scholarly journals Inflammation and Platelet Activation After COVID-19 Vaccines - Possible Mechanisms Behind Vaccine-Induced Immune Thrombocytopenia and Thrombosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Sisse R. Ostrowski ◽  
Ole S. Søgaard ◽  
Martin Tolstrup ◽  
Nina B. Stærke ◽  
Jens Lundgren ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Immune Thrombocytopenia ◽  
Thrombin Generation ◽  
High Titer ◽  
Adenovirus Vector ◽  
Activation Markers ◽  
Platelet Factor ◽  
Pronounced Increase ◽  
Impedance Aggregometry ◽  
The Impact

Introduction of vaccines against COVID-19 has provided the most promising chance to control the world-wide COVID-19 pandemic. However, the adenovirus-vector based Oxford/AstraZeneca [ChAdOx1] (AZ) and Johnson & Johnson [Ad26.CoV2.S] COVID-19 vaccines have been linked with serious thromboembolic events combined with thrombocytopenia, denominated Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). The pathogenesis of COVID-19 VITT remain incompletely understood; especially the initial events that trigger platelet activation, platelet factor (PF)4 release, complex formation and PF4 antibody production are puzzling. This is a prospective study investigating the impact of different COVID-19 vaccines on inflammation (CRP, TNF-α, IL-1β, IL-6, IL-8, IL-10), vascular endothelial activation (syndecan-1, thrombomodulin, E-selectin, ICAM-1, ICAM-3, VCAM-1), platelet activation (P-selectin, TGF-β, sCD40L) and aggregation (Multiplate® impedance aggregometry), whole blood coagulation (ROTEM®), thrombin generation and PF4 antibodies to reveal potential differences between AZ and mRNA vaccines in individuals without VITT. The study included 80 (55 AZ and 55 mRNA) vaccinated individuals and 55 non-vaccinated age- and gender matched healthy controls. The main findings where that both vaccines enhanced inflammation and platelet activation, though AZ vaccination induced a more pronounced increase in several inflammatory and platelet activation markers compared to mRNA vaccination and that post-vaccination thrombin generation was higher following AZ vaccination compared to mRNA vaccination. No difference in neither the PF4 antibody level nor the proportion of individuals with positive PF4 antibodies were observed between the vaccine groups. This is the first study to report enhanced inflammation, platelet activation and thrombin generation following AZ vaccination compared to mRNA vaccination in a head-to-head comparison. We speculate that specific components of the AZ adenovirus vector may serve as initial trigger(s) of (hyper)inflammation, platelet activation and thrombin generation, potentially lowering the threshold for a cascade of events that both trigger complications related to excessive inflammation, platelet and coagulation activation as observed in epidemiological studies and promote development of VITT when combined with high-titer functionally active PF4 antibodies.

Partially desulfated heparin modulates the interaction between anti-protamine/heparin antibodies and platelets

2016 ◽  
Vol 115 (02) ◽  
pp. 324-332 ◽  
Author(s):  
Rabie Jouni ◽  
Heike Zöllner ◽  
Ahmad Khadour ◽  
Jan Wesche ◽  
Anne Grotevendt ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Platelet Factor ◽  
Standard Drug ◽  
Platelet Surface ◽  
Minimal Impact ◽  
Platelet Survival ◽  
Heparin Complexes ◽  
The Impact

