Keith McCrae Lab | Lerner Research Institute

Principal Investigator

Keith McCrae, MD

Joint Appointment
Location: Cleveland Clinic Main Campus

Research

The McCrae laboratory's studies focus on translational research in vascular biology, including studies on endothelial cells, platelets and other blood cells. For many years we have worked on the "antiphospholipid syndrome", a disorder characterized by the development of blood clots in otherwise healthy individuals caused by autoantibodies against several targets, including β2-glycoprotein 1, a common plasma protein. We have shown that these autoantibodies activate endothelial cells, promoting arterial and venous thrombosis. Recent studies have demonstrated that patients with this disorder have circulating activated platelets that express increased amounts of anionic phospholipid on the cell surface, promoting phospholipid dependent coagulation processes.

Other studies have attempted to better understand the increased risk of thrombosis experienced by patients with cancer, including those treated with immune checkpoint inhibitors. Finally, we have studied in depth the contact activation system, including its role in promoting thrombosis, particularly in cancer, and mechanisms by which inorganic polyphosphate, a potent activator of the contact system, stimulates FXII activation in cancer patients and animal models. My lab has also been involved in several clinical trials, and I have recently led a multicenter study assessing the efficacy of pomalidomide in treated hereditary hemorrhagic telangiectasia, an inherited disorder leading to disrupted vascular, telangiectasias and arteriovenous malformations, and bleeding.

Biography

Dr. Keith McCrae is a physician-scientist with a primary appointment in the Taussig Cancer Institute, and a secondary appointment in the Department of Cardiovascular and Metabolic Sciences in the Lerner Research Institute. Dr. McCrae also holds appointments in the Department of Vascular Medicine in the Heart and Vascular Institute as well as in the Center for Immunotherapy and Precision Immuno-Oncology (CITI).

He has served as Director of the Classical Hematology in the Cancer Institute for 14 years, and is also Director of Physician-Scientist development in the Lerner Research Institute. Dr. McCrae is an active member of the American Society of Hematology (ASH) and has served on many scientific committees including chairing the Committee on Thrombosis and Vascular Biology. He currently is a member of the ASH ITP Guidelines Committee, and has recently been appointed as inaugural Editor-in-Chief of Blood Vessels, Thrombosis and Hemostasis, an ASH publication. As both an active clinician and scientist, Dr. McCrae brings a unique perspective to the studies pursued in his laboratory.

Education & Professional Highlights

Education & Fellowships

Fellowship - University of Pennsylvania School of Medicine
Hematology/Oncology
Philadelphia, PA USA
1989

Residency - Duke University Medical Center
Internal Medicine
Durham, NC USA
1985

Medical Education - Duke University School of Medicine
Durham, NC USA
1982

Undergraduate - Dartmouth College
Biochemistry
Hanover, NH USA
1978

Certifications

Internal Medicine
Internal Medicine - Medical Oncology
Internal Medicine - Hematology

Research

The McCrae laboratory studies several projects relevant to vascular function in health and disease. One involves the "antiphospholipid syndrome", a disorder characterized by of thrombosis and recurrent fetal loss in otherwise healthy individuals. Patients with this disorder have antibodies reactive with a plasma protein, beta2-glycoprotein 1, and we have shown that these antibodies activate endothelial cells in a beta2-GPI dependent manner. Activation is mediated through formation of a multiprotein complex on the endothelial surface that includes annexin A2 and TLR4, and we are characterizing this complex and the subsequent signaling pathway.

In a second project, we have studied the role of high molecular weight kininogen (HK) in regulating vascular function. We have prepared kininogen deficient mice, and found them to have enhanced angiogenesis and accelerated tumor growth. These mice are also protected from thrombosis and stroke yet do not have any predisposition to bleeding. We are currently developing strategies to deplete or inhibit kininogen in a therapeutic manner.

A third project focuses on the detection and function of microparticles in the development and propagation of vascular disease and cancer. Microparticles are subcellular particles derived from a number of cell types, that circulate in plasma. Microparticles promote thrombosis through expression of tissue factor, and carry mRNA and other genetic information that can be transferred among various cell types throughout the body. We will characterize the role of microparticles as an indicator of disease in humans, while further exploring their functions in vitro.

Our Team

Publications

Selected Publications

View publications for Keith McCrae, MD
(Disclaimer: This search is powered by PubMed, a service of the U.S. National Library of Medicine. PubMed is a third-party website with no affiliation with Cleveland Clinic.)

Hubben A, McCrae KR. How to diagnose and manage antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program. 2023 Dec 8;2023(1):606-613. PubMed Central PMCID: PMC10727028.

Alarabi A, Hubben A, Barnard J, Knight JS, McCrae KR. Transcriptome analysis suggests a central role for complement and C5aR1 in neutrophil activation in APS. Thromb Res. 2023 Oct;230:94-97. PubMed Central PMCID: PMC11077612.

Chaturvedi S, Braunstein EM, Yuan X, Yu J, Alexander A, Chen H, Gavriilaki E, Alluri R, Streiff MB, Petri M, Crowther MA, McCrae KR, Brodsky RA. Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS. Blood. 2020 Jan 23;135(4):239-251. PubMed Central PMCID: PMC6978159.

