact, the patient after whom FXII is named, John Hageman, died from a pulmonary embolism. These compounds could be particularly useful for reducing thrombosis in instances where blood encounters artificial surfaces on medical devices. That can include intravenous catheters, heart valves, circuits for extracorporeal membrane oxygenation (ECMO), cardiopulmonary bypass, and renal dialysis.

It has been observed in humans and animals that FXII deficiencies are not required to maintain hemostasis.  This is consistent with findings that FXIIa inhibitors do not induce bleeding in laboratory animals.  However, FXI deficient subjects may bleed abnormally.  FXI is activated by proteases other than FXIIa, such as thrombin. A FXI deficiency is known as Hemophilia C. Some subjects with severe FXI deficiency may not have a bleeding phenotype. Trauma to tissues of the mouth and urinary tract can cause severe bleeding.  However, factor replacement has not been needed in cases of surgery when performing appendectomy, cholecystectomy, and knee arthroplasty.  Spontaneous bleeds occurring in cases of heavy menstrual flow are rare.  GI bleeds are no more frequent than patients with normal FXI levels. Therefore, these findings suggest that targeting FXI and FXII will cause fewer disturbances of hemostasis than current anticoagulant therapies.

In humans, the issue of severe FXI deficiency is prevalent in the ethnic group of Ashkenazi Jews which occurs in approximately one of 450 persons. Interestingly in this population the severely depleted FXI subjects display significantly lower risk for VTE and ischemic stroke than those with normal FXI levels, and spontaneous bleeding is rare. This data supports levels found in the normal population which displays a direct correlation between plasma FXI concentration and risks for VTE and stroke.  Elevated FXI levels have been seen in some studies to increase the risk for myocardial infarction (MI). A severely low level of FXI may not protect the subjects in a VTE or stroke event.


Contact factors such as FXI and FXII in laboratory animals provide evidence of their contribution to thrombosis, despite their limited roles in bleeding.  FXI and FXII deficiencies in mice show that they are resistant to venous and arterial thrombotic issues. Rabbits with low levels of FXI and FXII block injury related to arterial and venous thrombosis.  Baboons with antibodies inhibiting FXII reduce thrombus formation but to a lesser degree than FXI inhibition. FXI reduction in baboons with antisense oligonucleotides (ASO) reduces thrombus growth in collagen-coated grafts in baboons, with an anti-thrombotic effected detected when FXI is reduced by as little as 50%. FXIIa and FXI directed antibodies stunt thrombosis in ECMO models of rabbits and baboons

Even though results in animal models show promise, these results must be verified in humans.  They may not coincide with human disorders like MI, stroke or VTE.


  Antibodies Small molecules Natural inhibitors ASOs Aptamers
Mechanism Bind target protein Bind target protein Bind target protein Blocks biosynthesis Bind target protein
Administration route IV or SC IV or oral IV SC IV or SC
Administration frequency Monthly Daily Daily Weekly to monthly Daily
Onset of action Rapid (hours to days) Rapid (minutes to hours) Rapid (minutes) Slow (weeks) Rapid (minutes to hours)
Offset of action Slow (weeks Rapid (minutes to hours) Rapid (hours) Slow (weeks) Rapid (minutes to hours)
Renal excretion No Yes Uncertain No No
CYP metabolism No Yes No No No
Potential for drug-drug interactions No Yes Unknown No No

Abbreviations: ASO antisense oligonucleotide; CYP: cytochrome P450; FXI, FXII;IV intravenous; SC: subcutaneous.

Fredenburgh JC, Weitz JI. New anticoagulants: Moving beyond the direct oral anticoagulants. J Thromb Haiemost. 2021;19:20-29.


Anticoagulants currently approved to inhibit Factor IIa and factor Xa or the precursors of these enzymes still have limits in their use, and their therapeutic dosing must balance the possibility of hemorrhage. It is anticipated that the new proposed inhibitors of FXI and FXII will place the patient at less risk of bleeding than the previously mentioned inhibitors of FXa and thrombin.

FXI and FXII targeting agents are not currently approved only up to Phase 2 studies.  These include monoclonal antibodies (IgGs) which bind to precursor and/or active forms of FXI and FXII, ASOs which may block synthesis of FXI, small molecules that inhibit the FXIa active site, nucleic acid aptamers that bind and inhibit FXI or FXII, and glycosaminoglycan mimetics that allosterically inhibit the FXIa active site.


Factor XI ASO: IONIS-FXIRx (BAY2306001) is one of the furthest along in the Phase II trials.  It is given subcutaneously.  It is a DNA based ASO specific for human FXI mRNA. The drug is taken up by several cell types including hepatocytes. The FXI mRNA bound to IONIS-FXIRx is degraded by endogenous RNase, resulting in reduced FXI synthesis. A phase II trial of 300 subjects undergoing elective knee arthroplasty compared IONIS-FXIRx with enoxaparin for VTE prophylaxis. The endpoint was detection of VTE by venography or clinically 8-12 days after surgery.  Doses of 200 and 300 mg of IONIS-FXIRx were started 35 days prior to the surgical procedure. This protocol reduced plasma FXI, on average, to 38% activity and 20% of the normal concentration by the day of surgery. A 200 mg dose of IONIS-FXIRx and enoxaparin (27% vs 38% respectively) resulted in VTE presence. The 300 mg dose of IONIS-FXIRx was superior to enoxaparin (4% VTE).

**Subjects that were on the IONIS-FXIRx arm of the study received the full dose during the surgery yet hemostasis was stable before and after the surgical procedure, with no complications.

A second Phase II trial is underway with renal dialysis patients.  Preliminary data show a good response with few complications to date.