SummaryProtamine (PRT) is the standard drug to neutralise heparin. PRT/heparin complexes induce an immune response similar to that observed in heparin-induced thrombocytopenia (HIT). Partially desulfated heparin (ODSH) was shown to interfere with anti-platelet factor 4/heparin antibodies (Abs), which are responsible for HIT. In this study, we analyse the impact of ODSH on the interaction between anti-PRT/heparin Abs and platelets. The ability of ODSH to prevent anti-PRT/heparin Ab-induced platelet destruction in vivo was investigated using the NOD/ SCID mouse model. ODSH improved platelet survival in the presence of PRT, heparin and anti-PRT/heparin Abs (median platelet survival after 300 minutes (min) with 20 μg/ml ODSH: 75 %, range 70–81 % vs without ODSH: 49%, range 44–59%, p=0.006). Furthermore, when ODSH was applied 60 min after Ab injection platelet survival was improved (median platelet survival after 300 min with ODSH: 83 %, range 77–93 % vs without ODSH: 59 %, range 29–61 %, p=0.02). In in vitro experiments ODSH inhibited platelet activation at concentrations > 16 μg/mL (p< 0.001), as well as PRT/heparin complex binding to platelets (mean fluorescence intensity [MFI] without ODSH: 85 ± 14 vs with ODSH: 15 ± 0.6, p=0.013). ODSH also displaced pre-bound complexes from the platelet surface (MFI without ODSH: 324 ± 43 vs with 32 μg/ml ODSH: 53 ± 9, p< 0.001). While interfering with platelet activation by anti-PRT/heparin Abs, up to a concentration of 16 μg/ml, ODSH had only minimal impact on neutralisation of heparin by PRT. In conclusion, our study shows that ODSH is able to inhibit platelet activation and destruction suggesting a potential clinical use to reduce anti-PRT/heparin Ab-mediated adverse effects.

The Effect of BIBT 986, a Novel Small Molecule Dual Inhibitor of Thrombin and Factor Xa, on Coagulation in a Model of Endotoxin Induced, Tissue Factor Triggered Coagulation Activation in Humans.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 912-912 ◽  
Author(s):  
Bernd Jilma ◽  
Judith M. Leitner ◽  
Francesco Cardona ◽  
Florian B. Mayr ◽  
Christa Firbas ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Platelet Activation ◽  
Thrombin Generation ◽  
Anticoagulant Activity ◽  
Thrombin Time ◽  
Coagulation Activation ◽  
Dual Inhibitor ◽  
Activation Markers ◽  
Markers Of Inflammation ◽  
Prolonged Aptt

Abstract Background: BIBT 986 is a novel potent anticoagulant that dually inhibits Factors Xa and IIa. We hypothesized that BIBT 986 would dose-dependently decrease endotoxin-induced, tissue factor triggered coagulation activation. Hence it was the aim of the study to compare with placebo the anticoagulant activity of three dosages of BIBT 986 on parameters of coagulation, platelet activation and inflammation and to examine the safety of BIBT 986 in this setting. Methods: This study was a prospective, randomized, double-blind, placebo-controlled, parallel-group dose escalation trial in 48 healthy male volunteers. Participants were randomised to receive bolus primed continuous infusions of one of the three doses of BIBT 986 or placebo. All of them received a bolus infusion of 2ng/kg body weight lipopolysaccharide (LPS). Results: BIBT dose-dependently increased anti-Xa activity, activated partial thromboplastin time (APTT), ecarin clotting time (ECT), thrombin time (TT) and the international normalisation ratio (INR). Importantly, BIBT 986 dose-dependently blocked the LPS-induced coagulation as assessed by the in vivo markers of thrombin generation and action: BIBT 986 doses that prolonged APTT by 25% were already effective. The BIBT dose that prolonged APTT by 100%, completely suppressed the increase in prothrombin fragment (F1+2), thrombin-antithrombin complexes (TAT) and D-dimer. BIBT 986 had no influence on activation markers of inflammation, fibrinolysis, endothelial or platelet activation. Conclusion: Infusion of BIBT 986 was safe and well tolerated. BIBT 986 specifically and dose-dependently blocked LPS-induced, tissue factor trigger coagulation. When compared to different anticoagulants tested previously in this standardized model, BIBT 986 was more effective in suppressing thrombin generation (F1+2 levels) than standard doses of danaparoid, dalteparin or lepirudin. BIBT 986 represents the first drug of a new class of dual FXa and FIIa inhibitors, and displays high potency.

scholarly journals Sample Preparation as a Critical Aspect of Blood Platelet Mitochondrial Respiration Measurements—The Impact of Platelet Activation on Mitochondrial Respiration

2021 ◽  
Vol 22 (17) ◽  
pp. 9332
Author(s):  
Karolina Siewiera ◽  
Magdalena Labieniec-Watala ◽  
Nina Wolska ◽  
Hassan Kassassir ◽  
Cezary Watala
Keyword(s):  
Platelet Activation ◽  
Mitochondrial Respiration ◽  
Blood Platelets ◽  
High Sensitivity ◽  
Blood Platelet ◽  
High Electron ◽  
Activation Markers ◽  
The Media ◽  
The Impact ◽  
Electron Transfer Capacity

