Plasma levels of platelet‐derived microvesicles are associated with risk of future venous thromboembolism

Author(s):  
Omri Snir ◽  
Line Wilsgård ◽  
Nadezhda Latysheva ◽  
Casper J. E. Wahlund ◽  
Sigrid K. Brækkan ◽  
...  
2000 ◽  
Vol 343 (7) ◽  
pp. 457-462 ◽  
Author(s):  
Paul A. Kyrle ◽  
Erich Minar ◽  
Mirko Hirschl ◽  
Christine Bialonczyk ◽  
Milena Stain ◽  
...  

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3987-3987
Author(s):  
Paolo Bucciarelli ◽  
Emanuele Previtali ◽  
Ida Martinelli ◽  
Andrea Artoni ◽  
Serena M Passamonti ◽  
...  

Abstract Abstract 3987 Poster Board III-923 Background Microparticles (MPs) are circulating, submicroscopic fragments (<1 μm of diameter) of membrane-bound cytoplasm that shed from the surface of an activated or apoptotic cell and play a role in coagulation, inflammation, cell remodelling and proliferation. There is increasing evidence that MPs are involved in thrombosis, but whether or not they are an independent risk factor for venous thromboembolism (VTE) is not established. Aim of the study To investigate the association between high plasma levels of MPs and risk of VTE Patients and Methods In a case-control study, 186 patients with a first episode of VTE (deep venous thrombosis and/or pulmonary embolism) and 418 healthy controls were included. MPs were analyzed by flow cytometry with a gate defined by a 1 μm beads and using APC-Annexin V together with FITC anti-CD41 or FITC anti-CD142 antibodies in order to identify platelet MPs (MP-Plts) and MPs exposing tissue factor (MP-TF), respectively. MPs levels were expressed as number/μL. Results Patients had significantly higher median plasma levels of both MPs-Plts and MPs-TF than controls [1942 vs 1519 (p<0.0001) and 579 vs 454 (p<0.0001)]. Higher median levels of MP-Plts and MP-TF were found in 41 patients who underwent blood sampling within 6 months from VTE than in those sampled later [2114 vs 1694 (p=0.086) and 652 vs 543 (p=0.120)]. Sex, age, body mass index and factor VIII plasma levels had no influence on MPs levels, as well as the use of oral contraceptives (this latter evaluated only in controls). In the whole study population, carriership of thrombophilia (antithrombin, protein C or protein S deficiency, factor V Leiden, prothrombin G20210A, antiphospholipid antibodies, hyperhomocysteinemia or combined abnormalities) had higher levels of MP-Plts and MP-TF than non-carriers [1907 vs 1565 (p=0.002) and 532 vs 468 (p=0.011)]. The odds ratio (OR) for VTE, adjusted for sex, age, body mass index and thrombophilia was 2.5-fold higher in individuals with MPs plasma levels >95th percentile of the control group (3633/μL for MPs-Plts and 1113/μL for MPs-TF) than in those with MPs levels ≤95th percentile [for MPs-Plts: OR=2.59 (95%CI 1.23 – 5.45); for MPs-TF: OR=2.38 (1.15 – 4.92)]. The risk increased in a dose-dependent manner for both MPs-Plts and MPs-TF, particularly above the 75th percentile of the distribution in controls. The exclusion of patients whose MPs levels were measured within 6 months from VTE (in order to avoid the possible effect of the acute phase on MPs measurements), did not change the results [adjusted OR: 2.63 (1.18 – 5.89) for MPs-Plts and 2.36 (1.10 – 5.19) for MPs-TF]. The Table shows the relative risks of VTE associated with the presence or absence of high MPs levels and thrombophilia. Individuals with MPs >95th percentile or thrombophilia alone had a 2 to 3-fold increased risk of VTE, whereas those with both MPs-Plts >95th percentile and thrombophilia had a 9-fold increased risk of VTE. This synergistic effect was confirmed also for MPs-TF and remained after the exclusion of patients whose blood sample was collected within 6 months from VTE [OR 7.72 (1.68-35.4) for MP-Plts and 8.14 (2.08-31.8) for MP-TF]. Conclusions Plasma levels of MPs are significantly higher in patients with VTE than in healthy controls. MPs levels >95th percentile are associated with a 2.5-fold increased risk of VTE. There is a synergistic interaction between high levels of MPs and thrombophilia on VTE risk. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3348-3348
Author(s):  
Luis Fernando Bittar ◽  
Bruna Mazetto Fonseca ◽  
Silmara Lima Montalvão ◽  
Fernanda Loureiro de Andrade Orsi ◽  
Erich V de Paula ◽  
...  

