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Heparin-functionalized polymer graft surface eluting MK2 inhibitory peptide to improve hemocompatibility and anti-neointimal activity.
Lee Y, Le Thi P, Seon GM, Ryu SB, Brophy CM, Kim Y, Park JC, Park KD, Cheung-Flynn J, Sung HJ
(2017) J Control Release 266: 321-330
MeSH Terms: Animals, Anticoagulants, Cell Movement, Cell Proliferation, Heparin, Humans, Myocytes, Smooth Muscle, Neointima, Peptides, Platelet Adhesiveness, Polyesters, Rats, Sprague-Dawley, Saphenous Vein, Thrombosis
Show Abstract · Added May 22, 2018
The leading cause of synthetic graft failure includes thrombotic occlusion and intimal hyperplasia at the site of vascular anastomosis. Herein, we report a co-immobilization strategy of heparin and potent anti-neointimal drug (Mitogen Activated Protein Kinase II inhibitory peptide; MK2i) by using a tyrosinase-catalyzed oxidative reaction for preventing thrombotic occlusion and neointimal formation of synthetic vascular grafts. The binding of heparin-tyramine polymer (HT) onto the polycarprolactone (PCL) surface enhanced blood compatibility with significantly reduced protein absorption (64.7% decrease) and platelet adhesion (85.6% decrease) compared to bare PCL surface. When loading MK2i, 1) the HT depot surface gained high MK2i-loading efficiency through charge-charge interaction, and 2) this depot platform enabled long-term, controlled release over 4weeks (92-272μg/mL of MK2i). The released MK2i showed significant inhibitory effects on VSMC migration through down-regulated phosphorylation of target proteins (HSP27 and CREB) associated with intimal hyperplasia. In addition, it was found that the released MK2i infiltrated into the tissue with a cumulative manner in ex vivo human saphenous vein (HSV) model. This present study demonstrates that enzymatically HT-coated surface modification is an effective strategy to induce long-term MK2i release as well as hemocompatibility, thereby improving anti-neointimal activity of synthetic vascular grafts.
Copyright © 2017 Elsevier B.V. All rights reserved.
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14 MeSH Terms
Clinical Risk Assessment in the Antiphospholipid Syndrome: Current Landscape and Emerging Biomarkers.
Chaturvedi S, McCrae KR
(2017) Curr Rheumatol Rep 19: 43
MeSH Terms: Antibodies, Antiphospholipid, Antiphospholipid Syndrome, Autoantibodies, Biomarkers, Humans, Risk Assessment, Risk Factors, Thrombosis
Show Abstract · Added July 17, 2017
PURPOSE OF REVIEW - Laboratory criteria for the classification of antiphospholipid syndrome include the detection of a lupus anticoagulant and/or anticardiolipin and anti-β2-glycoprotein I antibodies. However, the majority of patients who test positive in these assays do not have thrombosis. Current risk-stratification tools are largely limited to the antiphospholipid antibody profile and traditional thrombotic risk factors.
RECENT FINDINGS - Novel biomarkers that correlate with disease activity and potentially provide insight into future clinical events include domain 1 specific anti-βGPI antibodies, antibodies to other phospholipids or phospholipid/protein antigens (such as anti-PS/PT), and functional/biological assays such as thrombin generation, complement activation, levels of circulating microparticles, and annexin A5 resistance. Clinical risk scores may also have value in predicting clinical events. Biomarkers that predict thrombosis risk in patients with antiphospholipid antibodies have been long sought, and several biomarkers have been proposed. Ultimately, integration of biomarkers with established assays and clinical characteristics may offer the best chance of identifying patients at highest risk of APS-related complications.
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8 MeSH Terms
Cardiovascular and Thrombotic Complications of Novel Multiple Myeloma Therapies: A Review.
Li W, Garcia D, Cornell RF, Gailani D, Laubach J, Maglio ME, Richardson PG, Moslehi J
(2017) JAMA Oncol 3: 980-988
MeSH Terms: Antineoplastic Agents, Cardiovascular Diseases, Humans, Immunologic Factors, Lenalidomide, Multiple Myeloma, Proteasome Inhibitors, Risk Factors, Thalidomide, Thromboembolism, Thrombosis
Show Abstract · Added March 26, 2017
Importance - Multiple myeloma (MM) is the second most common hematological malignant abnormality. The introduction of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) has greatly improved the overall survival of patients with MM. Prevention and treatment of cardiovascular and thrombotic issues associated with novel MM therapies have emerged as important aspects of supportive care in patients with MM.
