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Complement-mediated thrombotic microangiopathy as a link between endothelial damage and steroid-refractory GVHD.

ABSTRACT: Transplant-associated thrombotic microangiopathy (TA-TMA), a complication of hematopoietic cell transplant (HCT), is associated with significant morbidity and mortality. The pathophysiology and overlap of TA-TMA with other posttransplant complications such as graft-versus-host disease (GVHD) is poorly understood. We retrospectively identified cases of TA-TMA among patients with grade 3/4 gastrointestinal (GI) GVHD, reviewed intestinal biopsy specimens, and performed correlative testing of biomarkers associated with TA-TMA. TA-TMA was more common in patients with steroid-refractory GVHD compared with steroid-responsive GVHD (79.3% vs 42.1%; P = .001). Among patients surviving 100 days post-HCT, 1-year survival from day 100 was significantly better for patients who had not developed TA-TMA in the first 100 days (69.5% vs 36.7%; P < .001). Only 1 of 7 proposed TA-TMA histology criteria (mucosal hemorrhage) differed significantly based on GVHD steroid response. In multivariable modeling, steroid-refractory GVHD was a risk factor for development of TA-TMA (hazard ratio, 3.09; 95% confidence interval, 1.68-5.67; P < .001). There were no differences in complement activation at GVHD onset; however, 2 to 6 weeks later, patients with TA-TMA had higher levels of BBPlus and C5b-9, markers of alternative and terminal pathway activation (BBPlus: median, 600 vs 209.3 ng/mL; P = .0045) (C5b-9: median, 425.9 vs 258.4 ng/mL; P = .029). TA-TMA is associated with poor overall survival (OS) following HCT and may be detected early by histologic findings and may be differentiated from GVHD by measurement of alternative and terminal complement pathway activation. It is unknown whether treatment of TA-TMA will improve survival in steroid-refractory GVHD.

SUBMITTER: Wall SA

PROVIDER: S-EPMC6199668 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Complement-mediated thrombotic microangiopathy as a link between endothelial damage and steroid-refractory GVHD.

Wall Sarah A SA Zhao Qiuhong Q Yearsley Martha M Blower Luke L Agyeman Akwasi A Ranganathan Parvathi P Yang Shangbin S Wu Haiwa H Bostic Matthew M Jaglowski Samantha S Brammer Jonathan E JE William Basem B Choe Hannah H Mims Alice S AS Penza Sam S Efebera Yvonne Y Devine Steven S Cataland Spero S Davies Stella M SM Vasu Sumithira S

Blood advances 20181001 20

Transplant-associated thrombotic microangiopathy (TA-TMA), a complication of hematopoietic cell transplant (HCT), is associated with significant morbidity and mortality. The pathophysiology and overlap of TA-TMA with other posttransplant complications such as graft-versus-host disease (GVHD) is poorly understood. We retrospectively identified cases of TA-TMA among patients with grade 3/4 gastrointestinal (GI) GVHD, reviewed intestinal biopsy specimens, and performed correlative testing of biomar ...[more]

PMID: 30327370

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Project description:Rationale & objectivePregnancy, delivery, and neonatal outcomes in women with complement-mediated thrombotic microangiopathy (cTMA) have not been well described. A better understanding of these outcomes is necessary to provide women with competent pregnancy counseling.Study designCohort study.Setting and participantsWomen with a history of cTMA and pregnancies enrolled into the Vienna thrombotic microangiopathy cohort.ExposureNew onset or relapses of cTMA.OutcomesPregnancy, delivery, and neonatal outcomes of pregnancies in women (a) before cTMA manifestation, (b) complicated by pregnancy-associated cTMA (P-cTMA), and (c) after first manifestation of cTMA or P-cTMA.Analytical approachMixed models were used to adjust the comparison of pregnancy, delivery, and neonatal outcomes between conditions (before, with, and after cTMA) for repeated pregnancies using the mother's ID as random factor. In addition, the fixed factors, mother's age and neonate's sex, were used for adjustment. For (sex-adjusted and age-adjusted) centile outcomes, only the mother's age was used. Adjusted odds ratios were derived from a generalized linear mixed model with live birth as the outcome. Least squares means and pairwise differences between them were derived from the linear mixed models for the remaining outcomes.Results28 women reported 74 pregnancies. Despite higher rates of fetal loss before the diagnosis of P-cTMA and preterm births with P-cTMA, most of the women were able to conceive successfully. Neonatal development in all 3 conditions of pregnancies was excellent. Pregnancy and neonatal outcomes were better in women with a pregnancy after the diagnosis of cTMA.LimitationsAlthough our data set comprises a considerable number of 74 pregnancies, the effective sample size is lower because only 28 mothers with multiple pregnancies were observed. The statistical power for detecting clinically relevant effects was probably low. A recall bias for miscarriages cannot be ruled out.ConclusionsPrepregnancy counseling of women with a history of cTMA can be supportive of their desire to become pregnant.

Dataset Information

Complement-mediated thrombotic microangiopathy as a link between endothelial damage and steroid-refractory GVHD.

Publications

Complement-mediated thrombotic microangiopathy as a link between endothelial damage and steroid-refractory GVHD.

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