FACTOR XIa mAb: osocimab (BAY1213790):  A fully humanized IgG monoclonal antibody using a phage display which is a laboratory technique for the study of protein-protein interactions. Osocimab binds the active site or phage display of FXIa. When given in a single IV bolus to healthy subjects, the osocimab prolonged the aPTT in a concentration-dependent dose and had no effect on bleeding time. The drug was given in a study of 813 subjects undergoing total knee arthroplasty. The patients were randomized to doses of 0.3, 0.6, 1.2, or 1.8 mg/kg or preop infusions of 0.3 or 1.8 mg/kg and compared with 10 days of postop enoxaparin (40 mg/day) or apixaban (2.5 mg/day.) The primary outcome was evidence of symptomatic VTE or VTE, 10-13 days postop, identified with venography.  All doses, with the exception of the 0.3 mg/kg, were noninferior to enoxaparin. The 1.8 mg/kg was superior to enoxaparin. (11.3% vs 26.3% incidence) and similar to apixaban (14.5%). Evidence of major of clinically relevant bleeding was seen in 4.7% of osocimab, 5.9% on enoxaparin and 2% on apixaban.

FACTOR XIa SMALL MOLECULE ACTIVE SITE INHIBITOR: JNJ70033093 (BMS-986177): BMS-986177 is an orally administered small molecule selective inhibitor that binds to the FXIa active site.  It has completed Phase I testing in healthy volunteers and in patients with ESRD or liver disorders.  Two Phase II trials are underway.  The BMS-986177 is being compared with a placebo for secondary prevention of stroke in subjects with small ischemic strokes of high-risk TIAs who are on dual-platelet therapy with aspirin and clopidogrel. BMS-986177 is being compared to enoxaparin in the AXIOMATIC-TKR study.  The small molecule inhibitor is being compared with standard dose enoxaparin for prevention of VTE in patients undergoing TKR.

FACTOR XIIa mAb: garadacimab (CLS312):  Garadacimab is a humanized IgG MOAB against FXIIa. It is currently undergoing a Phase II trial evaluation in patients with hereditary angioedema for prevention of symptoms due to excessive bradykinin production.  Early data show its activity could be useful in preventing thrombus formation on artificial surfaces.  IgG 3F7, an early version of garadacimab was as effective as heparin in preventing clot formation in a rabbit ECMO model.

DISCUSSION: We have come a long way in 80 years in anticoagulation. First the heparins, then the VKA, anti-platelet medications then the DOACs.  However, with the good of helping to maintain hemostasis, they also give the possibility of excessive bleeding.  The new contact factor inhibitors primarily focusing on FXI and FXII may make it possible to control thrombotic issues without excessive hemorrhage in a multitude of situations.

Recent Phase II studies with IONIS-FXIRs and osocimab give us hope that the inhibition of FXIa reduces the incidence of VTE.  Close behind we should have information on the oral inhibitor BMS-986177.  Hopefully both of the Phase II protocols will lead to Phase III studies that will compare them to standard of care anticoagulation medications already in use.

The important hope is that the FXI and FXII inhibitors can be given in a predetermined dose that will control the thrombus formation without causing bleeding.

Personal note:  Being on the sidelines in semi-retirement is very frustrating for me while these new anticoagulants are in development.  I would love to be involved in the “wet work” on these fascinating studies.


Franchini M et al:  The evolution of anticoagulant therapy. Blood Tranfus 2016;14:173-84

Gailani D, Bane CE, Gruber A.  Factor XI and Contact Activation as Targets for Antithrombotic Therapy. HHS Public Access J Thromb Baemost. 2015;13(8): 1383-1395.

Srivastava P, Gailani D. The rebirth of the contact pathway: a new therapeutic target. HHS Public Access. Curr Opin Hematol; 2020 27(5):311-319.

Al-Horani. Factor XIa inhibitors for thrombosis: an updated patent review (2016-present). Esxpert Opin Ther Pat. 2020;30(1):39-55.

Fredenburgh JC, Weitz JI. New anticoagulants: Moving beyond the direct oral anticoagulants. J Thromb Haemost 2021;19:20-29.

Fredenburgh JC, Weitz JI. Factor XI as a Target for New Anticoagulants. Haemostaseologie 2021;41:104-110.

Kohs TCI et al: Development of Coagulation Factor XII Antibodies for Inhibiting Vascular Device-Related Thrombosis. Cellular and Molecular Bioengineering. 2021;14(2):161-175.

Thomas D et al: First evaluation of the sfety, pharmacokinetics, and pharmacodynamics of BAY 2433334, a small molecule targeting coagulation factor Xa. J Thromb Haemost 2021;19(10):2407-2416.

Beavers C, Wayne W Osocimab: A Novel Agent in Preventing Venous Thromboembolism. J Cardiovasc Pharmacol 2020;76(6):645-649.

Cave BE, Shah SP. Turning Up to Eleven: Factor XI inhibitors as Novel Agents to Maximize Safety and Maintain Efficacy in Thromboembolic Disease. Curr Probl Cardiol: 2021;46(3):100696.

Eikelboom J et al: Anticoagulation in patients with kidney failure on dialysis: factor XI as a therapeutic target. Kidney Int. 2021;100(6):1199-1207

Weitz J et al:Effect of Osocimab in Preventing Venous Thromboembolism Among Patients Undergoing Knee Arthroplasty. JAMA 2020;323(2):130-139.

Demoulin S, Godfroid E, Hermans C. Dual inhibition of factor XIIa and factor Xia as a therapeutic approach for safe thromboprotection. J Thromb Haemost. 2021;19(2):323-329.