Soluble P-Selectin, Von Willebrand Factor, And Adamts13 Levels As Risk Factors Of Deep Vein Thrombosis In Cancer Patients Undergoing Chemotherapy

Abstract Background There is a high number of deep vein thrombosis (DVT) incidence among cancer patients undergoing chemotherapy. Chemotherapy-induced vascular endothelial cell activation (VECA) is marked with increasing plasma levels of von Willebrand Factor (VWF) and soluble P-selectin (sP-selectin) leading to activation of endothelial cells and coagulation cascade. The biological role of a disintegrin-like and metalloproteinase with thrombospondin type 1, motif 13 (ADAMTS13) is to control the activity of VWF. The objectives of this study is to investigate the role of sP-selectin, VWF, and ADAMTS13 as risk factors for the incidence of DVT in cancer patients undergoing chemotherapy. Methods This prospective cohort study was conducted in Dr. Kariadi hospital, Semarang Indonesia, on 40 cancer patients. Soluble P-selectin, VWF, and ADAMS13 plasma levels were determined with enzyme-linked immunosorbent assay (ELISA) method, examined before and after chemotherapy. These patients were observed for the possibility of developing DVT during three months. Results Deep vein thrombosis was confirmed in 5 patients (12.5%) after a median period of 8 weeks. In patients with DVT, sP-selectin and VWF were significantly higher, while ADAMTS13 were significantly lower compared in cancer patients without DVT. Pre- and post-chemotherapy concentration of sP selectin, VWF, and ADAMTS13 could effectively predict the incidence of DVT in cancer patients undergoing chemotherapy. The levels of sP-selectin, VWF and ADAMTS13 pre-chemotherapy with cut-off point >106.7 ng/mL, >2.99 U/mL and <0,80 U/mL, respectively, had relative risk (RR) for DVT incidence being 16 (95% CI 2,06-124,25, p=0,001); 36 (95% CI 5,21-248,65, p=0,000) and 10,5 (95% CI 1,31-84,28, p=0,015), respectively, whereas the levels of sP-selectin, VWF and ADAMTS13 post-chemotherapy with cut-off point >111.7 ng/mL, >3,06 U/mL and <0,49 U/mL, respectively, had RR for DVT incidence being 8.7 (95% CI 1,01-74,39, p=0,045); 20,4 (95% CI 2,60-159,94, p=0,004) and 26,25 (95% CI 3,50-196,48, p=0,002), respectively. Pre-chemotherapy vWF levels (cut-off value >2.99 U/mL) was found to be independently predict DVT incidence with RR 11.1 (95% CI, 1.95-62.74, p=0.007). Conclusions Plasma levels of VWF more than 2.99 U/mL pre-chemotherapy was an independent risk factor for DVT incidence, which could be performed early and helpful for thromboprophylaxis therapy.

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Von Willebrand Factor:Antigen And Adamts-13 Level, But Not Soluble P-Selectin, Are Risk Factors For The First Asymptomatic Deep Vein Thrombosis In Cancer Patients Undergoing Chemotherapy

10.21203/rs.3.rs-34208/v3 ◽

2020 ◽

Author(s):

Budi Setiawan ◽

Cecilia Oktaria Permatadewi ◽

Baringin de Samakto ◽

Ashar Bugis ◽

Ridho M. Naibaho ◽

...

Keyword(s):

