Elevated plasma levels of syndecan-1 and soluble thrombomodulin predict adverse outcomes in thrombotic thrombocytopenic purpura

Abstract

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder resulting from acquired deficiency of plasma ADAMTS13 activity. Despite recent advances in early diagnosis and novel therapeutics, the mortality rate of acute iTTP remains as high as 10% to 20%. Moreover, a reliable clinical and laboratory parameter that predicts disease severity and outcomes is lacking. We show in the present study that plasma levels of syndecan-1 (Sdc-1) and soluble thrombomodulin (sTM) on admission were dramatically increased in patients with acute iTTP and remained substantially elevated in a subset of patients compared with healthy controls. The elevated admission plasma levels of Sdc-1 and sTM were associated with abnormal Glasgow coma scale scores, low estimated glomerular filtration rates, the need for intensive care, and in-hospital mortality rates. Moreover, a further simultaneous increase in plasma Sdc-1 and sTM levels at the time of clinical response/remission (eg, when normalization of platelet counts and substantial reduction of serum lactate dehydrogenase activity were achieved) was highly predictive of iTTP recurrence. These results demonstrate that endothelial injury, resulting from disseminated microvascular thromboses, is severe and persistent in patients with acute iTTP. Plasma levels of Sdc-1 and sTM on admission and in remission are predictive of in-hospital mortality and recurrence of acute iTTP, respectively. Thus, an incorporation of such novel plasma biomarkers into the risk assessment in acute iTTP may help implement a more vigorous and intensive therapeutic strategy for these patients.

The Effect of Sex-Mismatched Red Blood Cell Transfusion on Endothelial Cell Activation in Critically Ill Patients

“…Despite the relatively small difference in syndecan-1 and sTM between sex-matched and sex-mismatched groups, a recent study has related such relatively minor changes to disease severity [34]. In addition, all of the changes noted in the current study pointed towards the same direction, which is endothelial activation associated with sex-mismatched transfusions.…”

Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19

“…[61][62][63] In the context of COVID-19, impaired MERTK signaling has been proposed as a link between the hyperinflammatory and hypercoagulative state observed in patients with severe disease. 61,[86][87][88] In the model proposed by Lemke et al, sequestration of MERTK-ligand protein spike (S) by developing blood clots results in impaired MERTK signaling in neighboring macrophages and increased pro-inflammatory cytokine production. 61 Sequestration of protein S by sMERTK may also contribute to this effect.…”

Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19

“…Through its role in both endothelial integrity in the lung and immunoregulation, dysregulated MERTK could potentially be a central player in the development of severe COVID-19. In addition, MERTK also plays a role in platelet aggregation (Sather et al, 2007), and its observed higher plasma levels in patients with the severe disease together with increased plasma levels of other proteins involved in hemostasis (Hrycek and Cieslik, 2012; Ikeda et al, 2018; Lu et al, 2020a) suggests an increased risk for coagulation and thrombosis. Coagulopathy and thrombosis have been observed in many patients that presented with severe COVID-19 (Gao et al, 2020; Levi et al, 2020).…”