Understanding the Pathophysiology of Thrombotic APS through Animal Models

Gandhi, Alex A.; Estes, Shanea K.; Rysenga, Christine E; Knight, Jason S.

doi:10.3390/ijms22052588

Cited by 12 publications

(7 citation statements)

References 67 publications

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Section: Limitationsmentioning

confidence: 83%

“…Indeed, the collateral circulation was observed on day 7 after the ligation in our renal congestion model [ 14 ]. Fourth, IVC complete or partial ligation of the upstream left renal vein is a commonly utilized model of venous thrombosis [ 59 , 60 ]. Although SD rats used in this study did not have a thrombus phenotype during the experiment, a preliminary examination of our renal congestion model using C57BL6, FVB, CBA, and DBA mice showed a high mortality rate within one day with thrombus formation.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of platelet-derived growth factor pathway suppresses tubulointerstitial injury in renal congestion

Matsuki

Hirose

Ohsaki

et al. 2022

Journal of Hypertension

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Objective: Increased central venous pressure in congestive heart failure is responsible for renal dysfunction, which is mediated by renal venous congestion. Pericyte detachment from capillaries after renal congestion might trigger renal fibrogenesis via pericyte-myofibroblast transition (PMT). Platelet-derived growth factor receptors (PDGFRs), which are PMT indicators, were upregulated in our recently established renal congestion model. This study was designed to determine whether inhibition of the PDGFR pathway could suppress tubulointerstitial injury after renal congestion. Methods: The inferior vena cava between the renal veins was ligated in male Sprague-Dawley rats, inducing congestion only in the left kidney. Imatinib mesylate or vehicle were injected intraperitoneally daily from 1 day before the operation. Three days after the surgery, the effect of imatinib was assessed by physiological, morphological and molecular methods. The inhibition of PDGFRs against transforming growth factor-β1 (TGFB1)-induced fibrosis was also tested in human pericyte cell culture. Results: Increased kidney weight and renal fibrosis were observed in the congested kidneys. Upstream inferior vena cava (IVC) pressure immediately increased to around 20 mmHg after IVC ligation in both the imatinib and saline groups. Although vasa recta dilatation and pericyte detachment under renal congestion were maintained, imatinib ameliorated the increased kidney weight and suppressed renal fibrosis around the vasa recta. TGFB1-induced elevation of fibrosis markers in human pericytes was suppressed by PDGFR inhibitors at the transcriptional level. Conclusion: The activation of the PDGFR pathway after renal congestion was responsible for renal congestion-induced fibrosis. This mechanism could be a candidate therapeutic target for renoprotection against renal congestion-induced tubulointerstitial injury.

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Section: Limitationsmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Inhibition of platelet-derived growth factor pathway suppresses tubulointerstitial injury in renal congestion

Matsuki

Hirose

Ohsaki

et al. 2022

Journal of Hypertension

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“…RI+ IgG with β2GPI induced endothelial activation by expressing E-selectin, VCAM, and consequent monocyte adhesion to the endothelium. Both molecules increased by aPL indicate endothelial activation associated with thrombus formation ( Gandhi et al, 2021 ). In our experimental model, VTI IgG did not induce endothelial dysfunction as evaluated with NO synthesis.…”

Section: Discussionmentioning

confidence: 99%

Differences in Endothelial Activation and Dysfunction Induced by Antiphospholipid Antibodies Among Groups of Patients With Thrombotic, Refractory, and Non-refractory Antiphospholipid Syndrome

