scholarly journals Prothrombotic Phenotype in COVID-19: Focus on Platelets

2021 ◽  
Vol 22 (24) ◽  
pp. 13638
Author(s):  
Cristina Barale ◽  
Elena Melchionda ◽  
Alessandro Morotti ◽  
Isabella Russo
Keyword(s):  
Organ Damage ◽  
Small Cells ◽  
Common Finding ◽  
Significant Finding ◽  
Platelet Factor ◽  
Cytokines And Chemokines ◽  
Cell Membrane Disruption ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Cell Fragments

COVID-19 infection is associated with a broad spectrum of presentations, but alveolar capillary microthrombi have been described as a common finding in COVID-19 patients, appearing as a consequence of a severe endothelial injury with endothelial cell membrane disruption. These observations clearly point to the identification of a COVID-19-associated coagulopathy, which may contribute to thrombosis, multi-organ damage, and cause of severity and fatality. One significant finding that emerges in prothrombotic abnormalities observed in COVID-19 patients is that the coagulation alterations are mainly mediated by the activation of platelets and intrinsically related to viral-mediated endothelial inflammation. Beyond the well-known role in hemostasis, the ability of platelets to also release various potent cytokines and chemokines has elevated these small cells from simple cell fragments to crucial modulators in the blood, including their inflammatory functions, that have a large influence on the immune response during infectious disease. Indeed, platelets are involved in the pathogenesis of acute lung injury also by promoting NET formation and affecting vascular permeability. Specifically, the deposition by activated platelets of the chemokine platelet factor 4 at sites of inflammation promotes adhesion of neutrophils on endothelial cells and thrombogenesis, and it seems deeply involved in the phenomenon of vaccine-induced thrombocytopenia and thrombosis. Importantly, the hyperactivated platelet phenotype along with evidence of cytokine storm, high levels of P-selectin, D-dimer, and, on the other hand, decreased levels of fibrinogen, von Willebrand factor, and thrombocytopenia may be considered suitable biomarkers that distinguish the late stage of COVID-19 progression in critically ill patients.

Studies of α-granule proteins in cultured human megakaryocytes

2003 ◽  
Vol 90 (11) ◽  
pp. 844-852 ◽  
Author(s):  
Dragoslava Veljkovic ◽  
Elisabeth Cramer ◽  
Gulie Alimardani ◽  
Serge Fichelson ◽  
Jean-Marc Massé ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Protein Processing ◽  
Platelet Factor ◽  
Protein Storage ◽  
Granule Protein ◽  
Granule Proteins ◽  
Processing And Storage ◽  
Von Willebrand ◽  
And Storage ◽  
Willebrand Factor

Summaryα-Granule protein storage is important for producing platelets with normal haemostatic function. The low to undetectable levels of several megakaryocyte-synthesized α-granule proteins in normal plasma suggest megakaryocytes are important to sequester these proteins in vivo. α-Granule protein storage in vitrohas been studied using other cell types, with differences observed in how some proteins are processed compared to platelets. Human megakaryocytes, cultured from cord blood CD34+cells and grown in serum-free media containing thrombopoietin, were investigated to determine if they could be used as a model for studying normal α-granule protein processing and storage. ELISA indicated that cultured megakaryocytes contained the α-granule proteins multimerin, von Willebrand factor, thrombospondin-1, β-thromboglobulin and platelet factor 4, but no detectable fibrinogen and factor V. A significant proportion of the α-granule protein in megakaryocyte cultures was contained within the cells (averages: 41 – 71 %), consistent with storage. Detailed analyses of multimerin and von Willebrand factor confirmed that α-granule proteins were processed to mature forms and were predominantly located in the α-granules of cultured megakaryocytes. Thrombopoietin-stimulated cultured megakaryocytes provide a useful model for studying α-granule protein processing and storage.

scholarly journals Cost effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura

Blood ◽  
2020 ◽  
Author(s):  
George Goshua ◽  
Pranay Sinha ◽  
Jeanne Elise Hendrickson ◽  
Christopher A Tormey ◽  
Pavan Bendapudi ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Organ Damage ◽  
Hospital Length Of Stay ◽  
Sensitivity Analyses ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Relapse Rates

Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by thrombotic microangiopathy leading to end-organ damage. The standard of care (SOC) treatment is therapeutic plasma exchange (TPE) alongside immunomodulation with steroids, with increasing use of rituximab +/- other immunomodulatory agents. The addition of caplacizumab, a nanobody targeting von Willebrand factor, was shown to accelerate platelet count recovery and reduce TPE treatments and hospital length of stay in TTP patients treated in the TITAN and HERCULES trials. The addition of caplacizumab to SOC also led to increased bleeding due to transient reductions in von Willebrand factor and increased relapse rates. Using data from TITAN and HERCULES on caplacizumab, we performed the first-ever cost effectiveness analysis in TTP. Over a 5-year period, the projected incremental cost effectiveness ratio (ICER) in our Markov model was $1,482,260, significantly above the accepted 2019 US willingness-to-pay of $195,300. One-way sensitivity analyses showed the utility of the well state and the cost of caplacizumab to have the largest effects on ICER, with a reduction in caplacizumab cost demonstrating the greatest impact on lowering the ICER. In a probabilistic sensitivity analysis, SOC was favored over caplacizumab in 100% of 10,000 iterations. Our data indicate that the addition of caplacizumab to SOC in treatment of acquired TTP is not cost effective due to the high cost of the medication and its failure to improve relapse rates. The potential impact of caplacizumab on health system cost using longer-term follow-up data merits further study.

scholarly journals Recognition of PF4-VWF complexes by heparin-induced thrombocytopenia antibodies contributes to thrombus propagation

Blood ◽  
2020 ◽  
Vol 135 (15) ◽  
pp. 1270-1280 ◽  
Author(s):  
Ian Johnston ◽  
Amrita Sarkar ◽  
Vincent Hayes ◽  
Gavin T. Koma ◽  
Gowthami M. Arepally ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Complex Formation ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Microfluidic System ◽  
Microfluidic Channels ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by complexes between platelet factor 4 (PF4) and heparin or other polyanions, but the risk of thrombosis extends beyond exposure to heparin implicating other PF4 partners. We recently reported that peri-thrombus endothelium is targeted by HIT antibodies, but the binding site(s) has not been identified. We now show that PF4 binds at multiple discrete sites along the surface of extended strings of von Willebrand factor (VWF) released from the endothelium following photochemical injury in an endothelialized microfluidic system under flow. The HIT-like monoclonal antibody KKO and HIT patient antibodies recognize PF4-VWF complexes, promoting platelet adhesion and enlargement of thrombi within the microfluidic channels. Platelet adhesion to the PF4-VWF-HIT antibody complexes is inhibited by antibodies that block FcγRIIA or the glycoprotein Ib-IX complex on platelets. Disruption of PF4-VWF-HIT antibody complexes by drugs that prevent or block VWF oligomerization attenuate thrombus formation in a murine model of HIT. Together, these studies demonstrate assembly of HIT immune complexes along VWF strings released by injured endothelium that might propagate the risk of thrombosis in HIT. Disruption of PF4-VWF complex formation may provide a new therapeutic approach to HIT.

scholarly journals Binding of fibronectin to alpha-granule-deficient platelets.

1983 ◽  
Vol 97 (2) ◽  
pp. 571-573 ◽  
Author(s):  
M H Ginsberg ◽  
J D Wencel ◽  
J G White ◽  
E F Plow
Keyword(s):  
Surface Expression ◽  
Plasma Fibronectin ◽  
Platelet Factor ◽  
Fibronectin Receptor ◽  
Platelet Binding ◽  
Protein Functions ◽  
Fibronectin Binding ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Molecular Nature

Most of the proposed functions for fibronectin involve its interaction with cells, yet the molecular nature of cellular fibronectin binding site(s) has remained obscure. Thrombin induces saturable platelet binding sites for plasma fibronectin and concurrently stimulates surface expression of a number of platelet alpha-granule constituents including thrombospondin and fibrin which are known to interact with fibronectin. To test the hypothesis that these (or other alpha-granule proteins) mediate plasma fibronectin binding, we used platelets of patients with the Gray Platelet Syndrome. These cells were deficient in thrombospondin, beta-thromboglobulin, platelet factor 4, fibronectin, and fibrinogen as measured in radioimmunoassay. They also had reduced von Willebrand factor content as judged by immunofluorescence. At plasma fibronectin inputs from 0.03 to 3 times the apparent kilodalton, these Gray platelets bound virtually identical quantities of fibronectin as normal cells. Thus, platelets containing 1,500 molecules of thrombospondin per platelet could bind more than 100,000 molecules of plasma fibronectin per cell following thrombin stimulation. These data preclude any simple model in which newly surface expressed thrombospondin (or other alpha-granule protein) functions as the major thrombin-stimulated plasma fibronectin receptor in this cell type.

