Elevated plasma levels of procoagulant microparticles are a novel risk factor for thrombosis in patients with myeloproliferative neoplasms

Taniguchi, Yasuhiro; Tanaka, Hirokazu; Espinoza, J. Luis; Sakai, Kazuko; Kumode, Takahiro; Sano, Keigo; Serizawa, Kentarou; Rai, Shinya; Morita, Yasuyoshi; Hanamoto, Hitoshi; Tsubaki, Kazuo; Nishio, Kazuto; Matsumura, Itaru

doi:10.1007/s12185-017-2302-5

Cited by 22 publications

(29 citation statements)

References 36 publications

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“…The aim of this study is to investigate a link between the parameters of circulat ing MPs and thrombotic complications in MPN patients. Like others [22,24], we observed a significantly higher procoagulant activity [22,24] and level of MPs [25,26] in comparison with control groups. These results can demonstrate the persistent prothrombotic state in patients with MPN.…”

Section: Discussionsupporting

confidence: 80%

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High Level of Circulating Microparticles in Patients with BCR/ ABL Negative Myeloproliferative Neoplasm – a Pilot Study

et al. 2019

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Background: Microparticles (MPs) are small (0.1-1 μm) cell-derived vesicles released during activation or apoptosis, with a surface-exposed phosphatidylserine along with antigens indicat ing the cellular origin. The level of MPs is known to be elevated in thromboembolic dis eases and malignancies; it is believed that MPs are not only amplify ing but can also initiate the thrombogenesis processes. BCR/ ABL negative myeloproliferative neoplasms (MPNs) are clonal haematopoietic dis eases, which include polycythemia vera, essential thrombocythemia and primary myelofibrosis. One of the main problems of MPN patients is high risk and incidence of thrombosis which affect the survival, quality of life and life expectancy. Patients and methods: The clinical significance of circulat ing MPs was assessed in a group of 179 patients with BCR/ ABL-negative MPNs. Analysis of MPs was done us ing flow cytometry on 417 samples, and MPs procoagulation activity was performed us ing a functional assay called Zymuphen MP-activity (Hyphen Biomed, Neuville-sur-oise, France) on 274 samples. Results: Significantly higher absolute and relative count of platelet MPs was found in MPN patients when compared with healthy group, respectively (p = 0.001, p = 0.043). Erythrocyte MPs were also significantly higher in MPN patients than in the healthy group (p < 0.001). Procoagulation activity of MPs was as well significantly higher in patients compared to the control group (p < 0.001). Patients with primary myelofibrosis had decreased absolute and relative count of platelet MPs compared to polycythemia vera and essential thrombocythemia patients, respectively (p = 0.008, p = 0.014). Presence of JAK2V617F mutation was associated with higher absolute and relative count of platelet MPs, respectively (p = 0.045, p = 0.029). Conclusion: Although some literature data support the hypothesis of a direct relation between MPs and thrombotic events in MPN patients, further studies are needed to evaluate the clinical implication of MPs in the hypercoagulation state of MPN patients.

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Section: Discussionsupporting

confidence: 80%

“…The disadvantage of this study is the lack of MPs analysis in context with treatment. As previously documented in other studies [16,22,26], the patients with cytoreductive ther apy were characterised by lower procoagulant activity of MPs than patients without cytoreduction. This analysis could clarify these results.…”

Section: Discussionsupporting

confidence: 76%

High Level of Circulating Microparticles in Patients with BCR/ ABL Negative Myeloproliferative Neoplasm – a Pilot Study

et al. 2019

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“…In human studies, a case-control study comparing cancer patients with and without acute VTD demonstrated an association between elevated TF þ EVs and VTD-associated cancer [31]. Similar results were found by other groups [32,33]. However inconsistent retrospective observations have been published in which multivariate analysis failed to show a significant association between elevated TF þ EVs and VTD in cancer patients [34].…”

Section: Discussionsupporting

confidence: 66%

Differential biomarker profiles between unprovoked venous thromboembolism and cancer

