Venous thromboembolism treatment failure during use of factor Xa inhibitors-association with thoracic outlet syndrome and development of chronic thromboembolic pulmonary hypertension

Abstract

Background: Factor Xa inhibitors (FXaI) are recommended for treatment of venous thromboembolism (VTE). However, in FXaI trials there is a 2-3% treatment failure rate. This observational study aimed to elucidate factors associated with recurrent VTE during coagulation FXaI treatment.

Methods: Ten consecutive FXaI failure cases were included. Various thrombosis risk scores were assessed, thrombophilia was screened, and coagulation activity was followed-up, to tailor individual anticoagulation strategies.

Results: Our patients were young (mean age 37.5 years, range 22-55), six being women. Index VTE was pulmonary embolism (PE) in eight patients, and upon recurrent PE, six of them developed chronic thromboembolic pulmonary hypertension (CTEPH). Although initially many patients appeared to have unprovoked VTE, all had major VTE risk factors. Seven patients had chronic venous obstruction: five subclavian (thoracic outlet syndrome, TOS) even though only two had upper extremity deep vein thrombosis at index thrombosis, plus one common iliac, and one with chronic paraplegia. Five patients had multiple VTE risk factors and four had thrombophilia. VTE risk scores varied from the lowest (TOS patients) to the highest risk (multiple risk factors/thrombophilia). FXaI failure occurred on average at 97 days of therapy (range 15-279) without evident noncompliance. D-dimer levels declined from the index thrombosis to FXaI failure, and re-thrombosis resisted further anticoagulation, low D-dimer referring to impaired fibrinolysis. The majority (8/10) of patients required mechanical/surgical interventions.

Conclusions: Our results underline careful risk assessment upon PE and reoccurrence, with inclusion of TOS as a risk factor of VTE and CTEPH.

Keywords: Venous thromboembolism; chronic thromboembolic pulmonary hypertension; factor Xa inhibitor; thoracic outlet syndrome.

Figure 1.

Long-term antithrombotic treatment. Long-term antithrombotic treatment was individually tailored to each of the 10 patients. The use of different treatment combinations is shown. In one patient without CTEPH antithrombotic treatment was discontinued after operation for TOS. LMWH; low-molecular-weight heparin, ASA; acetylsalicylic acid, CTEPH; chronic thromboembolic pulmonary hypertension, TOS; thoracic outlet syndrome.

Figure 2.

Evolution of hemoglobin (a), platelet count (b), C-reactive protein (CRP) (c), and D-dimer (d) from index thrombosis to FxaI failure. *p < 0.01, **p < 0.05, FxaI;coagulation factor Xa inhibitor.