scholarly journals On the Role of Hemostasis Variables in Cardiometabolic Outcomes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4266-4266
Author(s):  
Alberto D. Lopez ◽  
Kanisha Patel ◽  
Vincent P. Diego ◽  
Marcio A. Almeida ◽  
John Blangero ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Endothelial Dysfunction ◽  
Von Willebrand Factor ◽  
Mexican American ◽  
Conflicts Of Interest ◽  
Hdl Cholesterol ◽  
Coagulation System ◽  
Low Hdl ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background: Hemostasis variables represent well-known pathogenic determinants of venous-thromboembolism and are hypothesized to influence risk for cardiometabolic outcomes (CMOs) by effecting susceptibility to vascular inflammation and/or endothelial dysfunction. Methods: We investigated in Mexican American (MA)-participants of the San Antonio Family Study the effects of 20 measured hemostasis variables on CMOs including type-2 diabetes (T2D), impaired-fasting glucose (IFG), insulin resistance (IR), hypertension, obesity based on sex-specific waist circumference (OBWC), low high-density lipoprotein (Low-HDL)-cholesterol, hypertriglyceridemia, and a heart distress (HD) variable comprised of history of heart attack and/or heart surgery. The hemostasis variables included PT, aPTT, TFPI, aPC-ratio, fibrinogen, von Willebrand Factor (VWF), ADAMST-13, D-dimer, fPS, tPS, plasminogen, and factor (F)II, FV, FVII, FVIII, FX, FXI, and FXII of the coagulation system. We used a backward stepwise-regression selection approach to identify the preliminary sets of hemostasis predictors. Results: Our final regression models consisted of the final set of hemostasis variables while accounting for age and sex as covariates. For the T2D, IFG, and HD outcomes, VWF was the only significant hemostasis predictor (p<0.05). In each case, VWF was positively associated with the outcome. The hemostasis variable fibrinogen was a significant positive predictor for the IR, OBWC, and Low-HDL-cholesterol outcomes (p<0.05). For OBWC, FV was an additional significant positive predictor (p<0.05). Finally, no hemostasis variables significantly predicted hypertension or hypertriglyceridemia. Conclusions: Our results demonstrate that, among the MA-population, all measured CMOs-except hypertension and hypertriglyceridemia-are significantly influenced by individual-variability in several hemostasis parameters with most important predictors being VWF and fibrinogen. Keywords: Hemostasis; Venous-thromboembolism; Cardiovascular diseases/disorders; Metabolic syndrome; Inflammation; Endothelial dysfunction; Mexican American; Coagulation factors; von Willebrand Factor; and Fibrinogen Disclosures No relevant conflicts of interest to declare.

Combined effects of plasma von Willebrand factor and platelet measures on the risk of incident venous thromboembolism

Blood ◽  
2021 ◽  
Author(s):  
Magnus Sandvik Edvardsen ◽  
Ellen-Sofie Hansen ◽  
Kristian Hindberg ◽  
Vânia Maris Morelli ◽  
Thor Ueland ◽  
...  
Keyword(s):  
Platelet Count ◽  
Venous Thromboembolism ◽  
Von Willebrand Factor ◽  
Platelet Reactivity ◽  
High Plasma ◽  
Combined Effects ◽  
Exposure Group ◽  
Increased Risk ◽  
Von Willebrand ◽  
Willebrand Factor

Plasma von Willebrand factor (VWF) and platelet reactivity are both risk factors for venous thromboembolism (VTE), and VWF can promote hemostasis by interaction with platelets. In this study, we explored the combined effects of plasma VWF and platelet measures on the risk of incident VTE. A population-based nested case-control study with 403 cases and 816 controls was derived from the Tromsø Study. VWF, platelet count and mean platelet volume (MPV) were measured in blood samples drawn at baseline. Odds ratios (ORs) with 95% confidence intervals (CIs) for VTE were estimated across VWF tertiles, within predefined MPV (<8.5, 8.5-9.5, ≥9.5 fL) and platelet count (<230, 230-299, ≥300·109 L-1) strata. Here, participants with VWF levels in the highest tertile and MPV ≥9.5 fL had an OR of 1.98 (95% CI 1.17-3.36) for VTE compared with those in the lowest VWF tertile and with MPV <8.5 fL in the age- and sex-adjusted model. In the joint exposure group, 48% (95% CI 15% to 96%) of VTEs were attributable to the biological interaction between VWF and MPV. Similarly, individuals with VWF in the highest tertile and platelet count ≥300·109 L-1 had an OR of 2.91 (95% CI 1.49-5.67) compared with those with VWF in the lowest tertile and platelet count <230, and 39% (95% CI -2% to 97%) of VTEs in the joint exposure group were explained by the interaction. Our results suggest that both platelet reactivity and platelet count interact biologically with high plasma VWF, resulting in an increased risk of incident VTE.

