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Review
. 2020 Aug;190(4):508-519.
doi: 10.1111/bjh.16621. Epub 2020 Apr 21.

Endothelial cell function and endothelial-related disorders following haematopoietic cell transplantation

Gerhard C Hildebrandt  1 , Nelson Chao  2
Affiliations
Review

Endothelial cell function and endothelial-related disorders following haematopoietic cell transplantation

Gerhard C Hildebrandt et al. Br J Haematol. 2020 Aug.

Abstract

Use of haematopoietic cell transplantation (HCT) in the treatment of haematologic and neoplastic diseases may lead to life-threatening complications that cause substantial morbidity and mortality if untreated. In addition to patient- and disease-related factors, toxicity associated with HCT puts patients at risk for complications that share a similar pathophysiology involving endothelial cells (ECs). Normally, the endothelium plays a role in maintaining homeostasis, including regulation of coagulation, vascular tone, permeability and inflammatory processes. When activated, ECs acquire cellular features that may lead to phenotypic changes that induce procoagulant, pro-inflammatory and pro-apoptotic mediators leading to EC dysfunction and damage. Elevated levels of coagulation factors, cytokines and adhesion molecules are indicative of endothelial dysfunction, and endothelial damage may lead to clinical signs and symptoms of pathological post-HCT conditions, including veno-occlusive disease/sinusoidal obstruction syndrome, graft-versus-host disease, transplant-associated thrombotic microangiopathy and idiopathic pneumonia syndrome/diffuse alveolar haemorrhage. The endothelium represents a rational target for preventing and treating HCT complications arising from EC dysfunction and damage. Additionally, markers of endothelial damage may be useful in improving diagnosis of HCT-related complications and monitoring treatment effect. Continued research to effectively manage EC activation, injury and dysfunction may be important in improving patient outcomes after HCT.

Keywords: chimeric antigen receptor T-cell (CAR-T) therapy; endothelial cell dysfunction; endothelial-related disorders; haematopoietic cell transplantation; treatment for post-HCT complications.

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Conflict of interest statement

GCH has stocks/ownership interests in Sangamo Bioscience, Axim Biotechnologies, Juno Therapeutics, Kite Pharma, Novartis, Insys Therapeutics, Abbvie, GW Pharmaceuticals, Cardinal Health, Immunomedics, Endocyte, Clovis Oncology, Cellectis, Aetna, CVS Health, Celgene, Bluebird Bio, Bristol‐Myers Squibb/Medarex, crispr Therapeutics, IDEXX Laboratories, Johnson & Johnson, Pfizer, Procter & Gamble, Vertex, Bayer, Scotts‐Miracle, Charlottes Webb CWBHF, Almmune Therapeutics Inc AIMT, Medical PPTYS TR Inc. MPW, Caretrust Reit Inc CTRE, ANGI Homeservices Inc ANGI, and Bayer AG BAYRY; has served in advisory/consulting roles for Pfizer, Kite Pharma, Incyte, and Jazz Pharmaceuticals; has received research funding from Takeda, Astellas, Incyte, Jazz Pharmaceuticals, and Pharmacyclics; and has received travel, accommodations, and/or expense reimbursement from Kite Pharma, Incyte, Pfizer, Falk Foundation, Jazz Pharmaceuticals, and Astellas Pharma. NC has nothing to disclose.

Figures

Fig 1
Fig 1
Normal function and physiology of endothelial cells. Ang‐1, angiopoetin‐1; Ang‐2, angiopoetin‐2; ICAM‐1, intercellular adhesion molecule 1; IL‐1β, interleukin 1 beta; NO, nitric oxide; TF, tissue factor; Tie‐2, receptor tyrosine kinase; TNFα, tumour necrosis factor alpha; VCAM, vascular adhesion molecule; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor; WBC, white blood cell; WNT2 and WNT9B, protein coding genes.
Fig 2
Fig 2
Progression of endothelial activation to endothelial dysfunction leading to different complications associated with HCT. Figure adapted and reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature Bone Marrow Transplantation. 2011;46(12):1495–1502. Carreras, E. & Diaz‐Ricart, M. The role of the endothelium in the short‐term complications of haematopoietic SCT. ©2011. CAR‐T, CAR‐T‐associated neurotoxicity; DAH, diffuse alveolar haemorrhage; EHPF, endothelial hyperpolarizing factor; GvHD, graft‐versus‐host disease; HCT, haematopoietic cell transplantation; ICAM‐1, intercellular adhesion molecule 1; IL1‐β, interleukin 1 beta; IPS, idiopathic pneumonia syndrome; NO, nitric oxide; PA‐1, plasminogen activator inhibitor 1; TA‐TMA, transplant‐associated thrombotic microangiopathy; TF, tissue factor; TM, thrombomodulin; TNF, tumour necrosis factor; t‐PA, tissue plasminogen activator; VCAM‐1, vascular adhesion molecule 1; VOD/SOS, veno‐occlusive disease/sinusoidal obstruction syndrome; vWF, von Willebrand factor.
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