Risk Factors ◽

Logistic Regression ◽

Deep Vein Thrombosis ◽

Cancer Patients ◽

Plasma Levels ◽

Blood Type ◽

Vein Thrombosis ◽

Soluble P ◽

Von Willebrand ◽

Deep Vein

Abstract BackgroundThere is a high incidence of deep vein thrombosis (DVT) among cancer patients undergoing chemotherapy. Chemotherapy-induced vascular endothelial cell activation (VECA) is characterized by increased plasma levels of von Willebrand factor (vWF) and soluble P-selectin (sP-selectin), leading to the activation of endothelial cells and signaling cascades. The biological role of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS-13) is to control the activity of vWF and consequently the risk of thrombosis. The objective of this study was to investigate the roles of sP-selectin, vWF, and ADAMTS-13 as risk factors for the first episode of DVT in cancer patients undergoing chemotherapy.MethodsThis prospective cohort study was conducted at Dr. Kariadi Hospital, Indonesia, on 40 cancer patients. Prechemotherapy (baseline) and postchemotherapy sP-selectin, vWF antigen (vWF:Ag), and ADAMTS-13 plasma levels were determined with ELISAs before and 3 months after chemotherapy. The clinical characteristics of the patients, cancer type, cancer stage, chemotherapy regimen, ABO blood type, D-dimer level and Khorana risk score were also analyzed using logistic regression. Patients were observed for the possibility of developing DVT during chemotherapy.ResultsDVT was confirmed in 5 patients (12.5%) after a period of 3 months. In patients with DVT, sP-selectin and vWF were significantly higher while ADAMTS-13 was lower than in their counterparts. The levels of baseline vWF:Ag and ADAMTS-13, with cut-off points ≥ 2.35 IU/mL and ≤ 1.03 IU/mL, respectively, were found to independently predict the incidence of DVT. In the multivariate logistic regression analysis, the relative risk (RR) for DVT in patients with high vWF:Ag was 3.80 (95% CI 1.15-12.48, p=0.028), and that for patients with low ADAMTS-13 was 2.67 (95% CI 1.22-23.82, p=0.005). The vWF:Ag/ADAMTS-13 ratio and both vWF:Ag and ADAMTS-13 dynamics during treatment were also able to differentiate those with prospective DVT. However, sP-selectin and other covariates showed no statistical significance. ConclusionPrechemotherapy plasma levels of vWF:Ag ≥ 2.35 IU/mL and ADAMTS-13 ≤ 1.03 IU/mL are independent risk factors for DVT incidence.

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Von Willebrand factor:antigen and ADAMTS-13 level, but not soluble P-selectin, are risk factors for the first asymptomatic deep vein thrombosis in cancer patients undergoing chemotherapy

Thrombosis Journal ◽

10.1186/s12959-020-00247-6 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Budi Setiawan ◽

Cecilia Oktaria Permatadewi ◽

Baringin de Samakto ◽

Ashar Bugis ◽

Ridho M. Naibaho ◽

...

Keyword(s):

Risk Factors ◽

Logistic Regression ◽

Deep Vein Thrombosis ◽

Cancer Patients ◽

Plasma Levels ◽

Blood Type ◽

Vein Thrombosis ◽

Soluble P ◽

Von Willebrand ◽

Deep Vein

Abstract Background There is a high incidence of deep vein thrombosis (DVT) among cancer patients undergoing chemotherapy. Chemotherapy-induced vascular endothelial cell activation (VECA) is characterized by increased plasma levels of von Willebrand factor (vWF) and soluble P-selectin (sP-selectin), leading to the activation of endothelial cells and signaling cascades. The biological role of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS-13) is to control the activity of vWF and consequently the risk of thrombosis. The objective of this study was to investigate the roles of sP-selectin, vWF, and ADAMTS-13 as risk factors for the first episode of DVT in cancer patients undergoing chemotherapy. Methods This prospective cohort study was conducted at Dr. Kariadi Hospital, Indonesia, on 40 cancer patients. Prechemotherapy (baseline) and postchemotherapy sP-selectin, vWF antigen (vWF:Ag), and ADAMTS-13 plasma levels were determined with ELISAs before and 3 months after chemotherapy. The clinical characteristics of the patients, cancer type, cancer stage, chemotherapy regimen, ABO blood type, D-dimer level and Khorana risk score were also analyzed using logistic regression. Patients were observed for the possibility of developing DVT during chemotherapy. Results DVT was confirmed in 5 patients (12.5%) after a period of 3 months. In patients with DVT, sP-selectin and vWF were significantly higher while ADAMTS-13 was lower than in their counterparts. The levels of baseline vWF:Ag and ADAMTS-13, with cut-off points ≥ 2.35 IU/mL and ≤ 1.03 IU/mL, respectively, were found to independently predict the incidence of DVT. In the multivariate logistic regression analysis, the relative risk (RR) for DVT in patients with high vWF:Ag was 3.80 (95% CI 1.15–12.48, p = 0.028), and that for patients with low ADAMTS-13 was 2.67 (95% CI 1.22–23.82, p = 0.005). The vWF:Ag/ADAMTS-13 ratio and both vWF:Ag and ADAMTS-13 dynamics during treatment were also able to differentiate those with prospective DVT. However, sP-selectin and other covariates showed no statistical significance. Conclusion We found that prechemotherapy plasma levels of vWF:Ag ≥ 2.35 IU/mL and ADAMTS-13 ≤ 1.03 IU/mL are independent risk factors for DVT incidence among cancer patients.