Mechanism of action of antiplatelet drugs on decompression sickness in rats: a protective effect of anti-GPIIbIIIa therapy

2015 ◽  
Vol 118 (10) ◽  
pp. 1234-1239 ◽  
Author(s):  
Kate Lambrechts ◽  
Jean-Michel Pontier ◽  
Aleksandra Mazur ◽  
Michaël Theron ◽  
Peter Buzzacott ◽  
...  
Keyword(s):  
Protective Effect ◽  
Vascular Function ◽  
Decompression Sickness ◽  
Statistical Significance ◽  
Thiobarbituric Acid ◽  
Platelet Factor ◽  
Hyperbaric Exposure ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Acetyl Salicylate

Literature highlights the involvement of disseminated thrombosis in the pathophysiology of decompression sickness (DCS). We examined the effect of several antithrombotic treatments targeting various pathways on DCS outcome: acetyl salicylate, prasugrel, abciximab, and enoxaparin. Rats were randomly assigned to six groups. Groups 1 and 2 were a control nondiving group (C; n = 10) and a control diving group (CD; n = 30). Animals in Groups 3 to 6 were treated before hyperbaric exposure (HBE) with either prasugrel ( n = 10), acetyl salicylate ( n = 10), enoxaparin ( n = 10), or abciximab ( n = 10). Blood samples were taken for platelet factor 4 (PF4), thiobarbituric acid reactive substances (TBARS), and von Willebrand factor analysis. Onset of DCS symptoms and death were recorded during a 60-min observation period after HBE. Although we observed fewer outcomes of DCS in all treated groups compared with the CD, statistical significance was reached in abciximab only (20% vs. 73%, respectively, P = 0.007). We also observed significantly higher levels of plasmatic PF4 in abciximab (8.14 ± 1.40 ng/ml; P = 0.004) and enoxaparin groups (8.01 ± 0.80 ng/ml; P = 0.021) compared with the C group (6.45 ± 1.90 ng/ml) but not CD group (8.14 ± 1.40 ng/ml). Plasmatic levels of TBARS were significantly higher in the CD group than the C group (49.04 ± 11.20 μM vs. 34.44 ± 5.70 μM, P = 0.002). This effect was prevented by all treatments. Our results suggest that abciximab pretreatment, a powerful glycoprotein IIb/IIIa receptor antagonist, has a strong protective effect on decompression risk by significantly improving DCS outcome. Besides its powerful inhibitory action on platelet aggregation, we suggest that abciximab could also act through its effects on vascular function, oxidative stress, and/or inflammation.

scholarly journals Human platelet surface binding of endogenous secreted factor VIII-von Willebrand factor and platelet factor 4

Blood ◽  
1982 ◽  
Vol 59 (1) ◽  
pp. 194-197 ◽  
Author(s):  
JN George ◽  
AR Onofre
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Membrane Surface ◽  
Platelet Factor 4 ◽  
Secreted Proteins ◽  
Surface Binding ◽  
Platelet Factor ◽  
Platelet Surface ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Washed human platelets in buffers containing either 2 mM Ca++ or 4 mM EDTA were stimulated by human alpha-thrombin to induce secretion. The binding of two endogenous secreted proteins, factor-VIII-related protein (VIII-R) (von Willebrand factor) and platelet factor 4, was measured by reacting thrombin-treated and control platelets with specific antibodies to these proteins, then quantifying antibody binding with 125I-staphylococcal protein A. Both of these granule proteins were associated with the platelet membrane surface by a calcium-dependent mechanism after thrombin-induced secretion. This ability to bind endogenous secreted proteins to the plasma membrane surface may provide a mechanism by which the platelet can concentrate and organize its secreted proteins for subsequent physiologic reactions.