scholarly journals Von Willebrand Factor, Factor VIII, and Other Acute Phase Reactants as Biomarkers of Inflammation and Endothelial Dysfunction in Chronic Graft-Versus-Host Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Antonela Lelas ◽  
Hildegard Theresia Greinix ◽  
Daniel Wolff ◽  
Günther Eissner ◽  
Steven Zivko Pavletic ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Factor Viii ◽  
Acute Phase ◽  
Von Willebrand Factor ◽  
Graft Versus Host Disease ◽  
Acute Phase Reactants ◽  
Graft Versus Host ◽  
Immune Mediated ◽  
Von Willebrand ◽  
Willebrand Factor

Chronic graft-versus-host disease (cGvHD) is an immune mediated late complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). Discovery of adequate biomarkers could identify high-risk patients and provide an effective pre-emptive intervention or early modification of therapeutic strategy, thus reducing prevalence and severity of the disease among long-term survivors of alloHSCT. Inflammation, endothelial injury, and endothelial dysfunction are involved in cGvHD development. Altered levels of acute phase reactants have shown a strong correlation with the activity of several immune mediated disorders and are routinely used in clinical practice. Since elevated von Willebrand factor (VWF) and factor VIII (FVIII) levels have been described as acute phase reactants that may indicate endothelial dysfunction and inflammation in different settings, including chronic autoimmune diseases, they could serve as potential candidate biomarkers of cGvHD. In this review we focused on reported data regarding VWF and FVIII as well as other markers of inflammation and endothelial dysfunction, evaluating their potential role in cGvHD.

von Willebrand Factor and Venous Thromboembolism: Pathogenic Link and Therapeutic Implications

2017 ◽  
Vol 44 (03) ◽  
pp. 249-260 ◽  
Author(s):  
Paolo Calabrò ◽  
Felice Gragnano ◽  
Enrica Golia ◽  
Erik Grove
Keyword(s):  
Venous Thromboembolism ◽  
Venous Thrombosis ◽  
Von Willebrand Factor ◽  
Gene Mutations ◽  
Selective Inhibition ◽  
Therapeutic Implications ◽  
Vein Thrombosis ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractVenous thromboembolism (VTE) is a frequent cause of disability and mortality worldwide. Von Willebrand factor (VWF) is a major determinant of hemostasis and clot formation, in both arteries and veins. Although VWF is mainly known for its role in arterial thrombosis, several studies suggest a pathogenic role for VWF and its regulator ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in venous thrombosis. Nongenetic and genetic factors, including gene mutations and polymorphisms, aging, hormone status, ABO blood groups, and systemic inflammation, have been involved in the modulation of both VTE predisposition and plasma levels of VWF. In several clinical settings, including inflammatory disease and cancer, VWF and ADAMTS-13 are currently investigated as possible determinants of vein thrombosis. These data indicate VWF as a potential therapeutic target in the management of VTE. Several studies report unselective antagonism of VWF for drugs used in daily clinical practice, including heparin and statins. Selective inhibition of VWF pathway has recently been tested in animal models of arterial and venous thrombosis as a novel therapeutic strategy to prevent platelet aggregation and thrombosis, promote vein lumen recanalization, and improve vein valve competency with excellent safety profile. In this review, we summarize the role of VWF in VTE, focusing on clinical and potential therapeutic implications.

scholarly journals von Willebrand Factor and Its Propeptide in Children with Diabetes. Relation between Endothelial Dysfunction and Microalbuminuria

2003 ◽  
Vol 53 (3) ◽  
pp. 382-386 ◽  
Author(s):  
Alberto Verrotti ◽  
Rita Greco ◽  
Fania Basciani ◽  
Guido Morgese ◽  
Francesco Chiarelli
Keyword(s):  
Endothelial Dysfunction ◽  
Von Willebrand Factor ◽  
Von Willebrand ◽  
Willebrand Factor