et al. 2020

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Background: The relationship between cancer and venous thromboembolic disease (VTD) are complex because the activated coagulation factors are not only involved in thrombosis but also in malignant processes, such as angiogenesis and metastasis. Objective: To compare phenotypes of extracellular vesicles (EVs), and levels of D-dimer, soluble P-selectin (sP-selectin) and antigenic tissue factor (TF) between unprovoked VTD patients, who did not develop cancer during one-year follow-up, and those with advanced stage of cancer but not associated with VTD. Methods: A prospective study in which we included 138 unprovoked VTD patients and 67 advanced cancer patients, who did not develop thrombosis. Levels of EVs of different cellular origin (platelet, endothelium and leukocyte), EVs positive for tissue factor (TF) and P-selectin glycoprotein ligand 1 were quantified by flow cytometry. D-dimer, soluble P-selectin (sP-selectin) and antigenic TF were determined by ELISA. Results: TF-positive EVs, D-dimer, and sP-selectin were markedly elevated in unprovoked VTD patients compared to cancer patients without association with thrombosis. Conclusions: Levels of TF-positive EVs, D-dimer and sP-selectin are able to discriminate between unprovoked VTD patients not related to cancer and cancer patients not associated with VTD. These results could lead to the application of EVs as biomarkers of both diseases. Key messages: Circulating EVs, specifically TF-positive EVs, in combination with plasmatic markers of hypercoagulable states, such as D-dimer, sP-selectin and antigen TF, are able to discriminate between cancer patients without thrombosis and patients with unprovoked VTD. Research fields could be opened. Future studies will assess if these biomarkers together serve as predicting thrombotic events in cancer populations

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“…Since increased MP levels seem to improve haemostasis and might represent an endogenous compensation mechanism, the additional administration of pro-haemostatic agents might lead to spontaneous clotting resulting in thromboembolic events. Aside from trauma, elevated levels of circulating MP are associated with thrombotic events in cancer patients [ 24 , 25 ]. However, in the present cohort we observed only one thromboembolic event 14 days after trauma.…”

Section: Discussionmentioning

confidence: 99%

Temporal phenotyping of circulating microparticles after trauma: a prospective cohort study

Fröhlich

Schäfer

Caspers

et al. 2018

Scand J Trauma Resusc Emerg Med

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BackgroundAfter severe polytrauma the dynamic process of coagulation may deteriorate towards a trauma-induced coagulopathy (TIC) promoting a dramatic increase in morbidity and mortality. Recent evidence suggests that microparticles (MPs) play a pivotal role at the interface between cellular and plasmatic coagulation systems. However, the impact of MPs on functional coagulation has not been clarified yet in the setting of traumatic injuries. We assessed the temporal patterns of circulating MP concentrations including their cellular origin in the context of clinical presentation and global coagulation assays.MethodsBlood samples from 22 consecutive polytrauma patients (ISS ≥16) from 2015 were collected at hospital admission, after 24 and 72 h and compared to those from healthy individuals and minor injured patients with isolated extremity fractures. Flow cytometry (BD Accuri C6; Heidelberg/Germany) was used to determine MP concentrations and cellular origin using cell-specific markers (platelet derived (PDMP): CD42b+, CD61+, CD62p+; endothelial cell derived (EDMP): CD144+, CD62e+, CD144+/62e+). Results were correlated with clinical data and results from viscoelastic testing (ROTEM).ResultsTwenty two polytrauma patients (17 males, agemedian 60 yrs) with a median ISS 26.5 (IQR 14.5) were assessed. PDMP and EDMP concentrations increased significantly in polytrauma patients as compared to healthy individuals and minor injured patients. MP concentrations correlated with injury severity (CD144+: ρsp = 0.79, p < 0.001; CD42b+: ρsp = 0.61, p < 0.001). EDMP displayed a negative correlation with aPTT (CD144/62e+, ρsp = − 0.55, p < 0.05), INR (CD144/62e+, ρsp = − 0.61, p < 0.05) and ROTEM-INTEM CT (CD144/62e+, ρsp = − 0.68, p < 0.05) reflecting increased dynamics of clot formation and an overall procoagulative effect. Additionally, EDMP showed a negative association with FIBTEM values (10 min amplitude, maximum clot firmness) indicating a fibrinolytic potential.DiscussionIn a small cohort, analysing most severly injured patients, the association of increased MP levels and altered coagulation parameters could be demonstrated. However, these findings are based on correlation analysis, which do not enable causel evidence. Therefore, further in-vitro studies are needed analysing the underlying pathomechanisms.ConclusionIn conclusion, this study could demonstrate that PDMP and EDMP levels increase significantly following polytrauma correlating with injury severity. Although severe coagulopathy was not observed, EDMP levels were associated with improved coagulation parameters suggesting their essential role for regulating blood coagulation after trauma.

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Elevated plasma levels of procoagulant microparticles are a novel risk factor for thrombosis in patients with myeloproliferative neoplasms

Cited by 22 publications

References 36 publications

High Level of Circulating Microparticles in Patients with BCR/ ABL Negative Myeloproliferative Neoplasm – a Pilot Study

High Level of Circulating Microparticles in Patients with BCR/ ABL Negative Myeloproliferative Neoplasm – a Pilot Study

Differential biomarker profiles between unprovoked venous thromboembolism and cancer

Temporal phenotyping of circulating microparticles after trauma: a prospective cohort study

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