scholarly journals Release of endogenous chondroitin sulfate and heparin as consequence of dysregulated proteolysis in COVID-19

2021 ◽  
Author(s):  
Marco Ruggiero
Keyword(s):  
Adverse Effect ◽  
Platelet Aggregation ◽  
Chondroitin Sulfate ◽  
Plasma Proteins ◽  
Adverse Reactions ◽  
Proteolytic Enzymes ◽  
Protective Role ◽  
Platelet Factor ◽  
Sequential Release ◽  
Immune Mediated

Abstract Infection by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), the pathogen responsible for COVID-19, is associated with immune-mediated responses that lead to dysregulated activation of proteolytic enzymes; these contribute to damage to the endothelium, thrombosis, hypercoagulability, and other hematologic complications that include thrombotic thrombocytopenia, a complication of severe COVID-19 as well as a potentially fatal adverse effect of COVID-19 vaccination. Here, it is demonstrated that proteolysis of plasma proteins leads to sequential release of endogenous glycosaminoglycans (GAGs), first chondroitin sulfate (CS), followed by heparin (HP). The extension and degree of what is called "proteolytic storm" determines whether only one endogenous type of GAGs (CS), or both (CS and HP), are released. Sulfated GAGs such as CS and HP exert a protective role against SARS-CoV-2 infection. However, sustained and excessive release of endogenous HP may be responsible for thrombotic thrombocytopenia just as it happens in HP-induced thrombocytopenia (HIT) a well-known side effect of HP administration that results in thromboembolisms in atypical sites, thrombocytopenia, and synthesis of autoantibodies directed against platelet factor 4 (PF4) that contribute to platelet aggregation. It is concluded that release of endogenous HP as consequence of dysregulated proteolysis occurring during COVID-19 or COVID-19 vaccination may play a fundamental role in the pathophysiology of the disease as well as in adverse reactions to vaccination.

scholarly journals Release of endogenous chondroitin sulfate and heparin as consequence of dysregulated proteolysis in COVID-19

2021 ◽  
Author(s):  
Marco Ruggiero
Keyword(s):  
Adverse Effect ◽  
Platelet Aggregation ◽  
Chondroitin Sulfate ◽  
Plasma Proteins ◽  
Adverse Reactions ◽  
Proteolytic Enzymes ◽  
Protective Role ◽  
Platelet Factor ◽  
Sequential Release ◽  
Immune Mediated

Abstract Infection by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), the pathogen responsible for COVID-19, is associated with immune-mediated responses that lead to dysregulated activation of proteolytic enzymes; these contribute to damage to the endothelium, thrombosis, hypercoagulability, and other hematologic complications that include thrombotic thrombocytopenia, a complication of severe COVID-19 as well as a potentially fatal adverse effect of COVID-19 vaccination. Here, it is demonstrated that proteolysis of plasma proteins leads to sequential release of endogenous glycosaminoglycans (GAGs), first chondroitin sulfate (CS), followed by heparin (HP). The extension and degree of what is called "proteolytic storm" determines whether only one endogenous type of GAGs (CS), or both (CS and HP), are released. Sulfated GAGs such as CS and HP exert a protective role against SARS-CoV-2 infection. However, sustained and excessive release of endogenous HP may be responsible for thrombotic thrombocytopenia just as it happens in HP-induced thrombocytopenia (HIT) a well-known side effect of HP administration that results in thromboembolisms in atypical sites, thrombocytopenia, and synthesis of autoantibodies directed against platelet factor 4 (PF4) that contribute to platelet aggregation. It is concluded that release of endogenous HP as consequence of dysregulated proteolysis occurring during COVID-19 or COVID-19 vaccination may play a fundamental role in the pathophysiology of the disease as well as in adverse reactions to vaccination.

