Use of XARELTO in Patients with Prior HIT

Summary

• In a retrospective chart review of 8 adult patients with refractory thrombosis who received dabigatran + oral factor Xa (FXa) inhibitor (apixaban or XARELTO) simultaneously (dual direct oral anticoagulant [DOAC] therapy) following treatment failure with ≥1 anticoagulant, 5 patients had a positive heparin-induced thrombocytopenia (HIT) screen and 2 had confirmed HIT based on serotonin release assay (SRA) testing. During dual DOAC therapy, none of the patients had recurrent deep vein thrombosis (DVT), pulmonary embolism (PE), or bleeding events.¹
• In a multicenter, retrospective cohort study to evaluate the efficacy and safety of DOACs (apixaban, XARELTO, and dabigatran) in patients with a diagnosis of laboratory-confirmed HIT, no thrombotic events were observed in patients receiving DOAC as HIT monotherapy. In patients receiving parenteral non-heparin anticoagulation before DOAC initiation, 9 patients experienced the primary outcome of HIT-related thrombotic events.²
• In a multicenter, prospective cohort study, the efficacy and safety of XARELTO were evaluated as a treatment option in 22 patients with suspected or confirmed HIT.³
• In a series of in vitro tests, XARELTO dissolved in dimethyl sulfoxide (DMSO) solution had no effect on platelet factor 4 (PF4) expression on HEK-293 cells, PF4 or PF4/heparin complex binding to platelets, antibody (Ab) binding to PF4/heparin complexes, or platelet activation by anti-PF4/heparin. The XARELTO/DMSO solution increased PF4 binding, but the same effect was seen in DMSO solution without the presence of XARELTO. Since XARELTO is administered orally, the in vitro effects of DMSO do not have clinical relevance.⁴
• In an in vitro study, XARELTO did not cross-react with HIT antibodies or promote platelet activation or aggregation in the presence of HIT antibodies. XARELTO did not interact with or further promote the release of PF4 over a range of concentrations, including therapeutic levels. These findings suggest that XARELTO may have the potential to be used for the management of thrombosis in patients with clinically suspected HIT.⁵
• Additional references identified during a literature search are included in the reference section for your review.^6-8

CLINICAL STUDIEs

Chornenki et al (2024)¹ conducted a retrospective chart review of 8 adult patients with refractory thrombosis treated between 2012 and 2022 who received dabigatran and an oral FXa inhibitor (apixaban or XARELTO) simultaneously (dual DOAC therapy) following treatment failure with ≥1 anticoagulant.

• The median age of patients was 54 years (range, 23-69 years), and 75% of patients were male.
• Known thrombotic risk factors for patients at presentation included a remote history of venous thromboembolism (VTE; 2/8), antiphospholipid syndrome (1/8), anabolic stroid use (1/8), homozygous factor V Leiden (1/8), oral contraceptive use (1/8), obesity (4/8), and metastatic malignancy (1/8).
• Two patients presented with the index VTE after recent exposure to unfractionated heparin (UFH); one was exposed in the setting of non-ST elevation myocardial infarction and coronary artery bypass graft, while the other received 6 days of UFH thromboprophylaxis during hospitalization. In both patients, SRA testing confirmed HIT.
• The remaining 6 patients had no prior heparin exposure but were tested for HIT after developing recurrent thrombosis while receiving UFH or low-molecular-weight heparin (LMWH) for their index VTE; all tested negative for HIT.
• Index thrombotic events comprised DVT (8/8), PE (7/8), bilateral lower limb arterial ischemia with aortic thrombus (1/8), and cerebral venous thrombosis (1/8).
• The median time from the index event to first recurrence was 19 days (range, 3-49 days). Before initiating dual DOAC therapy, patients received a median of 3 subsequent treatment lines (range, 1-5).
• After dual DOAC therapy was initiated, no further additional breakthrough venous thrombotic events occurred, and all patients were discharged from hospital on dual DOAC therapy with dabigatran and either apixaban (2/8) or XARELTO (6/8) as the second DOAC.
• During dual DOAC therapy, 1 patient had superficial thrombophlebitis at 54 months, and 1 patient had an arterial thrombotic event at 3 months. Another 2 patients experienced subsequent thrombotic events at 1 month and 71 months after discontinuation of dual DOAC therapy; both had arterial events (stroke and ischemic limb) while on a single anticoagulant.
• The median follow-up duration was 32 months (range, 6-103 months).
• None of the patients died during follow-up.

Davis et al (2022)² conducted a multicenter, retrospective cohort study between January 2013-2020 that evaluated the efficacy and safety of DOACs (apixaban, XARELTO, or dabigatran) in adult patients with a laboratory-confirmed HIT diagnosis.