The Interaction of Von Willebrand Factor with GPIb-IX Initiates Platelet Apoptosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3002-3002
Author(s):  
Suping Li ◽  
Zhicheng Wang ◽  
Yi Liao ◽  
Guanglei Liu ◽  
Weilin Zhang ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Intracellular Signaling ◽  
Conflicts Of Interest ◽  
Cytoplasmic Domain ◽  
Shear Stresses ◽  
Apoptotic Signaling ◽  
Platelet Apoptosis ◽  
Signaling Events ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Abstract 3002 Poster Board II-979 Background: The interaction of glycoprotein (GP) Ibalpha with von Willebrand factor (VWF) initiates the adherence of platelets to sites of vascular injury, simultaneously triggers intracellular signaling events such as elevation of cytoplasmic calcium and activations of multiple protein kinase pathways which result in the activation of the ligand binding function of GPIIb/IIIa, leading to platelet activation and thrombus formation. The intracellular signaling protein 14-3-3ζ and the membrane skeleton protein filamin A have been confirmed to interact with the intracellular domain of GPIbalpha and play important roles in the regulation of platelet function. The signaling events elicited by GPIbalpha-VWF interaction, such as calcium mobilization and phosphatidylserine (PS) exposure are similar to those occurring during apoptosis. Particularly, the 14-3-3ζ binding domain of GPIbalpha has been reported to involve in the regulation of cell proliferations. However, it is still unclear whether the GPIbalpha-VWF interaction induces platelet apoptosis. Objectives: To investigate whether the GPIbalpha-VWF interaction induces platelet apoptosis and the role of 14-3-3ζ in apoptotic signaling. Methods: Apoptotic events were assessed in platelets or Chinese hamster ovary (CHO) cells expressing GPIb-IX (1b9) interacted with VWF by flow cytometry or Western blotting. Results: Ristocetin induced GPIbalpha-VWF interaction elicited apoptotic events in platelets, including phosphatidylserine exposure, elevations of Bax and Bak, gelsolin cleavage, and depolarization of mitochondrial inner transmembrane potential. Apoptotic events were also elicited in platelets exposed to pathologic shear stresses in the presence of VWF, however, the shear-induced apoptosis was eliminated by anti-GPIbalpha antibody AK-2. Furthermore, apoptotic events occurred in 1b9 cells stimulated with VWF and ristocetin, but were significantly diminished in two CHO cell lines expressing mutant GPIb-IX with truncation of the cytoplasmic domain of GPIbalpha or a serine-to-alanine mutation at 14-3-3ζ binding site in GPIbalpha. Conclusions: This study demonstrates that the GPIbalpha-VWF interaction induces apoptotic events in platelets and association of 14-3-3ζ with the cytoplasmic domain of GPIbalpha is essential for apoptotic signaling. The finding may suggest a novel mechanism for platelet clearance or some thrombocytopenic diseases. The reagents that block 14-3-3ζ-GPIbalpha interaction might be potentially useful in platelet storage or anti-thrombocytopenia. Disclosures: No relevant conflicts of interest to declare.

Association of Quantitative and Qualitative Abnormalities of Von Willebrand Factor and Risk of Death In Hemodialysis Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2217-2217
Author(s):  
Rachel Holden ◽  
Angie Tuttle ◽  
Francis MacLeod ◽  
Toni Burbidge ◽  
Carol Hegadorn ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Disease ◽  
Von Willebrand Factor ◽  
Functional Activity ◽  
Conflicts Of Interest ◽  
Proteolytic Processing ◽  
Risk Of Death ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Abstract 2217 In order to evaluate the possible role of abnormalities of von Willebrand factor in the hemostatic defects seen in indivdiuals with chronic kidney disease (CKD), a cohort study was performed evaluating pre- and post-dialysis levels of von Willebrand factor (VWF), VWF multimer profiles and levels of its cleaving protease, ADAMTS-13. There were 57 subjects (31 males, 26 females) enrolled with CKD with a mean age of 75 years (range 60 – 90). Subjects with known vascular disease were recruited; 49 (86%) had documented ischemic heart disease, 16 (29%) had cerebrovascular disease and 17 (31%) had peripheral vascular disease. A little over half had diabetes mellitus (30 subjects or 54%), 37 (67%) were on antiplatelet therapy and 7 (13%) were chronically anticoagulated with warfarin. Blood samples were drawn immediately pre- and again post-dialysis and all results were compared with a group of age-matched normal controls (Table 1). As has been previously reported, VWF antigen levels (VWF:Ag) and VWF functional activity as measured by the ristocetin cofactor assay (VWF:RCo) were higher in the pre-dialysis samples compared with controls, and both levels were increased even further following dialysis. Additionally, the percentage of high molecular weight VWF multimers (% HMWM) were significantly increased in the pre-dialysis samples compared with controls. This is a novel finding, and the level of % HMWM seen in the subjects is similar to what has been reported in individuals with Thrombotic Thrombocytopenic Purpura (TTP). This difference decreased following dialysis, potentially due to the effect of shear stress on VWF and the resultant proteolytic processing, however still remained significantly higher when compared with controls. ADAMTS-13 functional activity was lower in the subjects compared with controls, providing a possibly explanation for the increase in % HMWM. IL-6 levels are higher in subjects compared with controls. IL-6, which is an inflammatory cytokine known to be increased in patients with CKD, has been previously reported as a marker of inactivation of ADAMTS-13. Two years after enrollment, follow up of the subjects revealed that 22 had died, 17 from documented cardiovascular events. Higher VWF levels at the time of enrollment significantly correlated with risk of death (p=0.041) during the study period. The increase in % HMWM suggests that a “TTP-like phenotype” may also be playing a role. Taken together, these data suggest that both quantitative and qualitative abnormalities of VWF contribute to the risk of thrombotic death in chronic kidney disease. Disclosures: No relevant conflicts of interest to declare.