Beta - ThrombogloBulin And HA - Platelet Factor 4 In Multiple Myeloma, Hodgkin Disease And Malig - Nant Lymphoma - Effects Of Therapy

1981 ◽  
Author(s):  
H G Klingemann ◽  
R Eqbrinq ◽  
K Havemann
Keyword(s):  
Multiple Myeloma ◽  
Platelet Aggregation ◽  
Malignant Lymphoma ◽  
Proteolytic Enzymes ◽  
Platelet Factor 4 ◽  
Hodgkin Disease ◽  
In Vitro Tests ◽  
Clotting Factors ◽  
Platelet Factor ◽  
Specific Proteins

Determination of platelet specific proteins Beta-Thromboglobulin ( β-TG) and High Affinity Platelet Factor 4 (PF 4) in plasma has been proved as useful marker for an enhanced release reaction in some diseases, mostly due to an in - creased platelet aggregation. To evaluate suit - able marker for a prethrombotic state in some myeloproliferative diseases ue investigated patients suffering from multiple myeloma, Hodgkin disease and malignant lymphoma. β- TG and PF 4 were measured in platelet poor plasma using RIA - kits (Amersham-Buchler / Abbott Labor.). In addition ue determined; platelet count, spontaneous and collagen induced platelet aggregation, the activity of AT III and of the clotting factors I, V, VIII, XIII and the concentration of FDP.RESULTS: Normal range was found to be 0-55 ng/ml forβ-TG and 0-12 ng/ml for PF 4. Both release proteins were increased in 17 out of 25 patients with myeloma, in 13 out of 15 patients with Hodgkin disease and in 10 out of 12 patients with malignant lymphoma. A correlation to the severity of the diseases were demonstrable. Chemotherapy caused a decrease of β -TG and PF 4 levels in some cases. However no correlation could be found between β- TG and PF 4 levels and in vitro tests of platelet aggregation. Further clotting assay provided evidence for an activation of clotting (like DIC) in a few patients. Other possibilities - like the release of the platelet specific proteins by immunocomplexes, prostaglandins or proteolytic enzymes from granulocytes must taken into account.

scholarly journals May propylthiouracil induce autoimmune-related immunotoxicity?

2021 ◽  
pp. 67-67
Author(s):  
Ivana Bajkin ◽  
Sonja Golubovic ◽  
Tijana Icin ◽  
Kristina Stepanovic ◽  
Tatjana Ilic
Keyword(s):  
Adverse Effect ◽  
Case Report ◽  
Adverse Reactions ◽  
Antithyroid Drug ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Potential Explanation ◽  
Immune Mediated ◽  
Stimulating Factor ◽  
Direct Toxicity

Introduction. The use of propylthiouracil can be associated with mild adverse reactions, but severe complications like agranulocytosis and vasculitis can also be seen. Direct toxicity and immune-mediated induction of anti-neutrophile cytoplasmic antibodies have been described as possible mechanisms responsible for agranulocytosis. The majority of vasculitis are antimyeloperoxidase antibodies associated, but the exact mechanism for anti-neutrophile cytoplasmic antibodies-associated vasculitis as an adverse effect of propylthiouracil treatment is still unclear. Case report. Here we present a case of a female patient who presented with fever and throat pain two weeks after propylthiouracil therapy was initiated. Agranulocytosis alongside with basal left sided pneumonia was noted. Propylthiouracil was discontinued, and the treatment with broad spectrum antibiotics was started, as well as Lugol?s solution, methylprednisolone, and granulocyte-colony stimulating factor. The following course of treatment was complicated by the occurrence of a generalized erythematous-papullomatous rash. The patient was diagnosed with agranulocytosis and antimyeloperoxidase, anti-neutrophile cytoplasmic antibodies positive vasculitis as an adverse effect of propylthiouracil. Conclusion. Patients presenting with concomitant agranulocytosis and anti-neutrophile cytoplasmic antibodies-associated vasculitis as a complication of propylthiouracil therapy for Graves?s disease are rare in clinical practice. Prompt discontinuation of antithyroid drug is of great importance. Similarities in the pathogenesis of both conditions could be the potential explanation for these two adverse events occurring at the same time which points out to the need for a deeper understanding of this topic.