• Key inclusion criteria were an intermediate or high pre-test probability for HIT (4Ts score ≥4) and a positive anti-PF4/heparin complex assay (enzyme-linked immunosorbent assay [ELISA) optical density [OD] >0.4 and >50% inhibition with heparin), positive latex immunoturbidimetric assay (>0.1), or SRA (>20% with
  low-dose heparin [0.2 IU/mL] or <20% with high-dose heparin [100 IU/mL]).
• The primary outcome was a composite of newly diagnosed venous or arterial thromboembolism, gangrene, or severe limb ischemia requiring amputation at 3 months following DOAC initiation.
• The secondary outcomes were major bleeding and clinically relevant nonmajor bleeding (CRNMB) at 90 days, time to platelet recovery, hospital length of stay, and all-cause mortality at 30 days and 90 days.
• The trial included a total of 77 patients ([apixaban, n=51], [XARELTO, n=24], and [dabigatran, n=2]). The median 4Ts score was 5 (interquartile range, 4.5-6), and 38 patients (49.4%) had a diagnosis of HIT with thrombosis. Sixty-three patients (81.8%) received parenteral non-heparin anticoagulation (argatroban or bivalirudin or fondaparinux) before DOAC initiation, and 14 patients (18.2%) received DOAC as HIT monotherapy.
• In the apixaban group, the dosages varied from 2.5 mg twice daily to 10 mg twice daily. In the XARELTO group, the dosages ranged from 15 mg once daily to 20 mg once daily, while patients in the dabigatran group received 150 mg twice daily.
• 9/77 patients (11.7%) experienced the primary composite endpoint of HIT-related thrombotic events. Of those treated patients who experienced the primary outcome, the highest incidence was found in apixaban treated patients (n=7, [77.8%]), followed by XARELTO (n=2, [22.22%]).
• All patients who experienced the primary outcome received initial parenteral anticoagulation with variable DOAC dosing. In the apixaban group, 4 patients received 5 mg twice daily, and each of the 3 remaining patients received 10 mg twice daily for 7 days followed by 5 mg twice daily, 10 mg twice daily for 3 days followed by 5 mg twice daily, or 2.5 mg twice daily. In the XARELTO group, both patients received 15 mg twice daily for 21 days followed by 20 mg daily. None of the patients treated with DOAC therapy alone experienced the primary outcome.
• Major bleeding occurred in 5/77 patients (6.5%), and CRNMB was reported in 9/77 patients (11.7%). One patient (1.3%) died within 30 days, and 5 patients (6.5%) died within 90 days.

Linkins et al (2016)³ conducted a Canadian, multicenter, prospective, cohort study to evaluate the efficacy and safety of XARELTO in 22 participants (12 HIT positive) with suspected or confirmed HIT. Participants were given XARELTO 15 mg twice daily until platelet recovery (or at least day 21 if they had acute thrombosis at study entry), then XARELTO 20 mg once daily until day 30.

• Patients were included if they had an intermediate or high clinical probability of HIT (4Ts score ≥4 points).³ The 4Ts is a scoring system for HIT that incorporates the magnitude of thrombocytopenia, timing of thrombocytopenia with respect to heparin exposure, thrombosis or other sequelae of HIT, and the likelihood of other thrombocytopenia causes. The results yield a score between 0 and 8, with ≥4 classified as intermediate or high probability of HIT.⁹
• 'HIT positive’ was defined as a 4Ts score ≥ 4 plus positive SRA with mean serotonin release ≥50% as well as inhibition (< 20% release or > 50% inhibition) at 100 U/mL heparin and in the presence of the Fc receptor-blocking monoclonal antibody.
• The primary study outcome was to determine the incidence of new symptomatic venous and arterial thromboembolism in the combined cohort of participants with suspected and confirmed HIT at 30-days.
• After 371 days of exposure to XARELTO in the combined cohort, one HIT-positive participant had symptomatic recurrent VTE (4.5%; 95% confidence interval [CI],
  0-23.5%). The thrombotic event rate in HIT positive participants was 8.3% (95% CI, 0.1-37.5%). Nine out of ten HIT positive participants achieved platelet recovery with a mean time to recovery of 11 days.
• One HIT positive patient had major bleeding 9 days after XARELTO was held. There were 4 deaths.

In Vitro Studies

Krauel et al (2012)⁴ assessed the interactions of dabigatran, XARELTO, and 2-O, 3-O desulfated heparin (ODSH) with PF4 and anti-PF4/heparin antibodies. The following concentrations were used:

• Dabigatran (5 mg/mL) dissolved in 95% DMSO and 50 mM HCl
• XARELTO (0.5 mg/mL) dissolved in 100% DMSO
• ODSH (50 mg/mL)
• UFH (150 IU/mg)

For study results, see Table: Interactions Assessed of Dabigatran, XARELTO, and ODSH with PF4 and Anti-PF4/Heparin Antibodies

Walenga et al (2008)⁵ conducted a comparative, in vitro analysis of XARELTO and other anticoagulants (UFH, enoxaparin, fondaparinux, and argatroban) to evaluate the potential for XARELTO to be used as an alternative anticoagulant agent in patients with HIT.

• In vitro studies were performed on serum collected from patients with clinically suspected HIT following recent exposure to a heparin agent (UFH or a low molecular weight heparin). Patients providing the serum samples had drops of ≥30% in platelet counts, HIT antibody titers > 0.8, and positive responses in the 14C-SRA.
• XARELTO did not activate platelets or demonstrate a concentration-dependent increase in the percentage of serotonin that was released in the presence of HIT antibodies. XARELTO did not promote platelet aggregation in the presence of HIT antibodies over a range of concentrations, including therapeutic levels.
• In the presence of tissue factor-activated platelets in whole blood, XARELTO did not enhance the release of PF4, but lowered PF4 levels to less than those observed with a saline control. The anti-factor Xa activity of XARELTO (1 mcg/mL) did not change in the presence or absence of purified PF4 (10 mcg/mL), which supports the finding that XARELTO does not interact with PF4.
• The authors concluded that XARELTO does not cross-react with HIT antibodies.

CASE REPORTS

There have been several case reports published documenting the use of XARELTO in patients with suspected or confirmed HIT.^10-38 Another case report described a patient who developed HIT while receiving XARELTO after knee replacement surgery.³⁹

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 27 July 2026.