Blood platelets are considered as promising candidates as easily-accessible biomarkers of mitochondrial functioning. However, their high sensitivity to various stimulus types may potentially affect mitochondrial respiration and lead to artefactual outcomes. Therefore, it is crucial to identify the factors associated with platelet preparation that may lead to changes in mitochondrial respiration. A combination of flow cytometry and advanced respirometry was used to examine the effect of blood anticoagulants, the media used to suspend isolated platelets, respiration buffers, storage time and ADP stimulation on platelet activation and platelet mitochondria respiration. Our results clearly show that all the mentioned factors can affect platelet mitochondrial respiration. Briefly, (i) the use of EDTA as anticoagulant led to a significant increase in the dissipative component of respiration (LEAK), (ii) the use of plasma for the suspension of isolated platelets with MiR05 as a respiration buffer allows high electron transfer capacity and low platelet activation, and (iii) ADP stimulation increases physiological coupling respiration (ROUTINE). Significant associations were observed between platelet activation markers and mitochondrial respiration at different preparation steps; however, the fact that these relationships were not always apparent suggests that the method of platelet preparation may have a greater impact on mitochondrial respiration than the platelet activation itself.

Correlation of Specific Platelet Activation Markers with Carotid Arterial Wall Thickness

1995 ◽  
Vol 74 (03) ◽  
pp. 943-948 ◽  
Author(s):  
Habib M Ghaddar ◽  
Jorge Cortes ◽  
Veikko Salomaa ◽  
Jeremy D Kark ◽  
C Edward Davis ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Platelet Activation ◽  
Wall Thickness ◽  
Arterial Wall ◽  
White Men ◽  
Basic Question ◽  
Activation Markers ◽  
Platelet Factor ◽  
Arterial Wall Thickness ◽  
Carotid Arterial

SummaryMany studies have shown inereased platelet activation in patients with coronary artery, cerebrovascular and peripheral vascular diseases. However, the temporal relationship between platelet activation and arterial atherosclerosis is unclear. To answer this basic question, we measured the plasma concentrations of two specific platelet activation markers, β-thromboglobulin (βTG) and platelet factor 4 (PF4) in 459 cases with increased carotid arterial wall thickness and 459 age-, sex- and race-matched controls selected from a cohort of 15,800 men and women, aged 45-64 who participated in the Atherosclerosis Risk in Communities Study. These participants had no acute vascular symptoms or known cardiovascular disease. The mean values of βTG and PF4 were significantly higher in cases than in controls. However, when analyzed by quartiles using conditional logistic regression, only βTG exhibited a significant association with carotid wall thickness, while PF4 did not. The odds ratio (OR) determined by multivariate logistic regression analysis was significantly higher for the uppermost quartile of βTG (OR=1.7, 95% Cl 1.1-2.5) compared to the lower 3 quartiles. This OR was 2.3 in white men (95% Cl 1.2-4.2), 1.4 in white women (95% Cl 0.6-3.0) and 1.0 in blacks (95% Cl 0.4-2.5).This study indicates that plasma βTG may be useful as a marker for early atherosclerosis in middle aged adults, particularly in white men. It also suggests that platelet activation has an independent role in the pathogenesis of atherosclerosis, although the possibility that this may be a response to carotid atherosclerosis cannot be excluded.

scholarly journals Effect of ultrapure lipopolysaccharides derived from diverse bacterial species on the modulation of platelet activation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Thomas M. Vallance ◽  
Divyashree Ravishankar ◽  
Dina A. I. Albadawi ◽  
Harry Layfield ◽  
Jonathan Sheard ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Platelet Reactivity ◽  
Platelet Rich Plasma ◽  
Bacterial Species ◽  
Human Platelets ◽  
Innate Immune Responses ◽  
Experimental Conditions ◽  
Activation Markers ◽  
The Impact ◽  
Inside Out

