Complement activation, inflammation and relative ADAMTS13 deficiency in secondary thrombotic microangiopathies

Farkas, Péter; Csuka, Dorottya; Mikes, Bálint; Sinkovits, György; Réti, Marienn; Németh, Endre; Rácz, Kristóf; Madách, Krisztina; Gergely, M; Demeter, Judit; Prohászka, Zoltán

doi:10.1016/j.imbio.2016.10.014

Cited by 25 publications

(19 citation statements)

References 41 publications

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“…Secondary TMA patients in our study cohort had an overall 30.2% in-hospital mortality, which is comparable to observations reported in literature (23, 36). Acute phase disease mortality was associated with a higher median PTX3 level in secondary TMA, and this relationship was independent of the hemoglobin and creatinine levels, but was non-independent of platelet and LDH.…”

Section: Discussionsupporting

confidence: 89%

“…Endothelial damage and subsequent microvascular thrombosis are key pathogenic factors in all forms of this disease (19, 20), despite differences in the clinical course and management of TMAs with distinct etiologies. Microvascular thrombosis has been linked to excessive complement activation in all forms of TMA (21–23) together with neutrophil activation and neutrophil extracellular trap (NET) release (24–28), which may provide excess PTX3 at the site of tissue injury (29) and thus influence the local complement activity.…”

Section: Introductionmentioning

confidence: 99%

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Elevated Systemic Pentraxin-3 Is Associated With Complement Consumption in the Acute Phase of Thrombotic Microangiopathies

et al. 2019

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Pentraxin-3 (PTX3) and C-reactive protein (CRP) have been shown to regulate complement activation in vitro , but their role has not been investigated in complement consumption in vivo . Thrombotic microangiopathies (TMA) are often accompanied by complement overactivation and consumption, therefore we analyzed the relation of the systemic pentraxin levels to the complement profile, laboratory parameters and clinical outcome of TMA patients. We determined the PTX3 and CRP levels, complement factor and activation product concentrations in blood samples of 171 subjects with the diagnosis of typical hemolytic uremic syndrome (STEC-HUS) ( N = 34), atypical HUS (aHUS) ( N = 44), secondary TMA ( N = 63), thrombotic thrombocytopenic purpura (TTP) ( N = 30) and 69 age-matched healthy individuals. Clinical data, blood count and chemistry were collected from medical records. To determine the in vitro effect of PTX3 on alternative pathway (AP) activation, sheep red blood cell-based hemolytic assay and AP activity ELISA were used. We found that PTX3 levels were elevated in the acute phase of STEC-HUS, aHUS and secondary TMA, whereas PTX3 elevation was exceptional is TTP. Conversely, a significantly higher median CRP was present in all patient groups compared to controls. PTX3, but not CRP was associated with signs of complement consumption in vivo , and PTX3 significantly decreased the AP hemolytic activity in vitro . Our results provide a detailed description of acute phase-TMA patients' complement profile linked to changes in the systemic pentraxin levels that may support further molecular studies on the function of PTX3 in disease pathogenesis and add to the laboratory assessment of complement consumption in TMA.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Elevated Systemic Pentraxin-3 Is Associated With Complement Consumption in the Acute Phase of Thrombotic Microangiopathies

et al. 2019

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“…In animal models of SARS-CoV-2 infection, recent reports indicate the activation of both lectin and alternative complement pathways. The beneficial therapeutic effects of either C5 or C3 blockers described in patients with SARS-CoV-2 infection further support the clinical importance of TMA secondary to COVID-19 [ 7 ]. Taken together these findings further support a possible link between SARS-CoV-2 infection and secondary TMA.…”

mentioning

confidence: 88%

“…Moreover, to the best of our knowledge, our data are the first suggesting a relative decrease of ADAMTS13 activity in patients with SARS-CoV2 severe infection, thereby addressing for a potential role for ADAMTS13 impairment in COVID-19 [ 6 ]. Relative ADAMTS13 deficiency has been previously reported in severe inflammation or infection, as poor prognosis marker [ 7 ]. Endothelial dysfunction plays a key role in microvascular thrombosis secondary to amplified inflammatory response.…”

mentioning

confidence: 99%

A relative ADAMTS13 deficiency supports the presence of a secondary microangiopathy in COVID 19

Martinelli

Montagnana

Pizzolo

et al. 2020

Thrombosis Research

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“…Patients with increased complement activation as evidenced by higher sC5b-9 and C3a levels, also had higher mortality rates. 12 …”

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confidence: 99%

None of the above: thrombotic microangiopathy beyond TTP and HUS

Masias

Vasu

Cataland

2017

Blood

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Acquired thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are appropriately at the top of a clinician’s differential when a patient presents with a clinical picture consistent with an acute thrombotic microangiopathy (TMA). However, there are several additional diagnoses that should be considered in patients presenting with an acute TMA, especially in patients with nondeficient ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity (>10%). An increased awareness of drug-induced TMA is also essential because the key to their diagnosis more often is an appropriately detailed medical history to inquire about potential exposures. Widespread inflammation and endothelial damage are central in the pathogenesis of the TMA, with the treatment directed at the underlying disease if possible. TMA presentations in the critically ill, drug-induced TMA, cancer-associated TMA, and hematopoietic transplant–associated TMA (TA-TMA) and their specific treatment, where applicable, will be discussed in this manuscript. A complete assessment of all the potential etiologies for the TMA findings including acquired TTP will allow for a more accurate diagnosis and prevent prolonged or inappropriate treatment with plasma exchange therapy when it is less likely to be successful.

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Complement activation, inflammation and relative ADAMTS13 deficiency in secondary thrombotic microangiopathies

Cited by 25 publications

References 41 publications

Elevated Systemic Pentraxin-3 Is Associated With Complement Consumption in the Acute Phase of Thrombotic Microangiopathies

Elevated Systemic Pentraxin-3 Is Associated With Complement Consumption in the Acute Phase of Thrombotic Microangiopathies

A relative ADAMTS13 deficiency supports the presence of a secondary microangiopathy in COVID 19

None of the above: thrombotic microangiopathy beyond TTP and HUS

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