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Von Willebrand Factor: Antigen and Adamts-13 Level, but not Soluble P-Selectin, are Risk Factors for the First Asymptomatic Deep Vein Thrombosis in Cancer Patients Undergoing Chemotherapy

10.21203/rs.3.rs-34208/v4 ◽

2020 ◽

Author(s):

Budi Setiawan ◽

Cecilia Oktaria Permatadewi ◽

Baringin de Samakto ◽

Ashar Bugis ◽

Ridho M. Naibaho ◽

...

Keyword(s):

Risk Factors ◽

Logistic Regression ◽

Deep Vein Thrombosis ◽

Cancer Patients ◽

Von Willebrand Factor ◽

Plasma Levels ◽

Vein Thrombosis ◽

Von Willebrand ◽

Deep Vein ◽

Willebrand Factor

Abstract Background There is a high incidence of deep vein thrombosis (DVT) among cancer patients undergoing chemotherapy. Chemotherapy-induced vascular endothelial cell activation (VECA) is characterized by increased plasma levels of von Willebrand factor (vWF) and soluble P-selectin (sP-selectin), leading to the activation of endothelial cells and signaling cascades. The biological role of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS-13) is to control the activity of vWF and consequently the risk of thrombosis. The objective of this study was to investigate the roles of sP-selectin, vWF, and ADAMTS-13 as risk factors for the first episode of DVT in cancer patients undergoing chemotherapy.Methods This prospective cohort study was conducted at Dr. Kariadi Hospital, Indonesia, on 40 cancer patients. Prechemotherapy (baseline) and postchemotherapy sP-selectin, vWF antigen (vWF:Ag), and ADAMTS-13 plasma levels were determined with ELISAs before and 3 months after chemotherapy. The clinical characteristics of the patients, cancer type, cancer stage, chemotherapy regimen, ABO blood type, D-dimer level and Khorana risk score were also analyzed using logistic regression. Patients were observed for the possibility of developing DVT during chemotherapy.Results DVT was confirmed in 5 patients (12.5%) after a period of 3 months. In patients with DVT, sP-selectin and vWF were significantly higher while ADAMTS-13 was lower than in their counterparts. The levels of baseline vWF:Ag and ADAMTS-13, with cut-off points ≥ 2.35 IU/mL and ≤ 1.03 IU/mL, respectively, were found to independently predict the incidence of DVT. In the multivariate logistic regression analysis, the relative risk (RR) for DVT in patients with high vWF:Ag was 3.80 (95% CI 1.15-12.48, p=0.028), and that for patients with low ADAMTS-13 was 2.67 (95% CI 1.22-23.82, p=0.005). The vWF:Ag/ADAMTS-13 ratio and both vWF:Ag and ADAMTS-13 dynamics during treatment were also able to differentiate those with prospective DVT. However, sP-selectin and other covariates showed no statistical significance.Conclusion We found that prechemotherapy plasma levels of vWF:Ag ≥ 2.35 IU/mL and ADAMTS-13 ≤ 1.03 IU/mL are independent risk factors for DVT incidence among cancer patients.