AbstractPlatelets are small circulating blood cells that play essential roles in the maintenance of haemostasis via blood clotting. However, they also play critical roles in the regulation of innate immune responses. Inflammatory receptors, specifically Toll-like receptor (TLR)-4, have been reported to modify platelet reactivity. A plethora of studies have reported controversial functions of TLR4 in the modulation of platelet function using various chemotypes and preparations of its ligand, lipopolysaccharide (LPS). The method of preparation of LPS may explain these discrepancies however this is not fully understood. Hence, to determine the impact of LPS on platelet activation, we used ultrapure preparations of LPS from Escherichia coli (LPSEC), Salmonella minnesota (LPSSM), and Rhodobacter sphaeroides (LPSRS) and examined their actions under diverse experimental conditions in human platelets. LPSEC did not affect platelet activation markers such as inside-out signalling to integrin αIIbβ3 or P-selectin exposure upon agonist-induced activation in platelet-rich plasma or whole blood whereas LPSSM and LPSRS inhibited platelet activation under specific conditions at supraphysiological concentrations. Overall, our data demonstrate that platelet activation is not largely influenced by any of the ultrapure LPS chemotypes used in this study on their own except under certain conditions.

Platelet-specific markers are associated with monocyte-platelet aggregate formation and thrombin generation potential in advanced atherosclerosis

2016 ◽  
Vol 115 (03) ◽  
pp. 615-621 ◽  
Author(s):  
Cihan Ay ◽  
Julia Riedl ◽  
Christoph W. Kopp ◽  
Beate Eichelberger ◽  
Renate Koppensteiner ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Thrombin Generation ◽  
Thrombus Formation ◽  
Cd40 Ligand ◽  
Aggregate Formation ◽  
Soluble Cd40 Ligand ◽  
Platelet Factor ◽  
Platelet Aggregate ◽  
Angioplasty And Stenting

SummaryPlatelet activation and thrombin generation are crucial steps in primary and secondary haemostasis. However, both also play major roles in intravascular thrombus formation and therefore in the development of adverse cardiovascular events. In the current study, we first sought to investigate the associations of the platelet biomarkers platelet factor (PF)-4, thrombospondin (TSP)-1, soluble CD40 ligand (sCD40L), and soluble P-selectin (sP-selectin) with each other and with monocyte-platelet aggregate (MPA) formation in 316 patients undergoing angioplasty and stenting. To better understand the interplay between platelet activation and thrombin generation, we subsequently investigated the associations of the platelet biomarkers with thrombin generation potential. The mostly platelet-specific markers PF-4, TSP-1 and sCD40L correlated strongly with each other (all p < 0.001), and the best correlation was observed between PF-4 and TSP-1 (r=0.91). In contrast, sP-selectin, which derives from platelets and endothelial cells, correlated rather poorly with TSP-1 (r=0.12, p=0.04), and did not correlate with PF-4 and sCD40L. While PF-4, TSP-1 and sP-selectin correlated significantly with in vivo MPA formation (all p < 0.001), no such association was found between sCD40L and MPA formation. PF-4, TSP-1 and sCD40L correlated strongly with peak thrombin generation (all p < 0.001) with the best correlation between PF-4 and peak thrombin generation (r=0.55), whereas sP-selectin did not correlate with peak thrombin generation. Likewise, PF-4, TSP-1 and sCD40L correlated significantly with the area under the thrombin generation curve (AUC; all p< 0.01), whereas sP-selectin did not correlate with the AUC. In conclusion, platelet-specific markers are associated with MPA formation and thrombin generation potential in patients with advanced atherosclerosis.

Aspirin-Responsive, Migraine-Like Transient Cerebral and Ocular Ischemic Attacks and Erythromelalgia in JAK2V617F-Positive Essential Thrombocythemia and Polycythemia Vera

2014 ◽  
Vol 133 (1) ◽  
pp. 56-63 ◽  
Author(s):  
Jan Jacques Michiels ◽  
Zwi Berneman ◽  
Alain Gadisseur ◽  
King H. Lam ◽  
Hendrik De Raeve ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Platelet Activation ◽  
Essential Thrombocythemia ◽  
Ex Vivo ◽  
Time Lapse ◽  
Blurred Vision ◽  
Activation Markers ◽  
Platelet Factor ◽  
Cox 1