Factor VIII ectopically expressed in platelets: efficacy in hemophilia A treatment

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 4006-4013 ◽  
Author(s):  
Helen V. Yarovoi ◽  
Dubravka Kufrin ◽  
Don E. Eslin ◽  
Michael A. Thornton ◽  
Sandra L. Haberichter ◽  
...  
Keyword(s):  
Factor Viii ◽  
Human Factor ◽  
Mice Model ◽  
Platelet Factor ◽  
Thrombosis Model ◽  
Human Factor Viii ◽  
Transgenic Lines ◽  
Cdna Construct ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Activated platelets release their granule content in a concentrated fashion at sites of injury. We examined whether ectopically expressed factor VIII in developing megakaryocytes would be stored in α-granules and whether its release from circulating platelets would effectively ameliorate bleeding in a factor VIIInull mice model. Using the proximal glycoprotein 1bα promoter to drive expression of a human factor VIII cDNA construct, transgenic lines were established. One line had detectable human factor VIII that colocalizes with von Willebrand factor in platelets. These animals had platelet factor VIII levels equivalent to 3% to 9% plasma levels, although there was no concurrent plasma human factor VIII detectable. When crossed onto a factor VIIInull background, whole blood clotting time was partially corrected, equivalent to a 3% correction level. In a cuticular bleeding time study, these animals also had only a partial correction, but in an FeCl3 carotid artery, thrombosis assay correction was equivalent to a 50% to 100% level. These studies show that factor VIII can be expressed and stored in platelet α-granules. Our studies also suggest that platelet-released factor VIII is at least as potent as an equivalent plasma level and perhaps even more potent in an arterial thrombosis model. (Blood. 2003;102:4006-4013)

scholarly journals Von Willebrand Factor, Soluble P-Selectin, and Target Organ Damage in Hypertension

Hypertension ◽  
2002 ◽  
Vol 40 (1) ◽  
pp. 61-66 ◽  
Author(s):  
Charles G.C. Spencer ◽  
David Gurney ◽  
Andrew D. Blann ◽  
D. Gareth Beevers ◽  
Gregory Y.H. Lip
Keyword(s):  
Von Willebrand Factor ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Target Organ ◽  
Soluble P ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Antigen and substrate withdrawal in the management of autoimmune thrombotic disorders

Blood ◽  
2012 ◽  
Vol 120 (20) ◽  
pp. 4134-4142 ◽  
Author(s):  
Douglas B. Cines ◽  
Keith R. McCrae ◽  
X. Long Zheng ◽  
Bruce S. Sachais ◽  
Eline T. Luning Prak ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Antiphospholipid Syndrome ◽  
Von Willebrand Factor ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Thrombocytopenic Purpura ◽  
Heparin Induced Thrombocytopenia ◽  
Systemic Anticoagulation ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractPrevailing approaches to manage autoimmune thrombotic disorders, such as heparin-induced thrombocytopenia, antiphospholipid syndrome and thrombotic thrombocytopenic purpura, include immunosuppression and systemic anticoagulation, though neither provides optimal outcome for many patients. A different approach is suggested by the concurrence of autoantibodies and their antigenic targets in the absence of clinical disease, such as platelet factor 4 in heparin-induced thrombocytopenia and β2-glycoprotein-I (β2GPI) in antiphospholipid syndrome. The presence of autoantibodies in the absence of disease suggests that conformational changes or other alterations in endogenous protein autoantigens are required for recognition by pathogenic autoantibodies. In thrombotic thrombocytopenic purpura, the clinical impact of ADAMTS13 deficiency caused by autoantibodies likely depends on the balance between residual antigen, that is, enzyme activity, and demand imposed by local genesis of ultralarge multimers of von Willebrand factor. A corollary of these concepts is that disrupting platelet factor 4 and β2GPI conformation (or ultralarge multimer of von Willebrand factor oligomerization or function) might provide a disease-targeted approach to prevent thrombosis without systemic anticoagulation or immunosuppression. Validation of this approach requires a deeper understanding of how seemingly normal host proteins become antigenic or undergo changes that increase antibody avidity, and how they can be altered to retain adaptive functions while shedding epitopes prone to elicit harmful autoimmunity.

Sign in / Sign up

Export Citation Format

Share Document