Allen KL, Hamik A, Jain MK, McCrae KR. Endothelial cell activation by antiphospholipid antibodies is modulated by Kruppel-like transcription factors. Blood. 2011 Jun 9;117(23):6383-91. PubMed Central PMCID: PMC3122956.

Grover SP, Kawano T, Wan J, Tanratana P, Polai Z, Shim YJ, Snir O, Brækkan S, Dhrolia S, Kasthuri RR, Bendapudi PK, McCrae KR, Wolberg AS, Hansen JB, Farkas H, Mackman N. C1 inhibitor deficiency enhances contact pathway-mediated activation of coagulation and venous thrombosis. Blood. 2023 May 11;141(19):2390-2401. PubMed Central PMCID: PMC10273165.

Khorana AA, Barnard J, Wun T, Vijapurkar U, Damaraju CV, Moore KT, Wildgoose P, McCrae KR. Biomarker signatures in cancer patients with and without venous thromboembolism events: a substudy of CASSINI. Blood Adv. 2022 Feb 22;6(4):1212-1221. PubMed Central PMCID: PMC8864658.

Shim YJ, Chatterjee V, Swaidani S, Alluri RK, Kundu S, Merkulova A, Angelini D, You D, Whitney SA, Feener EP, Barnard J, Schmaier AH, Khorana AA, McCrae KR. Polyphosphate expression by cancer cell extracellular vesicles mediates binding of factor XII and contact activation. Blood Adv. 2021 Nov 23;5(22):4741-4751. PubMed Central PMCID: PMC8759128.

Roopkumar J, Swaidani S, Kim AS, Thapa B, Gervaso L, Hobbs BP, Wei W, Alban TJ, Funchain P, Kundu S, Sangwan N, Rayman P, Pavicic PG Jr, Diaz-Montero CM, Barnard J, McCrae KR, Khorana AA. Increased Incidence of Venous Thromboembolism with Cancer Immunotherapy. Med. 2021 Apr 9;2(4):423-434. PubMed Central PMCID: PMC8143033.

Mohammed BM, Sun MF, Cheng Q, Litvak M, McCrae KR, Emsley J, McCarty OJT, Gailani D. High molecular weight kininogen interactions with the homologs prekallikrein and factor XI: importance to surface-induced coagulation. J Thromb Haemost. 2024 Jan;22(1):225-237. PubMed Central PMCID: PMC10841474.

Henderson MW, Sparkenbaugh EM, Wang S, Ilich A, Noubouossie DF, Mailer R, Renné T, Flick MJ, Luyendyk JP, Chen ZL, Strickland S, Stravitz RT, McCrae KR, Key NS, Pawlinski R. Plasmin-mediated cleavage of high-molecular-weight kininogen contributes to acetaminophen-induced acute liver failure. Blood. 2021 Jul 22;138(3):259-272. PubMed Central PMCID: PMC8310429.

Sparkenbaugh EM, Kasztan M, Henderson MW, Ellsworth P, Davis PR, Wilson KJ, Reeves B, Key NS, Strickland S, McCrae K, Pollock DM, Pawlinski R. High molecular weight kininogen contributes to early mortality and kidney dysfunction in a mouse model of sickle cell disease. J Thromb Haemost. 2020 Sep;18(9):2329-2340. PubMed Central PMCID: PMC8043232.

McCrae KR. Novel Mechanism of Cancer Thrombosis Induced by Microvesicles. Arterioscler Thromb Vasc Biol. 2018 Apr;38(4):692-694. PubMed PMID: 29563113.

Ghosh A, Li W, Febbraio M, Espinola RG, McCrae KR, Cockrell E, Silverstein RL. Platelet CD36 mediates interactions with endothelial cell-derived microparticles and contributes to thrombosis in mice. J Clin Invest. 2008 May;118(5):1934-43. PubMed Central PMCID: PMC2323190.

Allen KL et al. A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2GPI antibodies. Blood 119:884-93, 2012.

Cheng V, Kashyap SR, Schauer PR, Kirwan JP, McCrae KR. Restoration of glycemic control in patients with type 2 diabetes mellitus after bariatric surgery is associated with reduction in microparticles. Surg Obes Related Dis (epub Oct, 2011).

Allen KL, Hamik A, Jain MK, McCrae KR. Endothelial activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors. Blood 117:6383-91, 2011.

Ghosh A, Lei W, Febbraio M, Espinola RG, Cockrell E, McCrae KR, Silverstein RL. Platelet CD36 mediates interactions with endothelial cell-derived microparticles and contributes to thrombosis in vivo. J Clin Invest 118:1934-1943, 2008.

Merkoulov S, Zhang WM, Komar AA, Schmaier AH, Barnes E, Zhou Y, Luo G, Lu X, Iwaki T, Castellino FJ, McCrae KR. Deletion of murine kininogen gene 1 causes loss of plasma kininogen and delays thrombosis. Blood 111:1274-1281, 2008.

Careers

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