Migraine-like cerebral transient ischemic attacks (MIAs) and ocular ischemic manifestations were the main presenting features in 10 JAK2V617F-positive patients studied, with essential thrombocythemia (ET) in 6 and polycythemia vera (PV) in 4. Symptoms varied and included cerebral ischemic attacks, mental concentration disturbances followed by throbbing headaches, nausea, vomiting, syncope or even seizures. MIAs were frequently preceded or followed by ocular ischemic events of blurred vision, scotomas, transient flashing of the eyes, and sudden transient partial blindness preceded or followed erythromelalgia in the toes or fingers. The time lapse between the first symptoms of aspirin-responsive MIAs and the diagnosis of ET in 5 patients ranged from 4 to 12 years. At the time of erythromelalgia and MIAs, shortened platelet survival, an increase in the levels of the platelet activation markers β-thromboglobulin and platelet factor 4 and also in urinary thromboxane B2 were clearly indicative of the spontaneous in vivo platelet activation of constitutively JAK2V617F-activated thrombocythemic platelets. Aspirin relieves the peripheral, cerebral and ocular ischemic disturbances by irreversible inhibition of platelet cyclo-oxygenase (COX-1) activity and aggregation ex vivo. Vitamin K antagonist, dipyridamole, ticlopidine, sulfinpyrazone and sodium salicylate have no effect on platelet COX-1 activity and are ineffective in the treatment of thrombocythemia-specific manifestations of erythromelalgia and atypical MIAs. If not treated with aspirin, ET and PV patients are at a high risk of major arterial thrombosis including stroke, myocardial infarction and digital gangrene.

scholarly journals High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass

Blood ◽  
2013 ◽  
Vol 121 (15) ◽  
pp. 2828-2835 ◽  
Author(s):  
Grace M. Lee ◽  
Ian J. Welsby ◽  
Barbara Phillips-Bute ◽  
Thomas L. Ortel ◽  
Gowthami M. Arepally
Keyword(s):  
Cardiopulmonary Bypass ◽  
Platelet Activation ◽  
High Titer ◽  
Platelet Factor 4 ◽  
Antigen Specificity ◽  
Single Exposure ◽  
Platelet Factor ◽  
Key Points ◽  
High Incidence ◽  
Heparin Complexes

Key PointsA single exposure to protamine and heparin during CPB is highly sensitizing; 29% of patients develop Abs to PRT/H complexes by day 30 after CPB. PRT/H Abs share several features with platelet factor 4/heparin Abs, including high titer formation after CPB, heparin dependence, antigen specificity, and platelet activation.

scholarly journals Low-Level Laser Irradiation Exerts Antiaggregative Effect on Human Platelets Independently on the Nitric Oxide Metabolism and Release of Platelet Activation Markers

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Piotr Rola ◽  
Adrian Doroszko ◽  
Ewa Szahidewicz-Krupska ◽  
Paweł Rola ◽  
Piotr Dobrowolski ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Platelet Aggregation ◽  
Laser Irradiation ◽  
Platelet Activation ◽  
Activation Markers ◽  
Platelet Factor ◽  
Low Level ◽  
Low Level Laser ◽  
Level Laser ◽  
No Bioavailability

Aim. The goal of the study is to develop a model allowing to investigate precisely the effect of low-level laser therapy (LLLT) on platelet aggregation and to verify the hypothesis regarding the role of the nitric oxide (NO) bioavailability and platelet activation markers in modulating platelet aggregation. Methods. A total of 41 healthy volunteers at the age of 21–45 years were investigated. At first, platelet aggregation in response to three agonists (TRAP, ADP, and collagen) was evaluated following previous exposure to different doses of laser radiation (λ = 662 nm) to assess the dose-response effect. Subsequently, plasma levels of platelet activation markers (PF4—platelet factor-4 and sP-selectin) as well as the substrate for nitric oxide synthase, L-arginine, and its competitive inhibitors (ADMA—asymmetric dimethylarginine and SDMA—symmetric dimethylarginine) were measured. Results. All doses of laser irradiation significantly reduced the aggregation. However, the most pronounced effect was observed for 19.7 J/cm2. No significant differences in the levels of platelet activation markers nor in the nitric-oxide-metabolic-pathway compounds between analyzed groups were noted. Conclusions. We have demonstrated in the established in vitro experimental model that the LLLT in a reproducible manner decreases the whole blood platelet aggregation regardless of the NO bioavailability or changes in the platelet activation markers.

Sign in / Sign up

Export Citation Format

Share Document