scholarly journals Platelets and Matrix Metalloproteinases: A Bidirectional Interaction with Multiple Pathophysiologic Implications

2021 ◽  
Vol 41 (02) ◽  
pp. 136-145
Author(s):  
P. Gresele ◽  
E. Falcinelli ◽  
S. Momi ◽  
E. Petito ◽  
M. Sebastiano
Keyword(s):  
Matrix Metalloproteinases ◽  
Vessel Wall ◽  
Thrombus Formation ◽  
Cancer Development ◽  
Platelet Response ◽  
Therapeutic Approaches ◽  
Health And Disease ◽  
Neoplastic Disorders ◽  
Wall Injury ◽  
Pathogenic Effects

AbstractPlatelets contain and release several matrix metalloproteinases (MMPs), a highly conserved protein family with multiple functions in organism defense and repair. Platelet-released MMPs as well as MMPs generated by other cells within the cardiovascular system modulate platelet function in health and disease. In particular, a normal hemostatic platelet response to vessel wall injury may be transformed into pathological thrombus formation by platelet-released and/or by locally generated MMPs. However, it is becoming increasingly clear that platelets play a role not only in hemostasis but also in immune response, inflammation and allergy, atherosclerosis, and cancer development, and MMPs seem to contribute importantly to this role. A deeper understanding of these mechanisms may open the way to novel therapeutic approaches to the inhibition of their pathogenic effects and lead to significant advances in the treatment of cardiovascular, inflammatory, and neoplastic disorders.

Oxidative Stress and Atherosclerosis: Its Relationship to Growth Factors, Thrombus Formation and Therapeutic Approaches

1999 ◽  
Vol 82 (S 01) ◽  
pp. 32-37 ◽  
Author(s):  
Karlheinz Peter ◽  
Wolfgang Kübler ◽  
Johannes Ruef ◽  
Thomas K. Nordt ◽  
Marschall S. Runge ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Factors ◽  
Vessel Wall ◽  
Inflammatory Responses ◽  
Plaque Rupture ◽  
Thrombus Formation ◽  
Vascular Lesion ◽  
Coagulation System ◽  
Therapeutic Approaches ◽  
Causative Relationship

SummaryThe initiating event of atherogenesis is thought to be an injury to the vessel wall resulting in endothelial dysfunction. This is followed by key features of atherosclerotic plaque formation such as inflammatory responses, cell proliferation and remodeling of the vasculature, finally leading to vascular lesion formation, plaque rupture, thrombosis and tissue infarction. A causative relationship exists between these events and oxidative stress in the vessel wall. Besides leukocytes, vascular cells are a potent source of oxygen-derived free radicals. Oxidants exert mitogenic effects that are partially mediated through generation of growth factors. Mitogens, on the other hand, are potent stimulators of oxidant generation, indicating a putative self-perpetuating mechanism of atherogenesis. Oxidants influence the balance of the coagulation system towards platelet aggregation and thrombus formation. Therapeutic approaches by means of antioxidants are promising in both experimental and clinical designs. However, additional clinical trials are necessary to assess the role of antioxidants in cardiovascular disease.

Vessel Injury, Thrombosis And Platelet Survival

1981 ◽  
Author(s):  
P D Winocour ◽  
M Cattaneo ◽  
R L Kinlough-Rathbone ◽  
J F Mustard
Keyword(s):  
Vascular Disease ◽  
Vessel Wall ◽  
Thrombus Formation ◽  
Experimental Thrombosis ◽  
Platelet Survival ◽  
Vessel Injury ◽  
Wall Injury