ADAMTS13 In 4 Different VWF/VIII Concentrates and Its Impact on Therapy.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3677-3677
Author(s):  
Mirjeta Qorraj ◽  
Tanja Falter ◽  
Sarah Steinemann ◽  
Thomas Vigh ◽  
Inge Scharrer
Keyword(s):  
Von Willebrand Factor ◽  
Gel Electrophoresis ◽  
Conflicts Of Interest ◽  
Von Willebrand Disease ◽  
Relative Reduction ◽  
Hemorrhagic Diathesis ◽  
Adamts13 Activity ◽  
Kinetic Measurements ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Abstract 3677 Introduction: The hemostatic activity of von Willebrand Factor (VWF) is mainly controlled by the plasma metalloprotease ADAMTS13, which cleaves ultralarge VWF multimers. A qualitative or quantitative deficiency of VWF induces the most common hemorrhagic diathesis, the von Willebrand Disease (VWD). The current classification graduates the VWD in three major types. Depending on severity and the type of VWD the treatment with VWF/FVIII concentrates may by necessary. The commercially available VWF/FVIII concentrates differ in their multimer structure and furthermore also in their pharmacokinetics. We investigated commercial VWF concentrates with respect to their ADAMTS 13 activity and antigen levels with the newest available methods. Moreover, to detect a possible correlation, we analysed the VWF multimer structure of the concentrates. Methods: We analysed 4 human derived VWF/VIII-concentrates (over all 7charges) after reconstitution according to the manufacturer's instructions in different dilutions. Following methods were used: BCS Method according to Böhm detects the capacity of the concentrates for autoproteolysis. The VWF solutions were diluted with 5mol/l urea and then incubated for 14–16h at 37°C in low ionic TRIS buffer containing BaCl2 and different plasma samples: pool plasma; plasma from patients with TTP with neutralizing ADAMTS13 auto-antibodies; plasma from patients with TTP without auto-antibodies. The residual VWF:Ristocetin Cofactor (VWF:RCo) activity was subsequently measured using the BC von Willebrand Reagent from Dade Behring. ELISA Technozym®ADAMTS13 and Actifluor TM ADAMTS13 are based on the kinetic measurements of the activity with fluorescence resonance energy transfer (FRET). ADAMTS13 antigen was measured by use of the Technozym ELISA kit. SDS-Gel electrophoresis in 1% Agarose Gel was used to investigate the structure of VWF multimers. Results: The BCS Method according to Böhm is an indirect measurement for endogenous ADAMTS13 activity in the investigated concentrate. Important is the loss of the residual VWF:RCo in the concentrates in presence of TTP-plasma without antibodies and pool plasma compared to the residual VWF:RCo in presence of TTP-plasma with antibodies. All concentrates show some ADAMTS13 activity, however product 1 contains more ADAMTS13 than the other concentrates. The results of the two FRETS-assays correspond very well to the BCS-method results; in addition the assays detect directly the ADAMTS13 activity also in very low measurement range. In a dilution of 16U VWF per ml concentrate the ADAMTS13 activity in product 1 with 4.3% was the highest compared to product 2: 3.2%, product 3: 2.6% and product 4: 2%. The great variability of the test results in higher concentrations may be caused by interferences between some constituents of the concentrates and the analysis. In the same sample set and dilution the ADAMTS13 antigen values correlate very well with ADAMTS13 activity values. The SDS gel electrophoresis reveals the different VWF structure of product1; it has less large and ultralarge multimers. There could be a correlation to the relatively higher ADAMTS13 activity and antigen level. Conclusion: All the investigated VWF/VIII concentrates contain some ADAMTS13 activity and antigen. This was found especially by FRETs assay due to the high sensitivity. Because of the correlation between ADAMTS13 activity and modified VWF multimer structure we like to conclude that ADAMTS13 has influence on stability and therefore also on quality of the concentrates. This might have a therapeutic consequence especially for VWD type 2A. Type 2A is characterized by a relative reduction of intermediate and large VWF multimer. The multimeric abnormalities are commonly the result of in vivo proteolytic degradation of the von Willebrand factor caused by ADAMTS13. Disclosures: No relevant conflicts of interest to declare.

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