How I treat thrombotic microangiopathy in the era of rapid genomics

Abstract

Thrombotic microangiopathy (TMA) encompasses various genetically driven diseases. The emergence of ultra-fast genomic sequencing has recently opened up new avenues of research for genetic investigations in the setting of intensive care units. TMA is likely to be a suitable focus for fast-track genomic sequencing. By establishing an expeditious molecular diagnosis of patients with complement-dependent hemolytic uremic syndrome, fast-track genomic sequencing allows for the timely implementation or withdrawal of anti-C5 treatment while averting unnecessary, costly, and potentially harmful therapy in patients testing negative. Furthermore, genomics has the potential to reshape the taxonomic classification of TMA thanks to comprehensive genomic analysis. The most significant results arising from such analysis can be categorized as i) new descriptions of genetic diseases previously not recognized as associated with TMA, and ii) an enrichment of the phenotypic spectrum of diseases traditionally related to TMA. The latter draws on the concept of retrophenotyping, whereby genomic investigation precedes full clinical description. By taking precedence over a phenotypic approach, an unbiased genomic-focused analysis maximizes the chances of discovering new descriptions related to a given variant. Presented here are four cases of TMA which highlight these issues and substantiate the promise of fast-track genomic sequencing.

Role of the I416L Variant of Complement Factor I in Thrombotic Microangiopathy Among Patients of African Ancestry

“…Streamlined genotyping of patients may detect pathogenic variants in patients otherwise deemed unlikely to carry the disease based on purely clinical features. 6 In this case, the results suggest that aHUS may go unrecognized or mimic vascular nephropathy as was the case for 5 of the patients, because none of them were suspected to have aHUS, and in some cases despite extensive investigations and a protracted follow-up. 7 Malignant hypertension complicated by TMA has recently been contemplated as a promising application for anti-C5 treatment, irrespective of genetic background.…”

Complement‐driven hemolytic uremic syndrome

“…This groundbreaking report raises the hope that rapid‐sequencing‐based diagnosis could be applied to the deciphering of HUS in emergency settings. As a matter of fact, a very recent report from Mesnard et al demonstrated the ability of rapid exome sequencing to reshape the diagnosis and guide highly tailored therapy within a few weeks in patients with TMA 83 . Ultrarapid nanopore genome sequencing can even further shorten the turnaround time, providing genetic testing on a daily timeframe, to guide clinical management in critically ill patients 84 …”

Von Willebrand factor as a potential predictive biomarker of early complications of endothelial origin after allogeneic hematopoietic stem cell transplantation

“…As endothelial dysfunction remains a clinical challenge 19,20 and is increasingly involved in many complications after alloHCT, it is therefore crucial to develop new tools to easily assess the risk for each patient and to help predict transplantation-related mortality. In this setting, we conducted a retrospective study in order to assess the role of VWF as a potential predictive biomarker of transplant-related endothelial dysfunction and complications after alloHCT.…”