Venous Thromboembolism Incidence in Patients with Cancer and Factor XI Deficiency

Background: Individuals with inherited Factor XI (FXI) deficiency have a significantly lower risk of venous thromboembolism (VTE) compared to the general population, and typically do not experience spontaneous bleeding. FXI inhibitors have shown promise in preventing VTE in patients undergoing orthopedic surgery and are currently being studied for VTE treatment in patients with cancer. Whether patients with cancer and FXI deficiency have a lower VTE risk remains to be determined.

Aim: To compare the incidence of VTE between patients with cancer and FXI deficiency and patients with cancer and normal partial thromboplastin time (PTT).

Methods: A retrospective study was conducted at Memorial Sloan Kettering Cancer Center (MSKCC) on patients treated for cancer from 2010 to 2024. The exposure cohort included patients found to have FXI <50% at any point in their lives, excluding cases of FXI deficiency due to cirrhosis or disseminated intravascular anticoagulation. Controls were patients with normal PTT at index point who had no documented FXI test. Index point was defined as the first appointment for cancer at MSKCC. We excluded patients on therapeutic anticoagulation at index point and those positive for antiphospholipid syndrome antibodies. The primary outcome was VTE. Participants were followed from the index point until the first episode of VTE, death, their last visit or end of 12-month follow up, whichever occurred first. Patients with FXI deficiency were 1:1 matched with controls for age (up to 3 years difference), sex, hemoglobin level (6-8, 8-10, 10-12, 12+ g/dl), platelets (<25, 25-50, 50-100, 100+ × 10⁹/L), surgery within 30 days after index point (endoscopy was not considered surgery), cancer type and cancer stage (in situ, stage I-II, III, IV). Cumulative incidence for VTE was calculated at 1, 6 and 12 months in the FXI deficient and control cohorts with death as a competing risk. Cumulative incidence at 12 months was compared using the Grey test.

Results: We included 73 patients with FXI deficiency and cancer with median age 64 with 40% (29/73) females. The median FXI level, representing the lowest value on record for each patient, was 27% (interquartile range 10 – 42%). Within the FXI deficient cohort, 77% (56/73) had solid cancer: breast 20% (11/56), gastrointestinal 16% (9/56) and prostate 7% (4/56); 23% (17/73) had hematologic cancer. From the patients with solid cancer, 55% (31/56) had Stage I-II and 36% (20/56) had Stage III-IV. Matched controls with cancer and normal PTT were identified for 65/73 patients from the FXI deficient cohort. Age, sex, prior VTE, hemoglobin and platelet levels at index, cancer type/stage and surgery within 30 days after index were not statistically different between the FXI deficient cohort and matched controls. The mean difference between the index points of each matched pair was 1.8 years (interquartile range 0 – 2).

The cumulative incidence for VTE at 6 months was 2.8% (95% confidence interval [CI] 0.52 - 8.7%) in the FXI deficient cohort compared to 9.3% (95% CI 3.7 – 18%) in the control cohort. The 12-month cumulative VTE incidence was 4.2% (95% CI 1.1 – 11%) in the FXI deficient cohort versus 12% (95% CI 5.8 – 22%) in matched controls (Grey test p=0.08).

Comparable results were demonstrated in the 32 patients with severe FXI deficiency with levels <20%; the cumulative incidence for VTE at 12 months was 3.1% (95% CI 0.22 – 14%) in FXI deficient patients compared to 12% (95% CI 5.8 – 22%) in controls (Grey test p=0.14).

Conclusion: Patients with factor XI deficiency appear to have comparatively low rates of VTE in the setting of cancer. These data further support the investigation of factor XI inhibitors to prevent thrombosis in high-risk cancer settings.