Abstract Abstract 3348 Introduction: Venous thromboembolism (VTE) is a multifactorial disease, and increased levels of coagulation factor VIII (FVIII) has been demonstrated as risk factor for first and recurrent episodes of VTE. Some authors reported that these high levels of FVIII were still persistent after 4 years of the episode, but median follow-up in these studies are relatively short. The aim of the study was investigate if after a long-term follow-up of 4–15 years (median of 10 years), patients with high levels of FVIII after anticoagulant treatment still showed this alteration. Design and Methods: Previously, we selected 174 adult patients with a first episode of acute VTE between January 1990 and September 2004. One hundred seventy four healthy adult individuals selected from blood donors were chosen as controls, from the same geographic area of origin. Of this group of VTE patients, 68 patients with plasma FVIII: C levels above the 90th percentile were selected. FVIII levels (FVIII:C) were measured by a one-stage clotting assay with FVIII-deficient plasma in duplicate in an automated coagulometer. Levels were measured twice, in 2004 and then in 2011. C-reactive protein (CRP) levels were determined in the same samples by a nephelometric method to evaluate the influence of inflammation on FVIII levels. For individuals with CRP values higher than 1mg/dL, an additional blood sample was analyzed. High FVIII levels were only considered for further analysis when in the presence of normal CRP levels. The presence of post-thrombotic syndrome (PTS) was evaluated and classified clinically by the Clinical-Etiologic-Anatomic-Pathophysiologic (CEAP) classification System. Results: 68 patients with VTE and high levels of FVIII (19M:49F) with a median age of 47 years (range 20–70) were included in the study. The control group consisted of 59 subjects (42M:17F) with a median age of 35 years (range 21–56 years). VTE was spontaneous in 26 (38.2%) patients and secondary to an acquired risk factor in 61.8%. In the 1st evaluation, in 2004, patients with VTE had higher plasma levels of FVIII:C (median 235.8 IU/dL vs. 127.0 IU/dL; p<0.001) compared to controls. In 2011, seven years after the first evaluation and after a median follow-up of 10 years after the first VTE episode, this difference was still present (median 144.6 IU/dL vs. 96.4 IU/dL; p<0.001). Patients with severe PTS (167 IU/dL) showed higher plasma levels of FVIII when compared with patients without PTS (median 141.4 IU/dL), mild PTS patients (median 142.8 IU/dL), and moderate PTS patients (median 143.2); p=0.04. Conclusions: Our results show that even after a median of 10 years of VTE, patients still have increased levels of FVIII. Moreover, there seems to be a relationship between severe post-thrombotic syndrome and increased plasma levels of FVIII. Disclosures: No relevant conflicts of interest to declare.


2000 ◽  
Vol 83 (01) ◽  
pp. 5-9 ◽  
Author(s):  
Pieternella in 't Anker ◽  
Marianne Koopman ◽  
Pieter Reitsma ◽  
Martin Prins ◽  
Abraham van den Ende ◽  
...  

