The role of SERPIN citrullination in thrombosis

Tilvawala, Ronak; Nemmara, Venkatesh V.; Reyes, Archie C.; Sorvillo, Nicoletta; Salinger, Ari J.; Cherpokova, Deya; Fukui, Saeko; Gutch, Sarah; Thompson, Paul R.

doi:10.1016/j.chembiol.2021.07.009

Cited by 15 publications

(18 citation statements)

References 61 publications

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“…These strings are naturally degraded by ADAMTS13, a metalloproteinase, but citrullination of ADAMTS13 dramatically reduces the endogenous enzymatic activity [ 134 ]. In line with these findings, studies have shown that a class of serpins with an arginine residue in the P1 position (including antithrombin, C1INH, 1-antiplasmin, PAI1/PAI2) is inhibited by citrullination [ 135 , 136 ], thus unleashing the proteolytic power of the serine proteases thrombin, plasmin and tissue plasminogen activator in the thrombo-inflammatory microenvironment. PAD4-guided thrombin activation may then further facilitate thrombus maturation by FXIII-mediated cross-linking [ 123 ].…”

Section: Extracellular Chromatin Moonlighting Diseasesmentioning

confidence: 91%

Moonlighting chromatin: when DNA escapes nuclear control

et al. 2023

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Extracellular chromatin, for example in the form of neutrophil extracellular traps (NETs), is an important element that propels the pathological progression of a plethora of diseases. DNA drives the interferon system, serves as autoantigen, and forms the extracellular scaffold for proteins of the innate immune system. An insufficient clearance of extruded chromatin after the release of DNA from the nucleus into the extracellular milieu can perform a secret task of moonlighting in immune-inflammatory and occlusive disorders. Here, we discuss (I) the cellular events involved in the extracellular release of chromatin and NET formation, (II) the devastating consequence of a dysregulated NET formation, and (III) the imbalance between NET formation and clearance. We include the role of NET formation in the occlusion of vessels and ducts, in lung disease, in autoimmune diseases, in chronic oral disorders, in cancer, in the formation of adhesions, and in traumatic spinal cord injury. To develop effective therapies, it is of utmost importance to target pathways that cause decondensation of chromatin during exaggerated NET formation and aggregation. Alternatively, therapies that support the clearance of extracellular chromatin are conceivable.

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Section: Extracellular Chromatin Moonlighting Diseasesmentioning

confidence: 91%

Moonlighting chromatin: when DNA escapes nuclear control

et al. 2023

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“…However, H3cit negatively correlated with Trop US, in SS non-survivor patients, and with APC. These results suggest that NETosis may induce coagulopathies in septic patients, and this process may be a consequence of the release of other proteins during the NETosis process, such as PAD proteins [ 67 , 68 , 69 , 70 , 71 ], not only because of the release of H3cit. In fact, we found using in vitro experiments that H3cit has a protective role, especially in comparison with circulating histones.…”

Section: Discussionmentioning

confidence: 99%

Histone Citrullination Mediates a Protective Role in Endothelium and Modulates Inflammation

Osca-Verdegal

Beltrán-García²,

Paes

et al. 2022

Cells

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NETosis is a key host immune process against a pathogenic infection during innate immune activation, consisting of a neutrophil “explosion” and, consequently, NET formation, containing mainly DNA, histones, and other nuclear proteins. During sepsis, an exacerbated immune host response to an infection occurs, activating the innate immunity and NETosis events, which requires histone H3 citrullination. Our group compared the circulating histone levels with those citrullinated H3 levels in plasma samples of septic patients. In addition, we demonstrated that citrullinated histones were less cytotoxic for endothelial cells than histones without this post-translational modification. Citrullinated histones did not affect cell viability and did not activate oxidative stress. Nevertheless, citrullinated histones induced an inflammatory response, as well as regulatory endothelial mechanisms. Furthermore, septic patients showed elevated levels of circulating citrullinated histone H3, indicating that the histone citrullination is produced during the first stages of sepsis, probably due to the NETosis process.

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“…It has been shown that histone citrullination and reduced levels of antithrombin play a significant role in COVID-19 disease compared to non-coronavirus sepsis patients in the ICU ( 52 ). However, also antithrombin can be citrullinated, decreasing its effective biological activity even further ( 53 ). Lowered and dysfunctional antithrombin could in part explain the insufficient inhibitory potential of heparin in severe COVID-19 patients as heparin inhibits thrombin and FXa by potentiating antithrombin binding.…”

Section: Discussionmentioning

confidence: 99%

Serial thrombin generation and exploration of alternative anticoagulants in critically ill COVID-19 patients: Observations from Maastricht Intensive Care COVID Cohort

Berg

Mulder²,

Alnima³

et al. 2022

Front. Cardiovasc. Med.

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BackgroundCOVID-19 associated coagulopathy (CAC) is associated with an increase in thromboembolic events. Current guidelines recommend prophylactic heparins in the management of CAC. However, the efficacy of this strategy in the intensive care population remains uncertain.ObjectiveWe aimed to measure thrombin generation (TG) to assess CAC in intensive care unit (ICU) patients receiving thromboprophylaxis with low molecular weight heparin (LMWH) or unfractionated heparin (UFH). In addition, we performed statistical modeling to link TG parameters to patient characteristics and clinical parameters. Lastly, we studied the potency of different anticoagulants as an alternative to LMWH treatment in ex vivo COVID-19 plasma.Patients/MethodsWe included 33 patients with confirmed COVID-19 admitted at the ICU. TG was measured at least twice over the course of 6 weeks after admission. Thrombin generation parameters peak height and endogenous thrombin potential (ETP) were compared to healthy controls. Results were subsequently correlated with a patient characteristics and laboratory measurements. In vitro spiking in TG with rivaroxaban, dabigatran, argatroban and orgaran was performed and compared to LMWH.ResultsAnti-Xa levels of all patients remained within the therapeutic range throughout follow-up. At baseline, the mean (SE) endogenous thrombin potential (ETP) was 1,727 (170) nM min and 1,620 (460) nM min for ellagic acid (EA) and tissue factor (TF), respectively. In line with this we found a mean (SE) peak height of 353 (45) nM and 264 (96) nM for EA and TF. Although fluctuating across the weeks of follow-up, TG parameters remained elevated despite thromboprophylaxis. In vitro comparison of LMWHs and direct thrombin inhibitors (e.g., agratroban, dabigatran) revealed a higher efficacy in reducing coagulation potential for direct thrombin inhibition in both ellagic acid (EA) and tissue factor (TF) triggered TG.ConclusionIn a sub-group of mechanically ventilated, critically ill COVID-19 patients, despite apparent adequate anti-coagulation doses evaluated by anti-Xa levels, thrombin generation potential remained high during ICU admission independent of age, sex, body mass index, APACHE II score, cardiovascular disease, and smoking status. These observations could, only partially, be explained by (anti)coagulation and thrombosis, inflammation, and multi-organ failure. Our in vitro data suggested that direct thrombin inhibition compared with LMWH might offer an alternate, more effective anticoagulant strategy in COVID-19.

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The role of SERPIN citrullination in thrombosis

Cited by 15 publications

References 61 publications

Moonlighting chromatin: when DNA escapes nuclear control

Moonlighting chromatin: when DNA escapes nuclear control

Histone Citrullination Mediates a Protective Role in Endothelium and Modulates Inflammation

Serial thrombin generation and exploration of alternative anticoagulants in critically ill COVID-19 patients: Observations from Maastricht Intensive Care COVID Cohort

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