Imaging Predictors of Intracerebral Hemorrhage in Patients with Brain Tumors Treated with Anticoagulation
Authors: Barnea Rani , Naftali Jonathan , Hamulyák Eva N. , Peseski Andrew M. , Wang Tzu-Fei , Baumann Kreuziger Lisa , Iyengar Varun , Carney Brian J. , Özdemir Berna , Cordova Serrano Rosana D. , Sanfilippo Kristen M. , Rozenblatt Shira , Beenen Ludo F.M. , Yust-Katz Shlomit , Halperin Erez , Lubetsky Aaron , Derkach Andriy , Nemirovsky David , Carrier Marc , Massat Ben , Arad Ariela , Broen Martinus P.G. , Cesarman-Maus Gabriela N. , Hoeben Ann , Hoffmann Michele , Kalish Yossi , Middeldorp Saskia , Raanani Pia , Ten Cate Hugo , Tvito Ariella , Büller Harry , Spectre Galia , Zwicker Jeffrey I. , Auriel Eitan , Leader Avi 
Published: December 2024

Introduction
Spontaneous intracerebral hemorrhage (sICH) frequently occurs in patients with primary or metastatic brain tumors treated with anticoagulation and presents primarily as intratumoral bleeding. While an association between the burden of cerebral small vessel disease (CSVD) on brain magnetic resonance imaging (MRI) and sICH has been observed in patients receiving anticoagulation, it is unknown whether this holds true for patients with brain tumors. Intratumoral siderosis, a marker of prior subclinical sICH, represents a potential risk factor for subsequent sICH.
Aim
To evaluate whether markers of CSVD on brain MRI and intratumoral siderosis are associated with sICH in patients with brain tumors treated with anticoagulation.
Methods
This was a preplanned sub-study of the ABC study, a retrospective multinational cohort study which included 745 adults with primary or metastatic brain tumors treated with therapeutic-dose anticoagulation (low molecular weight heparin [LMWH] or direct oral anticoagulant [DOAC]) for any indication or duration (1/1/2014 - 1/1/2022), with 12 month follow up.
All patients in whom baseline MRI images were available were included in the current study. MRI scans were analyzed for imaging markers of CSVD that are known to be independently associated with sICH in the general population, including white matter hyperintensities graded by Fazekas score (to reflect CSVD burden) and cerebral microbleeds. Baseline MRI scans were read and analyzed according to STRIVE-2 classification by a neurovascular research group specialized in CSVD imaging with excellent interrater reliability for these measures (Naftali 2023. PMID: 37978833). Intratumoral siderosis were also analyzed.
The study outcome was sICH over 12 months follow-up, identified by record review and confirmed by a neuroradiologist, who was blinded to baseline MRIs. Baseline MRI readers were blinded to occurrence of sICH outcomes during follow up. Univariate analysis assessed associations between baseline MRI parameters and sICH, stratified for study center and adjusted for stopping anticoagulation. An additional analysis adjusted for cancer type as well.
Results
This analysis included 294 with baseline MRI of the 745 ABC patients. The median age was 63.0 years and 148 (50%) were female. Cancer types included primary brain tumors (123; 42.0%), metastases from primary lung (105; 36.0%), breast (29; 9.9%), and melanoma grouped with renal cell carcinoma tumors (12; 4.1%), as well as other types of cancer (25; 8.5%). The indication for anticoagulation was venous thromboembolism in 265 (90%) patients; 169 (57.5%) patients were treated with LMWH and 125 (42.5%) were treated with a DOAC.
The 12-month cumulative incidence of sICH was 7.9% (95% confidence interval [CI] 5.3%-12.0%); 20/22 sICH events were intratumoral. The baseline MRI was performed at a median of 14 days (IQR 0-39) before study index date (i.e., first day of concurrent anticoagulation and brain tumor). Cerebral microbleeds and intratumoral siderosis could be assessed in the 224/294 patients with susceptibility weighted imaging (SWI) sequences performed. Fazekas score could be evaluated in the 290/294 patients with fluid attenuated inversion recovery (FLAIR) sequences. Nineteen of 224 (8.5%) patients had extratumoral cerebral microbleeds. Intratumoral siderosis was demonstrated in 83/224 (37%) patients. The Fazekas score was 0 or 1 (no or mild CSVD burden) in 261/290 (90%) patients and 2 or 3 (moderate to severe CSVD burden) in 29/290 (10%) patients.
On univariable analysis, intratumoral siderosis (hazard ratio [HR] 3.44; 95% CI 1.01-11.7); cerebral microbleeds (HR 8.13; 95% CI 1.81-36.6) and moderate to severe CSVD burden (HR 4.71; 95% CI 1.89-11.7) were associated with sICH. Adjustment for cancer type demonstrated similar associations for intratumoral siderosis (HR 2.59; 95% CI 0.70-9.67), cerebral microbleeds (HR 11.4; 95% CI 1.71 - 76.1) and moderate to severe CSVD burden (HR 5.28; 95% CI 1.94 - 14.4). In a cross-correlation analysis, no statistically significant associations between the 3 MRI parameters were observed at baseline.
Conclusion
Baseline MRI findings appear to be predictive of sICH in patients with brain tumors treated with anticoagulation. Future studies should assess whether these parameters can guide management of anticoagulation in this population.