SummaryEstablished risk factors, including deficiencies of protein C, protein S or antithrombin and the factor V Leiden and prothrombin mutation, are present in about one third of unselected patients with venous thromboembolism. In addition to these inherited thrombophilic defects, elevated plasma levels of factor VIIIc have been suggested to be important in the pathogenesis of (recurrent) venous thromboembolism. The objective of this study was to assess the relevance of factor VIIIc plasma concentration in consecutive patients with venous thromboembolism.We studied the prevalence of elevated plasma levels of factor VIIIc in 65 patients with a proven single episode and in 60 matched patients with documented recurrent venous thromboembolism. The reference group consisted of 60 ageand sex-matched patients who were referred for suspected venous thromboembolism, which was refuted by objective testing and longterm clinical follow-up. To minimalize the influence of the acute phase, blood was obtained at least 6 months after the thromboembolic event and results were adjusted for fibrinogen and C-reactive protein. Factor VIIIc was re-determined several years after the first measurement in a subset of patients to evaluate the variability over time. To study a possible genetic cause, a family study was done.In the control, single and recurrent episode group, the prevalences of plasma levels of factor VIIIc above 175 IU/dl (90th percentile of controls) were 10% (95% CI: 4 to 21%), 19% (95% CI: 10 to 30%) and 33% (95% CI: 22 to 47%), respectively. For each 10 IU/dl increment of factor VIIIc, the risk for a single and recurrent episode of venous thrombosis increased by 10% (95% CI: 0.9 to 21%) and 24% (95% CI: 11 to 38%), respectively. Both low and high plasma levels of factor VIIIc were consistent over time (R = 0.80, p = 0.01). A family study indicated a high concordance for elevated factor VIIIc plasma concentrations among first degree family members. Adjustment for fibrinogen, C-reactive protein and known thrombophilic risk factors did not change the observed association of elevated factor VIIIc with thrombosis.Elevated plasma levels of factor VIIIc are a significant, prevalent, independent and dose-dependent risk factor for venous thromboembolism. It also predisposes to recurrent venous thromboembolism.


2019 ◽  
Vol 17 (10) ◽  
pp. 1661-1669 ◽  
Author(s):  
Robin A. Liang ◽  
Ina I. Høiland ◽  
Thor Ueland ◽  
Pål Aukrust ◽  
Omri Snir ◽  
...  

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3829-3829
Author(s):  
Doyeun Oh ◽  
Mun Ju Jang ◽  
Sun Joo Lee ◽  
Soo-Mee Bang ◽  
Seonyang Park ◽  
...  

Abstract Background: Microparticles (MP) are small membrane vesicles released from a variety of cells including platelet, leukocyte, endothelial cell which mediate intravascular coagulation. In this study, the plasma levels of total microparticle (TMP), platelet microparticle (PMP) and endothelial microparticle (EMP) in patients with venous thromboembolism (VTE) were investigated to test their clinical utilities. Methods: Subjects were divided to 3 groups consisted of 119 patients with VTE, 72 cancer without VTE and 93 healthy controls. MP were assayed by flow-cytometry using non-washed, frozen platelet-poor plasma samples. TMP, PMP and EMP were identified using antibodies against Annexin V, CD41a, and CD144 respectively. Results: The mean levels of plasma TMP, PMP, but not EMP in VTE without caner group (n=77) were significantly increased compared with those in healthy controls (n=93); 1972.9/μl vs 917.0/μl, p=0.001; 1496.6/μl, 586.5/μl, p=0.001; 108.0/μl vs 97.8/μl, p=0.321). In the VTE without cancer group, the mean levels of plasma TMP, PMP, but not EMP in newly diagnosed VTE group (n=59) were significantly increased compared with previously diagnosed VTE group (n=18); 2242.5/μl vs 1089.1/μl, p=0.008; 1728.6/μl vs 735.9/μl, p=0.005; 101.8/μl vs 84.6/μl, p=0.885). Mean peak thrombin generations in VTE samples (n=9) were increased in platelet poor plasma (385.2 nM vs 163.1 nM, p=0.002) but not in microparticle free plasma (MFP) (86.2 nM vs 22.6 nM, p=NS) as compared with those of controls (n=10) suggesting the thombin generation is originated from MP of plasma. But, the mean levels of plasma TMP, PMP, but not EMP in VTE with caner group (n=42) were not increased compared with those in cancer controls without VTE (n=72); 2158.1/μl vs 1644.2/μl, p=0.094; 1637.2/μl vs 1246.8/μl, p=0.168; 86.0/μl vs86.0/μl, p=0.996). The plasma levels of B-TG were well correlated with those of PMP. The levels of plasma TMP, PMP, and EMP did not show any correlation with the level of D-dimer. Conclusion: The plasma levels of TMP and PMP are significantly increased in VTE patients and the levels are normalized after anticoagulation, suggesting MP may be used as surrogate markers for monitoring of VTE.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3345-3345
Author(s):  
Mandy N Lauw ◽  
Bronno Van der Holt ◽  
Saskia Middeldorp ◽  
Joost CM Meijers ◽  
Bart J Biemond