et al. 2021

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Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by pregnancy morbidity or thrombosis and persistent antiphospholipid antibodies (aPL) that bind to the endothelium and induce endothelial activation, which is evidenced by the expression of adhesion molecules and the production of reactive oxygen species (ROS) and subsequent endothelial dysfunction marked by a decrease in the synthesis and release of nitric oxide (NO). These endothelial alterations are the key components for the development of severe pathological processes in APS. Patients with APS can be grouped according to the presence of other autoimmune diseases (secondary APS), thrombosis alone (thrombotic APS), pregnancy morbidity (obstetric APS), and refractoriness to conventional treatment regimens (refractory APS). Typically, patients with severe and refractory obstetric APS exhibit thrombosis and are classified as those having primary or secondary APS. The elucidation of the mechanisms underlying these alterations according to the different groups of patients with APS could help establish new therapies, particularly necessary for severe and refractory cases. Therefore, this study aimed to evaluate the differences in endothelial activation and dysfunction induced by aPL between patients with refractory obstetric APS and other APS clinical manifestations. Human umbilical vein endothelial cells (HUVECs) were stimulated with polyclonal immunoglobulin-G (IgG) from different groups of patients n = 21), including those with primary (VTI) and secondary thrombotic APS (VTII) and refractory primary (RI+), refractory secondary (RII+), and non-refractory primary (NR+) obstetric APS. All of them with thrombosis. The expression of adhesion molecules; the production of ROS, NO, vascular endothelial growth factor (VEGF), and endothelin-1; and the generation of microparticles were used to evaluate endothelial activation and dysfunction. VTI IgG induced the expression of adhesion molecules and the generation of microparticles and VEGF. RI+ IgG induced the expression of adhesion molecules and decreased NO production. RII+ IgG increased the production of microparticles, ROS, and endothelin-1 and reduced NO release. NR+ IgG increased the production of microparticles and endothelin-1 and decreased the production of VEGF and NO. These findings reveal differences in endothelial activation and dysfunction among groups of patients with APS, which should be considered in future studies to evaluate new therapies, especially in refractory cases.

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“…45 Experts consider antiphospholipid antibodies to be central to the pathogenesis of APS, with numerous cellular and subcellular mechanisms proposed. 46,47 One possible unifying antiphospholipid-mediated mechanism for APS morbidity and CAPS is complement-mediated inflammation. [47][48][49] Complement activation was observed in the sera of more than 80% of individuals with CAPS in one study.…”

Section: Pathophysiology and Epidemiologymentioning

confidence: 99%

Differentiating and Managing Rare Thrombotic Microangiopathies During Pregnancy and Postpartum

Lim

Abou‐Ismail

Branch

2022

Obstetrics &Amp; Gynecology

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The most common thrombotic microangiopathy (TMA) of pregnancy is the well-recognized syndrome of preeclampsia with hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. However, rare TMAs, including thrombotic thrombocytopenic purpura, complement-mediated hemolytic-uremic syndrome, and catastrophic antiphospholipid syndrome, may occur during pregnancy or postpartum and present with features similar to those of preeclampsia with severe features. Early recognition and treatment of these infrequently encountered conditions are key for avoiding serious maternal morbidities with long-term sequelae and possible maternal or fetal death. Differentiating between preeclampsia with severe features and these rare TMAs is diagnostically challenging as there is significant overlap in their clinical and laboratory presentation. Given the rarity of these TMAs, high-quality evidencebased recommendations on diagnosis and management during pregnancy are lacking. Using current objective information and recommendations from working groups, this report provides practical clinical approaches to diagnose and manage these rare TMAs. This report also discusses how to manage individuals with a history of these rare TMAs who are planning to conceive. To optimize favorable outcomes, a multidisciplinary approach including obstetricians, maternalfetal medicine specialists, hematologists, and nephrologists alongside close clinical and laboratory monitoring is vital.

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Understanding the Pathophysiology of Thrombotic APS through Animal Models

Cited by 12 publications

References 67 publications

Inhibition of platelet-derived growth factor pathway suppresses tubulointerstitial injury in renal congestion

Inhibition of platelet-derived growth factor pathway suppresses tubulointerstitial injury in renal congestion

Differences in Endothelial Activation and Dysfunction Induced by Antiphospholipid Antibodies Among Groups of Patients With Thrombotic, Refractory, and Non-refractory Antiphospholipid Syndrome

Differentiating and Managing Rare Thrombotic Microangiopathies During Pregnancy and Postpartum

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