Jeffrey Weitz, MD, is a professor of medicine, biochemistry, and biomedical sciences at McMaster University, executive director of the Thrombosis and Atherosclerosis Research Institute in Hamilton, Ontario, and current Secretary General of the ISTH.

Jeffrey Weitz, MD

AXIOMATIC-TKR: Milvexian Decouples Thrombosis, Hemostasis in DVT

A new analysis of the AXIOMATIC-TKR trial has demonstrated milvexian’s potential to inhibit intrinsic pathway thrombin generation (TG) without significantly impacting extrinsic pathway TG, thereby “decoupling” thrombosis from hemostasis in patients with 

Presented at the International Society on Thrombosis and Hemostasis (ISTH) 2026 Congress in Paris, France, by Madhu Chintala, PhD, senior director of thrombosis research at the Janssen Pharmaceutical Companies of Johnson & Johnson, these data reflect the investigative factor XIa (FXIa) inhibitor’s potential to substantially reduce disease severity and burden.

“The holy grail of anticoagulation therapy is to attenuate thrombosis without disrupting hemostasis,” Jeffrey Weitz, MD, professor of medicine, biochemistry, and biomedical sciences at McMaster University, executive director of the Thrombosis and Atherosclerosis Research Institute in Hamilton, Ontario, and current Secretary General of the ISTH, told 

 in an exclusive interview. “Uncoupling thrombosis and hemostasis is what anticoagulation therapy is all about, and I think the FXIa inhibitors take us closer to that goal than anything we have right now.”

AXIOMATIC-TKR was a parallel-group, phase 2 trial including patients undergoing elective unilateral total knee arthroplasty. Patients were eligible if they were ≥50 years of age and were determined to be medically stable and appropriate for anticoagulant prophylaxis, as determined by the investigators. Patients with a history of severe hepatic impairment or who had a planned bilateral revision or unicompartmental procedure were excluded, among other criteria.

Patients were then randomly assigned in a 1:1:1:1:1:1:2 ratio to 1 of 8 parallel treatment groups – these included 4 twice-daily milvexian regimens of 25 mg, 50 mg, 100 mg, and 200 mg, 3 once-daily regimens of 25, 50, or 200 mg, and enoxaparin 40 mg once daily. Patients in the milvexian groups were administered 4 capsules of either active drug or matching placebo per day, 2 in the morning and 2 in the evening. The enoxaparin group received their treatment subcutaneously. Treatment was administered for 10-14 days following surgery.

The study’s primary efficacy outcome was venous thromboembolism, a composite of asymptomatic DVT, confirmed symptomatic venous thromboembolism, or all-cause mortality. Secondary efficacy outcomes included proximal DVT, distal DVT, nonfatal pulmonary embolism, and death. The primary safety outcome was bleeding of any severity.

A total of 1242 patients were enrolled in the trial; of these, venous thromboembolism developed in 27 of 129 patients taking 25 mg milvexian twice daily, in 14 of 124 taking 50 mg, in 12 of 134 taking 100 mg, and in 10 of 131 taking 200 mg. Among patients assigned to once-daily milvexian, venous thromboembolism occurred in 7 of 28 taking 25 mg, in 30 of 127 taking 50 mg, and in 8 of 123 taking 200 mg. 54 of 252 patients taking enoxaparin exhibited venous thromboembolism.

In the present exploratory analysis, Chintala and colleagues assessed thrombus burden via venography. TG was assessed ex vivo following stimulation with kaolin or high tissue factor, triggering the intrinsic and extrinsic coagulation pathways, respectively. They found that milvexian numerically reduced the average severity score of DVT compared to enoxaparin at all doses except 25 mg once daily. Initiation of TG with kaolin in plasma demonstrated a reduced overall amount of thrombin generated and peak levels of thrombin in a dose-dependent manner. Milvexian also had a minimal impact on TF-stimulated thrombin generation over time.

Ultimately, the team established that milvexian selectively uncouples the 2 pathways of thrombin generation while potentially reducing thrombus burden in DVT compared with enoxaparin treatment.

“We need to confirm that FXIa inhibition can indeed uncouple thrombosis and hemostasis and see how these agents work when given compared with placebo on top of antiplatelet therapy, or when given compared with a current standard-of-care anticoagulant,” Weitz said. “So, more to come and more to learn.”

Editors’ Note: Weitz reports disclosures with Anthos, Bayer, Bristol Myers Squibb, Ionis, Janssen, Merck, and others.

Chintala M, Strony J, Damaraju CV, et al. Decoupling thrombosis from hemostasis: the effect of milvexian on thrombus burden and thrombin generation in the phase 2 AXIOMATIC-TKR study. Abstract presented at the International Society on Thrombosis and Haemostasis (ISTH) 2026 Congress, Paris, France. July 11-15, 2026.

Weitz JI, Strony J, Ageno W, et al. Milvexian for the Prevention of Venous Thromboembolism. N Engl J Med. 2021;385(23):2161-2172. 

Janssen Research & Development. A Study of JNJ-70033093 (BMS-986177) Versus Subcutaneous Enoxaparin in Participants Undergoing Elective Total Knee Replacement Surgery (AXIOMATIC-TKR). ClinicalTrials.gov Identifier: NCT03891524. Updated March 30, 2025. Accessed July 14, 2026. 

https://clinicaltrials.gov/study/NCT03891524

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Jeffrey Weitz, MD, secretary general of the ISTH, discusses the recent analysis of the AXIOMATIC-TKR trial and its implications for FXIa inhibition.

Jeffrey Weitz, MD

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