Observations - We searched PubMed and the Cochrance database for studies published from March 2001 to January 2016. Emerging evidence suggests that both IMiDs and PIs can have cardiovascular (CV) sequelae, which include thromboembolic complications, cardiac, and vascular toxic effects. These complications occur against the backdrop of a high prevalence of CV disease in the MM population as well as the adverse cardiac and vascular effects of MM itself.
Conclusions and Relevance - This review provides an overview of the incidences, clinical presentations, and mechanisms of CV complications in the MM population. We conclude that more research is needed for better screening and preventive strategies to abrogate these toxic effects and improve patient care.
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11 MeSH Terms
First Implantation of Silicon Nanopore Membrane Hemofilters.
Kensinger C, Karp S, Kant R, Chui BW, Goldman K, Yeager T, Gould ER, Buck A, Laneve DC, Groszek JJ, Roy S, Fissell WH
(2016) ASAIO J 62: 491-5
MeSH Terms: Animals, Dogs, Hemofiltration, Humans, Membranes, Artificial, Nanopores, Pilot Projects, Silicon, Thrombosis
Show Abstract · Added April 11, 2016
An implantable hemofilter for the treatment of kidney failure depends critically on the transport characteristics of the membrane and the biocompatibility of the membrane, cartridge, and blood conduits. A novel membrane with slit-shaped pores optimizes the trade-off between permeability and selectivity, enabling implanted therapy. Sustained (3-8) day function of an implanted parallel-plate hemofilter with minimal anticoagulation was achieved by considering biocompatibility at the subnanometer scale of chemical interactions and the millimeter scale of blood fluid dynamics. A total of 400 nm-thick polysilicon flat sheet membranes with 5-8 nm × 2 micron slit-shaped pores were surface-modified with polyethylene glycol. Hemofilter cartridge geometries were refined based on computational fluid dynamics models of blood flow. In an uncontrolled pilot study, silicon filters were implanted in six class A dogs. Cartridges were connected to the cardiovascular system by anastamoses to the aorta and inferior vena cava and filtrate was drained to collection pouches positioned in the peritoneum. Pain medicine and acetylsalicylic acid were administered twice daily until the hemofilters were harvested on postoperative days 3 (n = 2), 4 (n = 2), 5 (n = 1), and 8 (n = 1). No hemofilters were thrombosed. Animals treated for 5 and 8 days had microscopic fractures in the silicon nanopore membranes and 20-50 ml of transudative (albumin sieving coefficient θalb ~ 0.5 - 0.7) fluid in the collection pouches at the time of explant. Shorter experimental durations (3-4 days) resulted in filtration volumes similar to predictions based on mean arterial pressures and membrane hydraulic permeability and (θalb ~ 0.2 - 0.3), similar to preimplantation measurements. In conclusion, a detailed mechanistic and materials science attention to blood-material interactions allows implanted hemofilters to resist thrombosis. Additional testing is needed to determine optimal membrane characteristics and identify limiting factors in long-term implantation.
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9 MeSH Terms
The antiphospholipid syndrome: still an enigma.
Chaturvedi S, McCrae KR
(2015) Hematology Am Soc Hematol Educ Program 2015: 53-60
MeSH Terms: Administration, Oral, Antibodies, Antiphospholipid, Anticoagulants, Antiphospholipid Syndrome, Female, Heparin, Low-Molecular-Weight, Humans, Hydroxychloroquine, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Immune System, Inflammation, Lupus Coagulation Inhibitor, Pregnancy, Pregnancy Complications, Cardiovascular, Protein Binding, Protein Structure, Tertiary, Risk, Thrombosis, Treatment Outcome, beta 2-Glycoprotein I
Show Abstract · Added December 16, 2015
Antiphospholipid syndrome (APS) is defined by clinical manifestations that include thrombosis and/or fetal loss or pregnancy morbidity in patients with antiphospholipid antibodies (aPL). Antiphospholipid antibodies are among the most common causes of acquired thrombophilia, but unlike most of the genetic thrombophilias are associated with both venous and arterial thrombosis. Despite an abundance of clinical and basic research on aPL, a unified mechanism that explains their prothrombotic activity has not been defined; this may reflect the heterogeneity of aPL and/or the fact that they may influence multiple pro- and/or antithrombotic pathways. Antiphospholipid antibodies are directed primarily toward phospholipid binding proteins rather than phospholipid per se, with the most common antigenic target being β2-glycoprotein 1 (β2GPI) although antibodies against other targets such as prothrombin are well described. Laboratory diagnosis of aPL depends upon the detection of a lupus anticoagulant (LA), which prolongs phospholipid-dependent anticoagulation tests, and/or anticardiolipin and anti-β2-glycoprotein 1 antibodies. Indefinite anticoagulation remains the mainstay of therapy for thrombotic APS, although new strategies that may improve outcomes are emerging. Preliminary reports suggest caution in the use of direct oral anticoagulants in patients with APS-associated thrombosis. Based on somewhat limited evidence, aspirin and low molecular weight heparin are recommended for obstetrical APS. There remains a pressing need for better understanding of the pathogenesis of APS in humans, for identification of clinical and laboratory parameters that define patients at greatest risk for APS-related events, and for targeted treatment of this common yet enigmatic disorder.
