Risk of Hemorrhagic Strokes in Patients with Adenosine Deaminase 2 Deficiency

Patrycja M. Hoffmann¹, Amanda Ombrello¹, Deborah L. Stone², Dean Follmann³, Karyl Barron⁴, Anne Jones⁵, Tina Romeo¹, Camilo Toro⁶, Ariane Soldatos⁷, Arielle Hay⁸, Qing Zhou⁹, Ivona Aksentijevich¹⁰ and Daniel L. Kastner⁵, ¹NHGRI, National Institutes of Health, Bethesda, MD, ²Inflammatory Disease Section, NHGRI/NIH, Bethesda, MD, ³NIAID, Bethesda, MD, ⁴National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, ⁵Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, ⁶NIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, ⁷NINDS, National Institutes of Health, Bethesda, MD, ⁸Nicklaus Children’s Hospital, Miami, FL, ⁹China, ¹⁰Metabolic, Cardiovascular, and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Aspirin and inflammation

Session Information

Date: Tuesday, October 23, 2018

Title: Miscellaneous Rheumatic and Inflammatory Diseases Poster III: Sarcoid, Inflammatory Eye Disease, and Autoinflammatory Disease

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive condition characterized by recurrent fevers, early-onset ischemic strokes, livedo racemosa, polyarteritis nodosa, portal hypertension, immune deficiencies, and cytopenias. Additionally, several patients with DADA2 have had hemorrhagic strokes. DADA2 is caused by biallelic loss-of-function mutations in the ADA2 gene (formerly known as CECR1), resulting in very low ADA2 levels in the blood, vasculopathy, and M1 skewing of macrophage differentiation. The use of tumor necrosis factor (TNF) inhibitors has significantly reduced the risk of recurrent stroke. In this abstract, we report two TNF-inhibitor naïve cases who cumulatively developed three spontaneous hemorrhagic strokes on no anticoagulants/antiplatelets. Additionally, we examine the safety of anticoagulants/antiplatelets in patients with DADA2.

Methods: A single center study evaluated 24 patients who had biallelic germline mutations in the ADA2 gene. Patients were subdivided into those with a history of hemorrhagic stroke versus those without. We then identified the patients with hemorrhagic strokes on no anticoagulant/antiplatelet treatment, ASA alone, and other anticoagulants/antiplatelets versus patients without hemorrhagic stroke on no anticoagulant/antiplatelet treatment, ASA alone, and other anticoagulants/antiplatelets. None of the patients had been on TNF inhibitors at the time of the analysis. The primary outcome measure was to determine occurrence of hemorrhagic strokes in patients with DADA2 and if there is increased risk on anticoagulant/antiplatelet treatment.

Results: Among the 24 patients, 6 (25%) had hemorrhagic strokes and of those 1 was on ASA alone, 3 were on anticoagulants/antiplatelets, and 2 were on no anticoagulants/antiplatelets. The remaining 18 patients did not have a hemorrhagic stroke and of those, 8 were on ASA alone, 3 were on anticoagulants/antiplatelets, and 7 were on no anticoagulants/antiplatelets. The probability of a hemorrhagic stroke following anticoagulant/antiplatelet therapy is 4/13 (31%) while the probability of a hemorrhagic stroke following no such therapy is 2/11 (18%). A Fisher’s exact test showed a p-value of 0.6494 (NS). The prevalence of patients with hemorrhagic strokes on ASA alone, no anticoagulant/antiplatelets, and on anticoagulants/antiplatelets were 1:6, 2:6, 3:6 respectively. A Fisher’s exact test showed a p-value of 0.263 (NS).

Conclusion: In patients with DADA2, we have shown that there is a strong baseline risk of hemorrhagic strokes as evidenced by the two patients who cumulatively suffered three hemorrhagic strokes on no anticoagulant or antiplatelet treatment. The risk of hemorrhagic stroke was not significantly increased on anticoagulants/antiplatelet agents possibly due to the small sample size. However, given the baseline risk of hemorrhagic stroke in DADA2, and the (non-significant) increase in that risk on anticoagulants and antiplatelet agents, such agents should probably not be used in DADA2 except under extraordinary circumstances.

Disclosure: P. M. Hoffmann, None; A. Ombrello, None; D. L. Stone, None; D. Follmann, None; K. Barron, None; A. Jones, None; T. Romeo, None; C. Toro, None; A. Soldatos, None; A. Hay, None; Q. Zhou, None; I. Aksentijevich, None; D. L. Kastner, None.

To cite this abstract in AMA style:

Hoffmann PM, Ombrello A, Stone DL, Follmann D, Barron K, Jones A, Romeo T, Toro C, Soldatos A, Hay A, Zhou Q, Aksentijevich I, Kastner DL. Risk of Hemorrhagic Strokes in Patients with Adenosine Deaminase 2 Deficiency [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/risk-of-hemorrhagic-strokes-in-patients-with-adenosine-deaminase-2-deficiency/. Accessed .

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