Platelets Contribution to Thrombin Generation in Philadelphia-Negative Myeloproliferative Neoplasms: The “Circulating Wound” Model

Lucchesi, Alessandro; Napolitano, Roberta; Bochicchio, Maria Teresa; Giordano, Giulio; Napolitano, Mariasanta

doi:10.3390/ijms222111343

Cited by 7 publications

(5 citation statements)

References 108 publications

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“…It should be also mentioned that C1INH promoted the inhibitory effect on thrombin mediated exposure of platelet fibrinogen receptors (PFR) measured by PAC1 binding, this serine protease inhibitor might play a role in pathophysiologic reductions of PFR exposure in the cases of myeloproliferative neoplasms. 38,39 Further studies in this area of research may afford new information about the mechanisms of hematologic cancers.…”

Section: Discussionmentioning

confidence: 99%

C1-inhibitor influence on platelet activation by thrombin receptors agonists

Tarandovskiy

Buehler

Karnaukhova

2022

Clin Appl Thromb Hemost

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Introduction Protease activated receptors 1 (PAR1) and 4 (PAR4) agonists are used to study platelet activation. Data on platelet activation are extrapolated across experimental settings. C1-inhibitor (C1INH) is a protease inhibitor present in plasma but not in isolated platelet suspensions. Here we show that C1INH affects platelet activation through PAR1 and PAR4 agonists. Methods Platelets were isolated from healthy donor whole blood and then labeled with anti-CD62P and PAC1 antibodies. The platelet suspensions were exposed to PAR1 agonists SFLLRN, TFLLR and TFLLRN; PAR4 agonists AYPGKF and GYPGQV; ADP and thrombin. Flow-cytometric measurements were performed in 5, 10 and 15 min after activation. Results 0.25 mg/ml C1INH addition made platelets to faster expose CD62P and glycoprotein IIb/IIIa complex after activation with PAR1 agonists. Conversely, C1INH addition led to inhibition of platelet activation with PAR4 agonists and thrombin. Activation with ADP was not affected by C1INH. Conclusions Our results suggest that C1INH can modify platelet activation in the presence of synthetic PAR agonists used in platelet research. These observations may be relevant to the development of new methods to assess platelet function.

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Section: Discussionmentioning

confidence: 99%

C1-inhibitor influence on platelet activation by thrombin receptors agonists

Tarandovskiy

Buehler

Karnaukhova

2022

Clin Appl Thromb Hemost

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“…In patients with cancer, platelets are activated by ADP, thrombin, some metalloproteases, and interleukin (IL)-6 produced by tumor cells that induce the expression of adhesion molecules on platelet surface (e.g., P-selectin) increasing their tendency to aggregation [ 21 ]. Platelets contribute to thrombin generation, which may, in turn, trigger a vicious circle promoted by the protease-activated receptors (PARs)/tumor growth factor (TGF)-beta signaling [ 22 ].…”

Section: Pathogenesismentioning

confidence: 99%

The Role of Injectables in the Treatment and Prevention of Cancer-Associated Thrombosis

Napolitano,

Siragusa

2023

Cancers

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Cancer-associated thrombosis (CAT) is a leading cause of death among patients with cancer. CAT can manifest itself as venous thromboembolism (VTE), in the form of deep vein thrombosis or pulmonary embolism, or arterial thromboembolism. The pathophysiology of CAT is complex and depends on cancer-, patient-, treatment- and biomarkers-related factors. Treatment of VTE in patients with cancer is complex and includes three major classes of anticoagulant agents: heparin and its derivatives, e.g., low molecular weight heparins, direct oral anticoagulants (DOACs), and vitamin K inhibitors. Given the tremendous heterogeneity of clinical situations in patients with cancer and the challenges of CAT, there is no single universal treatment option for patients suffering from or at risk of CAT. Initial studies suggested that patients seemed to prefer an anticoagulant that would not interfere with their cancer treatment, suggesting the primacy of cancer over VTE, and favoring efficacy and safety over convenience of route of administration. Recent studies show that when the efficacy and safety aspects are similar, patients prefer the oral route of administration. Despite this, injectables are a valid option for many patients with cancer.

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“…The pathogenetic model of the “circulating wound”, recently proposed by our research team, would, thus, undergo dampening [ 27 ]. A similar benefit seems to be offered by anti-JAK1/2 targeted therapies (e.g., ruxolitinib) that are capable of calming the cytokine storm, modulating the expression of endothelial integrins, and reducing the pro-adhesive capacities of circulating cells [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Circulating Endothelial Cell Levels Correlate with Treatment Outcomes of Splanchnic Vein Thrombosis in Patients with Chronic Myeloproliferative Neoplasms

Giordano

Napolitano²,

Cellurale

et al. 2022

JPM

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Circulating endothelial cells (CECs) are viable, apoptotic or necrotic cells, identified by CD 146 surface antigen expression, considered a biomarker of thrombotic risk, given their active role in inflammatory, procoagulant and immune processes of the vascular compartment. Growing evidence establishes that CECs are also involved in the pathogenesis of several hematological and solid malignancies. The primary aim of this study was to verify if CEC levels could predict both the course and treatment responses of splanchnic vein thrombosis (SVT), either in patients affected by myeloproliferative neoplasms (MPNs) or liver disease. Thus, a retrospective multicenter study was performed; fifteen patients receiving anticoagulant oral treatment with vitamin k antagonists (VKA) for SVT were evaluated. Nine patients were affected by MPN, and all of them received cytoreduction in addition to anticoagulant therapy; four of these patients had primary myelofibrosis (PMF) and were treated with ruxolitinib (RUX), and one patient with primary myelofibrosis, two patients with essential thrombocythemia (ET), and two patients with polycythemia vera (PV) were treated with hydroxyurea (HU). Six patients affected by liver diseases (three with liver cirrhosis and three with hepatocellular carcinoma) were included as the control group. CECs were assayed by flow cytometry on peripheral blood at specific time points, for up to six months after enrollment. The CEC levels were related to C-reactive protein (CRP) levels, splenic volume reduction, and thrombus recanalization, mainly in MPN patients. In patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC), for which the mechanism of SVT development is quite different, the relationship between CEC and SV reduction was absent. In conclusion, the CEC levels showed a significant correlation with the extent of venous thrombosis and endothelial cell damage in myeloproliferative neoplasm patients with splanchnic vein thrombosis. Although preliminary, these results show how monitoring CEC levels during cytoreductive and anticoagulant treatments may be useful to improve SVT outcome in MPN patients.

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Platelets Contribution to Thrombin Generation in Philadelphia-Negative Myeloproliferative Neoplasms: The “Circulating Wound” Model

Cited by 7 publications

References 108 publications

C1-inhibitor influence on platelet activation by thrombin receptors agonists

C1-inhibitor influence on platelet activation by thrombin receptors agonists

The Role of Injectables in the Treatment and Prevention of Cancer-Associated Thrombosis

Circulating Endothelial Cell Levels Correlate with Treatment Outcomes of Splanchnic Vein Thrombosis in Patients with Chronic Myeloproliferative Neoplasms

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