© 2015 by The American Society of Hematology. All rights reserved.
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20 MeSH Terms
Effects of Acute and Antecedent Hypoglycemia on Endothelial Function and Markers of Atherothrombotic Balance in Healthy Humans.
Joy NG, Tate DB, Younk LM, Davis SN
(2015) Diabetes 64: 2571-80
MeSH Terms: Adult, Biomarkers, Blood Glucose, Endothelium, Vascular, Female, Fibrinolysis, Humans, Hypoglycemia, Inflammation, Male, Platelet Activation, Thrombosis
Show Abstract · Added July 30, 2015
The aim of this study was to determine the effects of single and repeated episodes of clamped hypoglycemia on fibrinolytic balance, proinflammatory biomarkers, proatherothrombotic mechanisms, and endothelial function. Twenty healthy individuals (12 male and 8 female) were studied during separate 2-day randomized protocols. Day 1 consisted of either two 2-h hyperinsulinemic (812 ± 50 pmol/L)-euglycemic (5 ± 0.1 mmol/L) or hyperinsulinemic (812 ± 50 pmol/L)-hypoglycemic (2.9 ± 0.1 mmol/L) clamps. Day 2 consisted of a single 2-h hyperinsulinemic-hypoglycemic clamp. Two-dimensional Doppler ultrasound was used to determine brachial arterial endothelial function. Plasminogen activator inhibitor 1, vascular cell adhesion molecule-1, intracellular adhesion molecule-1, E-selectin, P-selectin, TAT (thrombin/antithrombin complex), tumor necrosis factor-α, and interleukin-6 responses were increased (P < 0.05) during single or repeated hypoglycemia compared with euglycemia. Endogenous and exogenous nitric oxide (NO)-mediated vasodilation were both impaired by repeated hypoglycemia. Neuroendocrine and autonomic nervous system (ANS) responses were also blunted by repeated hypoglycemia (P < 0.05). In summary, acute moderate hypoglycemia impairs fibrinolytic balance; increases proinflammatory responses, platelet activation, and coagulation biomarkers; and reduces NO-mediated endothelial function in healthy individuals. Repeated episodes of hypoglycemia further impair vascular function by additionally reducing exogenously NO-mediated endothelial function and increasing coagulation biomarkers. We conclude that despite reduced neuroendocrine and ANS responses, antecedent hypoglycemia results in greater endothelial dysfunction and an increased proatherothrombotic state compared with a single acute episode of hypoglycemia.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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12 MeSH Terms
Inflammatory cytokine TSLP stimulates platelet secretion and potentiates platelet aggregation via a TSLPR-dependent PI3K/Akt signaling pathway.
Dong J, Dong J, Lin J, Wang B, He S, Wu C, Kushwaha KK, Mohabeer N, Su Y, Fang H, Huang K, Li D
(2015) Cell Physiol Biochem 35: 160-74
MeSH Terms: Androstadienes, Animals, Blood Platelets, Carotid Artery Thrombosis, Chlorides, Chromones, Cytokines, Disease Models, Animal, Ferric Compounds, Humans, Immunoglobulins, Mice, Mice, Inbred C57BL, Mice, Knockout, Morpholines, P-Selectin, Phosphatidylinositol 3-Kinases, Phosphorylation, Platelet Activation, Platelet Aggregation, Platelet Glycoprotein GPIIb-IIIa Complex, Proto-Oncogene Proteins c-akt, Receptors, Cytokine, Signal Transduction, Wortmannin
Show Abstract · Added January 20, 2015
AIMS - Thymic stromal lymphopoietin (TSLP) plays an important role in inflammatory diseases and is over-expressed in human atherosclerotic artery specimens. The present study investigated the role of TSLP in platelet activation and thrombosis models in vitro and in vivo, as well as the underlying mechanism and signaling pathway.