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Von Willebrand Factor:Antigen And Adamts-13 Level, But Not Soluble P-Selectin, Are Risk Factors For The First Asymptomatic Deep Vein Thrombosis In Cancer Patients Undergoing Chemotherapy

10.21203/rs.3.rs-34208/v2 ◽

2020 ◽

Author(s):

Budi Setiawan ◽

Cecilia Oktaria Permatadewi ◽

Baringin de Samakto ◽

Ashar Bugis ◽

Ridho M. Naibaho ◽

...

Keyword(s):

Risk Factors ◽

Deep Vein Thrombosis ◽

Cancer Patients ◽

Logistic Regression Model ◽

Everyday Clinical Practice ◽

Vein Thrombosis ◽

Patients With Cancer ◽

Chemotherapy Induction ◽

Von Willebrand ◽

Deep Vein

Abstract METHODS: We measured sP-selectin, vWF:Ag and ADAMTS-13 levels at baseline RESULTS: Forty patients with cancer were included in the study, all were recuited before their first chemotherapy induction. vWF:Ag and ADAMTS-13 were significantly associated with cancer chemotherapy accounting to increased RR for first asymptomatic DVT in the logistic regression model.CONCLUSIONS: Further research is needed to determine whether incorporating vWF:Ag and ADAMTS-13 levels wil find use in everyday clinical practice. Once validated, these results may specify particular cancer patients to be treated with prophylactic anticoagulant.

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Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis

The Lancet ◽

10.1016/s0140-6736(95)90166-3 ◽

1995 ◽

Vol 345 (8943) ◽

pp. 152-155 ◽

Cited By ~ 715

Author(s):

T. Koster ◽

J.P. Vandenbroucke ◽

F.R. Rosendaal ◽

E. Briët ◽

F.R. Rosendaal ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Factor Viii ◽

Von Willebrand Factor ◽

Clotting Factor ◽

Vein Thrombosis ◽

Von Willebrand ◽

Deep Vein ◽

Willebrand Factor

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Clinical Evaluation for the Role of High-Sensitivity C-Reactive Protein in Combination with D-Dimer and Wells Score Probability Test to Predict the Incidence of Deep Vein Thrombosis Among Cancer Patients

International Journal of General Medicine ◽

10.2147/ijgm.s261718 ◽

2020 ◽

Vol Volume 13 ◽

pp. 587-594

Author(s):

Budi Setiawan ◽

Rosalina Rosalina ◽

Eko Adhi Pangarsa ◽

Damai Santosa ◽

Catharina Suharti

Keyword(s):

Deep Vein Thrombosis ◽

Cancer Patients ◽

High Sensitivity ◽

C Reactive Protein ◽

Vein Thrombosis ◽

Reactive Protein ◽

Wells Score ◽

Deep Vein ◽

D Dimer

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Synergic effect of GPIBA and von Willebrand factor in pathogenesis of deep vein thrombosis

Vascular ◽

10.1177/1708538119896446 ◽

2020 ◽

Vol 28 (3) ◽

pp. 309-313

Author(s):

Da Li ◽

Xiaosong Zhang ◽

Honggang Zhang ◽

Xiaoqiang Li

Keyword(s):

Cardiovascular Disease ◽

Deep Vein Thrombosis ◽

Membrane Protein ◽

Von Willebrand Factor ◽

Integrin Subunit ◽

Dynamic Changes ◽

Vein Thrombosis ◽

Von Willebrand ◽

Deep Vein ◽

Willebrand Factor

Objectives In cardiovascular disease, deep vein thrombosis is one of the vital symptoms causing pulmonary thromboembolism. However, the pathogenesis of deep vein thrombosis is still not clear. One of the critical factors leading to deep vein thrombosis is the platelet aggregation that is mediated by a set of key genes including platelet membrane protein coded by platelet glycoprotein Ib alpha chain (GPIBA). Methods Deep vein thrombosis model was established according to the previous protocol, and venous blood and thrombi were collected for further analysis. Results The dynamic changes of GPIBA and coagulation factor, von Willebrand factor, were observed in deep vein thrombosis models. Meanwhile, critical proteins participating in adhesion and binding of platelets such as epithelial membrane protein 2 (EMP2), vascular cell adhesion protein 1 (VCAM1), immunoreceptor tyrosine-based activation motif 1 (ITAM1), integrin subunit alpha M (ITGAM), or fibronectin were also differentially expressed in deep vein thrombosis models. Conclusions Application of heparin could reverse these dynamic changes in deep vein thrombosis models. Thus, we explained the potential synergic role of GPIBA and von Willebrand factor in regulating the occurrence of deep vein thrombosis and provide therapeutic target against cardiovascular disease.