In vascular disease it is unclear whether shortened platelet survival (PS) primarily reflects vessel injury or thrombosis. In rabbits and rats (4-6 animals per group) we examined the relations among experimental thrombosis, vessel wall injury and platelet survival and turnover. In rabbits preinjected with autologous 51Cr-platelets, a 20 cm intra-aortic-catheter in situ for 4 days resulted in a thrombus (mean wt. 23.4 mg). A significant amount of 51Cr was associated with the aorta (0.53 ± 0.13% of total 51cr circulating before surgery). PS was reduced (no catheter 62.4 ± 8.8; catheter 37.0 ± 5.6 hr, p<0.05). With a 10 cm catheter, thrombus wt. was similar (mean 24.0 mg). 51cr associated with the aorta was 0.25% ± 0.06% but PS was unaffected (no catheter 55.4 ± 6.8; catheter 53.8 ± 3.6 hr). In other experiments, sham-operated controls were compared with rabbits with 20 cm catheters. Mean thrombus wt. was 30.2 mg and 0.53 ± 0.11% of the 51cr was associated with the aorta. PS was significantly shorter in the catheter rabbits (36.7 ± 2.8 hr) vs sham-operated controls (68.0 ± 10.4 hr, pp<0.02); platelet turnover was significantly increased (14,500 ± 970 vs 9,950 ± 1,020 per mm3/hr, pp<0.01). Three groups of rats preinjected with homologous 51Icr- platelets were studied: a) sham-operated, b) aortic catheter 7.5 cm, c) aortic catheter 12.5 cm. No macroscopic thrombi were observed at any time during the 4 days that catheters were in situ. Mean PS was: a) 97.7 ± 2.4, b) 88.5 ± 2.6 and c) 63.7 ± 5.1 hr (pp<0.001, a vs c). Platelet turnover was a) 8,400 ± 720, b) 8,900 ± 870 and c) 11,000 ± 1,150 per mm3/hr. 51Cr associated with the aortae was a) 0.004 ± 0.001, b) 0.013 ± 0.006 and c) 0.027 ± 0.011% of total (pp<0.05, a vs c). Thus in rats, catheters shorten PS without thrombosis. Therefore, with catheter-induced vessel injury PS appears directly related to length of catheter and extent of injury. Shortened PS can occur without thrombus formation and thrombus formation can occur without changing PS or platelet turnover.

scholarly journals Endothelium-derived but not platelet-derived protein disulfide isomerase is required for thrombus formation in vivo

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4665-4674 ◽  
Author(s):  
Reema Jasuja ◽  
Bruce Furie ◽  
Barbara C. Furie
Keyword(s):  
Endothelial Cells ◽  
Protein Disulfide Isomerase ◽  
Vessel Wall ◽  
Thrombus Formation ◽  
In Vivo Studies ◽  
Disulfide Isomerase ◽  
Platelet Thrombus ◽  
Wall Injury ◽  
Protein Disulfide

Protein disulfide isomerase (PDI) catalyzes the oxidation reduction and isomerization of disulfide bonds. We have previously identified an important role for extracellular PDI during thrombus formation in vivo. Here, we show that endothelial cells are a critical cellular source of secreted PDI, important for fibrin generation and platelet accumulation in vivo. Functional PDI is rapidly secreted from human umbilical vein endothelial cells in culture upon activation with thrombin or after laser-induced stimulation. PDI is localized in different cellular compartments in activated and quiescent endothelial cells, and is redistributed to the plasma membrane after cell activation. In vivo studies using intravital microscopy show that PDI appears rapidly after laser-induced vessel wall injury, before the appearance of the platelet thrombus. If platelet thrombus formation is inhibited by the infusion of eptifibatide into the circulation, PDI is detected after vessel wall injury, and fibrin deposition is normal. Treatment of mice with a function blocking anti-PDI antibody completely inhibits fibrin generation in eptifibatide-treated mice. These results indicate that, although both platelets and endothelial cells secrete PDI after laser-induced injury, PDI from endothelial cells is required for fibrin generation in vivo.

Affinity-Purified Anti-Beta-2 Glycoprotein-1 Antibodies from a Patient with Lupus Anticoagulant-Associated Thrombosis Amplify Thrombus Formation in the Living Mouse.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 146-146
Author(s):  
Ariela Arad ◽  
Richard A Furie ◽  
Barbara C Furie ◽  
Bruce Furie
Keyword(s):  
Intravital Microscopy ◽  
Lupus Anticoagulant ◽  
Vessel Wall ◽  
Thrombus Formation ◽  
Dependent Manner ◽  
Human Igg ◽  
Normal Human ◽  
Platelet Thrombus ◽  
Beta 2 ◽  
Wall Injury