METHODS AND RESULTS - Western blotting and flow cytometry demonstrated that the TSLP receptor was expressed on murine platelets. According to flow cytometry, platelet stimulation with TSLP induced platelet degranulation and integrin αIIbβ3 activation. A TSLPR deficiency caused defective platelet aggregation, defective platelet secretion and markedly blunted thrombus growth in perfusion chambers at both low and high shear rates. TSLPR KO mice exhibited defective carotid artery thrombus formation after exposure to FeCl3. TSLP increased Akt phosphorylation, an effect that was abrogated by the PI3K inhibitors wortmannin and LY294002. The PI3K inhibitors further diminished TSLP-induced platelet activation. TSLP-mediated platelet degranulation, integrin αIIbβ3 activation and Akt phosphorylation were blunted in platelets that lacked the TSLP receptor.
CONCLUSION - This study demonstrated that the functional TSLPR was surface-expressed on murine platelets. The inflammatory cytokine TSLP triggered platelet activation and thrombus formation via TSLP-dependent PI3K/Akt signaling, which suggests an important role for TSLP in linking vascular inflammation and thrombo-occlusive diseases.
© 2015 S. Karger AG, Basel.
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25 MeSH Terms
Factor XI antisense oligonucleotide for prevention of venous thrombosis.
Büller HR, Bethune C, Bhanot S, Gailani D, Monia BP, Raskob GE, Segers A, Verhamme P, Weitz JI, FXI-ASO TKA Investigators
(2015) N Engl J Med 372: 232-40
MeSH Terms: Adult, Aged, Anticoagulants, Arthroplasty, Replacement, Knee, Blood Coagulation, Clinical Protocols, Enoxaparin, Factor XI, Female, Hemorrhage, Humans, Length of Stay, Male, Middle Aged, Oligonucleotides, Oligonucleotides, Antisense, Partial Thromboplastin Time, Postoperative Complications, Venous Thrombosis
Show Abstract · Added January 20, 2015
BACKGROUND - Experimental data indicate that reducing factor XI levels attenuates thrombosis without causing bleeding, but the role of factor XI in the prevention of postoperative venous thrombosis in humans is unknown. FXI-ASO (ISIS 416858) is a second-generation antisense oligonucleotide that specifically reduces factor XI levels. We compared the efficacy and safety of FXI-ASO with those of enoxaparin in patients undergoing total knee arthroplasty.
METHODS - In this open-label, parallel-group study, we randomly assigned 300 patients who were undergoing elective primary unilateral total knee arthroplasty to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily. The primary efficacy outcome was the incidence of venous thromboembolism (assessed by mandatory bilateral venography or report of symptomatic events). The principal safety outcome was major or clinically relevant nonmajor bleeding.
RESULTS - Around the time of surgery, the mean (±SE) factor XI levels were 0.38±0.01 units per milliliter in the 200-mg FXI-ASO group, 0.20±0.01 units per milliliter in the 300-mg FXI-ASO group, and 0.93±0.02 units per milliliter in the enoxaparin group. The primary efficacy outcome occurred in 36 of 134 patients (27%) who received the 200-mg dose of FXI-ASO and in 3 of 71 patients (4%) who received the 300-mg dose of FXI-ASO, as compared with 21 of 69 patients (30%) who received enoxaparin. The 200-mg regimen was noninferior, and the 300-mg regimen was superior, to enoxaparin (P<0.001). Bleeding occurred in 3%, 3%, and 8% of the patients in the three study groups, respectively.
CONCLUSIONS - This study showed that factor XI contributes to postoperative venous thromboembolism; reducing factor XI levels in patients undergoing elective primary unilateral total knee arthroplasty was an effective method for its prevention and appeared to be safe with respect to the risk of bleeding. (Funded by Isis Pharmaceuticals; FXI-ASO TKA ClinicalTrials.gov number, NCT01713361.).
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19 MeSH Terms
Circulating microparticles in patients with antiphospholipid antibodies: characterization and associations.
