Brain Tumors Enhance Plasmatic Coagulation: The Role of Hemeoxygenase-1

Nielsen, Vance G. MD*; Lemole, G. Michael Jr. MD; Matika, Ryan W. MD*; Weinand, Martin E. MD; Hussaini, Sana MD*; Baaj, Ali A. MD; Steinbrenner, Evangelina B. CCRC*

doi: 10.1213/ANE.0000000000000048
Cardiovascular Anesthesiology: Research Report

BACKGROUND: Patients with brain tumors suffer significant thrombotic morbidity and mortality. In addition to increased thrombin generation via tumor release of tissue factor-bearing microparticles and hyperfibrinogenemia, brain tumors and surrounding normal brain likely generate endogenous carbon monoxide (CO) via the hemeoxygenase-1 (HO-1) system. CO has been shown to enhance plasmatic coagulation via formation of carboxyhemefibrinogen (COHF). Thus, our goals in this study were to determine whether patients with brain tumors had increased HO-1 upregulation/CO production, plasmatic hypercoagulability, and formation of COHF.

METHODS: Patients with brain tumors (N = 20) undergoing craniotomy had blood collected for determination of carboxyhemoglobin as a marker of HO-1 activity, plasmatic hypercoagulability (defined as clot strength > 95% confidence interval value of normal subject plasma), and COHF formation (determined with a thrombelastograph®-based assay). Plasma obtained from commercially available normal subjects (N = 30) was used for comparison with brain tumor patient samples.

RESULTS: Brain tumor patients had carboxyhemoglobin concentrations of 1.5% ± 0.5% (mean ± SD), indicative of HO-1 upregulation. Compared with normal subject plasma, brain tumor patient plasma had significantly (P < 0.0001) greater clot formation velocity (5.2 ± 1.5 vs 9.5 ± 2.3 dynes/cm2/s, respectively) and significantly (P = 0.00016) stronger final clot strength (166 ± 28 vs 230 ± 78 dynes/cm2, respectively). Ten of the brain tumor patients had plasma clot strength that exceeded the 95% confidence interval value observed in normal subjects, and 12 of the brain tumor patients had COHF formation. Five of the brain tumor patients in the hypercoagulable subgroup had COHF formation. Last, 5 of the hypercoagulable patients had primary brain tumors, whereas the other 5 patients had metastatic tumors or an inflammatory mass lesion.

CONCLUSIONS: A subset of patients with brain tumors has increased endogenous CO production, plasmatic hypercoagulability, and COHF formation. Future investigation of the role played by HO-1 derived CO in the pathogenesis of brain tumor-associated thrombophilia is warranted.

Published ahead of print Jan 9, 2014.

From the Departments of *Anesthesiology, and Surgery, The University of Arizona, Tucson, Arizona.

Accepted for publication October 11, 2013.

Published ahead of print Jan 9, 2014.

Funding: This study was funded by departmental sources.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Vance G. Nielsen, MD, Department of Anesthesiology, The University of Arizona College of Medicine, P.O. Box 245114, 1501 North Campbell Ave., Tucson, AZ 85724-5114. Address e-mail to

© 2014 International Anesthesia Research Society