scholarly journals Polyphosphate/platelet factor 4 complexes can mediate heparin-independent platelet activation in heparin-induced thrombocytopenia

2016 ◽  
Vol 1 (1) ◽  
pp. 62-74 ◽  
Author(s):  
Douglas B. Cines ◽  
Serge V. Yarovoi ◽  
Sergei V. Zaitsev ◽  
Tatiana Lebedeva ◽  
Lubica Rauova ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Cell Surface ◽  
Chondroitin Sulfate ◽  
Platelet Activation ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Activated Platelets ◽  
Key Points

Key Points Polyphosphates form antigenic complexes with PF4 that are recognized by HIT antibodies. Polyphosphate/PF4 complexes released by activated platelets can mediate platelet aggregation by HIT antibodies in the absence of heparin or cell-surface chondroitin sulfate.

Plasma Components which Interfere with Ristocetin-induced Platelet Aggregation

1975 ◽  
Vol 33 (03) ◽  
pp. 540-546 ◽  
Author(s):  
Robert F Baugh ◽  
James E Brown ◽  
Cecil Hougie
Keyword(s):  
Platelet Aggregation ◽  
Human Plasma ◽  
Plasma Proteins ◽  
Binding Protein ◽  
Plasma Heating ◽  
Protein S ◽  
Fold Increase ◽  
Normal Human Plasma ◽  
Preliminary Examination ◽  
Normal Human

SummaryNormal human plasma contains a component or components which interfere with ristocetin-induced platelet aggregation. Preliminary examination suggests a protein (or proteins) which binds ristocetin and competes more effectively for ristocetin than do the proteins involved in ristocetin-induced platelet aggregation. The presence of this protein in normal human plasma also prevents ristocetin-induced precipitation of plasma proteins at levels of ristocetin necessary to produce platelet aggregation (0.5–2.0 mg/ml). Serum contains an apparent two-fold increase of this component when compared with plasma. Heating serum at 56° for one hour results in an additional 2 to 4 fold increase. The presence of a ristocetin-binding protein in normal human plasma requires that this protein be saturated with ristocetin before ristocetin-induced platelet aggregation will occur. Variations in the ristocetin-binding protein(s) will cause apparent discrepancies in ristocetin-induced platelet aggregation in normal human plasmas.

The Inhibition of Platelet Aggregation by an Aorta Intima Extract

1974 ◽  
Vol 32 (02/03) ◽  
pp. 417-431 ◽  
Author(s):  
A. du P Heyns ◽  
D. J van den Berg ◽  
G. M Potgieter ◽  
F. P Retief
Keyword(s):  
Platelet Aggregation ◽  
Degradation Products ◽  
Adenosine Diphosphate ◽  
Inhibitory Effect ◽  
Protective Role ◽  
Vascular Trauma ◽  
Wear And Tear ◽  
Sequential Addition ◽  
Aggregation Activity

SummaryThe platelet aggregating activity of extracts of different layers of the arterial wall was compared to that of Achilles tendon. Arterial media and tendon extracts, adjusted to equivalent protein content as an index of concentration, aggregated platelets to the same extent but an arterial intima extract did not aggregate platelets. Platelet aggregation induced by collagen could be inhibited by mixing with intima extract, but only to a maximum of about 80%. Pre-mixing adenosine diphosphate (ADP) with intima extracts diminished the platelet aggregation activity of the ADP. Depending on the relationship between ADP and intima extract concentrations aggregating activity could either be completely inhibited or inhibition abolished. Incubation of ADP with intima extract and subsequent separation of degradation products by paper chromatography, demonstrated a time-dependent breakdown of ADP with AMP, adenosine, inosine and hypoxanthine as metabolic products; ADP removal was complete. Collagen, thrombin and adrenaline aggregate platelets mainly by endogenous ADP of the release reaction. Results of experiments comparing inhibition of aggregation caused by premixing aggregating agent with intima extract, before exposure to platelets, and the sequential addition of first the intima extract and then aggregating agent to platelets, suggest that the inhibitory effect of intima extract results from ADP breakdown. It is suggested that this ADP degradation by intima extract may play a protective role in vivo by limiting the size of platelet aggregates forming at the site of minimal “wear and tear” vascular trauma.