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Abstract 522: Activated FXI Regulates the Catalytic Activity of Adamts13 by Removing the CUB Domains

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.522 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Cristina Puy ◽

Kathleen S Garland ◽

Toshiaki Shirai ◽

Stephanie E. Reitsma ◽

Jevgenia Zilberman-Rudenko ◽

...

Keyword(s):

Thrombus Formation ◽

Adamts13 Activity ◽

Binding Interaction ◽

Vein Thrombosis ◽

Cub Domain ◽

A Cell ◽

Von Willebrand ◽

Deep Vein ◽

Willebrand Factor

Background: ADAMTS13 cleaves and inactivates von Willebrand factor (VWF), which binds collagen, facilitating platelet adhesion under vascular injury. But is still uncertain how ADAMTS13 activity is regulated. Thrombin and plasmin have been shown to cleave ADAMTS13. Based on the fact that elevated levels of FXI is an independent risk factor for deep vein thrombosis and ischemic stroke, we hypothesize that FXIa inactivates ADAMTS13 leading to platelet aggregation and thrombus formation. Aim: To determine the functional role of inactivation of ADAMTS13 by FXIa. Methods and Results: Recombinant ADAMTS13 (250 nM) was incubated with FXIa (50 nM) for increasing times (0-3 hours) at 37 o C before being analyzed by western blot using an anti-ADAMTS13 antibody against the two CUB domains (C-terminal) or against the metalloproteinase (MET) domain (N-terminal). Our results show that FXIa caused the disappearance of the ADAMTS13 band (~200 kDa) and the appearance of a band at ~150 kDa when the samples were analyzed with the anti-MET antibody and a ~50 kDa band when the samples were analyzed with the anti-CUB antibody. The presence of aprotinin, which inhibits FXIa activity, blocked the degradation of ADAMTS13. Kallikrein or FXIIa were unable to cleave ADAMTS13. Using a cell surface immunoassay we observed that after incubation with FXIa, the detection of the CUB domain from ADAMTS13 was lost from endothelial cells surface. The incubation of ADAMTS13 with FXIa caused an increase in ADAMTS13 activity as measured by a fluorogenic substrate (FRETS). Conclusion: ADAMTS13 circulates in a closed conformation, which is maintained by a CUB-spacer domain binding interaction. ADAMTS13 becomes conformationally activated through interaction of its CUBs domains with VWF. Here we show that FXIa-mediated deletion of ADAMTS13-CUB domains enhances its capacity to cleave FRETS and blocks the interaction with VWF. Our results suggest that FXIa may limit ADAMTS13-mediated VWF inactivation.

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Thromboinflammation and Vascular Dysfunction

Hämostaseologie ◽

10.1055/s-0038-1676130 ◽

2018 ◽

Vol 39 (02) ◽

pp. 180-187 ◽

Cited By ~ 2

Author(s):

Susanne Karbach ◽

Jérémy Lagrange ◽

Philip Wenzel

Keyword(s):

Risk Factors ◽

Immune Response ◽

Deep Vein Thrombosis ◽

Vascular Dysfunction ◽

Adaptive Immune Response ◽

The Novel ◽

Vein Thrombosis ◽

Adaptive Immune ◽

Deep Vein

AbstractThromboinflammation and vascular dysfunction are inseparably combined with the innate and the adaptive immune response. While the role of this interplay has gained considerable attention in the arena of atherosclerosis/atherothrombosis and in deep vein thrombosis, its role in other forms of vascular disease and risk factors is currently emerging. In this brief review, we will focus on thromboinflammation with regard to cytokine signalling as well as on the novel role of a vascular coagulation-inflammatory circuit in arterial hypertension.

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