Abstract: The Frequency of Anticardiolipin Antibodies and Genetic Mutations Associated with Hypercoagulability Among Patients with Wegener's Granulomatosis with and without History of a Thrombotic Event

The Frequency of Anticardiolipin Antibodies and Genetic Mutations Associated with Hypercoagulability Among Patients with Wegener's Granulomatosis with and without History of a Thrombotic Event

JODI K. SEBASTIAN, BARBARA VOETSCH, JOHN H. STONE, ZURINA ROMAY-PENABAD, GRACE H. LO, NANCY B. ALLEN, JOHN C. DAVIS Jr, GARY S. HOFFMAN, W. JOSEPH McCUNE, E. WILLIAM St. CLAIR, ULRICH SPECKS, ROBERT SPIERA, JOSEPH LOSCALZO, SILVIA PIERANGELI, and PETER A. MERKEL, for the Wegener's Granulomatosis Etanercept Trial Research Group

ABSTRACT.

Objective. Venous thrombotic events (VTE), including both deep venous thrombosis and pulmonary emboli, are now recognized as an important complication of Wegener's granulomatosis (WG), but the mechanism(s) of this occurrence is unclear. The frequency of anticardiolipin antibodies (aCL), anti-ß₂-glycoprotein antibodies (anti-ß₂-GP), and several genetic hypercoagulable factors were examined in a large cohort of patients with WG.

Methods. One hundred eighty patients with active WG had serum and DNA samples collected upon entry into a clinical trial. Of the 180 patients, 29 patients had VTE — 13 before trial entry, 16 during trial. aCL (IgG, IgM, and IgA) and anti-ß₂-GP (IgG and IgM) were evaluated in 176 patients. Factor V Leiden (FVL), the prothrombin gene mutation (G20210A, PGM), and methylenetetrahydrofolate reductase (MTHFR) gene mutation were tested in the 29 patients with thrombotic events, and 36 patients without.

Results. aCL occurred with increased frequencies in patients with WG when compared to the general population (1%–5%): 12% had aCL and 3% had anti-ß₂-GP. There was no difference in the prevalences of aCL or anti-ß₂-GP based on clotting status. The prevalence of the genetic hypercoagulable factors examined in patients with WG was comparable to the reported rates in the general population.

Conclusion. Although the incidence of clinically significant VTE is increased in patients with WG, this increased risk is not explained by increased prevalences of aCL, anti-ß₂-GP, FVL, or mutations in PGM or MTHFR. These observations suggest a need to search for new genetic or acquired prothrombotic abnormalities to account for the increased thrombotic event rate in patients with active WG. (First Release Oct 1 2007; J Rheumatol 2007;34:2446-50)

Key Indexing Terms:

ANTICARDIOLIPIN ANTIBODIES
WEGENER'S GRANULOMATOSIS
THROMBOTIC EVENTS

From Boston University School of Medicine; Tufts University School of Medicine; Brigham and Women's Hospital, Boston, Massachusetts; Johns Hopkins University, Baltimore, Maryland; University of Texas Medical Branch, Galveston, Texas; Duke University, Durham, North Carolina; University of California San Francisco, San Francisco, California; Cleveland Clinic, Cleveland, Ohio; University of Michigan, Ann Arbor, Michigan; Mayo Clinic, Rochester, Minnesota; and Hospital for Special Surgery, New York, New York, USA.

Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH P60 AR047785-06.

The WGET trial was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH N01-AR92240, and the Office of Orphan Products, FDA (grant FD-R-001652), General Clinical Research Center Grants M01-RRO-00533 (Boston University), M01-RRO-0042 (The University of Michigan), MO1-RR-30 (Duke University), and M01-RRO-2719 (Johns Hopkins University School of Medicine), from the National Center for Research Resources/NIH. Drs. Stone, Merkel, and St. Clair were supported by NIAMS grants K24 AR049185-01, K24 AR2224-01A1, and K24 AR02126-04. Dr. Loscalzo's laboratory is supported by NHLBI grants R01 HL617995, R01 HL58796, P01 HL55993, and P01 HL28178. Dr. Pierangeli's laboratory is supported by NIH grants G12-RR-03034 and SO2-GMM-08248.

J.K. Sebastian, MD; B. Voetsch, MD, PhD; P.A. Merkel, MD, MPH, Boston University School of Medicine; J.H. Stone, MD, MPH, Johns Hopkins University; Z. Romay-Penabad, PhD; S. Pierangeli, PhD, University of Texas Medical Branch; G.H. Lo, MD, MPH, Tufts University School of Medicine; N.B. Allen, MD; E.W. St. Clair, MD, Duke University; J.C. Davis Jr, MD, MPH, University of California, San Francisco; G.S. Hoffman, MD, MS, Cleveland Clinic; W.J. McCune, MD, University of Michigan; U. Specks, MD, Mayo Clinic; R. Spiera, MD, Hospital for Special Surgery; J. Loscalzo, MD, PhD, Brigham and Women's Hospital.

Address reprint requests to Dr. P.A. Merkel, Section of Rheumatology and the Clinical Epidemiology Unit, Vasculitis Center, E533, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118. E-mail: pmerkel@bu.edu

Accepted for publication June 27, 2007