Abstract Abstract 146 Antiphospholipid syndrome (APS) is characterized by thrombosis, recurrent fetal loss and the presence of the lupus anticoagulant, anticardiolipin antibodies or anti-beta-2 glycoprotein 1 antibodies. Sera from patients with APS contain polyclonal antibodies that bind to various plasma proteins including beta-2 glycoprotein 1. Although beta-2 glycoprotein 1 antibodies have been well-documented as a biomarker for the diagnosis of APS, their direct role in the pathogenesis of thrombosis is unknown. Here, we have demonstrated using intravital microscopy that purified anti-beta-2 glycoprotein 1 antibodies isolated from the serum of a patient with APS greatly amplify thrombus size following laser-induced vessel wall injury in live mice. A patient with systemic lupus and APS complicated by pulmonary embolism was studied. IgG was isolated from serum by affinity chromatography using a Protein A/G column. Anti-beta-2 glycoprotein 1 antibodies in the IgG fraction were affinity-purified using homogeneous beta-2 glycoprotein 1 covalently bound to CNBr-activated agarose beads. Purified anti-beta-2 glycoprotein 1 antibodies were eluted at low pH. Patient IgG depleted of anti-beta-2 glycoprotein 1 antibodies was obtained by repeated chromatography over the beta-2 glycoprotein 1 column. The effects of (a) purified anti-beta-2 glycoprotein 1 antibodies, (b) anti-beta-2 glycoprotein 1 antibody-depleted patient IgG, and (c) IgG from normal human sera on thrombus formation were studied quantitatively in the live mouse. Intravital microscopy was performed using the cremaster muscle as a vascular window, and thrombus formation was initiated by laser injury to the arteriolar wall. Five minutes prior to vessel wall injury, purified anti-beta-2 glycoprotein 1 antibodies, anti-beta-2 glycoprotein 1 antibody-depleted patient IgG, or normal human IgG were infused via a jugular catheter. Platelet thrombus size was determined by widefield microscopy and Alexa 647-conjugated Fab fragments of an anti-CD 41 monoclonal antibody. Up to 10 thrombi were generated per mouse, and the median integrated fluorescence for 25-30 thrombi determined. Infusion of anti-beta-2 glycoprotein 1 antibodies increased thrombus size in a dose-dependent manner. Infusion of purified anti-beta-2 glycoprotein 1 antibodies at 0.12 μg/g mouse and 0.40 μg/g mouse increased thrombus size by about 18-fold and 122-fold respectively over thrombi formed in untreated mice. However, anti-beta-2 glycoprotein 1 antibody-depleted patient IgG and normal human IgG did not affect platelet thrombus size. These results indicate that the anti-beta-2 glycoprotein 1 antibodies isolated from APS patient serum are responsible for markedly increased thrombus size in this thrombosis model. The target cellular antigen of the anti-beta-2 glycoprotein 1 antibodies and the mechanism of enhanced thrombus formation remain unknown. However, these results provide evidence that anti-beta-2 glycoprotein 1 antibodies are not only a marker but are directly involved in the pathogenesis of thrombosis. This in vivo animal model offers an approach to identifying inhibitors of anti-beta-2 glycoprotein 1-mediated thrombosis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Both platelet- and endothelial cell–derived ERp5 support thrombus formation in a laser-induced mouse model of thrombosis

Blood ◽  
2015 ◽  
Vol 125 (14) ◽  
pp. 2276-2285 ◽  
Author(s):  
Freda H. Passam ◽  
Lin Lin ◽  
Srila Gopal ◽  
Jack D. Stopa ◽  
Lola Bellido-Martin ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Mouse Model ◽  
Vessel Wall ◽  
Thrombus Formation ◽  
Family Members ◽  
Key Points ◽  
Wall Injury

Key Points ERp5, like its family members PDI and ERp57, accumulates at sites of vessel wall injury. Both platelets and endothelium secrete ERp5 on activation and contribute ERp5 necessary for thrombus formation in vivo.

Inhibition of Platelet Recruitment to Arterial Lesions by Predeposition of Platelets Containing Encapsulated lloprost

1994 ◽  
Vol 72 (04) ◽  
pp. 604-610 ◽  
Author(s):  
George Pfliegler ◽  
Basiouny El-Gamal ◽  
Juan José Badimon ◽  
Lina Badimon ◽  
Neville Crawford
Keyword(s):  
Vessel Wall ◽  
Thrombus Formation ◽  
Blood Platelets ◽  
Inhibitory Effect ◽  
High Shear ◽  
Sustained Drug Release ◽  
Tunica Media ◽  
Reversible Electroporation ◽  
Significant Difference ◽  
Wall Injury

SummaryDrugs can be encapsulated within blood platelets by reversible electroporation and can be haemostatically targeted to vessel wall injury sites. Initial studies with iloprost-loaded pig platelets and pig aorta tunica media in perfusion circuits are presented. After autologous reconstitution into blood, no significant difference was observed in the deposition of 111Indium labelled sham-loaded and untreated platelets onto the tunica media during perfusion under low and high shear conditions. In paired experiments (n = 10 pairs), the deposition of iloprost-loaded platelets was significantly lower (mean 61%) after 5 min perfusion than the deposition from blood containing sham-loaded (control) platelets. A similar significant reduction (mean 54%) was seen after 10 min perfusion. Pre-perfusion of iloprost-loaded platelets for 10 min under low shear conditions (212/s), followed by 5 min perfusion of 111Indium labelled normal platelets, significantly reduced the secondary platelet deposition (p <0.01) when compared with the deposition seen when control untreated platelets were preperfused. Significant differences (p <0.001) in secondary deposition were also observed when primary and secondary platelet perfusions were made under high shear (1690/s).Histology of the tunica media segments post perfusion, supported the inhibitory effect of predeposited iloprost-loaded platelets on secondary platelet recruitment. By exploiting their natural haemostatic propensity, drug-loaded platelets can be targeted to vessel wall injury sites. Appropriate drugs could be packaged that may passivate the carrier platelets at the lesion inhibiting thrombus formation or they may act as a depot for sustained drug release. This platelet drug delivery strategy may have application in the prevention of the thrombotic and reste-notic events that can occur post angioplasty, or following therapy with thrombolytics, or after more invasive surgical procedures involving vascular reconstruction or prosthetic implantation.