The Action Mechanism of the Purified Platelet Aggregation Principle of Trimeresurus mucrosquamatus Venom

1979 ◽  
Vol 41 (03) ◽  
pp. 475-490 ◽  
Author(s):  
Chaoho Ouyang ◽  
Che-Ming Teng
Keyword(s):  
Platelet Aggregation ◽  
Adenine Nucleotides ◽  
Muscle Relaxants ◽  
Prostaglandin Synthesis ◽  
Action Mechanism ◽  
Crude Venom ◽  
Platelet Factor ◽  
Induce Platelet Aggregation ◽  
Minimal Concentration ◽  
Aggregation Principle

SummaryThe minimal concentration of the platelet aggregation principle (Platelet Aggregoserpen- tin, PAS) necessary to induce platelet aggregation was 10 ng/ml, about one-hundredth of that of the crude venom. PAS induced the release of platelet factors 3 and 4 from platelets, but the released platelet factor 3 was easily inactivated by the anti-phospholipid effect of PAS. Pretreatment of platelets with neuraminidase potentiated PAS-induced platelet aggregation. PAS-induced platelet aggregation was independent on released ADP; it could occur in the ADP-removing systems, such as apyrase or a combination of phosphoenolpyruvate and pyruvate kinase. However, PAS-induced platelet aggregation could be inhibited by adenine nucleotides and adenosine.PAS-induced platelet aggregation was inhibited by some anti-inflammatory agents, antimalarial drugs, local anesthetics, antihistamine and smooth muscle relaxants. After deaggregation of PAS-treated platelets, thrombin and sodium arachidonate could further induce platelet aggregation, but ADP and second dose of PAS could not. It is concluded that PAS-induced platelet aggregation is due to prostaglandin synthesis. Recent literatures on the mechanism of platelet aggregation were surveyed and the actions of PAS were discussed.

Essential Athrombia

1975 ◽  
Vol 33 (02) ◽  
pp. 278-285 ◽  
Author(s):  
Şeref Inceman ◽  
Yücel Tangün
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Bleeding Tendency ◽  
Clot Retraction ◽  
Platelet Factor ◽  
Prolonged Bleeding Time ◽  
Normal Platelet ◽  
Aggregation Response ◽  
Platelet Disorder ◽  
Fibrinogen Content

SummaryA constitutional platelet function disorder in a twelve-year-old girl characterized by a lifelong bleeding tendency, prolonged bleeding time, normal platelet count, normal clot retraction, normal platelet factor 3 activity and impaired platelet aggregation was reported.Platelet aggregation, studied turbidimetrically, was absent in the presence of usual doses of ADP (1–4 μM), although a small wave of primary aggregation was obtained by very large ADP concentrations (25–50 μM). The platelets were also unresponsive to epinephrine, thrombin and diluted collagen suspensions. But an almost normal aggregation response occurred with strong collagen suspensions. The platelets responded to Ristocetin. Pelease of platelet ADP was found to be normal by collagen and thrombin, but impaired by kaolin. Platelet fibrinogen content was normal.The present case, investigated with recent methods, confirms the existence of a type of primary functional platelet disorder characterized solely by an aggregation defect, described in 1955 and 1962 under the name of “essential athrombia.”