Chaturvedi S, Cockrell E, Espinola R, Hsi L, Fulton S, Khan M, Li L, Fonseca F, Kundu S, McCrae KR
(2015) Thromb Res 135: 102-8
MeSH Terms: Adult, Antibodies, Anticardiolipin, Antibodies, Antiphospholipid, Antigens, CD, Antiphospholipid Syndrome, Blood Platelets, Cadherins, Cell-Derived Microparticles, Endoglin, Endothelial Cells, Female, Flow Cytometry, Humans, Lipopolysaccharide Receptors, Male, Middle Aged, Partial Thromboplastin Time, Receptors, Cell Surface, Thromboplastin, Thrombosis, beta 2-Glycoprotein I
Show Abstract · Added August 1, 2015
The antiphospholipid syndrome is characterized by venous or arterial thrombosis and/or recurrent fetal loss in the presence of circulating antiphospholipid antibodies. These antibodies cause activation of endothelial and other cell types leading to the release of microparticles with procoagulant and pro-inflammatory properties. The aims of this study were to characterize the levels of endothelial cell, monocyte or platelet derived, and tissue factor-bearing microparticles in patients with antiphospholipid antibodies, to determine the association of circulating microparticles with anticardiolipin and anti-β2-glycoprotein antibodies, and to define the cellular origin of microparticles that express tissue factor. Microparticle content within citrated blood from 47 patients with antiphospholipid antibodies and 144 healthy controls was analyzed within 2hours of venipuncture. Levels of Annexin-V, CD105 and CD144 (endothelial derived), CD41 (platelet derived) and tissue factor positive microparticles were significantly higher in patients than controls. Though levels of CD14 (monocyte-derived) microparticles in patient plasma were not significantly increased, increased levels of CD14 and tissue factor positive microparticles were observed in patients. Levels of microparticles that stained for CD105 and CD144 showed a positive correlation with IgG (R=0.60, p=0.006) and IgM anti-beta2-glycoprotein I antibodies (R=0.58, p=0.006). The elevation of endothelial and platelet derived microparticles in patients with antiphospholipid antibodies and their correlation with anti-β2-glycoprotein I antibodies suggests a chronic state of vascular cell activation in these individuals and an important role for β2-glycoprotein I in development of the pro-thrombotic state associated with antiphospholipid antibodies.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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21 MeSH Terms
α2β1 integrin, GPVI receptor, and common FcRγ chain on mouse platelets mediate distinct responses to collagen in models of thrombosis.
Marjoram RJ, Li Z, He L, Tollefsen DM, Kunicki TJ, Dickeson SK, Santoro SA, Zutter MM
(2014) PLoS One 9: e114035
MeSH Terms: Animals, Blood Platelets, Collagen, Disease Models, Animal, Integrin alpha2beta1, Mice, Mice, Knockout, Platelet Activation, Platelet Membrane Glycoproteins, Rats, Receptors, IgG, Thrombosis
Show Abstract · Added February 12, 2015
OBJECTIVE - Platelets express the α2β1 integrin and the glycoprotein VI (GPVI)/FcRγ complex, both collagen receptors. Understanding platelet-collagen receptor function has been enhanced through use of genetically modified mouse models. Previous studies of GPVI/FcRγ-mediated collagen-induced platelet activation were perfomed with mice in which the FcRγ subunit was genetically deleted (FcRγ-/-) or the complex was depleted. The development of α2β1-/- and GPVI-/- mice permits side-by-side comparison to address contributions of these collagen receptors in vivo and in vitro.
APPROACH AND RESULTS - To understand the different roles played by the α2β1 integrin, the GPVI receptor or FcRγ subunit in collagen-stimulated hemostasis and thrombosis, we compared α2β1-/-, FcRγ-/-, and GPVI-/- mice in models of endothelial injury and intravascular thrombosis in vivo and their platelets in collagen-stimulated activation in vitro. We demonstrate that both the α2β1 integrin and the GPVI receptor, but not the FcRγ subunit influence carotid artery occlusion in vivo. In contrast, the GPVI receptor and the FcRγ chain, but not the α2β1 integrin, play similar roles in intravascular thrombosis in response to soluble Type I collagen. FcRγ-/- platelets showed less attenuation of tyrosine phosphorylation of several proteins including RhoGDI when compared to GPVI-/- and wild type platelets. The difference between FcRγ-/- and GPVI-/- platelet phosphotyrosine levels correlated with the in vivo thrombosis findings.
CONCLUSION - Our data demonstrate that genetic deletion of GPVI receptor, FcRγ chain, or the α2β1 integrin changes the thrombotic potentials of these platelets to collagen dependent on the stimulus mechanism. The data suggest that the FcRγ chain may provide a dominant negative effect through modulating signaling pathways in platelets involving several tyrosine phosphorylated proteins such as RhoGDI. In addition, these findings suggest a more complex signaling network downstream of the platelet collagen receptors than previously appreciated.
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12 MeSH Terms