Gene Induction in Vessel Wall Injury

1993 ◽  
Vol 70 (01) ◽  
pp. 180-183 ◽  
Author(s):  
Mark B Taubman
Keyword(s):  
Vessel Wall ◽  
Gene Induction ◽  
Wall Injury

The Effects of Heparin and Annexin V on Fibrin Accretion after Injury in the Jugular Veins of Rabbits

1993 ◽  
Vol 69 (03) ◽  
pp. 227-230 ◽  
Author(s):  
J Van Ryn-McKenna ◽  
H Merk ◽  
T H Müller ◽  
M R Buchanan ◽  
W G Eisert
Keyword(s):  
Vessel Wall ◽  
Thrombin Generation ◽  
Antithrombin Iii ◽  
Specific Effect ◽  
Annexin V ◽  
Inhibitory Effect ◽  
Jugular Veins ◽  
Prothrombinase Complex ◽  
Wall Injury

SummaryWe compared the relative abilities of unfractionated heparin and annexin V to prevent fibrin accretion onto injured jugular veins in vivo. Heparin was used to accelerate the inhibition of thrombin by antithrombin III, and annexin V was used to inhibit the assembly of the prothrombinase complex on phospholipid surfaces, thereby blocking thrombin generation. Rabbit jugular veins were isolated in situ, a 2 cm segment was injured by perfusing it with air, and then blood flow was re-established. Five minutes later, each rabbit was injected with heparin (20 U/kg) or annexin V (0.3 mg/kg) and then with 125I-fibrinogen. The amount of 125I-fibrin accumulation onto each injured vessel wall segment was measured 4 h later. Each injured vessel was completely deendothelialized as a result of the air perfusion as demonstrated by electron microscopy. 125I-fibrin accretion onto the injured jugular veins was enhanced 2.4-fold as compared to the uninjured veins in sham-operated animals. Heparin treatment did not reduce fibrin accretion, whereas, annexin V treatment decreased fibrin accretion by 60%, p <0.05. This latter effect was achieved without sustained circulating anticoagulation. Additional experiments confirmed that the inhibitory effect of annexin V on fibrin accretion was associated with a surface specific effect, since more annexin V bound to the injured jugular vein segments as compared to the non-injured jugular veins. We conclude that, i) mild vessel wall injury (selective de-endothelialization) in veins results in a thrombogenic vessel wall; ii) the thrombogenecity of which is not inhibited by prophylactic doses of heparin; but iii) is inhibited by annexin V, which binds to injured vessel wall surface, and inhibits thrombin generation independently of antithrombin III.

An Electron Microscopic Study of Platelet Thrombus Formation in the Rabbit with Particular Regard to 5-Hydroxytryptamine Release

1967 ◽  
Vol 18 (03/04) ◽  
pp. 592-604 ◽  
Author(s):  
H. R Baumgartner ◽  
J. P Tranzer ◽  
A Studer
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Vessel Wall ◽  
Thrombus Formation ◽  
Endothelial Damage ◽  
Electron Microscopic ◽  
Rabbit Ear ◽  
Basement Lamina ◽  
Platelet Thrombus

SummaryElectron microscopic and histologic examination of rabbit ear vein segments 4 and 30 min after slight endothelial damage have yielded the following findings :1. Platelets do not adhere to damaged endothelial cells.2. If the vessel wall is denuded of the whole endothelial cell, platelets adhere to the intimai basement lamina as do endothelial cells.3. The distance between adherent platelets as well as endothelial cells and intimai basement lamina measures 10 to 20 mµ, whereas the distance between aggregated platelets is 30 to 60 mµ.4. 5-hydroxytryptamine (5-HT) is released from platelets during viscous metamorphosis at least in part as 5-HT organelles.It should be noted that the presence of collagen fibers is not necessary for platelet thrombus formation in vivo.

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