The Mechanism of Platelet Aggregation Induced by HLA-Related Antibodies

1996 ◽  
Vol 76 (05) ◽  
pp. 774-779 ◽  
Author(s):  
John T Brandt ◽  
Carmen J Julius ◽  
Jeanne M Osborne ◽  
Clark L Anderson
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Complement Activation ◽  
Thromboembolic Disease ◽  
Clinical Samples ◽  
Hla Antigen ◽  
Aggregation Response ◽  
Immune Mediated ◽  
Dependent Pathway

SummaryImmune-mediated platelet activation is emerging as an important pathogenic mechanism of thrombosis. In vitro studies have suggested two distinct pathways for immune-mediated platelet activation; one involving clustering of platelet FcyRIIa, the other involving platelet-associated complement activation. HLA-related antibodies have been shown to cause platelet aggregation, but the mechanism has not been clarified. We evaluated the mechanism of platelet aggregation induced by HLA-related antibodies from nine patients. Antibody to platelet FcyRIIa failed to block platelet aggregation with 8/9 samples, indicating that engagement of platelet FcyRIIa is not necessary for the platelet aggregation induced by HLA-related antibodies. In contrast, platelet aggregation was blocked by antibodies to human C8 (5/7) or C9 (7/7). F(ab’)2 fragments of patient IgG failed to induce platelet activation although they bound to HLA antigen on platelets. Intact patient IgG failed to aggregate washed platelets unless aged serum was added. The activating IgG could be adsorbed by incubation with lymphocytes and eluted from the lymphocytes. These results indicate that complement activation is involved in the aggregation response to HLA-related antibodies. This is the first demonstration of complement-mediated platelet aggregation by clinical samples. Five of the patients developed thrombocytopenia in relationship to blood transfusion and two patients developed acute thromboembolic disease, suggesting that these antibodies and the complement-dependent pathway of platelet aggregation may be of clinical significance.

The Effect of Dimethyl Sulfoxide on In Vitro Platelet Function

1976 ◽  
Vol 36 (01) ◽  
pp. 221-229 ◽  
Author(s):  
Charles A. Schiffer ◽  
Caroline L. Whitaker ◽  
Morton Schmukler ◽  
Joseph Aisner ◽  
Steven L. Hilbert
Keyword(s):  
Platelet Count ◽  
Platelet Aggregation ◽  
Dimethyl Sulfoxide ◽  
Platelet Function ◽  
Platelet Volume ◽  
Short Term ◽  
Platelet Factor ◽  
Short Term Exposure ◽  
Structural Abnormalities

SummaryAlthough dimethyl sulfoxide (DMSO) has been used extensively as a cryopreservative for platelets there are few studies dealing with the effect of DMSO on platelet function. Using techniques similar to those employed in platelet cryopreservation platelets were incubated with final concentrations of 2-10% DMSO at 25° C. After exposure to 5 and 10% DMSO platelets remained discoid and electron micrographs revealed no structural abnormalities. There was no significant change in platelet count. In terms of injury to platelet membranes, there was no increased availability of platelet factor-3 or leakage of nucleotides, 5 hydroxytryptamine (5HT) or glycosidases with final DMSO concentrations of 2.5, 5 and 10% DMSO. Thrombin stimulated nucleotide and 5HT release was reduced by 10% DMSO. Impairment of thrombin induced glycosidase release was noted at lower DMSO concentrations and was dose related. Similarly, aggregation to ADP was progressively impaired at DMSO concentrations from 1-5% and was dose related. After the platelets exposed to DMSO were washed, however, aggregation and release returned to control values. Platelet aggregation by epinephrine was also inhibited by DMSO and this could not be corrected by washing the platelets. DMSO-plasma solutions are hypertonic but only minimal increases in platelet volume (at 10% DMSO) could be detected. Shrinkage of platelets was seen with hypertonic solutions of sodium chloride or sucrose suggesting that the rapid transmembrane passage of DMSO prevented significant shifts of water. These studies demonstrate that there are minimal irreversible alterations in in vitro platelet function after short-term exposure to DMSO.

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