New oral anticoagulants may not be effective to prevent venous thromboembolism in patients with antiphospholipid syndrome
Authors: Khine Win, George M. Rodgers
Journal: American Journal of Hematology (2014)

To the editor: Antiphospholipid syndrome (APS) is a serious acquired thrombophilic condition, which may be associated with both arterial and venous thromboembolism (VTE). Current standard treatment is warfarin, but the anticoagulant effect needs to be monitored closely using the International Normalized Ratio (INR). However, INR test may not be accurate in some APS patients as prothrombin time reagents show variable responses in the presence of lupus anticoagulants 1. Rivaroxaban and dabigatran are novel oral anticoagulants (NOAC), recently approved for the treatment of deep venous thrombosis (DVT) and pulmonary embolism. However, the efficacy of these drugs for treatment of VTE in high-risk APS patients is still uncertain. Even though APS patients were not specifically excluded in the RE-COVER study or EINSTEIN studies, the efficacy of NOAC in APS patients were not reported specifically in those trials. However, some investigators have already proposed using NOAC in APS patients 2-4. NOAC may become the standard therapy for VTE in the future. We report three patients with severe APS and history of multiple thrombotic complications who experienced recurrent thromboses while receiving rivaroxaban or dabigatran. A 46-year-old man with a history of severe APS, refractory to multiple immunosuppressive treatments, had multiple transient ischemic attacks (TIA), stroke, and recurrent DVT while on warfarin and enoxaparin. He had been off anticoagulation until 2013 when he started taking rivaroxaban 20 mg daily for VTE prophylaxis. Six months later, he presented to the hospital with left arm pain. He was diagnosed with extensive superficial venous thrombosis while taking rivaroxaban. He was treated with intravenous heparin initially and transitioned to fondaparinux 7.5 mg daily. His arm pain improved on fondaparinux and he has been doing well since April 2014. A 19-year-old woman developed acute superficial and DVT of her leg after starting oral contraceptive pills. She was initially treated with warfarin. However, her INR values were difficult to maintain within the therapeutic range due to poor dietary compliance. She was switched to rivaroxaban 20 mg daily. She was later diagnosed with APS, along with severe immune-mediated thrombocytopenia. In February 2014, she developed acute superficial venous thrombosis on her left foot while taking rivaroxaban. Rivaroxaban was then switched to enoxaparin and she has not had any recurrent thrombosis since. A 53-year-old Caucasian woman with history of recurrent unprovoked DVT, TIA manifested as acute visual loss and headaches, was diagnosed with antiphospholipid antibody syndrome in 2007. She was initially treated with warfarin, but INR values were difficult to manage. Her genetic testing of warfarin metabolism showed that she was homozygous for the vitamin K epoxide reductase complex subunit 1 and heterozygous for the cytochrome P450 isozyme 2C9 (CYP2C9) genotype. The patient was concerned about the variability of her INR values from warfarin sensitivity with her genetic predisposition. She was switched to dabigatran 150 mg twice daily in 2011. A year later, she started experiencing new neurologic symptoms with acute vision changes, transient weakness in her extremities, presyncopal events, and memory loss. Brain MRI did not show any significant findings to explain her symptoms. Eventually, dabigatran was switched to twice daily therapeutic enoxaparin. She has not had any recurrent symptoms for nine months since starting enoxaparin. All patients had severe APS with multiple thrombotic complications. They had either failed warfarin or had difficulties adjusting warfarin dosing to keep INR values within the therapeutic range before starting NOAC. Two patients had recurrent venous thromboses while on rivaroxaban. One patient was taking dabigatran when she developed recurrent TIA. All patients improved clinically after switching to subcutaneous enoxaparin or fondaparinux. We have not noticed this extent of anticoagulation failure in non-APS patients receiving NOAC therapy. At this time, none of our APS patients are receiving NOAC therapy. Compared with warfarin, NOAC have many advantages, including no dietary or drug interactions, no requirement for laboratory monitoring, and lower risk of life-threatening bleeding complications. Currently, a prospective randomized controlled trial of warfarin versus rivaroxaban is ongoing in patients with thrombotic APS, named Rivaroxaban in Antiphospholipid Syndrome. It is expected to end in January 2015 5. In the meantime, the use of NOAC in severe APS patients should be carefully considered. Khine Win1* and George M. Rodgers2 1Department of Medicine, University of Utah Health Science Center, Salt Lake City, Utah 2Division of Hematology and Hematologic Malignancies, University of Utah Health Science Center, Salt Lake City, Utah