Abstract Abstract 3345 Background: Acute lymphoblastic leukemia (ALL) is frequently complicated by venous thromboembolism (VTE). The reported incidence varies from 2% to 37%, with the highest risk arising in the first weeks after treatment initiation. VTE leads to morbidity, mortality and premature termination of therapy. Prevention of VTE in ALL is complicated, as thrombotic and bleeding factors need to be balanced. The efficacy of prophylactic antithrombotic measures is not clear yet, and standardized guidelines are lacking. We assessed the effect of various prevention protocols on the VTE risk in adults treated for ALL. Methods: Between April 1999 and November 2005, 240 consecutive patients aged 16–59 years with newly diagnosed ALL were treated with the same anti-leukemic protocol in a Dutch-Belgian multicenter study, which included L-asparaginase in cycle 1 (5000 U/m2/day, day 15–28). All VTE events during treatment were prospectively recorded. VTE prophylaxis was applied only in cycle 1 during asparaginase administration, and varied between different centers: no prophylaxis, fresh frozen plasma (FFP), or antithrombin (AT) concentrate. A centers' prevention protocol was used as a proxy for all patients treated in that center. AT plasma levels were assessed of patients with VTE and 22 controls without VTE. We determined VTE incidence in cycle 1, the impact of the various prophylactic measures, and VTE incidence during the total treatment period for ALL. Secondly, we assessed the clinical relevance of VTE on ALL outcome. Results: 25 of 240 patients (10.4%; 95% CI 6.6–14.3) experienced objectively diagnosed, symptomatic VTE in cycle 1 (10 cerebral thromboses of which 8 in the sagittal sinus, 11 upper limb vein thromboses (10 central venous catheter (CVC)-related), 3 deep vein thromboses of the leg, 1 pulmonary embolism). VTE incidence in patients receiving FFP prophylaxis was reduced by 70% as compared to patients without prophylactic measures (7.2% vs. 23.9%; RR 0.3; 95% CI 0.1–0.6; Table 1). Age, sex, ALL-type and CVC-placement did not differ significantly between patients with and without FFP prophylaxis. The effect of prophylactic AT concentrate could not be properly assessed as it was only rarely given in two centers. Mean AT plasma levels did not differ significantly between VTE patients with or without FFP, neither between patients with VTE and controls without VTE (Figure 1). During the total treatment period, VTE occurred in 36 of 240 patients (15.0%; 95% CI 10.5–19.5). Patients with VTE in cycle 1 were less likely to obtain complete remission after cycle 1 (HR 0.5; 95% CI 0.3–0.9), but did not have a significantly decreased overall survival (HR 1.5; 95% CI 0.9–2.6). Conclusions: FFP significantly reduced VTE incidence by 70% during ALL treatment, without reversing the AT deficiency induced by asparaginase. Our observation is in contrast with two previous studies on the effect of FFP on VTE in ALL. The mechanisms by which FFP accomplishes this antithrombotic effect are not clear yet and require further investigation. Since this was a retrospective, observational study, the effect of prophylactic FFP on VTE risk in adults treated for ALL should be confirmed by a randomized controlled trial. Disclosures: No relevant conflicts of interest to declare.


2003 ◽  
Vol 115 (8) ◽  
pp. 601-605 ◽  
Author(s):  
Rossella Marcucci ◽  
Agatina Alessandrello Liotta ◽  
Anna Paola Cellai ◽  
Angela Rogolino ◽  
Anna Maria Gori ◽  
...  

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